Ralph Anthony DeFronzo, MD

Ralph Anthony DeFronzo, MD
Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA Jaime A. Davidson, MD President, Worldwide Initiative for Diabetes Education Clinical Professor of Internal Medicine Division of Endocrinology University of Texas Southwestern Medical School Dallas, Texas, USA

Professor Stefano Del Prato
Faculty Professor Stefano Del Prato Professor of Endocrinology and Metabolism School of Medicine University of Pisa Pisa, Italy Professor Rury Holman Professor of Diabetic Medicine Honorary Consultant Physician Diabetes Trials Unit University of Oxford Oxford, United Kingdom Professor Allan Vaag Chief Physician Steno Diabetes Center Gentofte, Denmark

Educational Objectives
Upon completion of this activity, participants will be able to Name 5 current challenges for glycemic control in individuals with type 2 diabetes List the key physiologic, biochemical, and molecular events involved in the renal regulation of glucose metabolism Understand the effects of inhibiting glucose reuptake by the kidney in individuals with type 2 diabetes Upon completion of this activity, participants will be able to Name 5 current challenges for glycemic control in individuals with type 2 diabetes. List the key physiologic, biochemical, and molecular events involved in the renal regulation of glucose metabolism. Understand the effects of inhibiting glucose reuptake by the kidney in individuals with type 2 diabetes.

Magnitude of the Diabetes Epidemic
5

Global Projections for the Diabetes Epidemic: 2007-2025
EUR NA 53.2 M 64.1 M 20% 28.3 M 40.5 M 43.0% EMME SEA 24.5 M 44.5 M 82% 46.5 M 80.3 M 73% WP 67.0 M 99.4 M 48% Current global estimates place diabetes prevalence at 246 million cases worldwide. By 2025, it has been estimated that there will be 380 million cases, an increase of 54%; as this figure shows, increased prevalence is currently projected in every part of the world. The most dramatic increases are expected in South and Central America, where diabetes rates are expected to rise by 102%, from 16.2 million in 2007 to million in 2025. Large increases are also expected in the Eastern Mediterranean and Middle East, Africa, and South-East Asia, with anticipated increases in prevalence in each region exceeding 70%. International Diabetes Federation. Diabetes Atlas. 3rd ed. Available at: Accessed April 7, 2009. AFR 10.4 M 18.7 M 80% World 2007=246 M 2025=380 M 54% SACA 16.2 M 32.7 M 102% 2007 2025 M=million; AFR=Africa; EMME=Eastern Mediterranean and Middle East; EUR=Europe; NA=North America; SACA=South and Central America; SEA=South-East Asia; WP=Western Pacific. International Diabetes Federation. Diabetes Atlas. 3rd ed. Available at: 6

Global Increase in Obesity
2002 2007 2015 Obese 356 million 523 million 704 million Overweight 1.4 billion 1.5 billion 2.3 billion 35 USA 30 25 UK Accompanying the rise in diabetes has been a global increase in obesity and overweight. Individuals who are overweight are defined as having a body mass index (BMI) ≥25 kg/m2. The criterion for obesity is a BMI ≥30 kg/m2, or for Asians, a BMI ≥28 kg/m2. In 2007, 523 million people met the criterion for obesity; this represented an increase of 167 million from the 2002 total of 356 million. By 2015, the projected global total will be 704 million cases. Observed global increases in rates of overweight are also severe, with a total of 1.5 billion overweight people in This represents an increase of 100 million from the 2002 total of 1.4 billion. Projected increases will bring the global total of overweight up to 2.3 billion people worldwide by 2015. Increases in obesity rates vary by country. Some countries, such as Japan, have seen a very small increase in prevalence, while other countries, such as Finland, have minimized increased obesity by direct intervention at the population level. The most dramatic increase has occurred in the United States, which now has an obesity prevalence >30%. James WP. The epidemiology of obesity: the size of the problem. J Intern Med. 2008;263: Australia 20 Finland Prevalence of Obesity (%) 15 Sweden Norway 10 Brazil Cuba 5 Japan 1970 1975 1980 1985 1990 1995 2000 2005 Overweight, BMI ≥25 kg/m2; obese, BMI >28 kg/m2 (Asian) or >30 kg/m2. James WP. J Intern Med. 2008;263:

Increasing Problem of Obesity and Diabetes: United States
92% increase 1998 2006 40 20 20% increase US Population (%) Over the past 20 years, the United States has experienced a severe increase in obesity. Obesity prevalence has nearly doubled, from 17.9% in 1998 to 34.3% in ,2 Aligned with this increase is a 20% increase in diabetes. Driven by the increase in obesity, diabetes prevalence in the United States increased from 6.5% in 1998 to 7.8% in ,4 Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, JAMA. 1999;282: Ogden CL, Carroll MD, McDowell MA, Flegal KM. Obesity among adults in the United States—no statistically significant change since 2003–2004. NCHS data brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the US: Diabetes Care. 2000;23: Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008. 1998 2007 *BMI ≥30 kg/m2. Centers for Disease Control and Prevention. National diabetes fact sheet. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008; Mokdad AH, et al. JAMA. 1999;282: ; Mokdad AH, et al. Diabetes Care. 2000;23: ; Ogden CL, et al. NCHS data brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007. 8 8

Increasing Problem of Obesity and Diabetes: Mexico
1993 2000 Men Women 40 20 21% increase 17% increase 1993 2000 Mexican Population (%) Mexico has also experienced an increase in obesity and diabetes prevalence. Although women in Mexico have a higher rate of obesity than men, the prevalence of obesity has increased for both genders, with an overall rise of 21% from 1993 to The prevalence of diabetes in Mexico increased from 7% in 1993 to 8.2% in 2000, a 17% increase.2,3 Sánchez-Castillo CP, Velásquez-Monroy O, Lara-Esqueda A, et al. Diabetes and hypertension increases in a society with abdominal obesity: result of the Mexican National Health Survey Public Health Nutr. 2005;8:53-60. Aguilar-Salinas CA, Rojas R, Gómez-Pérez FJ, et al. Prevalence and characteristics of early-onset type 2 diabetes in Mexico. Am J Med. 2002;113: Aguilar-Salinas CA, Velásquez-Monroy O, Gómez-Pérez FJ, et al. Characteristics of patients with type 2 diabetes in México. Diabetes Care. 2003;26: Aguilar-Salinas CA, et al. Am J Med. 2002;113: ; Aguilar-Salinas CA, et al. Diabetes Care. 2003;26: ; Sánchez-Castillo CP, et al. Public Health Nutr. 2005;8:53-60. 9

Increasing Problem of Obesity and Diabetes: China
1991 Men Women 10 5 169% increase 120% increase Chinese Population (%) In the decade that began in 1990, China experienced a dramatic increase in both obesity and diabetes. Obesity prevalence in China differs between men and women (with obesity being more common in women) and has increased overall by approximately 169% from 1991 to This has been accompanied by a corresponding 120% increase in diabetes.1,2 In 1994, the prevalence of diabetes in China was 2.5%.2 By 2001, diabetes prevalence was 5.5%.2 Note that the obesity criteria applied for China is the Asian-specific cut point of a BMI ≥28 kg/m2.1 Wildman RP, Dongfeng G, Muntner P, et al. Trends in overweight and obesity in Chinese adults: between 1991 and Obesity (Silver Spring). 2008;16: Gu D, Reynolds X, Duan X, et al. Prevalence of diabetes and impaired fasting glucose in the Chinese adult population: International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). Diabetologia. 2003;46: 1994 *Asian-specific obesity cut-point: BMI ≥28 kg/m2. Gu D, et al. Diabetologia. 2003;46: ; Wildman RP, et al. Obesity (Silver Spring). 2008;16: 10

Increasing Problem of Weight Gain and Diabetes: India
Overweight* Diabetes 750% increase 1989 2003 20 10 191% increase Rural Indian Population (%) Dramatic increases in overweight and diabetes have also occurred in the rural population of India. Overweight has increased by 750%, from 2.0% in 1989 to 17.1% in Rural Indians have also experienced a 191% increase in diabetes, from 2.2% in 1989 to 6.4% in 2003. Ramachandran A, Snehalatha C, Baskar AD, et al. Temporal changes in prevalence of diabetes and impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India. Diabetologia. 2004;47: 1989 2003 *BMI ≥25 kg/m2. Ramachandran A, et al. Diabetologia. 2004;47:

Hyperglycemia Biochemical marker by which the diagnosis of diabetes is made Assessed with HbA1c, daily SMBG, and eAG Major and treatable risk factor for microvascular disease (DCCT, UKPDS 33 and 35) Independent and treatable risk factor for macrovascular disease (DCCT-EDIC, UKPDS 35 and 80) Self-perpetuating cause of diabetes Glucotoxicity → insulin resistance and impaired insulin secretion As shown definitively in the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), hyperglycemia is responsible for microvascular complications.2,3 Several studies, including the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) and the second Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI 2) study, have also shown it is an independent risk factor for macrovascular complications.4,5 Hyperglycemia is the biochemical marker by which the diagnosis of diabetes is made. According to the World Health Organization and International Diabetes Federation, fasting plasma glucose (FPG) ≥7.0 mmol/L (126 mg/dL) or a 2-hour oral glucose tolerance test (OGTT) result of ≥11.1 mmol/L (200 mg/dL) are indicative of diabetes. Either test must be repeated on a different day to verify diagnosis.1 Finally, hyperglycemia is a self-perpetuating cause of type 2 diabetes. It results in glucotoxicity, which worsens both insulin resistance and impaired insulin secretion.6 World Health Organization / International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Report of a WHO/IDF consultation. Geneva: WHO, 2006. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329: United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141: Malmberg K, Rydén L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26: Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86: eAG=estimated average glucose. SMBG=self-monitoring of blood glucose. 12 12

HbA1c Is Correlated With Average Glucose
450 400 350 300 250 As shown in this linear regression from the A1C-Derived Average Glucose (ADAG) study, a strong correlation exists between HbA1c levels and average glucose. Average glucose was measured using a combination of frequent capillary glucose testing by finger-stick and continuous glucose monitoring. This correlation exists for both type 1 and type 2 diabetes. The ADAG results confirmed that HbA1c measurements could be used as a proxy to estimate a patient’s average glucose, thus providing a useful tool to patients and health care providers. Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31: AG (mg/dL) 200 150 100 50 3 5 7 9 11 13 15 HbA1c (%) AG=average glucose. Nathan DM, et al. Diabetes Care. 2008;31:

Diabetes Report Card: HbA1c Levels in the United States
100 6% >10.0 6% 11% 80 20% In recent years, US adults with diabetes have shown improvements in glycemic control. National Health and Nutrition Examination Survey (NHANES) data from indicate that a majority, or 56%, of US patients with diabetes had HbA1c levels <7% (the current American Diabetes Association [ADA] goal for glycemic control). This represents an improvement over previous NHANES results from and from , when the proportions of patients with diabetes with HbA1c levels <7% were 37% and 50%, respectively. In , poor glycemic control, indicated by HbA1c levels ≥9%, was found in 12% of patients with diabetes. Overall, the NHANES indicated that 43% of patients with diabetes did not achieve HbA1c levels <7%. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in US adults? Diabetes Care. 2008;31:81-86. 60 Patients (%) HbA1c (%) 40 35% 20 22% <6.0 Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. 14

Advances in Therapy, but Falling Short of Goals
1997: ADA lowered T2DM diagnosis from FPG ≥7.8 mmol/L to ≥7.0 mmol/L 1998: UKPDS results published 2003: ADA eliminated HbA1c “action point” of <8% from guidelines 2005: ADA added HbA1c goal of <6% for “individual patients” to guidelines 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published 2009: ADA added “less stringent” HbA1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy 10 Pre-DCCT 9.0% NHANES 7.8 9 NHANES 7.2 This timeline illustrates the progression of HbA1c values in US adults diagnosed with diabetes over the past few decades. As indicated by data from NHANES, mean HbA1c values have improved with the introduction of new diabetes medications.1,2 Alongside the introduction of new drugs such as metformin in 1995 and thiazolidinediones (TZDs) in 1998, mean HbA1c levels have steadily declined.1 It is possible that as newer medications become available, mean HbA1c levels will trend toward 6.0%. This slide is also animated to outline a series of milestones in type 2 diabetes diagnosis and management, which appear with each click: 1997: change in ADA diagnostic criteria for type 2 diabetes from an FPG ≥7.8 mmol/L (140 mg/dL) to ≥7.0 mmol/L (126 mg/dL). This increased the number of patients meeting the criteria for diabetes diagnosis.3 This led to a corresponding increase in mean HbA1c levels, observed in NHANES , as patients newly diagnosed with diabetes entered treatment. 1998: results from the UKPDS were published, demonstrating the benefits of intensive glucose control in type 2 diabetes.4 2003: elimination of the ADA’s “action point” of HbA1c <8.0%; the ADA recommended instead a general goal of <7.0% for all patients.3,5 2005: addition of the goal of <6.0% for “individual patients” to ADA guidelines.6 2008: publication of the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) studies showing no significant macrovascular benefits with intensive glucose control.7 2009: addition of a “less stringent” HbA1c goal for patients with significant comorbidities, risk for hypoglycemia, or short life expectancy.8 Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27:17-20. American Diabetes Association. Position statement. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26 (suppl 1):S33-S50. UKPDS Study Group. Intensive blood-gulcose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27: American Diabetes Association. Position statement. Standards of medical care in diabetes. Diabetes Care. 2004;27(suppl 1):S15-S35. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol. 2009;53: American Diabetes Association. Position statement. Standards of medical care in diabetes–2009. Diabetes Care. 2009;32(suppl 1):S13-S61. 8 HbA1c (%) General ADA Target: <7% NHANES 7.7 7 NHANES 7.5 Future 6.0% ? 6 SU / Insulin Metformin (1995) TZDs (1998) Incretins (2004) 5  1980s 1990s 2000s  SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. 15

