1. Type 2 Diabetes: Pathophysiology and Opportunities for Treatment
Tyler Aguinaldo, MD
Director, Center for Diabetes & Metabolism
Santa Clara Valley Medical Center
April 16, 2009

2. Objectives Review epidemiology of diabetes and pre-diabetes.
Distinguish diabetes type 1 and type 2
Describe the role of pancreatic islet cells ( and β) in maintaining normal glucose homeostasis.
Understand disturbances in insulin resistance, β-cell function, glucagon secretion, hepatic glucose production and incretin hormones in type 2 diabetes.
Summarize treatment options in type 2 diabetes.

3. Number (in Millions) and Percent of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, U.S., 1980–2006

4. National Diabetes Statistics, 2007
Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007:
Total: 23.6 million people — 7.8 percent of the population — have diabetes.
Diagnosed: 17.9 million people
Undiagnosed: 5.7 million people
Prevalence of Impaired Fasting Glucose in People Aged 20 Years or Older, United States, 2007
In 2003 to 2006, 25.9 percent of U.S. adults aged 20 years or older had IFG —35.4 percent of adults aged 60 years or older, yields an estimated 57 million American adults aged 20 years or older with IFG

6. The global diabetes epidemic 2000―2010 and beyond: prevalence of diabetes
26.5
84.5
14.2
32.9
132.3
17.5
+24%
+57%
+23%
URGENT NEED FOR ACTION
9.4
There is an urgent need to treat and prevent diabetes mellitus as the prevalence of the disease continues to rise globally.
Estimates predict an increase from 151 million in 2000 to 220 million sufferers by 2010.
Wild S, et al. Diabetes Care 2004;27:1047―53.
Zimmet P, et al. Nature 2001;414:782―7.
14.1
15.6
+50%
22.5
1.0
+44%
1.3
2000: 151 million
2010: 220 million + ~50%
2025: 300 million + ~100%
2030: 366 million + ~145%
+33%
Wild S, et al. Diabetes Care 2004;27:1047―53.
Adapted from Zimmet P, et al. Nature 2001;414:782―7.

7. 12.6M Treated With Oral Agents or Insulin
NHANES: Glycemic Control in the U.S.
20.8M Patients
12.6M Treated With Oral Agents or Insulin
Yet Average A1C
Is Increasing
NHANES
1999–2000
6.2M Undiagnosed
7.9
62%
2M D&E
A1C >7%
12.6M Rx Treated
Of the 20.8 million people with diabetes in the United States, 6.2 million remain undiagnosed, while 12.6 million people are being treated with oral agents or with insulin.1
According to the National Health and Nutrition Examination Survey (NHANES IV) , only 38% of treated diabetics achieved the target HbA1C (A1C) goal of < 7.0%.2 Although this figure did not change significantly from that reported in NHANES III (which encompassed the years 1988 to 1994), there was a 0.2% increase in the average A1C level from NHANES III to NHANES IV.
Thus, despite the availability of numerous treatments for diabetes, glycemic control is worsening.
1. National Diabetes Fact Sheet, Available at: Accessed December 2005.
2. NHANES IV. Available at:
NHANES
1988–1994
7.7
38%
A1C <7%
AACE A1C Goal = 6.5%
ADA A1C Goal = <7%
CDC 2005, NHANES 1999–2002

8. Criteria for the Diagnosis of Diabetes

9. Two Main Classes of Diabetes Mellitus
Type 1 Diabetes:
Insulin deficiency (usually auto-immune)
Accounts for 5-10% of total diabetes
Type 2 Diabetes:
Multi-factorial:
Insulin resistance
Relative insulin deficiency
Dysregulation of glucagon
Abnormalities in incretin hormones
Accounts for 90-95% of total diabetes
Associated with “Metabolic Syndrome”

10. Type 1 DM
Younger
More lean
Insulin-deficient
Low triglycerides
Type 2 DM
Older
Overweight
Insulin-resistant
High TG’s/Low HDL-C

11. The Normal Pancreatic Islet
“An understanding of the normal physiology of the pancreas is important for any discussion of type 2 diabetes. The pancreas is an organ that has both exocrine and endocrine functions. The endocrine tissue makes up only 1% to 5% of the total pancreatic mass in adults. It is randomly distributed throughout the exocrine pancreas, with a greater concentration in the head of the pancreas.1 The endocrine cells are arranged into units called islets of Langerhans. Each islet of Langerhans contains several types of cells, namely, alpha-, beta-, gamma-, and delta-cells. Beta-cells predominate and tend to be located in the center of the islet. Beta-cells make up approximately 70% to 80% of the islet mass. Gamma- and delta-cells constitute less than 10% of the islets. The alpha- and beta-cells both play important roles in glucose homeostasis.2 Beta-cells produce insulin and amylin, and alpha-cells produce glucagon. Both insulin and glucagon are essential for glucose homeostasis. When blood glucose is elevated after meals, beta-cells release insulin into the bloodstream. Alternatively, when blood glucose levels fall, alpha-cells release glucagon. These responses help maintain a normal glycemic state.”3,4
Gamma- and delta-cells also produce important substances. Gamma-cells produce pancreatic polypeptide (PP) and delta-cells produce somatostatin.2 In studies, exogenous administration of pancreatic polypeptide reduced gastric acid secretion mediated by cholecystokinin and increased transit times in the intestine. Somatostatin’s actions are inhibitory. In the pituitary, it inhibits the secretion of growth hormone and thyrotropin, and in the pancreas, it inhibits insulin, glucagon, and pancreatic polypeptide. Somatostatin also inhibits several gut peptides and gastric acid secretion. Pancreatic exocrine secretion is also affected by both pancreatic polypeptide and somatostatin.5
References:
1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–281.
2. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005: 21–39.
3. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.
4. Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–502.
5. Boushey RP, Drucker DJ. Gastrointestinal hormones and gut endocrine tumors. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003:1777–1796.

12. b- and a-Cells in the Pancreas of Normal Individuals
b-Cells
a-Cells
Comprise about 70%–80% of the endocrine mass of the pancreas1,2
Comprise about 15% of the endocrine mass of the pancreas1
Located in the central portion of the islet1,2
Located in the periphery of the islet1
Produce insulin and amylin3
Produce glucagon1
Insulin released in response to elevated blood glucose levels1
Glucagon released in response to low blood glucose levels1
b- and α-Cells in the Pancreas of Normal Individuals
Pancreatic islets of Langerhans occupy approximately 1% to 5% of the total pancreatic mass in human adults. They are randomly distributed throughout the exocrine pancreas but their density is slightly greater in the pancreatic head. Located within the pancreatic islets are endocrine cells known as pancreatic beta- and alpha-cells.1
Beta-cells, which comprise about 70% to 80% of the endocrine mass of the pancreas, are located in the central portion of the islet. Beta-cells produce insulin, which is released in response to elevated blood glucose levels.2,3 The hormone amylin is also produced by beta-cells.4 Patients with type 2 diabetes exhibit some deficit in amylin production.4,5
Alpha-cells, which comprise about 15% of the endocrine mass of the pancreas, are located in the periphery of the islets. Alpha-cells produce glucagon, which is released in response to low blood glucose levels.3
Glucose homeostasis requires the integrated functioning of beta- and alpha-cells.6
1. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21– Rhodes CJ. Science. 2005;307:380–384.
3. Kahn SE et al. Diabetes. 1998;47:640–645.
References:
1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–281.
2. Rhodes CJ. Type 2 diabetes—a matter of β-cell life and death? Science. 2005;307:380–384.
3. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir OC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:21–39.
4. Kahn SE, Verchere CB, Andrikopoulos S, et al. Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans. Diabetes. 1998;47:640–645.
5. Bryant E. Voice of the diabetic. Available at: Accessed October 14, 2005.
6. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.

13. Insulin Increases and Glucagon Falls in Response to Meals in Normal Subjects
180
mg/dL ( - )
Glucose
126 72
400
200
pM ( )
Insulin
105 75 45
ng/L ( )
Glucagon
Insulin Increases and Glucagon Falls in Response to Meals in Normal Subjects
This slide depicts the changes in glucose, insulin, and glucagon concentrations after meal intake in subjects with normal glucose tolerance.
The study measured glucose, insulin, and glucagon levels after ingestion of a 6-kcal/kg meal.1
It demonstrated that after the meal, Glucose began to rise. Baseline level was 83 ± 1.8 mg/dL, which increased to 146 ± 7.2 mg/dL at 60 minutes. Glucose returned to baseline levels by 240 minutes.1
Insulin followed a similar pattern.1
Glucagon, however, dropped to a low by 90 minutes, then increased to a level above that of the baseline level.1
–60 60
120
180
240
300
360
Minutes After Meal Ingestion
N=11.
Adapted with permission from Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.
Reference:
1. Woerle HJ, Meyer C, Dostou JM, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.

14. Insulin and Glucagon Regulate Normal Glucose Homeostasis
(alpha cell)
Fasting state
Fed state
Pancreas
Insulin
(beta cell)
Insulin and Glucagon Regulate Normal Glucose Homeostasis
Normal glucose homeostasis is maintained in large part through a feedback relationship between insulin, glucagon, and circulating glucose.1
Fasting state
In the fasting state, pancreatic alpha cells release glucagon.1,2 Glucagon release is triggered by a fall in the plasma glucose level.1 Concomitantly, the pancreatic beta cells secrete less insulin.
Glucagon directs the liver to break down stored glycogen into glucose (glycogenolysis).1 The liver also generates new glucose (gluconeogenesis) during fasting. The end result is that the liver releases glucose into the bloodstream, thereby raising the plasma glucose level and maintaining homeostasis.
Fed state
In the fed state, glucose enters the bloodstream, and the beta cells detect the rise in glucose level and respond by promptly releasing insulin.1
Insulin signals other tissues in the body to take in glucose to be used as energy or stored for later use.1 Insulin also signals the liver to decrease glucose production, thus suppressing hepatic glucose production. The net result is the lowering of the plasma glucose level.
In the fed state, release of glucagon is suppressed, which also contributes to a decrease in glucose production.1
Normal functioning of this feedback loop helps maintain glucose homeostasis.
Glucose output
Glucose uptake
Liver
Blood glucose   
Muscle
Adipose tissue
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
References:
1. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med ;18:247–254.
2. Unger RH. Glucagon and the insulin: Glucagon ratio in diabetes and other catabolic illnesses. Diabetes ;20:834–838.