Unmet Needs in Diabetes Care
Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Weight Management Type 2 Diabetes Hyperglycemia We now know that there are multiple unmet needs in diabetes care, including effective strategies to Manage patient weight. Address the multiple physiologic defects inherent in type 2 diabetes. Overcome adverse therapeutic effects. Adequately manage hyperglycemia and address multifaceted cardiovascular disease risk factors typical in patients with diabetes. CVD Risk (Lipid and Hypertension Control) CVD=cardiovascular disease. Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. 16 16

Relationship Between Hyperglycemia and Microvascular and Macrovascular Complications
17

Incidence of Microvascular Complications in IGT
Diabetic Retinopathy (%) IGT (HbA1c=5.9%) IGT………..…7.9% IGT (HbA1c=6.1%) T2DM………12.6% The Diabetes Prevention Program (DPP) recruited overweight and obese patients with elevated fasting glucose and impaired glucose tolerance (IGT) for weight loss intervention with the aim of diabetes prevention. A DPP substudy examined the frequency of retinopathy among a representative sample of participants who had not received a diabetes diagnosis by study end.1 At the start of the study, participants who developed diabetes had a mean baseline HbA1c level of 6.1%, while the mean baseline HbA1c of participants who did not develop diabetes was 5.9%.1 Of participants diagnosed with diabetes during the DPP, 12.6% developed diabetic retinopathy, compared with 7.9% of patients with IGT.1 Subjects with and without diabetes who participated in the Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Research in the Region of Augsburg Surveys (MONICA/KORA) were assessed for neuropathy. The prevalence of neuropathy in subjects with IGT was 13%.2 These data suggest that traditional cut points for diabetes diagnosis may be inappropriate, considering that DPP patients presented with diabetic complications, such as retinopathy, without a diabetes diagnosis. Diabetes Prevention Program Research Group (DPP Group). The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24: Ziegler D, Rathman W, Dickhaus T, Meisinger C, Mielck A, for the KORA Study Group. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and microangiopathy. Diabetes Care. 2008;31: Neuropathy (%) IGT………..…13%* *Prevalence. Diabetes Prevention Program Research Group. Diabet Med. 2007;24: ; Singleton JR, et al. Diabetes Care. 2001;24: ; Ziegler D, et al. Diabetes Care. 2008;31: 18 18

Diabetes Is a Cardiovascular Disease Risk Equivalent
Nondiabetic n=1373 Diabetic n=1059 P<0.001 50 45.0 40 7-Year Incidence Rate of MI (%) Results from a Finnish observational study of 7-year incidence of myocardial infarction (MI) in patients both with and without diabetes suggest that prior MI is a major risk factor for MI among all patients. These data also demonstrated the severity of MI risk in patients with diabetes. The risk of first MI for patients with diabetes is greater than even the risk for subsequent MI in patients without diabetes but with previous MI. Haffner SM, Letho S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339: 30 P<0.001 20.2 18.8 20 10 3.5 No DM No MI No DM MI DM No MI DM MI DM=diabetes mellitus; MI=myocardial infarction. Haffner SM, et al. N Engl J Med. 1998;339: 19

Incidence per 1000 Person-Years (%)
Historic Rationale for Improving Glycemia: Microvascular Risk Reduction 80 Microvascular Disease 70 Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001) 60 Incidence per 1000 Person-Years (%) 50 The UKPDS demonstrated a strong association between HbA1c levels and microvascular risk in patients with type 2 diabetes. An epidemiologic analysis of UKPDS data found that each 1% decrease in HbA1c level obtained in the UKPDS corresponded with a ~37% decrease in microvascular disease end points.1 Microvascular endpoints evaluated in the UKPDS included retinopathy requiring photocoagulation, vitreous hemorrhage, and or fatal or nonfatal renal failure.2 Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321: UKPDS Study Group. Intensive blood-gulcose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: 40 30 20 10 5 6 7 8 9 10 11 Mean HbA1c (%) Stratton IM, et al. BMJ. 2000;321: 20

Incidence per 1000 Person-Years (%)
Less Strong Association Between Hyperglycemia and Macrovascular Risk in Type 2 Diabetes 80 Microvascular Disease 70 Macrovascular Disease Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001) 60 Incidence per 1000 Person-Years (%) 50 Epidemiologic analysis of UKPDS data also demonstrated an association between HbA1c levels and macrovascualar risk in patients with type 2 diabetes. As shown, for each 1% decrease in HbA1c levels, risk for MI decreased by 14%. Overall, these findings show that HbA1c is not only strongly associated with microvascular complication risk, but also that HbA1c is associated with macrovascular complications. Moreover, decreases in HbA1c contribute to a decreased risk of either type of complication. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321: 40 Estimated 14% decrease in myocardial infarction risk for each 1% decrement in HbA1c (P<0.0001) 30 20 10 5 6 7 8 9 10 11 Mean HbA1c (%) Stratton IM, et al. BMJ. 2000;321: 21

Optimizing Glycemia in Advanced Type 2 Diabetes Exerts Unclear Macrovascular Benefit
ACCORD N=10,251 VADT N=1791 9 Conventional therapy Macro ↓13% P=0.12 8 Three recent studies collectively randomized a total of 23,182 adults with diabetes to receive either intensive or standard glucose control, in order to evaluate the effect of glucose control on cardiovascular risk: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Action to Control Cardiovascular Risk in Diabetes (ACCORD) Veterans Affairs Diabetes Trial (VADT) ADVANCE and ACCORD recruited participants with diabetes plus prior macrovascular events or elevated cardiovascular risk, while VADT recruited veterans with poorly controlled diabetes.1-3 On the slide, the arrows represent the difference in HbA1c level between the standard control (top of arrow) and intensive control (point of arrow) groups at each study’s endpoint. Mean HbA1c levels for all intensive treatment groups were ≥1% below the mean HbA1c level for the respective standard treatment group.1-3 As shown at the bottom of this slide, ADVANCE, ACCORD, and VADT showed decreases in macrovascular complications of 6%, 10%, and 13%, respectively; none of these decreases reached statistical significance.1-3 Additionally, after a 3.5-year follow-up, the ACCORD study found an increase in death from any cause in the intensive therapy group, resulting in the premature discontinuation of the study.1 ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360: Endpoint HbA1c (%) Macro ↓10% P=0.16 Macro ↓6% P=0.37 7 Intensive therapy 6 Primary Endpoint ACCORD Study Group. N Engl J Med. 2008;358: ; ADVANCE Collaborative Group. N Engl J Med. 2008;358: ; Duckworth W, et al. N Engl J Med. 2009;360: 22

Microvascular Disease Myocardial Infarction Post-trial Monitoring
Lasting Benefits of Early, Intensive Intervention: UKPDS “Legacy” Effect Any Diabetes Endpoint Microvascular Disease Myocardial Infarction All-cause Mortality P=0.44 Intervention P=0.029 P=0.052 The UKPDS randomized >3800 adults newly diagnosed with type 2 diabetes to conventional or intensive treatment over 10 years to compare treatment outcomes for micro- and macrovascular complications.1 At the trial’s end, the intensive treatment group showed a significant 12% decrease in any diabetes-related endpoint; this was driven by a 25% reduction in microvascular disease risk.1 A recently published 10-year follow-up study (UKPDS 80) showed a sustained benefit of early intervention. Specifically, even though the randomized UKPDS interventions were not maintained, at 10-year follow-up, patients who had received early, intensive treatment showed significant decreases in any diabetes-related endpoint and in microvascular disease of 9% and 24%, respectively.2 Patients not only experienced a continued benefit in terms of microvascular risk, but over the course of the follow-up, reductions in macrovascular risk—17% for diabetes-related death (not shown), 15% for MI, and 13% for all-cause mortality—all reached statistical significance.2 It is of interest that these benefits were apparent without a sustained difference in HbA1c levels maintained between the 2 groups, an outcome sometimes called the “legacy” effect.2 These findings demonstrate the importance of early, intensive treatment of type 2 diabetes. UKPDS Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: P=0.0099 Relative Risk Reduction (%) P=0.040 Post-trial Monitoring P=0.007 P=0.014 P=0.001 Holman RR, et al. N Engl J Med. 2008;359: ; UKPDS Study Group. Lancet. 1998;352:

Early vs Late Intervention in Type 2 Diabetes
Trial Intensive Arm HbA1c Reduction No Patients / Trial Duration Disease Severity Macrovascular Benefit ACCORD Goal: <6.0% Endpoint: 6.4% ↓1.4% from BL in 4 months N=10,251 3.4 yr CVD or 2 risk factors 10 yr from T2DM diagnosis No ADVANCE Goal: <6.5% Endpoint: 6.5% ↓0.6% from BL in 12 months N=11,140 5.0 yr Vascular disease or 1 risk factor 8 yr from T2DM diagnosis VADT Goal: ↓1.5% vs standard Endpoint: 6.9% ↓2.5% from BL in 3 months N=1791 5.6 yr 12 yr from T2DM diagnosis UKPDS 80 Goal: FPG <6.0 mmol/L (108 mg/dL) Intervention endpoint: 7.0% Follow-up: 7.7% N=4209 17 yr Newly diagnosed with T2DM Yes Results from 4 major studies evaluating intensive treatment for patients with type 2 diabetes demonstrate clearly that intensive treatment can be effectively applied to substantially lower HbA1c levels. Studies that recruited participants 8 to 12 years after diabetes diagnosis achieved no macrovascular benefit with intensive glycemic control.1-3 However, 10-year follow-up data from UKPDS 80 indicate that early, intensive intervention initiated soon after diabetes diagnosis may provide protection from future macrovascular complications.4 This table also suggests that the macrovascular benefits of glycemic control may be subtle and take many years, or even decades, to manifest. It is possible that had the ACCORD or ADVANCE trials run longer, or the VADT trial included a larger number of patients, the macrovascular risk reductions observed in those studies might have approached statistical significance. ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: ACCORD Study Group. N Engl J Med. 2008;358: ; ADVANCE Collaborative Group. N Engl J Med. 2008;358: ; Duckworth W, et al. N Engl J Med. 2009;360: ; Holman RR, et al. N Engl J Med. 2008;359:

Steno-2: Time to Cardiovascular Events
80 Conventional Treatment 60 Cumulative Incidence of Any CV Event (%) P<0.001 40 The Steno-2 study investigated the benefits of intensive risk factor treatment for patients with microalbuminuria and type 2 diabetes. Patients were randomized to stepwise intensive treatment or standard treatment for hyperglycemia, hypertension, dyslipidemia, and microalbuminuria.1 Patients were treated for a mean of 7.8 years, with a mean posttreatment follow-up of 5.5 years.2 At the end of follow-up, patients in the intensive treatment group had reduced risk for death from any cause by 20%, for cardiovascular death by 13%, for cardiovascular events by 29%, and for end-stage renal disease requiring dialysis by 6.3%.2 As seen on this slide, cardiovascular risk reduction observed in the Steno-2 intensive treatment group was maintained well beyond the controlled treatment period. Although events increased for both groups as participants aged, those who received prior intensive treatment maintained a rate of cardiovascular events lower than that of the standard treatment group.2 Gæde P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353: Gaede P, Lund-Anderson H, Parving HH, Pederson O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: 20 Intensive Treatment Intervention Follow-up 2 4 6 8 10 12 Years No. at Risk Conventional Intensive Gaede P, et al. N Engl J Med. 2008;358: 25

Steno-2: Goal Attainment
Intensive therapy Conventional therapy 100 P<0.001 P=0.21 80 P=0.005 60 P=0.001 Intervention 40 P=0.06 20 During treatment, compared with participants receiving conventional therapy, individuals in the Steno-2 intensive treatment group were more likely to reach goals for risk factors such as HbA1c, cholesterol levels, and systolic blood pressure. As this slide shows, after an average of 7.8 years of treatment and 5.5 years of follow-up, the observed differences between the intensive and conventional treatment groups had narrowed. This was a result of patients originally assigned to conventional treatment receiving more intensive therapy, as more intensive treatment became the norm in clinical practice. Even though both Steno-2 groups showed similar risk factor reductions at follow-up, patients in the original intensive treatment group showed decreased long-term risk for all assessed complications (ie, cardiovascular death, cardiovascular events, and end-stage renal disease, data not shown). This provides another example of the need for early and intensive intervention. Gaede P, Lund-Anderson H, Parving HH, Pederson O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358: Patients (%) 100 P=0.35 P=0.005 P=0.14 80 60 Follow-up 40 P=0.27 P=0.31 20 HbA1c <6.5% Cholesterol <175 mg/dL Triglycerides <150 mg/dL Systolic BP <130 mm Hg Diastolic BP <80 mm Hg BP=blood pressure. Gaede P, et al. N Engl J Med. 2008;358: 26

Etiology of Type 2 Diabetes
Insulin Resistance and -Cell Dysfunction 27

Etiology of Type 2 Diabetes
Primary Predisposing Factors Genes Adverse intrauterine environment Tertiary Accelerating Glucose and lipid toxicity Secondary Precipitating Factors Obesity Low physical activity Age Smoking Sleep disturbance Other Multiple factors contribute to the etiology of type 2 diabetes. These include Primary predisposing factors (ie, genetic and/or intrauterine). Modifiable and nonmodifiable secondary precipitating factors, such as obesity, physical inactivity, age, smoking, sleep disturbances. Tertiary factors, such as glucose and lipid toxicity, which can accelerate disease progression.

Type 2 Diabetes: A Heterogeneous Disorder
Functional -cell Failing -cell Insulin resistance Insulin resistance Current evidence suggests that type 2 diabetes is a heterogeneous disorder involving both genetic and acquired defects.1 Genetics play an important role in determining whether an individual’s β-cell function remains normal or becomes impaired over time.1 Insulin resistance is a major acquired factor and can occur in the presence of functional or failing β-cells.1 Although not depicted on this slide, intrauterine exposure to maternal glucose levels also increases the risk for future diabetes development. Specifically, it has been demonstrated that infants who are either small or large for gestational age are at risk for future type 2 diabetes.2 Decreases in β-cell functionality lead ultimately to hyperglycemia, while insulin resistance in obese patients is associated with the metabolic syndrome (eg, dyslipidemia, hypertension, IGT). The next step in disease progression is often the development of both micro- and macrovascular complications, such as retinopathy, nephropathy, neuropathy, MI, and stroke.1 The occurrence of microvascular events is also a predictor of macrovascular events in patients with type 2 diabetes. Gerich JE. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc. 2003;78: Jovanovic L. A tincture of time does not turn the tide: type 2 diabetes trends in offspring of diabetic mothers. Diabetes Care. 2000:23: Metabolic syndrome Hyperglycemia Heine RJ, Spijkerman AM 29 29

Type 2 Diabetes: Insulin Resistance Plus Impaired -Cell Function
Both insulin resistance and b-cell dysfunction are present at the time of diagnosis of type 2 diabetes Insulin resistance Normal -cell function Compensatory hyperinsulinemia Normoglycemia (Metabolic syndrome) Abnormal -cell function Relative insulin deficiency Hyperglycemia Type 2 diabetes Insulin resistance and β-cell dysfunction are key pathophysiologic triggers in the development of type 2 diabetes; both of these deficits tend to be present at the time of diagnosis. In individuals with normal β-cell function, insulin resistance leads to compensatory hyperinsulinemia and the development of metabolic syndrome, but glucose levels will remain normal. However, in individuals with impaired β-cell function, insulin resistance gives rise to relative insulin deficiency, hyperglycemia, and type 2 diabetes. Gerich JE. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc. 2003;78: 30

Natural History of Type 2 Diabetes
Insulin- Mediated Glucose Uptake (mg/m2 • min) 300 250 200 150 100 Mean Plasma Insulin During OGTT (µU/mL) Mean Plasma Glucose During OGTT (mg/dL) 140 60 20 400 OB- DM Lo INS Lean NGT Hi INS IGT OB The natural history of type 2 diabetes is reflected in the results of this study performed in lean and obese patients with varying levels of glucose tolerance. Patients received an OGTT followed by a euglycemic insulin clamp. In lean subjects with normal glucose tolerance (NGT), OGTT results included a mean plasma glucose level of 110 mg/dL (6.1 mmol/L) and a mean plasma insulin concentration of 60 U/mL (430.5 pmol/L), while insulin-mediated glucose uptake was approximately 300 mg/m2 per minute.1 Compared with lean controls, obese nondiabetic individuals experienced dramatic decreases in insulin sensitivity but retained NGT due to compensatory increases in insulin secretion.2,3 Obese patients with mild glucose intolerance demonstrated further decreases in insulin-mediated glucose uptake but only slight increases in mean plasma glucose; this was a result of compensatory augmentation of β-cell insulin release.1-3 In obese hyperinsulinemic type 2 diabetes patients, OGTT led to further increases in mean plasma glucose levels and a substantial decline in mean plasma insulin levels as β-cell secretory capacity deteriorated; no marked decreases in insulin sensitivity were observed at this stage.1-3 Finally, in obese hypoinsulinemic type 2 diabetes patients, mean plasma insulin levels during OGTT were dramatically decreased as glucose tolerance became severely impaired; at the same time, insulin resistance remained largely unchanged.2,3 These data support the need for type 2 diabetes medications that act to improve β-cell function and increase insulin sensitivity. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes. Diabetes. 2009;58: DeFronzo RA. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37: Jallut D, Golay A, Munger R, et al. Impaired glucose tolerance and diabetes in obesity: a 6-year followup study of glucose metabolism. Metabolism. 1990;39: DM=diabetes mellitus; IGT=impaired glucose tolerance; INS=insulin; NGT=normal glucose tolerance; OB=obesity. DeFronzo RA. Diabetes. 1988;37: ; Jallut D, et al. Metabolism. 1990;39: 31 31

Etiology of -Cell Dysfunction in Type 2 Diabetes
Age Genetics (TCF 7L2) ↓ Incretin Effect β-Cell failure in type 2 diabetes has a number of potential causes. First, studies have shown a progressive age-related decline in β-cell function. In addition, research has led to the identification of specific genes, such as transcription factor TCF 7L2, that are linked to β-cell dysfunction in patients with type 2 diabetes. Insulin resistance plays a major role in progressive β-cell failure by creating an ongoing demand for insulin hypersecretion. Evidence indicates that lipotoxicity, defined as an increase in plasma free fatty acid (FFA) concentrations, can impair β-cell function in genetically predisposed subjects. Research has shown that glucose toxicity, which refers to chronically elevated plasma glucose levels, also leads to reduced insulin secretion. Deposition of amyloid and islet amyloid-like polypeptide may play a role in progressive β-cell failure in type 2 diabetes as well. Finally, decreases in the incretin effect have been shown to be a major contributor to β-cell dysfunction. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes. Diabetes. 2009;58: Amyloid (Islet Amyloid Polypeptide) Deposition -Cell Dysfunction Insulin Resistance Lipotoxicity ↑ Free Fatty Acids Glucose Toxicity 32 32

Natural History of -Cell Dysfunction in Type 2 Diabetes
β-Cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated 33

San Antonio Metabolism and VAGES Studies
Normal glucose tolerance 318 Impaired glucose tolerance 259 Type 2 diabetes 201 Subjects Number Subjects were classified as Nonobese if BMI <30 kg/m2 Obese if BMI ≥30 kg/m2 The San Antonio metabolism study and Veterans Administration Genetic Epidemiology Study (VAGES) utilized OGTT and euglycemic insulin clamps to assess changes in insulin response and insulin sensitivity in lean and obese patients with NGT or IGT or overt type 2 diabetes.1-3 Subjects with a body mass index ≥30 kg/m2 were classified as obese; study results are depicted on the following slides. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA for the San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47:31-39. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90: Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006;55: Methods: OGTT and insulin clamp VAGES=Veterans Administration Genetic Epidemiology Study. Abdul-Ghani MA, et al. Diabetes. 2006;55: ; Ferrannini E, et al. J Endocrinol Metab. 2005;90: ; Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 34 34

Plasma Glucose and Insulin AUC
12 12 Q1 T2DM Q2 Q3 Q4 <160 <180 <200 IGT 8 8 NGT (mmol/L  120 min) Glucose AUC (pmol/L  120 min) Insulin AUC This slide depicts selected results from the San Antonio metabolism and VAGES studies. The San Antonio metabolism study was designed to examine the major determinants of glucose homeostasis, while VAGES evaluated changes in insulin secretion and resistance in subjects with impaired fasting glucose (IFG) and/or IGT.1, 2 Plasma glucose and insulin areas under the curve (AUC) during OGTT for individuals with NGT are shown in yellow, followed by subjects with IGT in green; the IGT group is subdivided into tertiles based on 2-hour plasma glucose levels.1,3 For patients with type 2 diabetes, results are divided into 4 equivalently distributed quartiles and appear in orange.3 Glucose clearance was reduced in subjects with IGT or type 2 diabetes; this led to increased glucose AUC in these subjects.1 The plasma insulin response has the typical inverted U-shape seen in Starling’s curve of the pancreas (blue arrow).1,3 The increase in plasma insulin concentration exhibited by subjects with IGT is not an indication that β-cell function is normal, but rather of the β-cell’s response to increases in plasma glucose levels in the presence of insulin resistance. Plasma insulin levels undergo a marked decline in the type 2 diabetes population as β-cells become incapable of secreting sufficient amounts of insulin to compensate for the effects of decreased insulin sensitivity.1,3 Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA for the San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47:31-39. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006;55: DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes. Diabetes. 2009;58: 4 4 Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 35 35

Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT
40 NGT Lean <100 <120 <140 Obese 30 ∆ I / ∆ G ÷IR 20 This slide depicts selected results from the San Antonio metabolism study.1 The graph shows the gold standard index for β-cell function, which consists of insulin secretion divided by insulin resistance (or disposition) on the Y-axis shown as a function of 2-hour plasma glucose concentration on the X-axis.1,2 Individuals with NGT are shown in yellow, while those with IGT are in green. Subjects in both of these categories were divided into 3 groups based on 2-hour plasma glucose levels during OGTT. Patients in the upper tertile of the NGT group have lost approximately two-thirds of their β-cell function.2 Patients with overt type 2 diabetes, shown in orange, have experienced and continue to experience substantial deterioration of β-cell function. By the time of diabetes diagnosis, >80% of β-cell functionality has been lost.2 Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA for the San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47:31-39. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58: 10 <180 IGT <200 <160 <240 <280 <360 <320 >400 <400 T2DM 2-Hour Plasma Glucose (mg/dL) G=glucose; I=insulin; IR=insulin resistance. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 36 36

Ln ∆I / ∆G ÷ IR (mL/min • kgFFM) Ln 2-Hour Plasma Glucose (mg/dL)
Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index 6 NGT IGT 4 T2DM 2 Ln ∆I / ∆G ÷ IR (mL/min • kgFFM) This slide depicts selected results from the San Antonio metabolism study.1 A graph of the natural log of the insulin secretion / insulin resistance index versus the natural log of the 2-hour plasma glucose concentration reveals that these parameters exhibit a strong inverse linear association (r=0.91).1,2 These data provide evidence of the correlation between the progressive decline in β-cell function and glucose tolerance and indicate that this relationship moves along a continuum from NGT to IGT to overt type 2 diabetes.1,2 Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA for the San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47:31-39. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58: -2 r=0.91 P< -4 4.0 4.5 5.0 5.5 6.0 6.5 Ln 2-Hour Plasma Glucose (mg/dL) Ln=log normalization. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 37 37