15. The Normal β-Cell Insulin Response to Intravenous (IV) Glucose Is Biphasic
500
400
1st phase
2nd phase
300
Plasma Insulin, pmol/L
200
The Normal β-Cell Insulin Response to Intravenous (IV) Glucose Is Biphasic
The normal beta-cell insulin response to IV glucose is biphasic. That is, there are 2 distinct phases noted.
In this study, healthy middle-aged and older men were administered continuous IV infusions of glucose using the hyperglycemic clamp technique.1 This technique allows the glucose concentration to be acutely raised by administering a priming glucose infusion. The desired glucose level can then be maintained by adjusting the glucose infusion.2 In this case, plasma glucose concentrations were maintained at 7.9 mmol/L (≈142 mg/dL) above basal level throughout the study, and plasma insulin concentrations, ie, insulin responses, were measured.1
The study demonstrated that normal insulin secretion in response to IV glucose has 2 distinct phases:
The first (early) phase consists of a rapid increase in insulin secretion that occurs immediately after exposure of the beta-cells to glucose. This phase is brief and is followed by a return to near basal levels within 10 minutes.1
A second (late) phase consists of a sustained increase in insulin secretion that begins 10 to 20 minutes after exposure to glucose. This phase can last for several hours.1
First-phase insulin secretion suppresses endogenous production of glucose. It may also prime insulin-sensitive tissues to increase the efficiency of glucose disposal. There is a shift that occurs within minutes, from the production of glucose to the disposal of glucose. Thus, first-phase insulin secretion is important in achieving this rapidly shifting metabolic state.1
100 20 40 60 80
100
120
Time, min
N=17 subjects. Hyperglycemic clamp technique was used.
Adapted with permission from Pratley RE et al. Diabetologia. 2001;44:929–945. © Springer-Verlag, 2001.
References:
1. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia. 2001;44:929–945.
2. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–E223.

16. Insulin Sensitivity Index, Si x 10–5 min–1/pM
Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects
2,000
1,500
1,000
500 5 10 15 20 25
95th
Men
Women
50th
AIRglucose, pM
AIRglucose = Acute (1st phase) insulin response
Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects
The product of insulin sensitivity and insulin response provides a measure of beta-cell function. Any change in insulin sensitivity is balanced by a reciprocal and proportionate change in beta-cell function.1 The first-phase insulin response is a useful measure of beta-cell function because it is relatively independent of the steady-state plasma glucose level and can be quantified by administration of a maximal glucose bolus without glucose matching.2
For glucose tolerance to remain constant as insulin sensitivity varies, a proportionate and reciprocal alteration in insulin output must occur.1
A cohort of apparently healthy subjects younger than 45 years of age was studied to assess the relationship between AIRglucose, or first-phase insulin response, and insulin sensitivity (Si).2
Insulin sensitivity is an estimate of the effect of insulin to augment the effect of hyperglycemia on glucose disposal.
The percentiles for the relationship between insulin sensitivity and insulin response will be shown.
[Advance build]
The reference line is the 50th percentile.
Percentiles above the 50th represent enhanced insulin response for the degree of insulin sensitivity. Reduced response is represented below the 50th percentile.1
The relationship between insulin sensitivity and acute insulin response appears to be similar in both men and women.
Compensatory β-Cell Insulin Secretion With Increasing Insulin Resistance
An important factor affecting the magnitude of the insulin response is the prevailing degree of insulin sensitivity.1
The relationship between insulin sensitivity and beta-cell function was examined in a cohort of healthy subjects under 45 years of age.
Beta-cell secretory capacity was quantified as the acute insulin response to arginine at maximal glycemic potentiation or “AIRmax.”1,2
Insulin sensitivity is an estimate of the effect of insulin to augment the effect of hyperglycemia on glucose disposal.2
Percentiles above the 50th represent enhanced beta-cell secretory capacity for the degree of insulin sensitivity. Reduced response is represented below the 50th percentile.
As shown by the graph, for glucose tolerance to remain constant when insulin sensitivity varies, any change in insulin sensitivity is balanced by a reciprocal and proportionate change in beta-cell response.1
Therefore, the normal compensation for insulin resistance is an increase in insulin secretion by beta-cells.2
Common causes of insulin resistance include genetic predisposition, obesity, inactivity, and aging.3
5th
Insulin Sensitivity Index, Si x 10–5 min–1/pM
AIRglucose=first-phase insulin response. Insulin response examined following intravenous administration of glucose.
N=93 apparently healthy subjects aged <45 yrs.
Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers; 2001;109–131. Figure 2. With kind permission from Springer Science and Business Media.
References:
1. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.
2. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and β-cell function in human subjects. Diabetes. 1993;42:1663–1672.

17. Islet Cell Dysfunction and Abnormal Glucose
Homeostasis in Type 2 Diabetes
Structural Changes in Islets With Type 2 Diabetes
In the normal pancreas, the exocrine cells make up the majority of the organ. The endocrine cells in the islets of Langerhans constitute about 1% to 5% of the pancreatic mass.1 There are between 300,000 and 1.5 million islets in the adult pancreas. Beta-cells, the insulin-producing cells, constitute approximately 70% to 80% of the islet mass.2 Beta-cell mass is determined by the balance between the production of beta-cells and the disappearance of beta-cells. The production of beta-cells is determined by the rates of neogenesis and replication. The disappearance of beta-cells is determined by the rate of cell death by necrosis or apoptosis.5
In type 2 diabetes, there are structural changes in the islets of the pancreas. Up to 90% of patients with type 2 diabetes develop amyloid deposits between the capillaries and the islets. These deposits form cords that compress the islets.3 Amylin, also referred to as islet amyloid polypeptide, is the peptide constituting the deposits and is normally produced by beta-cells. Where amyloid deposits are found, reduction in beta-cell mass of the islet is also observed. However, it is not known whether amyloid deposits cause a reduction in the number of beta-cells. The role of amylin is still being investigated.4 Beta-cell mass may be affected by impaired neogenesis and proliferation of beta-cells. In patients with type 2 diabetes there is an increased frequency of beta-cell apoptosis, also known as programmed cell death.5,6 This process leads to a reduction in insulin production. This illustrates structural changes in islets with type 2 diabetes.
References:
1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–270.
2. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir OC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:21–39.
3. Roth J, Komminoth P, Klöppel G, Heitz PU. Diabetes and endocrine pancreas. In: Damjanov I, Linder J, eds. Anderson’s Pathology. 10th ed. St. Louis, Mo: Mosby-Year Book Inc. 1996:2042–2070.
4. Leahy JL. β-cell dysfunction in type 2 diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Textbook of Diabetes. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:449–461.
5. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–110.
6. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 2004;89:5535–5541.

18. The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance1,2
Glucagon
(α-cell)
* Reduced effect of insulin indicating insulin resistance
Pancreas
Insulin
(β-cell) *
The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance
This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis.
In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1
Most patients with type 2 diabetes have insulin resistance. Normally, pancreatic beta- cells increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1
By the time of diagnosis of diabetes, beta-cell function has already decreased substantially and continues to decline over time.1
Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production, which gives rise to an increase in blood glucose.1
Likewise, with decreased secretion of insulin, there is less uptake of glucose by muscle and adipose tissue.2
Glucose output
Glucose uptake
Liver
Hyperglycemia
Muscle
1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
References:
1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.

19. Insulin resistance: A state in which a given concentration of insulin is associated with a subnormal glucose response (1)
Syndrome X, Insulin Resistance Syndrome: Insulin resistance and compensatory hyperinsulinemia associated with glucose intolerance, hypertension, dyslipidemia, CVD.
1-Moller DE & Flier JS, N Engl J Med 1991 Sep 26;325(13):
2- Reaven G, Banting Lecture 1988

21. Microvascular complications
Natural History of DM 2
Years from
diagnosis
-10 -5 5 10 15
Onset
Diagnosis
Insulin secretion
Insulin resistance
Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Pre-diabetes
Type 2 diabetes
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ;
Nathan DM. N Engl J Med ;347:

22. First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes
Normal
Type 2 Diabetes
120
120
100
100 80 80
Plasma Insulin, µU/mL 60
Plasma Insulin, µU/mL 60 40 40
First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes
In this study, the release of insulin from beta-cells was measured in normal subjects and patients with type 2 diabetes after they were given an intravenous glucose tolerance test with 20-g boluses.1,2
Normal subjects showed a sharp first-phase insulin response followed by persistent insulin secretion during the second phase, which lasts from 10 to 120 minutes.2
However, patients with type 2 diabetes showed an absent first-phase response,1 with preservation of the second-phase insulin response.2 20 20
–30 30 60 90
120
–30 30 60 90
120
Time, min
Time, min
n=9 normal; n=9 type 2 diabetes.
Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588. With permission from Excerpta Medica, Inc.
References:
1. Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–502.
2. Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med. 1981;70:579–588.