GENFIEV: Insulin Secretion as a Function of Insulin Sensitivity
Trend test P<0.001 Δ AUC C-peptide / Δ AUC Glucose ÷ HOMA-R The Genetics, Physiopathology and Evolution of Type 2 Diabetes (GENFIEV) study was a multicenter investigation designed to identify pheno- and genotypic features for subjects (N=1017) with a high risk of type 2 diabetes. Plasma glucose and C-peptide levels were assessed using OGTT. Fasting insulin values were also evaluated.1 Of study participants, 50% had NGT, 4% had IFG, 23% had IGT, 8% had IFG and IGT, and 15% were diagnosed with type 2 diabetes.1 Study results revealed that the C-peptide AUC to glucose AUC ratio decreased across the range of 2-hour plasma glucose values (r=-0.37, P<0.001), while the homeostasis model assessment index ratio (HOMA-IR), a measure of insulin sensitivity, increased (r=0.28; P<0.001, data not shown).1,2 As shown in this bar graph, the C-peptide AUC/glucose AUC to HOMA-IR ratio, a disposition index surrogate, decreased linearly (arrow) as a function of increasing 2-hour plasma glucose values (r=-0.44, P<0.001).1,2 This investigation provided evidence that changes in insulin secretion and sensitivity occur in a linear fashion as a function of decreasing glucose tolerance.1 Del Prato S for the GENFIEV Study Group. Insulin secretion and insulin action in individuals at high risk for type 2 diabetes. The GENFIEV Study of the Italian Society of Diabetology [abstract]. 66th Scientific Sessions of the American Diabetes Association; June 9-13, 2006; Washington, DC. Abstract 1381-P. GENFIEV. Genetics, Physiopathology and Evolution of Type 2 Diabetes. Available at: Accessed March 8, 2009. 2-Hour Plasma Glucose (mg/dL) HOMA-R=homeostasis model assessment index ratio. Diabetes. 2006;55(suppl 2):A322. 38

Insulin Secretion Rate
GeNFIEV: Stimulus-response Curve (Proportional Control) of Insulin Secretion GENFIEV: Stimulus-Response Curve (Proportional Control) of Insulin Secretion * Insulin Secretion Rate (pmol . min-1 . m-2) The GENFIEV Study Group also investigated β-cell response to the rate of increased glucose concentration, referred to as derivative control, and response to actual glucose concentration, or proportional control, following oral glucose administration in subjects with a range of FPG values and glucose tolerance levels.1 Two cohorts were selected from the GENFIEV database. Cohort A (n=134) was comprised of subjects with NGT and low-normal, high-normal, or impaired FPG. Cohort B (n=159) was comprised of subjects with normal FPG and low-normal, high-normal, impaired, or diabetic glucose tolerance.1 All subjects received OGTT, with derivative control and proportional control calculated based on glucose and C-peptide curves.1 As this graph of proportional control data shows, the insulin secretion rate as a function of plasma glucose concentration was highest in subjects with NFG/NGT, with decreasing values observed for those with IFG/NGT, NFG/IGT, IFG/IGT, NFG/DGT, DFG/IGT, IFG/DGT, and DFG/DGT. Proportional control values for both cohorts were lower in high-normal than in low-normal subjects (P<0.01) but were similar between impaired FPG and high-normal FPG, and between IGT and high NGT.1,2 Based on proportional control results, FPG and glucose tolerance were both found to be independent predictors of the decline in β-cell response to oral glucose administration in nondiabetic subjects.1 Bonadonna RC for the GENFIEV Study Group. Selective decline of β-cell function within the normal range of glucose concentration in humans [abstract]. 66th Scientific Sessions of the American Diabetes Association; June 9-13, 2006; Washington, DC. Abstract 2472-PO. GENFIEV. Genetics, Physiopathology and Evolution of Type 2 Diabetes. Available at: Accessed March 8, 2009. # Plasma Glucose (mmol/L) *P<0.01 vs NFG/NGT; §P<0.05 vs NFG/IGT and IFG/NGT; #P<0.05 vs IFG/IGT and NFG/DGT. Diabetes. 2006;55(suppl 2):A2472. 39

Decrease in AIR Necessary to Convert From NGT to IGT
Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT Decrease in AIR Necessary to Convert From NGT to IGT Pima Indian Latino/Hispanic White Δ AIR (%) A number of studies have provided evidence of a relationship between ethnicity and insulin sensitivity. For example, Pima Indian, Latino/Hispanic, and white populations are characterized by varying degrees of insulin resistance, with Pima Indians being most severe and whites being least severe.1 Research has shown that in Pima Indian, Latino/Hispanic, and white subjects with IGT, acute insulin response, an index of insulin secretion, is decreased by 8%, 18%, and 32%, respectively, relative to individuals with NGT.1 As such, populations with higher levels of insulin resistance require smaller decreases in β-cell function to progress from NGT to IGT.1,2 Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29: Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE for the American Diabetes Association GENNID Study Group. β-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes. 2002;51: Insulin resistance ↑↑↑ ↑↑ ↑ AIR=acute insulin response to glucose. Abdul-Ghani MA, et al. Diabetes Care. 2006;29:

Insulin Resistance and -Cell Dysfunction: Summary
Individuals with impaired glucose tolerance Are maximally or near-maximally insulin resistant Have lost ~80% of their -cell function Have an incidence of diabetic retinopathy of ~10% 41 41

Pathogenesis of Diabetes
Evolving Concepts 42

Pathogenesis of Type 2 Diabetes
Islet b-cell Impaired Insulin Secretion Any discussion of type 2 diabetes pathogenesis must begin with 3 etiologic considerations: Islet β-cell dysfunction and accompanying impaired insulin secretion. Increased hepatic glucose production (HGP). Decreased glucose uptake. After examining these 3 factors, we will look at additional processes that contribute to type 2 diabetes progression. Our first consideration will be the role of impaired β-cell function and its impact on insulin secretory capacity. Increased HGP Decreased Glucose Uptake HGP=hepatic glucose production. 43

Islet b-cell Impaired Insulin Secretion Time (minutes) 1st Phase 2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5 -10 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 100 95 Insulin Secretion Time (minutes) 1st Phase 2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5 -10 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 100 95 Insulin Secretion Research indicates that abnormalities in insulin action and secretion progress along a temporal pathway, with defects occurring early in disease development and manifesting differently depending on a patient’s glucose tolerance status.1 This slide illustrates β-cell function, expressed as insulin response to an intravenous glucose challenge, in individuals with NGT and type 2 diabetes.2 Individuals with NGT exhibit a compensatory reaction to hyperglycemia, marked by a rapid first-phase insulin response within 1 to 3 minutes of glucose intake. This is followed by a second-phase response, during which insulin peaks more gradually and in a manner related directly to elevated blood glucose levels.1, 2 Patients with diabetes, on the other hand, show defects in both insulin action and secretion in the form of an attenuated to nonexistent first-phase insulin response, coupled with a prolonged second-phase response.1,2 Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104: Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D. Pathophysiology of insulin secretion in non-insulin dependent diabetes mellitus. Diabetes Care. 1984;7: Increased HGP Decreased Glucose Uptake HGP=hepatic glucose production. Adapted from Weyer C, et al. J Clin Invest. 1999;104: ; Ward WK, et al. Diabetes Care. 1984;7: 44

Islet b-cell Impaired Insulin Secretion Next, we will look at the role of the liver and increased HGP and its effect on fasting glucose in patients with and without diabetes. Increased HGP Decreased Glucose Uptake 45

Islet b-cell Impaired Insulin Secretion Basal HGP (mg/kg • min) FPG (mg/dL) 2.0 2.5 3.0 3.5 4.0 100 200 300 r=0.85 P<0.001 Control T2DM Basal HGP (mg/kg• min) FPG (mg/dL) 2.0 2.5 3.0 3.5 4.0 100 200 300 r = 0.85 P<0.001 Control T2DM This slide shows the results of a study conducted in normal weight individuals with established type 2 diabetes (n=77) and age- and weight-matched healthy controls (n=72).1 The goal was to determine whether fasting hyperglycemia in patients with type 2 diabetes is caused by excessive HGP. HGP was assessed by conducting glucose turnover studies during the postabsorptive state.1 As shown, a progressive rise in HGP was observed in subjects with diabetes plus FPG levels >140 mg/dL (7.8 mmol/L); this corresponded closely (r=0.85, P<0.001) with FPG concentrations.1 Subjects with diabetes plus FPG levels <140 mg/dL (7.8 mmol/L), however, showed a similar hepatic response as controls; in these individuals, fasting hyperglycemia did not trigger HGP accelerations.1 These results indicate the presence of early, marked hepatic resistance to insulin action and that altered HGP plays a key role in maintaining the diabetic state. However, these findings also demonstrated that increased HGP is not likely to play an early role in the fasting hyperglycemia typical of type 2 diabetes.2 DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism. 1989;38: DeFronzo R. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37: Increased HGP Decreased Glucose Uptake DeFronzo RA, et al. Metabolism. 1989;38: 46

Islet b-cell Impaired Insulin Secretion Patients with type 2 diabetes also experience a progressive decline in glucose uptake as insulin production decreases and insulin resistance increases. Increased HGP Decreased Glucose Uptake 47

Islet b-cell Impaired Insulin Secretion T2DM Total Body Glucose Uptake (mg/kg • min) CON 7 6 5 4 3 2 1 P<0.01 12 (mg/kg leg wt per min) Leg Glucose Uptake Time (minutes) 180 140 100 60 40 8 T2DM Total Body Glucose Uptake (mg/kg•min) CON 7 6 5 4 3 2 1 P<0.01 P<0.05 12 (mg/kg leg wt per min) Leg Glucose Uptake Time (minutes) 180 140 100 60 40 8 This insulin clamp study was performed to assess insulin sensitivity in nonobese patients with type 2 diabetes. Investigators utilized insulin infusion to achieve physiologic hyperinsulinemia, and glucose was infused at a variable rate in order to maintain constant euglycemia.1 As shown on the left, mean total body glucose uptake in patients with type 2 diabetes was shown to be 25% lower than that of healthy controls (P<0.01).1 In a similar investigation, the euglycemic insulin clamp technique was combined with hepatic and femoral venous catheterization to analyze the mechanism and site of insulin resistance in nonobese patients with type 2 diabetes.2 Peripheral tissues were found to be the most important site of insulin resistance. Leg glucose uptake (shown on the right of the slide) in response to insulin infusion was delayed and reduced by 45% in those with type 2 diabetes compared with healthy controls (P<0.01).2 DeFronzo R, Deibert D, Hendler R, Felig P, Soman V. Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J Clin Invest. 1979;63: DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76: Increased HGP Decreased Glucose Uptake DeFronzo RA, et al. J Clin Invest. 1979;63: ; DeFronzo RA, et al. J Clin Invest. 1985;76: 48

The Disharmonious Quartet
Islet b-cell Impaired Insulin Secretion ↑ FFA Increased Lipolysis It is now time to consider the role of increased lipolysis, as fat cells, resistant to insulin, increase FFA production. This leads us to what we call the “disharmonious quartet.” Increased HGP Decreased Glucose Uptake FFA=free fatty acids. 49

Role of Free Fatty Acids Hyperglycemia
Increased Lipolysis  Lipolysis Research indicates that increased circulating FFA levels may play an important role in the development of hyperglycemia in type 2 diabetes.1,2 Elevated FFA concentrations are common in both obese individuals and in patients with type 2 diabetes and accompany increases in adipose tissue lipolysis, which may be stimulated by a demand for fuel or a reduction in insulin-mediated suppression of this process.2 Evidence suggests that high plasma FFA concentrations contribute to hyperglycemia through increases in FFA-derived long-chain acyl-coA esters, which, in turn, lead to suppression of glucose transport, glycogen synthesis and glycolysis in skeletal muscle, and increased gluconeogenesis and glucose production in the liver.2 Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians. 1999;111: Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur J Clin Invest. 2002;32(suppl 3):14-23.  Plasma FFA Muscle Liver  FACoA  FACoA  Glucose Utilization  Gluconeogenesis  HGP  HGP FACoA=FFA-derived long-chain acyl-CoA esters. Boden G. Proc Assoc Am Physicians. 1999;111: 50 50

Free Fatty Acids Impair -Cell Function
Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM Δ C-peptide Concentration (%)* Research has shown that chronic elevations in FFA concentrations can lead to β-cell dysfunction. This study investigated the effects of sustained plasma FFA increases on β-cell functionality in nondiabetic subjects with a genetic predisposition for type 2 diabetes.1,2 Following a 48-hour infusion of either saline or lipids, with the latter administered to achieve physiologic plasma FFA concentrations consistent with type 2 diabetes levels, a hyperglycemic clamp was utilized to assess patients’ insulin secretion in response to glucose.2 Measurement of first- and second-phase changes in C-peptide concentrations revealed that, compared with saline infusion, lipid infusion enhanced insulin secretion in control subjects but decreased the insulin response in those with a family history of type 2 diabetes (first phase: +75% versus -60%, P<0.001; second phase: +25% versus -35%, P<0.04).2 These results suggest that individuals who are at increased risk for type 2 diabetes may be more susceptible to β-cell lipotoxicity following prolonged exposure to elevated plasma FFA levels. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36(11-12): Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52: P<0.001 P<0.04 First Phase Second Phase *Percent difference between lipid infusion and saline infusion in subjects with family history of T2DM. Kashyap S, et al. Diabetes. 2003;52: 51