23. Inadequate Insulin Secretion and Insulin Action Occur Prior to the Development of Type 2 Diabetes
Overall Time Effect
P<0.0001
Overall Time Effect
P<0.0001
300 12 **
250 10 * **
200 8 **
mg/kg EMBS/min
M-High,
AIRglucose, µ/mL
150 6
Inadequate Insulin Secretion and Insulin Action Occur Early in the Development of Type 2 Diabetes
Defects in insulin secretion and insulin action have been demonstrated in the progression from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes.1
A longitudinal study was performed in 17 Pima Indians who progressed from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes over 5.1 ± 1.4 years.2
Insulin secretion was measured after an IV glucose tolerance test using a 25-g IV bolus of glucose in 11 of 17 progressors.2
AIRglucose is the acute insulin secretory response to IV glucose.2
It was found that AIRglucose decreased by 27% during the progression from normal glucose tolerance to IGT and an additional 51% during the procession from impaired glucose tolerance to type 2 diabetes.2
Insulin action was also assessed in this study using a 2-step hyperinsulinemic, euglycemic glucose clamp in which a low-dose priming continuous IV infusion of insulin was given for 100 minutes followed by a second high-dose infusion to achieve a steady-state plasma insulin concentration.2
M-high is the maximally insulin-stimulated glucose disposal.2
It was found that there was a 31% decrease in M-high during the progression from normal glucose tolerance to type 2 diabetes, indicating a decline in insulin action early in the disease process.2
This study indicates that both insulin secretion and insulin action are affected early in the development of type 2 diabetes.2
100 4 50 2
NGT
IGT
T2DM
NGT
IGT
T2DM
Longitudinal study over 5.1 ± 1.4 years; N=17 Pima Indians in whom glucose tolerance deteriorated from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes (T2DM).
AIRglucose=acute insulin response; M-high=maximally insulin-stimulated glucose disposal.
*P<0.05; **P<0.01. Adapted with permission from Weyer C et al. J Clin Invest. 1999;104:787–794.
References:
1. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003;1427–1483.
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;104:787–794.

24. The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes
100
200
300
400
500 1 2 3 4 5
T2DM
IGT
NGT
Nonprogressors
Progressors
AIRglucose, μU/mL
The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes
This graph is from a longitudinal study performed over 5.1 ± 1.4 years in which a high-risk population, Pima Indians, with normal glucose tolerance (NGT) at baseline, were followed.1,2
AIRglucose is the acute insulin response to glucose.2
AIRglucose was measured relative to changes in insulin sensitivity, which was measured by the clamp technique.2
M-low (on the x axis) represents total insulin stimulated glucose disposal at a low insulin concentration.2
Measurements were made in 11 progressors—those individuals in whom glucose tolerance deteriorated from NGT to impaired glucose tolerance (IGT) to diabetes—and in 23 nonprogressors who maintained NGT throughout.2
The lines represent the prediction line and the upper and lower limits of the 95% confidence interval.2
There is a hyperbolic relationship between insulin secretion and insulin action in individuals with NGT. That is, insulin secretion increased with decreasing insulin action and vice versa.1
Also, there is progressively impaired beta-cell function as a patient goes from NGT to IGT to type 2 diabetes (T2DM).2
In this study, it was found that in the nonprogressors, AIRglucose increased with decreasing M-low; thus the individuals were able to maintain normal beta-cell function.1,2
This indicates that the progressors had impaired beta-cell function.1,2
However, although the progressors had a similar baseline AIRglucose to nonprogressors relative to their degree of insulin resistence, AIRglucose was already too low; thus the individuals fell below the 95th confidence interval while still maintaining NGT.1
M-Low, mg/kg EMBS/min
N=277 Pima Indians; NGT=normal glucose tolerance; IGT=impaired glucose tolerance; T2DM=type 2 diabetes;
EMBS=estimated metabolic body size.
Changes in β-cell function, measured as acute insulin response to glucose (AIRglucose) relative to changes in insulin sensitivity, measured by clamp technique at a low insulin concentration (M-low).
Adapted with permission from Weyer C et al. J Clin Invest. 1999;104;787–794.
References:
1. 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;104:787–794.
2. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.

25. Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes
360
330
300
270
240
110 80
Meal
Glucose, mg %
Type 2 diabetes
Normal patients
120 90 60 30
Insulin, μ/mL
Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes (PowerPoint animation)
In normal individuals, insulin levels rise and glucagon levels fall after a meal. However, in persons with type 2 diabetes, insulin and glucagon dynamics are abnormal.1
[Advance build]
As shown by the graph at the top, glucose levels rise after a meal in both normal individuals and patients with type 2 diabetes, although they reach a higher, delayed, and sustained peak in patients with diabetes.1
As shown by the middle graph, insulin responses to a meal are delayed and decreased in magnitude in patients with diabetes.2
As shown by the bottom graph, glucagon levels fall after a meal in normal persons; however, glucagon levels fail to suppress in patients with diabetes.1
140
130
120
110
100 90
Glucagon, μμ/mL
n=12 normal; n=12 type 2 diabetes.
Adapted with permission in 2005 from Müller WA et al. N Engl J Med. 1970;283:109–115.
Copyright © 1970 Massachusetts Medical Society. All rights reserved.
–60 60
120
180
240
(minutes)
References:
1. 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;283:109–115.
2. Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003;46(suppl 1):M2–M8.

26. Pathophysiology of Type 2 Diabetes
In summary:
The pathophysiology of type 2 diabetes includes islet cell dysfunction, insulin resistance, and increased hepatic glucose output.1–3
Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin.1
Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time.1
Inside the Islet: Exploring Issues in Type 2 Diabetes
In summary:
The pathophysiology of type 2 diabetes includes beta-cell dysfunction, insulin resistance, and increased hepatic glucose output.1–3
Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin.1
Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time.1
1. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
2. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775– Del Prato S, Marchetti P. Diabetes Technol Ther. 2004;6:719–731.
References:
1. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.
2. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.
3. Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: the role of thiazolidinediones. Diabetes Technol Ther. 2004;6:719–731.

27. Treatment Options in Type 2 Diabetes
Why treat diabetes?
Therapeutic Lifestyle Changes
Oral medications
Insulin
Newer agents (incretins)
Gastric Bypass

28. Higher Blood Sugar Causes More Complications
Relative Risk
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
HbA1c (%) 15 13 11 9 7 5 3 1 6 8 10 12
Based on DCCT follow-up
Endocrinol Metab Clin North Am. 1996;25:

29. Intensive Therapy Group Various Endpoints in the UKPDS
Complication
Reduction in Risk
All microvascular
25% P<0.01
– Retinopathy progression
21% P<0.02
– Microalbuminuria
33% P<0.0001
Myocardial infarction
16% P=0.052
UKPDS data, nearly 4000 patients for intensively treated groups, no difference between SU or insulin
All diabetes-related endpoints studied
12% P<0.03
UKPDS Group. Lancet. 1998;352:

30. Intensive initial treatment with insulin, sulfonylurea in type 2 DM reduces microvascular and macrovascular complications and death

31. Therapeutic Lifestyle Changes (TLC)
Diet
Exercise

32. Major Targeted Sites of Oral Drug Classes
Pancreas
Beta-cell dysfunction
Sulfonylureas
Muscle and fat
Meglitinides
Liver
Hepatic glucose overproduction
↓Glucose level
Insulin resistance
Major Targeted Sites of Various Oral Drug Classes
Speaker notes
The various therapeutic agents currently available for the treatment of type 2 diabetes act on different pathways to control hyperglycemi.1,2
[Slide build for each drug class]
Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1
Meglitinides, another class of short-acting insulin secretagogue, also act in the pancreas, stimulating insulin release by binding to several sites on the beta-cells. They are used to control postprandial hyperglycemia.1
TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2
Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1
Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. It also enhances insulin sensitivity in muscle.1,3
Based on the different mechanisms of action of these agents, these drugs may be used in combination, as noted in the prescribing information for each product.1,2
Purpose:
To provide a high-level overview of the key mechanisms and target sites for the currently available antihyperglycemic classes.
Takeaway:
Different drug classes with different and complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and maximize A1C control.
Gut
Biguanides
TZDs
TZDs
Biguanides
Reduced glucose absorption
Alpha-glucosidase inhibitors
TZD = thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003:1427–1483.
References
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.
3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.

34. Modern insulin syringes, pens, delivery devices, rapid-acting insulin analogs
Modern insulin syringes with very fine needles (gauges range from 27-31)
Insulin pens allow patient to inject and carry insulin discreetly
Innolet device is a pre-filled insulin doser, easy to read with audible clicks
Needle-free delivery systems
New rapid-acting insulin analogs simulate physiologic insulin profiles allowing for greater flexibility with meal timing, carbohydrate content, etc.

35. Insulin delivery systems on the horizon...
Inhaled insulin – Came and went….

36. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
Incretin Overview
An incretin is a hormone with the following characteristics1:
It is released from the intestine in response to ingestion of food, particularly glucose.
The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin.
The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent).
Incretin Overview
Many of you already are somewhat familiar with incretins and their role. For the benefit of those who are not, let’s briefly consider, what are incretins?
Incretins
Are intestinal hormones released after meal ingestion
Play an important role in glucose homeostasis
Physiologically help regulate insulin release in a glucose-dependent manner
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