The Quintessential Quintet
Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis The next factor to consider in type 2 diabetes pathophysiology is the decreased incretin effect, which can be observed in the glucose response of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in patients with IGT or type 2 diabetes. This gives us the quintessential quintet. Increased HGP Decreased Glucose Uptake 52

GLP-1 and GIP Responses in Type 2 Diabetes
Postprandial GLP-1 Levels Are Decreased in Patients with IGT and T2DM GIP Levels Are Increased in T2DM NGT IGT T2DM * * 20 * * P<0.01 100 Meal * * * * An investigation of diminished incretin effect in type 2 diabetes analyzed postprandial GLP-1 concentrations (shown on the left) during a 4-hour mixed meal test in individuals with type 2 diabetes, IGT, or NGT.1 Compared with NGT subjects, those with type 2 diabetes had significant reductions (P<0.05) in postprandial GLP-1 levels.1 Further, after corrections for body mass index and gender, postprandial GLP-1 levels in patients with type 2 diabetes were also decreased relative to those with IGT.1 As shown on the right of the slide, another study of incretin hormones in type 2 diabetes found that GIP levels were significantly higher 30 to 90 minutes (P< ) after an OGTT in untreated patients with type 2 diabetes compared with healthy controls.2 Increased GIP levels in type 2 diabetes have been termed “GIP resistance.” However, as shown on the next slide, these findings have not been replicated, and the concept of GIP resistance remains under debate. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86: Jones IR, Owens DR, Luzio S, Williams S, Hayes TM. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32: * 80 15 * 60 GIP (pmol/L) 10 GLP-1 (pmol/L) * 40 5 20 60 120 180 240 -30 60 120 180 210 Time (min) Time (min) *P<0.05. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Jones IR, et al. Diabetologia. 1989;32: ; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86: 53

GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance
4 16 P<0.005 12 14 3 10 12 8 2 10 In this study, investigators studied GLP-1, GIP, and insulin AUC following an OGTT in identical twins discordant for type 2 diabetes. Significant decreases in insulin AUC were observed for twins with diabetes relative to their nondiabetic co-twins with NGT or IGT (P<0.0005) and relative to controls with NGT and no family history of diabetes (P< ). GLP-1 AUC was significantly lower in subjects with diabetes than in healthy controls (P<0.05). No significant differences in GIP AUC were observed between twins with diabetes, their nondiabetic co-twins, or controls. The finding that GIP levels remained unchanged in this study conflicts with the study shown on the previous slide. The impact of type 2 diabetes on GIP remains a subject of debate. Vaag AA, Holst JJ, Vølund A, Beck-Nielsen HB. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol. 1996;135: AUC1 GLP-1 (nmol/L · min) 6 AUC1 GIP (nmol/L · min) 8 AUC1 Insulin (mU/mL · min) 4 1 6 2 4 2 -2 -1 Controls NGT IGT T2DM Controls NGT IGT T2DM Controls NGT IGT T2DM Vaag AA, et al. Eur J Endocrinol. 1996;135:

Decreased Incretin Effect
The Setaceous Sextet Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Islet a-cell Increased Glucagon Secretion Next is the setaceous sextet, which takes into consideration the increased islet α-cell area and corresponding increased glucagon secretion and HGP in patients with type 2 diabetes. Increased Lipolysis Increased HGP Decreased Glucose Uptake 55

Pancreatic -Cells and -Cells in Normal Individuals
Endocrine mass ~50% ~35% Role Produce insulin and amylin Produce glucagon Mechanism of action Secrete insulin in response to blood glucose elevations Secrete glucagon in response to blood glucose decreases Metabolic effect Permit glucose uptake by peripheral tissues Suppress glucagon and HGP Stimulate HGP to meet energy needs between meals The islets of Langerhans occupy approximately 1% to 5% of the total pancreatic mass in human adults. The islets include both pancreatic β- and α-cells. β-Cells, which secrete insulin and amylin, comprise about 50% of the endocrine mass of the pancreas and reside in the central portion of the islet. Residing in the periphery of the islets, α-cells comprise about 35% of the endocrine mass of the pancreas. These cells produce glucagon, which is released in response to low blood glucose levels. Glucose homeostasis requires the integrated functioning of β- and α-cells. Insulin is a potent inhibitor of islet glucagon release; glucose indirectly suppresses glucagon secretion through increases in insulin. Cabrera O, et al. PNAS. 2006;103: Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39. Cabrera O, et al. PNAS. 2006;103: ; Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.

Area of -Cells Is Increased in Type 2 Diabetes
-Cell Islet Area (%) This slide shows α-cell mass as assessed from pancreatic postmortem analysis of subjects with type 2 diabetes (n=15) and age-matched controls (n=10). Compared with control subjects, those with type 2 diabetes demonstrated a 58% increase in pancreatic α-cell islet area (P<0.05). The authors proposed that this increase might contribute to the hyperglucagonemia and hyperglycemia typical in type 2 diabetes. Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 1988;9: (n=10) (n=15) Clark A, et al. Diabetes Res. 1988;9:

Plasma Glucagon (pg/mL)
Basal Glucagon Levels and Basal Hepatic Glucose Production in Type 2 Diabetes 160 250 200 120 P<0.001 T2DM + SRIF T2DM + SRIF 44% 58% 150 Basal HGP (mg/m2 • min) This study of the role of glucagon in HGP involved 13 individuals with NGT and 10 with type 2 diabetes. Basal HGP was measured isotopically and was also studied during infusion of somatostatin (SRIF) in conjunction with glucose and insulin replacement, which isolated the effect of glucagon on HGP. As shown on the right, glucagon levels were significantly higher in patients with type 2 diabetes versus control subjects (208±37 versus 104±15 pg/mL; P<0.001). As shown on the left, in the basal state, HGP was 66% greater among patients with type 2 diabetes (145 mg/m2 per min) than among control subjects (89 mg/m2 per min; P<0.01). During SRIF, glucagon decreased by 44% in subjects with type 2 diabetes, to 119±26 pg/mL. This decrease corresponded with a 58% reduction in HGP among the diabetic patients, to 82 mg/m2 per min (P<0.001). Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 1987;36: Plasma Glucagon (pg/mL) 80 100 40 50 NGT T2DM NGT T2DM SRIF=somatostatin infusion. Baron A, et al. Diabetes. 1987;36: 58

Hyperglucagonemia and Insulin- Mediated Glucose Metabolism
Plasma Glucose (mmol/L) Plasma Insulin (mU/L) This slide illustrates the outcomes of a series of experiments designed to measure the effect of chronic hyperglucagonemia on HGP and insulin-mediated glucose action, as assessed in 14 young, healthy adult volunteers. These figures show patients’ fasting concentrations of glucagon, plasma glucose, insulin, and FFAs at baseline and 24 and 48 hours following glucagon infusion and subsequent insulin clamp evaluation. Following glucagon infusion, subjects experienced a stable ~50% increase in plasma glucagon concentration (from 242±14 pg/mL to 414±24 pg/mL). FPG concentrations showed an approximate 20% increase at both 24 and 48 hours (from 76±4 mg/dL [4.2±0.2 mmol/L] at baseline to 93±2 mg/dL [5.2±0.1 mmol/L] at 48 hours). Fasting plasma insulin levels did not change substantially at either time point, while fasting FFAs showed progressive decline at both 24 and 48 hours (from 530±58 μmol/L at baseline to 410±47 and 354±33 μmol/L at 24 and 48 hours, respectively). These results provided early evidence to suggest that diabetes is a bi-hormonal disease, with both insulin and glucagon levels contributing to the metabolic alterations observed in patients with diabetes. Del Prato S, Castellino P, Simonson DC, DeFronzo RA. Hyperglucagonemia and insulin-mediated glucose metabolism. J Clin Invest. 1987;79: Plasma Glucagon (mU/L) 24 48 hr Plasma FFA (mol/l) 24 48 hr Del Prato S, et al. J Clin Invest. 1987;79:

Peak Postprandial Plasma Glucose Level (mmol/L)
Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGT 100 r=0.72 P<0.0001 r=-0.62 P<0.001 90 80 70 Glucose Appearance (mmol/5 hr) This slide illustrates outcomes from a 1992 study designed to assess the specific contributions of insulin deficiency and insulin resistance in metabolic response. To control for the progressive damage caused by hyperglycemia in type 2 diabetes, this experiment was conducted among both normal individuals (n=16) and individuals with IGT (n=15); both groups included obese and nonobese individuals, matched for age and weight across cohorts. Following glucose ingestion, subjects were evaluated for a number of physiologic parameters including peak postprandial glucose and plasma insulin and glucagon response. As shown, both obese and nonobese subjects with IGT exhibited elevated postprandial glucose peaks in the context of a strong positive correlative relationship (r=0.72, P<0.0001). This observed difference was caused by IGT subjects’ reduced suppression of hepatic glucose. Additionally, obese and nonobese subjects with IGT showed smaller reductions in plasma insulin-to-glucagon ratios, expressed as an inverse relationship (r=0.62, P<0.0001). Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992;326:22-29. 60 50 40 6 8 10 12 14 5 10 15 20 Peak Postprandial Plasma Glucose Level (mmol/L) Plasma Insulin:Glucagon Ratio Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese. Mitrakou A, et al. N Engl J Med. 1992;326:22-29.

Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 Diabetes
360 Type 2 diabetes (n=12) Normal subjects (n-=11) 330 Glucose (mg %) 300 270 240 110 80 120 This study of insulin, glucose, and glucagon dynamics involved patients with type 2 diabetes (n=12) versus nondiabetic control subjects (n=11). After a large carbohydrate meal, mean plasma glucose increased dramatically by 125 mg/100 mL, from 228 mg/100 mL to 353 mg/100 mL in patients with type 2 diabetes. In contrast, glucose rose by only 53 mg/100 mL from the baseline value of 84 mg/100 mL in normal subjects. In parallel, insulin rose sharply in the control subjects, from a mean fasting level of 13 µU/mL to a peak of 136 µU/mL within 45 minutes after the meal. In type 2 diabetes, however, the insulin response was delayed and suppressed, increasing from 21 µU/mL to only 50 µU/mL at 60 minutes. In the control group, mean plasma glucagon levels declined significantly from the fasting value of 126 pg/mL to 90 pg/mL at 90 minutes (P<0.01). In contrast, among diabetic patients the mean plasma glucagon level rose slightly to 142 pg/mL at 60 minutes, before returning to the baseline value of 124 pg/mL at 180 minutes. Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283: 90 Insulin (µU/mL) 60 Delayed/depressed insulin response 30 140 130 Nonsuppressed glucagon 120 Glucagon (pg/mL) 110 100 90 -60 60 120 180 240 Time (min) Müller WA, et al. N Engl J Med. 1970;283:

The Septicidal Septet Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet a-cell When increased glucose reabsorption is added to the mix of pathogenic factors, we are presented with the septicidal septet. We will now look at the role of the kidneys in the pathogenesis of type 2 diabetes. Increased Glucose Reabsorption Increased Glucagon Secretion Increased HGP Decreased Glucose Uptake 62

Renal Glucose Reabsorption in Type 2 Diabetes
Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Inhibition of sodium-glucose cotransporter 2 (SGLT2) protein is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide. First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity. This approach to therapy is simple and nonspecific, and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond. Wright EM, et al. J Intern Med. 2007;261:32-43. 63

Renal Handling of Glucose
(180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Approximately 180 L of plasma per day pass through the kidney’s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than passed out in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals.1 With a daily glomerular filtration rate of 180 L, approximately 162 g of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/L (101 mg/dL). As shown on the slide, reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1, which occurs in the straight section of the tubule (S3), is responsible for approximately 10% of glucose reabsorption in the kidney. The other 90% is mediated by SGLT2, which occurs in the convoluted section on the tubule (S1).1 Although it varies from person to person, the maximal reabsorptive capacity of the proximal tubule averages 375 mg per minute. Because the filtered glucose load in healthy nondiabetic subjects is less than this, all filtered glucose is returned to circulation and none is excreted in the urine.2 Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43. Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14: SGLT1 S3 90% 10% No Glucose 64 64

Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes
SGLT2 GLUT2 AMG Uptake 8 P<0.05 2000 P<0.05 6 1500 Human exfoliated proximal tubular epithelial cells (HEPTECs), which can be isolated from urine, continue to express a variety of proximal tubular markers, including SGLT2 through several subsequent subcultures. In this study, HEPTECs isolated from individuals with NGT and type 2 diabetes were cultured in a hyperglycemic environment. As shown in the left graph, the cells from the type 2 diabetes patients expressed significantly more SGLT2 and GLUT2 proteins than cells from NGT individuals. In addition, renal glucose uptake, measured using the glucose analogue methyl-α-D-[U14C]-glucopyranoside (AMG), was significantly greater in the type 2 diabetes HEPTECs than the NGT cells. These findings demonstrate that type 2 diabetes is associated with increases in renal glucose transporter expression and activity. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin- dependent diabetes. Diabetes. 2005;54: Normalized Glucose Transporter Levels CPM 4 1000 P<0.05 2 500 NGT T2DM NGT T2DM NGT T2DM AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54: 65