37. The Incretin Effect in Subjects With & W/O DM2
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1 80 60 40 20 80 60 40 20
The incretin effect is diminished
in type 2 diabetes.
Incretin Effect
nmol / L
nmol/L
IR Insulin, mU/L
IR Insulin, mU/L
The Incretin Effect in Subjects Without and With Type 2 Diabetes
In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the GI tract than when glucose was delivered via intravenous (IV) infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion.1,2
The incretin effect implies that nutrient ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the rise in glucose secondary to absorption of digested nutrients.1
Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect,3 stimulating insulin release when glucose levels are elevated.4,5
Although the incretin effect is detectable in both healthy subjects and those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide.6
In this study, patients with type 2 diabetes and weight-matched metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load.6
In those without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect)—that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the GI tract.6
In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished in magnitude.6
The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone.7,8 60
120
180 60
120
180
Time, min
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
References:
1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659.
4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.
7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes. 2001;109(suppl 2):S288–S303.
8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

38. GLP-1 and GIP Are Incretin Hormones
Is released from L cells in ileum and colon1,2
Is released from K cells in duodenum1,2
Stimulates insulin response from beta cells in a glucose-dependent manner1
Inhibits gastric emptying1,2
Has minimal effects on gastric emptying2
Reduces food intake and body weight2
Has no significant effects on satiety or body weight2
Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1
Does not appear to inhibit glucagon secretion from alpha cells1,2 (may even stimulate glucagon!)
GLP-1 and GIP Are Incretin Hormones
GLP-1 and GIP are the currently identified incretin hormones.
GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1
In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3
GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner.
GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.
GLP-1: glucagon-like peptide-1
GIP: glucose-dependent insulinotropic
Polypeptide (formerly gastric inhibitory
Polypeptide!)
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
References:
1. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
2. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.
3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206.
4. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

39. Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
15.0
250
12.5
Placebo
GLP-1
Glucose
mmol/L *
200
10.0
mg/dL
7.5
150
5.0
100
*P <0.05
Patients with type 2 diabetes (N=10)
2.5 50
250
When glucose levels
approach normal values,
insulin levels decreases. 40
Insulin
200
pmol/L 30
150 *
mU/L 20
100
Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic infusion of GLP-1. Ten patients with uncontrolled type 2 diabetes mellitus being treated with diet and oral hypoglycemic agents received an intravenous infusion of GLP-1 over 240 minutes. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, and glucagon levels. One day later, the procedure was repeated with a placebo infusion.
Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels in all patients, with significant mean reductions observed at all time points from 60 minutes onward (P<0.05 vs placebo). Initially, during GLP-1 infusion with a starting plasma glucose level of 12.7 mmol/L (228.6 mg/dL), plasma insulin increased and glucagon decreased. However, as plasma glucose approached normal basal levels, insulin and glucagon returned to baseline or near-baseline levels, thus demonstrating the glucose-dependent nature of the effects of GLP-1. 50 10 20 20
When glucose levels approach normal values, glucagon levels rebound.
Glucagon
pmol/L 15 15 *
pmol/L 10 10 5 5
Infusion
–30 60
120
180
240
Minutes
Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
Reference:
Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia ;36:741–744.

40. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GIP and GLP-1 release
DPP-4
Enzyme
GIP-(1–42)
GLP-1(7–36)
Intact
GIP-(3–42)
GLP-1(9–36)
Metabolites
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
GLP-1 and GIP have short biological half-lives; they are rapidly degraded by DPP-4.1–3
DPP-4 is a widely expressed enzyme present on cells in many tissues, including the kidney, GI tract, biliary tract and liver, placenta, uterus, prostate, skin, lymphocytes, and endothelial cells (which may be involved in the inactivation of circulating peptides).4
Rapid Inactivation
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
GIP and GLP-1 Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
References:
1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.
2. Kieffer TJ, McIntosh CHS, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology ;136:3585–3596.
3. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80:952–957.
4. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100.

42. The Beginning Exenatide
Synthetic version of salivary protein (exendin-4) found in the Gila monster
More than 50% amino acid sequence identity with human GLP-1
Binds to known human GLP-1 receptors on  cells (in vitro)‏
Resistant to DPP-IV inactivation
DISCUSSION POINTS:
Exenatide, which was discovered in the salivary secretions of the Gila monster, has 53% amino acid sequence identity with mammalian GLP-1
Exenatide binds in vitro to the known human GLP-1 receptors on  cells and mimics multiple glucoregulatory effects of GLP-1
The amino acid at position 2, the site of DPP-IV inactivation on the GLP-1 molecule, is different in exenatide – making exenatide resistant to DPP-IV enzymatic degradation
After a single subcutaneous (SC) injection, exenatide can be measured in the plasma for up to 10 hours
SLIDE BACKGROUND:
Following exenatide SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours
The mean terminal half-life of exenatide is 2.4 hours
Pharmacokinetic characteristics of exenatide are independent of the dose
In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose
Site of DPP-IV Inactivation
Following injection, exenatide is measurable in plasma for up to 10 hours
Adapted from Nielsen LL, et al. Regul Pept. 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:

43. Exenatide Lowered A1C Large Phase 3 Clinical Studies
Type 2 Diabetes
Placebo BID
5 µg Exenatide BID
10 µg Exenatide BID
MET
SFU
MET + SFU
0.5
0.5
0.5
0.2
0.1
0.1
DISCUSSION POINTS:
Significant A1C reductions were seen with the 5-µg and 10-µg exenatide treatment arms in all three studies (P<0.005 vs placebo)‏
The A1C lowering in the 10-µg arm was greater than in the 5-µg arm (P<0.05)
Baseline A1C: placebo group = 8.5%; 5-µg exenatide BID treatment arm = 8.4%; 10-µg exenatide BID treatment arm = 8.5%
Exenatide is associated with reduced A1C no matter the background oral therapy (MET and/or SFU), and disease duration (SFU + MET study patients had longer disease duration)‏
SLIDE BACKGROUND:
Three 30-week, placebo-controlled, double-blind, Phase 3 studies; patients with type 2 diabetes randomized to placebo or 5 µg or 10 µg exenatide BID with MET and/or SFU, N = 1446
Combined pivotals: MET, SFU, MET + SFU; 30-week, double-blind, Phase 3 studies; ITT patients with type 2 diabetes were randomized to placebo (n = 483), 5 µg exenatide BID (n = 480), or 10 µg exenatide BID (n = 483). The LOCF method was applied to the data
Individual pivotals
MET (placebo [n = 113 and baseline A1C = 8.2], 5 µg exenatide BID [n = 110 and baseline A1C = 8.3], 10 µg exenatide BID [n = 113 and baseline A1C = 8.2])‏
SFU (placebo [n = 123 and baseline A1C = 8.7], 5 µg exenatide BID [n = 125 and baseline A1C = 8.5], 10 µg exenatide BID [n = 129 and baseline A1C = 8.6])‏
MET + SFU (placebo [n = 247 and baseline A1C = 8.5], 5 µg exenatide BID [n = 245 and baseline A1C = 8.5], 10 µg exenatide BID [n = 241 and baseline A1C = 8.5])‏
-0.5 * *
-0.9
-0.6 * *
-0.8
A1C (%)‏
-0.5
-0.5
-0.5
-0.4 *
- 0.8 -1 -1 -1 *
ITT; N = 1446; Mean ± SE; *P<0.005 Data from DeFronzo RA, et al. Diabetes Care. 2005;28: ; Data from Buse JB, et al. Diabetes Care. 2004; 27: ; Data from Kendall DM, et al. Diabetes Care. 2005;28:

44. insulin from beta cells Glucose uptake by muscles
Summary
GI tract
Pancreas2,3
insulin from beta cells
(GLP-1 and GIP)
Glucose-dependent
2,4
Ingestion of food
Glucose uptake by muscles
Release of gut hormones — Incretins1,2
β-cells
α-cells
Blood glucose
Active
GLP-1 & GIP
Glucose production by liver X
Summary
After food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).1–3 Under normal circumstances, DPP-4 rapidly degrades these incretins to their inactive forms after their release into the circulation.1,2
Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.2,3 The subsequent increase in glucose uptake in muscles3,4 and reduced glucose output from the liver2 help maintain glucose homeostasis.
Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.2,3 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.2,5
Glucagon from alpha cells
(GLP-1)
Glucose dependent
DPP-4 Enzyme
Inactive GLP-1
and GIP
Active incretins physiologically regulate glucose by modulating insulin secretion in a glucose-dependent manner.
GLP-1 also modulates glucagon secretion in a glucose-dependent manner.
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
References:
1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.
5. Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

45. Clinical Pharmacology of JANUVIA (sitagliptin phosphate):
Pharmacodynamics:
JANUVIA led to inhibition of DPP-4 activity for a 24-hour period in patients with type 2 diabetes, resulting in:
2- to 3-fold  in levels of active GLP-1 and GIP
 glucagon concentrations
 responsiveness of insulin release to glucose
 fasting glucose and  glucose excursion after an oral glucose load or a meal
In healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia
Clinical Pharmacology of JANUVIA™ (sitagliptin phosphate): Pharmacodynamics
In patients with type 2 diabetes, administration of single oral doses of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After a meal, DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher insulin and C-peptide concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.

46. Diabetes and Bariatric Surgery
Buchwald et al (2004), in a meta-analysis of 22,094 patients undergoing gastric bypass surgery for morbid obesity found:
1417 of 1846 patients with diabetes (76.8%) experienced complete resolution of their diabetes
(Defined as ability to discontinue all diabetes-related medications and maintain blood glucose levels within the normal range)

47. Summary
1. Type 2 Diabetes (DM 2) is a multi-factorial disorder that is increasing in prevalence.
2. Insulin resistance, beta-cell & alpha-cell dysfunction and abnormal incretin function all contribute to the metabolic derangements seen in pre-diabetes and DM2.
3. Diabetes is associated with increase in both microvascular and macrovascular complications
4. Many therapeutic options exist to target the pathophysiologic features of DM 2, reduce hyperglycemia and can prevent/delay complications.

48. Thanks! Questions?