The Ominous Octet Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet a-cell Increased Glucagon Secretion Insulin and appetite interact in the brain when neurotransmitters in the hypothalamus signal satiety in response to increased insulin. Adding brain and neurotransmitter dysfunction to the pathogenic picture of type 2 diabetes gives us the ominous octet. Increased Glucose Reabsorption Neurotransmitter Dysfunction Increased HGP Decreased Glucose Uptake 66

Lower Posterior Hypothalamus Magnitude of Inhibitory
Altered Hypothalamic Function in Response to Glucose Ingestion in Obese Humans Lower Posterior Hypothalamus P<0.01 8 Magnitude of Inhibitory Response (%) 4 Several areas of the hypothalamus are known or hypothesized to play an integral part in hunger, satiety, and feeding behavior. It has been proposed, though not demonstrated, that an abnormality of the human hypothalamus may be responsible for excess food intake and obesity. Magnetic resonance imagining (MRI) has been used previously in animal models (not shown) to study hypothalamic function. Following glucose loading, MRI demonstrated an inhibitory response in the area between the hypothalamus and thalamus in normal rats, but not in diabetic rats. To investigate hypothalamic function following oral glucose intake, the current study enrolled 10 lean and 10 obese volunteers with NGT to undergo 50 minutes of functional MRI of the hypothalamus following ingestion of 75 mg of glucose. In the obese group, inhibitory response in the lower posterior hypothalamus was markedly attenuated (4.8±1.3%, P<0.05) compared with the lean group (7.9±0.6%), and time to maximum inhibitory response was significantly longer in the obese group (9.4±0.5 versus 6.4±0.5 minutes, P<0.01). FPG and insulin concentrations in both obese and lean subjects correlated with the time taken to reach maximum inhibitory response. This study demonstrates a difference in hypothalamic function in lean and obese subjects. These results suggest that, in obese individuals, impaired hypothalamic function may contribute to or result from the development of insulin resistance, impaired glucose homeostasis, and/or weight gain. Matsuda M. Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes ;48: Obese Lean 12 P<0.01 8 Time to Max Inhibitory Response (min) 4 Obese Lean Matsuda M, et al. Diabetes. 1999;48: 67

Treatment of Type 2 Diabetes
1. Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c 2. Will require multiple drugs in combination to correct multiple pathophysiologic defects 3. Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented 68

DPP-4=dipeptidyl peptidase-4.
Treatment of Type 2 Diabetes: A Sound Approach Based Upon Its Pathophysiology Islet b-cell Impaired Insulin Secretion TZDs GLP-1 analogues DPP-4 Inhibitors Sulfonylureas/ Meglitinides  Increased Lipolysis TZDs The soundest approach to developing treatment regimens for patients with type 2 diabetes will be predicated on addressing the disease’s multiple etiologic pathways. Agents that improve insulin resistance, such as TZDs and metformin, help to decrease HGP; these same agents also facilitate increased glucose uptake. Pharmacologic agents such as TZDs that decrease FFA expression may control increased lipolysis. Last, β-cell function and insulin secretion are improved by a variety of agents. TZDs, GLP-1 analogues, and dipeptidyl peptidase-4 (DPP-4) inhibitors have all been shown to improve β-cell function. The latter 2 agents as well as sulfonylureas and meglitinides also directly stimulate insulin secretion. Nevertheless, no single available antidiabetic agent addresses all of the underlying pathophysiologic mechanisms, and no agent has yet been shown to yield sustainable HbA1c reductions, as shown on the next 2 slides. Metformin TZDs TZDs Metformin  Increased HGP Decreased Glucose Uptake DPP-4=dipeptidyl peptidase-4. 69

UKPDS: Effect of Glibenclamide and Metformin Therapy on HbA1c
Conventional Glibenclamide Metformin 9 8 Median HbA1c (%) Despite advances in therapy, however, no single antidiabetic agent has been shown to sustain HbA1c levels over time. This slide shows the deterioration in glycemic control that occurred during the UKPDS, which compared conventional with intensive therapy in newly diagnosed patients with type 2 diabetes. At the start of the trial, HbA1c was approximately 7% across all groups. Median follow-up was 10.7 years. A secondary analysis, shown on this slide, compared glucose control among patients receiving metformin (n=342), glibenclamide (n=277), or conventional treatment (primarily diet; n=411). In the first year, HbA1c declined in all groups, with the greatest effect in the metformin and glibenclamide groups. In subsequent years, HbA1c in all groups rose steadily, exceeding 7% within approximately 2 years in the conventional treatment group. Median HbA1c in the glibenclamide and metformin groups exceeded 7% in 5 and 7 years, respectively. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet ;352: 7 IDF Treatment Goal: <6.5% 6 3 6 9 12 15 Years UKPDS Group. Lancet. 1998;352: 70

ADOPT: Effect of Glyburide, Metformin, and Rosiglitazone on HbA1c
Glyburide Metformin Rosiglitazone 7.6 7.2 6.8 6.4 1 2 3 4 5 -0.42% (P<0.001) -0.13% (P=0.002) HbA1c (%) This slide shows that a similar deterioration in glucose control occurred in A Diabetes Outcome Progression Trial (ADOPT), a double-blind, randomized, controlled trial that evaluated rosiglitazone, metformin, and glyburide as initial treatment for type 2 diabetes in 4360 patients. Within the first 6 months of treatment, HbA1c decreased in all treatment groups, with glyburide exerting the greatest initial effect. Subsequently, HbA1c levels increased in all groups at an annual rate of 0.24% for glyburide, 0.14% for metformin, and 0.07% for rosiglitazone. At the 4-year evaluation, 40% of rosiglitazone patients had an HbA1c level <7%, compared with 36% of metformin patients (P=0.03) and 26% of glyburide patients (P<0.001). At 5 years, the difference in HbA1c levels between the rosiglitazone and metformin groups was -0.13% (P=0.002), and -0.42% (P=0.001) between the rosiglitazone and glyburide groups. Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med ;355: IDF Treatment Goal: <6.5% Years Kahn SE, et al. N Engl J Med. 2006;355: 71

Unmet Needs in Diabetes Care
Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Weight Management Type 2 Diabetes Hyperglycemia Unmet needs in diabetes care are multifaceted, and include Recognition and identification of the multiple defects inherent in type 2 diabetes. Problems with adverse effects associated with current therapeutic options. Hyperglycemia. Associated cardiovascular risk. Difficulties with weight management. As discussed in the next section, there is a novel therapeutic approach to type 2 diabetes, which may help fulfill some of these needs. CVD Risk (Lipid and Hypertension Control) Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. 72 72

SGLT2 Inhibition A Novel Treatment Strategy for Type 2 Diabetes 73

Normal Glucose Homeostasis
Pancreas  Fat In normal individuals, the pancreas, liver, and peripheral tissues act in concert to ensure that energy needs are met in the fasting state by maintaining blood glucose levels of approximately 5 mmol/L (90 mg/dL). “Normal” fasting glucose varies among individuals, and may range between 3.9 and 5.6 mmol/L (70 and 101 mg/dL).1 Between meals, the pancreas secretes both insulin and glucagon. Released at a low, steady rate, basal insulin mediates the glucose uptake from the bloodstream by fat and muscle. At the same time, glucagon stimulates the processes of gluconeogenesis (the creation of glucose from amino acids) and glucogenolysis (the breakdown of glycogen into glucose) in the liver. The resulting hepatic glucose output is equivalent to not only insulin-mediated glucose uptake by fat and muscle but also insulin-independent glucose utilization by the brain, kidney, red blood cells, and other tissues.1,2 After a meal, various endocrine and neurologic signals, including the incretin hormones GIP and GLP-1 as well as elevated levels of glucose itself, stimulate the pancreas to decrease glucagon production and increase insulin secretion. As a result of suppressed glucagon and increased insulin levels, HGP decreases, and postmeal glucose levels remain below 11.1 mmol/L (200 mg/dL).1-3 DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37: Unger RH. Alpha- and beta-cell interrelationships in health and disease. Metabolism. 1974;23: Kieffer TJ. Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20: Liver 5 mmol/L Muscle Fasting Plasma Glucose 74 74

Pathophysiology of Type 2 Diabetes
Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP In persons with abnormal glucose tolerance, glucose homeostasis is disrupted by the combination of impaired insulin secretion and peripheral insulin resistance, along with increased HGP. These factors lead to increased levels of FPG by the increase from 5 to 10 mmol/L (90 to 180 mg/dL) on the slide.1 A fasting glucose this high is well into the diabetic range (>7.0 mmol/L [126 mg/dL]), but a fasting glucose >5.6 mmol/L (101 mg/dL) indicates impaired fasting glucose, a prediabetic state.2 If rising blood glucose levels remain unchecked, diabetes complications will result in time. In the short term, hyperglycemia results in glucotoxicity, which may occur well before the onset of diabetes. Glucotoxicity worsens the pathophysiologic factors that first led to hyperglycemia, and so begins a vicious circle.1,3 DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37: World Health Organization/International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Report of a WHO/IDF consultation. Geneva: WHO, 2006. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86: 10 mmol/L 5 mmol/L Fasting Plasma Glucose 75 75

Rationale for SGLT2 Inhibitors
Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond Inhibition of SGLT2 is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide. First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity. This approach to therapy is simple and nonspecific and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond. 76 76

Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP As demonstrated by this animation, if rising blood glucose levels remain unchecked, diabetes complications will result in time. In the short term, hyperglycemia results in glucotoxicity, which may occur well before the onset of diabetes. Glucotoxicity worsens the pathophysiologic factors that first led to hyperglycemia, and so begins a vicious circle.1,2 By increasing glucosuria, SGLT2 inhibition reduces plasma glucose levels toward the normal level of 5 mmol/L. With the reduction in glucotoxicity, insulin secretion improves and insulin sensitivity is enhanced. In turn, these decrease hepatic glucose output. Evidence supporting these actions is described in the following slides. DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37: Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86: 10 mmol/L Glucosuria Fasting Plasma Glucose 77 77

Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP By increasing glucosuria, SGLT2 inhibition reduces plasma glucose levels toward the normal level of 5 mmol/L (90 mg/dL). With the reduction in glucotoxicity, insulin secretion improves and insulin sensitivity is enhanced. In turn, these decrease hepatic glucose output. Evidence supporting these actions is described in the following slides. 10 mmol/L Glucosuria 5 mmol/L Fasting Plasma Glucose 78 78

Renal Handling of Glucose
(180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Approximately 180 L of plasma per day pass through the kidney’s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than passed out in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals. With a daily glomerular filtration rate of 180 L, approximately 162 g of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/L (101 mg/dL). As shown on the slide, reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, SGLT1 and SGLT2. SGLT1, which occurs in the straight section of the tubule (S3), is responsible for approximately 10% of glucose reabsorption in the kidney. The other 90% is mediated by SGLT2, which occurs in the convoluted section on the tubule (S1). Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med ;261:32-43. SGLT1 S3 90% 10% No Glucose 79 79

Sodium-Glucose Cotransporters
SGLT1 SGLT2 Site Intestine, kidney Kidney Sugar specificity Glucose or galactose Glucose Glucose affinity High Km=0.4 mM Low Km=2 mM Glucose transport capacity Role Dietary absorption of glucose and galactose Renal glucose reabsorption This slide describes the differences between the 2 sodium-glucose transport proteins. SGLT1 is a high-affinity, low-capacity transport protein that resides in both the gut and the proximal tubule in the kidney. It plays a role in both dietary absorption and renal reabsorption of glucose. Inhibition of SGLT1 can result in malabsorption of glucose and other nutrients from the intestine, leading to osmotic diarrhea. For example, in glucose-galactose malabsorption syndrome, mutations in the gene for SGLT1 result in impaired absorption of glucose and galactose and severe diarrhea. Individuals with this condition must receive all carbohydrates in the form of fructose, or malnutrition and even death may result. In contrast, SGLT2 is a low-affinity, high-capacity transport protein that resides in the proximal tubule alone. Specific inhibition of SGLT2 as a rational target of therapy for type 2 diabetes is based on familial renal glucosuria. Patients with this benign, inherited condition have a defective SGLT2 protein and excrete large amounts of glucose in their urine, with few if any adverse effects, as shall be discussed in later slides. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med ;261:32-43. 80

SGLT2 Mediates Glucose Reabsorption in the Kidney
Lumen Blood Na+ K+ ATPase Glucose SGLT2 S1 Proximal Tubule Na+ This slide shows the basic mechanism of SGLT2. On the luminal side of the early proximal tubule S1 segment, absorption of sodium across the cell membrane creates an energy gradient that in turn allows glucose to be absorbed. On the other side of the cell, sodium is reabsorbed through an ATPase-mediated sodium-potassium pump into the bloodstream in order to maintain intravascular volume. This exchange alters the concentration gradient within the cell so that glucose is reabsorbed into the bloodstream via the GLUT2 transporter. The GLUT2 transporter is present in red blood cells, the brain, and other tissues and thus is not a candidate for pharmacologic intervention. In contrast, SGLT2 is specific to the proximal tubule, so that pharmacologic inhibition will affect glucose reabsorption in the kidney but not in other tissues. Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev. 1994;74: Glucose GLUT2 Major transporter of glucose in the kidney Low affinity, high capacity for glucose Nearly exclusively expressed in the kidney Responsible for ~90% of renal glucose reabsorption in the proximal tubule Hediger MA, Rhoads DB. Physiol. Rev. 1994;74: 81

Renal Glucose Handling
TmG Splay Glucose Reabsorption and Excretion Reabsorption Excretion This slide shows a schematic of renal glucose reabsorption (yellow line) and excretion (green line) in normal individuals. The amount of glucose reabsorbed by the kidneys is essentially equivalent to the amount entering the system, with reabsorption increasing with glucose concentration up to approximately 11 mmol/L (198 mg/dL). At this threshold, the system becomes saturated and the maximal resabsorption rate, or glucose transport maximum (TmG), is reached. No more glucose can be absorbed, and instead the kidneys begin excreting it in the urine.1,2 Although 11 mmol/L (198 mg/dL) represents the theoretical threshold glucose concentration, the actual concentration varies due to nephron heterogeneity, resulting in slight differences in actual glucose reabsorption levels and TmG values between individual tubules. Thus, the actual threshold is not a single point but a curve, where excretion begins to occur at plasma glucose levels of ~10 mmol/L (180 mg/dL), and increases more gradually than sharply.1,2 Likewise, as reabsorption approaches the TmG, it tails off in parallel to the glucose concentration threshold. The difference between the actual and theoretical TmG is known as splay.1,2 Ganong WF. Review of Medical Physiology. 19th ed. Stamford, CT: Appleton & Lange; 1999: Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14: Actual Threshold Theoretical threshold 5 10 15 Plasma Glucose Concentration (mmol/L) 82 82

Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Design
Rat Group Pancreatectomy / Diabetic Status Phlorizin Meal Tolerance Test I (n=14) Sham Control – + II (n=19) 90% Diabetes III (n=10) IV (n=4) + / – 10-12 days after discontinuation of phlorizin Evidence that inhibiting renal glucose reabsorption would improve glycemic control initially came from animal studies using phlorizin, a compound that inhibits both SGLT1 and SGLT2. In the study shown on the slide, control rats underwent a sham pancreatectomy, while other rats were randomized to a 90% pancreatectomy that resulted in diabetes. Groups I and II received no treatment, but phlorizin was initiated in groups III and IV 2 weeks after the pancreatectomy and continued for 4 to 5 weeks, after which glucose testing was conducted in all groups. Group IV received an additional meal tolerance test 10 to 12 days after discontinuation of phlorizin treatment. Glucose and insulin levels were measured using the following tests: Two-step euglycemic insulin clamp (steady state plasma insulin = 80 to 90 and ~170 to 180 μU/mL [574 to 646 and ~1220 to 1292 pmol/L]) OGTT, with glucose given at a dose of 1g/kg. Meal tolerance test consisting of 4 g of rat chow given in an awake, unstressed state. All rats were fed the same amount of chow and body weight was similar in all 5 groups at the end of the study. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest ;79: Phlorizin treatment period: 4-5 weeks Diet was same for all groups; body weight was similar across groups at end of study Rossetti L, et al. J Clin Invest. 1987;79: 83 83

Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic Rats
† 8 20 * † 6 15 Fasting Glucose (mmol/L) 4 Fed Glucose (mmol/L) 10 As shown on this slide, fasting and fed glucose levels increased significantly to 6.80.3 mmol/L (1225 mg/dL; P<0.05) and 16.40.7 mmol/L (29512 mg/dL; P<0.001 versus control and phlorizin treatment), respectively, in the diabetic rats compared with the controls (fasting: [5.60.1 mmol/L [1012 mg/dL ]; fed: 7.80.06 mmol/L [140 1 mg/dL]). Phlorizin treatment, however, essentially normalized fasting glucose (5.50.2 mmol/L [1003 mg/dL]) and decreased fed glucose to 9.50.2 mmol/L (1714 mg/dL), which was not significantly different from the control level. Fasting glucose measured 10 to 12 days after discontinuation of phlorizin was numerically higher but not statistically different from control (6.20.2 mmol/L [1133 mg/dL]). Fed glucose, however, was significantly increased over the control level: 17.02.5 mmol/L (30645 mg/dL; P<0.001 versus control and phlorizin treatment). Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest ;79: 2 5 Control Diabetes Diabetes + Phlorizin Control Diabetes Diabetes + Phlorizin Diabetes +/- Phlorizin Diabetes +/- Phlorizin *P<0.05 vs control and phlorizin. †P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79: 84 84

Diabetes +/- Phlorizin
Insulin-Mediated Glucose Uptake in Diabetic Rats Following Phlorizin Treatment Diabetes +/- Phlorizin Diabetes + Phlorizin Diabetes Control 20 25 30 35 40 * Glucose Uptake (mg/kg ∙ min) Phlorizin treatment also improved insulin sensitivity in the pancreatectomized rats. Insulin-mediated glucose uptake measured during a euglycemic-insulin clamp was similar in the control (34.20.6 mg/kg • min) and phlorizin-treated diabetic rats (33.11.1 mg/kg • min). In untreated diabetic rats, glucose uptake was significantly reduced to 24.80.6 mg/kg • min (P<0.001 versus control and phlorizin treatment). Discontinuation of phlorizin treatment significantly reduced insulin-mediated glucose uptake to 25.21.3 mg/kg • min (P<0.001 versus control and phlorizin treatment). Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest ;79: *P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79: 85 85

Mechanism of Action of SGLT2 Inhibitors
Inhibition of SGLT2 Reversal of glucotoxicity Insulin sensitivity in muscle ↑ GLUT4 translocation ↑ Insulin signaling Other SGLT2 inhibitors improve glucose control by reducing plasma glucose levels, which in turn reverses the effects of glucotoxicity, as follows: Insulin sensitivity in muscle increases via increased GLUT4 translocation and insulin signaling as well as other mechanisms. Insulin sensitivity also improves in the liver, with a decrease in glucose-6-phosphatase levels. Gluconeogenesis in the liver decreases as a result of a reduction in the Cori cycle and decreased PEP carboxykinase. β-Cell function improves. Insulin sensitivity in liver ↓ Glucose- 6-phosphatase Gluconeogenesis Decreased Cori cycle ↓ PEP carboxykinase -Cell function 86 86

Effect of Phlorizin on -Cell Function in Diabetic Rats: Study Design
Rat Group Pancreactomy / Diabetic Status Phlorizin I Sham Control – II 90% Diabetes III 0.4 g/kg/day In a study of the effects of phlorizin treatment on β-cell function, male Sprague-Dawley rats were randomized to a sham or a 90% pancreatectomy. Pancreatectomized, diabetic animals were then randomized to treatment with phlorizin 0.4 g/kg/day or no treatment for 3 weeks. β-Cell function was measured using a 2 mM arginine clamp and a hyperglycemic (≥5.5 mmol/L) clamp. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80: Sprague-Dawley male rats weighing g Phlorizin treatment period: 3 weeks Arginine clamp (2 mM); hyperglycemic clamp (≥5.5 mmol/L) Rossetti L, et al. J Clin Invest. 1987;80: 87 87

Plasma Insulin Response to Glucose
First Phase Second Phase 6 4 Plasma Insulin (ng/mL ∙ min / g Pancreas) Phlorizin treatment dramatically improved both first- and second-phase insulin response to glucose. The first-phase insulin response was considered to occur during the first 80 to 90 minutes of the clamp procedure, while the second phase spanned 90 to 140 minutes. Peak first-phase plasma insulin responses, measured as ng/mL • min/g pancreas, were as follows: Control: 3.670.4. Untreated diabetic: 0.250.6 (P<0.001 versus control). Phlorizin-treated diabetic: 4.360.4. Peak second-phase plasma insulin responses were as follows: Control: 4.500.7. Untreated diabetic: 1.860.3 (P<0.001 versus control). Phlorizin-treated diabetic: 4.890.6. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80: * 2 * Control Diabetes Diabetes + Phlorizin Control Diabetes Diabetes + Phlorizin *P<0.001 vs control. Rossetti L, et al. J Clin Invest. 1987;80: 88 88

Glucose Infusion Rate (mg/kg • min)
Plasma Glucagon Concentration in Diabetic Dogs Before and After Phlorizin Glucose Infusion Rate (mg/kg • min) 2 6 8 12 16 24 SGLT2 inhibition with phlorizin also restores glucose-mediated suppression of glucagon in dogs with alloxan-induced diabetes. A glucose infusion of as little as 2 mg/kg • min reduced plasma glucagon levels in diabetic dogs that received phlorizin (green line) compared with those that did not (orange line). Increasing the rate of glucose infusion resulted in increasingly greater suppression of glucagon levels. Starke A, Grundy S, McGarry JD, Unger RH. Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes. Proc Natl Acad Sci U S A. 1985;82: Diabetic  Glucagon (pg/mL) -200 Diabetic + Phlorizin -400 Starke A, et al. Proc Natl Acad Sci. 1985;82: 89 89

Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition
90

Familial Renal Glucosuria
Presentation Glucosuria: g/day Asymptomatic Blood Normal glucose concentration No hypoglycemia or hypovolemia Kidney / bladder No tubular dysfunction Normal histology and function Complications No increased incidence of Chronic kidney disease Diabetes Urinary tract infection Familial renal glucosuria is a genetic condition that serves as a model for the effects of SGLT2 inhibition. Patients with this condition are asymptomatic but have impaired functioning of their SGLT2 proteins. As a result, they excrete between a few to ~100 g of glucose per day in their urine.1,2 In other respects, these individuals are normal. Blood glucose concentration is neither high nor low, and blood volume remains essentially normal due to sodium reabsorption through other channels. Kidney and bladder function remain unaffected, and this group of patients does not show an increased incidence of kidney disease, diabetes, or urinary tract infections.1,2 Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14: Santer R, et al. J Am Soc Nephrol. 2003;14: ; Wright EM, et al. J Intern Med. 2007;261:32-43. 91 91

Familial Renal Glucosuria
Theoretical Normal Observed Type B Glucose Reabsorption Type A This slide shows a schematic of glucose reabsorption in normal individuals and those with familial renal glucosuria. As mentioned, the glucose transport maximum (TmG) is approximately 11 mmol/L (198 mg/dL), although the actual threshold is less abrupt (dashed yellow line) and starts to taper off at a glucose concentration of about 10 mmol/L (180 mg/dL).1 Familial renal glucosuria can be divided into 2 main types. In type A, the TmG is lower than normal (orange line). These patients have reduced levels of the SGLT2 protein.2 In type B familial renal glucosuria, the SGLT2 protein has a diminished affinity for glucose, which results in an exaggerated splay (or the difference between the theoretical and actual glucose reabsorption threshold) but a normal TmG (green line).2 Ganong WF. Review of Medical Physiology. 19th ed. Stamford, CT: Appleton & Lange; 1999: Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14: 5 10 15 Plasma Glucose Concentration (mmol/L) Santer R, et al. J Am Soc Nephrol. 2003;14: 92 92

Analysis of SGLT2 Gene in Patients With Renal Glucosuria
23 families analyzed for mutations In 23 families, 21 different mutations were detected in SGLT2 Cause of glucosuria in other 2 families remains unknown The genetics of familial renal glucosuria have been studied in 23 families with the disorder, and 21 different mutations in the gene for SGLT2 were detected. Fourteen of 21 individuals were homozygous or compound heterozygous and had severe glucosuria of 15 to 200 g/day. Heterozygous family members had either no glucosuria or mild glucosuria of ≤4.4 g/day. In addition, various nonsense mutations, missense mutations, and small deletions were scattered over the SGLT2 coding sequence. The cause of glucosuria in the 2 remaining families remains unknown but may relate to mutations in GLUT2, the glucose transport protein residing on the basolateral membrane; HNF-1, which regulates SGLT2 transcription; or the genes for SGLT1 or SGLT3. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14: Santer R, et al. J Am Soc Nephrol. 2003;14: 93 93

Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes
SGLT2 GLUT2 AMG Uptake 8 P<0.05 2000 P<0.05 6 1500 Type 2 diabetes is associated with increases in renal glucose transporter expression and activity. Human exfoliated proximal tubular epithelial cells (HEPTECs), which can be isolated from urine, continue to express a variety of proximal tubular markers, including SGLT2 through several subsequent subcultures. In this study, HEPTECs isolated from individuals with NGT and type 2 diabetes were cultured in a hyperglycemic environment. As shown in the left graph, the cells from the type 2 diabetes patients expressed significantly more SGLT2 and GLUT2 proteins than cells from NGT individuals. In addition, renal glucose uptake, measured using the glucose analogue methyl-α-D-[U14C]-glucopyranoside (AMG), was significantly greater in the type 2 diabetes HEPTECs than the NGT cells. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54: Normalized Glucose Transporter Levels CPM 4 1000 P<0.05 2 500 NGT T2DM NGT T2DM NGT T2DM Rahmoune H, et al. Diabetes. 2005;54: 94

Implications An adaptive response to conserve glucose (ie, for energy needs) becomes maladaptive in diabetes Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal reabsorption of glucose Together, all the findings described on the preceding slides show that the conservation of glucose through the renal system to help meet energy needs between meals—an adaptive response that has evolved over eons—becomes maladaptive in diabetes. In diabetes, renal glucose reabsorption may be augmented in absolute terms by an increase in the renal Tm for glucose. 95 95

SGLT2 Inhibitors for the Treatment of Type 2 Diabetes
96

Effect of SGLT2 Inhibition on Renal Glucose Handling
TmG Splay Glucose Reabsorption and Excretion Reabsorption Excretion SGLT2 inhibition may reduce plasma glucose levels by decreasing TmG, increasing the glucose excretion rate, or both. In normal animals, SGLT2 inhibition has no effect on plasma glucose concentration, because the liver increases glucose production to compensate for glycosuria. In diabetic animals, however, administration of an SGLT2 inhibitor produces both dose-dependent glycosuria and a significant reduction in plasma glucose concentrations. In essence, SGLT2 inhibition “resets” the system by lowering the threshold for glucosuria; consequently, plasma glucose levels decrease and glucotoxicity declines. Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14: Actual Threshold Theoretical threshold 5 10 15 Plasma Glucose Concentration (mmol/L) 97 97

Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF Rats
Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg (n=6) 10 mg/kg (n=6) 400 * † 300 Dapagliflozin, an SGLT2 inhibitor currently in phase III development, is among the first of these compounds to be developed for the treatment of type 2 diabetes. This slide shows the effects of this agent on FPG levels in Zucker diabetic fatty (ZDF) rats.1,2 In this study, treatment with dapagliflozin in doses ranging from 0.1 to 10 mg/kg induced renal glucose excretion in both normal and diabetic rats. By day 8, FPG decreased significantly with all doses tested.1,2 Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57: Whaley J, Hagan D, Taylor J, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2007;56(suppl 2). Abstract 0559-P. FPG (mg/dL) 200 100 Baseline Day 8 Day 15 *P<0.05; †P< vs vehicle. ZDF=Zucker diabetic fatty. Han S, et al. Diabetes. 2008;57: ; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P. 98

Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Production in ZDF Rats 8.0 4.0 P<0.01 6.0 3.0 Hepatic Glucose Production (mg/kg • min) The same study of dapagliflozin in ZDF rats also evaluated insulin-stimulated glucose disposal and hepatic glucose output. The former, shown on the left of the slide, significantly increased after 2 weeks of treatment with dapagliflozin, while the latter significantly decreased, as shown on the right (P<0.01 versus controls for both).1 Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57: Glucose Infusion Rate (mg/kg • min) 4.0 2.0 P<0.01 2.0 1.0 CON DAPA CON DAPA CON=controls; DAPA=dapagliflozin. Han S, et al. Diabetes. 2008;57: 99 99

Dapagliflozin-Induced Glucosuria Reduces HbA1c: A Dose-Ranging Trial
Study design 12 week, double-blind, placebo-controlled Dapagliflozin: 2.5, 5, 10, 50 mg/day Metformin XR: 1500 mg/day Placebo Patients 389 drug-naive T2DM patients HbA1c >7.0% Measurements FPG, PPG, HbA1c The design of a phase II, randomized, double-blind, placebo-controlled, dose-ranging study of the effects of dapagliflozin in patients with type 2 diabetes is shown on this slide. A total of 389 treatment-naive patients with an HbA1c >7% were randomly assigned to treatment with increasing doses of dapagliflozin or placebo for 12 weeks. Metformin extended release (XR) was used as an active comparator, although no statistical comparisons were made. Glucose control assessments included FPG, postprandial glucose measured using a 3-hour OGTT, and HbA1c. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose co-transport inhibition with dapagliflozin in type 2 diabetes mellitus. Diabetes Care. 2009;32: List JF, et al. Diabetes Care. 2009;32: 100

Effect of Dapagliflozin on HbA1c
Baseline HbA1c (%) DAPA 2.5 DAPA 5 DAPA 10 DAPA 50 PBO MET XR 1500 -0.2 In a phase II, randomized, double-blind, placebo-controlled, dose-ranging study, 12 weeks of dapagliflozin treatment significantly reduced HbA1c in patients with type 2 diabetes, across all doses tested (P<0.01 versus placebo). Baseline HbA1c values ranged from 7.7% to 8.0% across all groups. Placebo-subtracted HbA1c reductions ranged from 0.5% to 0.7% and were similar to that achieved with metformin XR (-0.6%; no statistical comparisons were made among active treatments). List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose co-transport inhibition with dapagliflozin in type 2 diabetes mellitus. Diabetes Care. 2009;32: -0.4 Δ HbA1c (%) -0.6 -0.8 P<0.01 P<0.01 P<0.01 P<0.01 -1 All comparisons vs placebo; no statistical comparisons with metformin were made. List JF, et al. Diabetes Care. 2008;2009;32: 101

Dapagliflozin: Glucosuric and Metabolic Effects
Glucosuria ↑ g/day FPG ↓ mg/dL PPG ↓ mg/dL Body weight ↓ kg (↓ 2.5%-3.4%) Urine volume ↑ mL/day A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of dapagliflozin treatment for 12 weeks in patients with type 2 diabetes demonstrated significant improvements in a variety of metabolic parameters. Dapagliflozin increased mean glucosuria by 52 to 85 g/day, which in turn reduced mean FPG by 16 to 30 mg/dL (0.9 to 1.7 mmol/L) and mean postprandial glucose by 23 to 29 mg/dL (1.3 to 1.6 mmol/L). Mean body weight also declined by 2.2 to 3.2 kg, a 2.5% to 3.4% reduction. Finally, small increases in urine volume of 107 to 470 mL per day occurred.1 List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose co-transport inhibition with dapagliflozin in type 2 diabetes mellitus. Diabetes Care. 2009;32: List JF, et al. Diabetes Care. 2009;32: 102 102

Adverse Events With Dapagliflozin
PBO (n=54) Met 1500 mg QD (n=56) Dapa 2.5 mg QD (n=59) Dapa 5 mg QD (n=58) Dapa 10 mg QD (n=47) Dapa 20 mg QD (n=59) Dapa 50 mg QD (n=56) Hypoglycemia, n (%) 2 (4) 5 (9) 4 (7) 6 (10) 3 (6) UTIs, n (%) 3 (5) 5 (11) 7 (12) Genital infection, n (%) 0 (0) 1 (2) 2 (3) Hypotensive event, n (%) This slide lists adverse events recorded during a 12-week, placebo-controlled, dose-ranging study of dapagliflozin.1 Possible safety considerations with SGLT2 inhibitors include the risk of urinary tract infection; intravascular volume depletion, which may result in osmotic diuresis; electrolyte imbalance; nephrotoxicity due to accumulation of advanced glycation end products; nocturia; and drug interactions.2 Further study is needed to quantify the safety and tolerability of these agents. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose co-transport inhibition with dapagliflozin in type 2 diabetes mellitus. Diabetes Care. 2009;32: Abdul-Ghani MA. Inhibition of renal glucose absorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14: UTI=urinary tract infection. List JF, et al. Diabetes Care. 2009;32: 103 103

Investigational SGLT2 Inhibitors
Agent Manufacturer Phase III Dapagliflozin AstraZeneca/Bristol-Myers Squibb Phase II AVE-2268 sanofi-aventis BI 10773 Boehringer Ingelheim JNJ Johnson & Johnson Remogliflozin Sergliflozin GSK/Kissei TS-033 Taisho YM-543 Astellas/Kotobuki Pharmaceuticals Phase I CSG-452A Chugai/Roche SAR-7226 TA-7284 Mitsubishi Tanabe/Johnson & Johnson A large number of SGLT2 inhibitors are under investigation. 104

ISIS 388626 – A Specific SGLT2 Antisense Oligonucleotide
Highly specific for the kidney and SGLT2 transporter ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1 Marked reduction in FPG, PPG, and HbA1c in all three species No changes in plasma or urine electrolytes One SGLT2 inhibitor with a unique mechanism of action is ISIS This compound is an SGLT2 antisense oligonucleotide that is highly specific for the kidney and SGLT2 transporter. In rats and dogs, treatment with ISIS reduced SGLT2 mRNA/protein by ~80% without any demonstrable effect on SGLT1. Marked reductions in FPG, PPG, and HbA1c were also observed in experimental animals, with no changes in plasma or urine electrolytes.1 Wancewicz EV, Siwkowski A, Meibohm B, et al. Long term safety and efficacy of ISIS , an optimized SGLT2 antisense inhibitor, in multiple diabetic and euglycemic species. Diabetes ;57(suppl 2). Abstract 334-OR. Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR. 105 105

Unanswered Questions About SGLT2 Inhibition
Durability The efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range Safety and tolerability The long-term safety of this class remains to be proven Risk of nocturia and genitourinary infections may limit use in some patients Renal impairment SGLT2 inhibition may not be effective in patients with renal impairment SGLT2 inhibitors are unlikely to be effective in patients with renal insufficiency due to reductions in glomerular filtration rate as well as other reasons under investigation. Studies are also being conducted to identify glomerular filtration rate cut points beyond which SGLT2 inhibitors would be contraindicated. 106

SGLT2 Inhibition: Meeting Unmet Needs in Diabetes Care
Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia CVD Risk (Lipid and Hypertension Control) Corrects a Novel Pathophysiologic Defect No Hypoglycemia Complements Action of Other Antidiabetic Agents Promotes Weight Loss Improves Glycemic Control Note: this slide builds, with each unmet need changing to a possible answer with each click. This slide revisits the various unmet needs of type 2 diabetes identified earlier. SGLT2 inhibition may provide solutions to these unresolved issues in the following way: Weight management: SGLT2 inhibitors promote weight loss by increasing glucosuria, which drains glucose from the bloodstream and stimulates breakdown of fat cells for fuel. Multiple defects of type 2 diabetes: Increased renal glucose reabsorption has recently been identified in type 2 diabetes. SGLT2 inhibitors correct this novel defect. Adverse effects of therapy: Among adverse events, hypoglycemia may pose the greatest barrier to optimal glycemic control because of acute safety concerns as well as long-term risk of hypoglycemia unawareness (which develops from repeated episodes of hypoglycemia). Because their function is completely independent of insulin, SGLT2 inhibitors do not increase the risk of hypoglycemia. Hyperglycemia: Treating to HbA1c targets ≤7% in the years immediately following diabetes diagnosis is associated with long-term reduction in the risk of diabetic complications. The unique mechanism of action of SGLT2 inhibitors complements those of other antidiabetic agents, making them extremely suitable for combination therapy. CVD risk (lipid and hypertension control): The improvements in weight and glycemia achieved with SGLT2 inhibition will support treatments that more directly reduce CV risk (eg, statins and antihypertensive agents). Improvements in Glucose and Weight Support Other CVD Interventions 107 107

Conclusions SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity Restores normoglycemia Improves -cell function and insulin sensitivity 108

Conclusions Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes 109

Overall Conclusions Understanding of the pathophysiology of type 2 diabetes is an evolving process As new concepts emerge, there is potential for new treatment modalities Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis 110

Ralph Anthony DeFronzo, MD

Similar presentations

Presentation on theme: "Ralph Anthony DeFronzo, MD"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Ralph Anthony DeFronzo, MD

Similar presentations

Presentation on theme: "Ralph Anthony DeFronzo, MD"— Presentation transcript:

Similar presentations

About project

Feedback