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© 2008 © 2010 The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH VOMA 27 April 2012.

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Presentation on theme: "© 2008 © 2010 The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH VOMA 27 April 2012."— Presentation transcript:

1 © 2008 © 2010 The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH VOMA 27 April 2012

2 The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M. Girman, MD, MPH The following potential conflict of interest relationships are germane to my presentation: Equipment: None Speakers Bureau: None Stock Shareholder: None Grant/Research Support: None Consultant: None Employment: Genova Diagnostics Status of FDA devices used for the material being presented: NA/Non-Clinical Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation: NA/Non-Clinical

3 © Continuum of PreD: Conversation Goals Examine the focus on obesity as major identifier of people at risk for Type 2 DM Identify an underlying driver of progression to Type 2 Diabetes: Inflammation Define the Stages of Pre-Diabetes progression Consider Stage-specific Therapeutic Interventions ~ Lifestyle +/- Meds

4 © Obesity: Challenging Assumptions Many clinicians assume that they can accurately predict patient risk for diabetes based on obesity. If this is true, are tests designed to assess risk of diabetes really needed?

5 © Defining Overweight/Obesity

6 © Overweight/Obesity Worldwide % Population (2007) New Zealand62.6% United Kingdom61.0% Iceland60.2% Luxembourg54.8% Ireland51% Finland48.9% Canada46.8% Slovak Republic46.2% Italy45.5% Netherlands45.5% Sweden44.0% Switzerland37.3%

7 © Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% 30%

8 © Rates of CardioMetabolic Syndrome BMI < 25BMI 25-30BMI >30 MEN 30%51%71% WOMEN 21%43%65% TOTAL 26%46%68%

9 © CDC: Only 40% of the risk of developing diabetes occurs in people who are obese. How do we find the 60% of people at risk for developing diabetes who are NOT obese?

10 © PreD Assessment & Clinical Utility Identify patients who are at risk for diabetes & who are not obese Define that individuals stage of progression to Type 2 Diabetes (i.e. Insulin Resistance/Cardio-Metabolic Syndrome) Provide stage-specific therapeutic interventions.

11 © The Significance of Type 2 Diabetes Mellitus According to the CDC, 10% of the US population has diabetes today. By the year 2050, the CDC projects that % will be diagnosed with diabetes. This will lead to a 2-4x increase in health care costs, or approximately $171 billion per year.

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13 © Type 2 DM Pathophysiology Initial compensation of IR by increased pancreatic β-cell insulin secretion –Lifestyle considerations leading to IR Insulin drives differentiation of mesenchymal stem cells into pre- adipocytes and adipose tissue Concomitant qualitative β-cell dysfunction as cellular cleavage capacity of proinsulin to insulin exhausted –Added adipogenic effect of proinsulin

14 © Type 2 DM Pathophysiology Increased hormonal secretion & increased caloric intake = increased production of visceral adipose tissue Visceral adipose tissue is metabolically active –Cytokines (adipokines) which negatively influence IR –Supression of adiponectin secretion by mature adipose tissue = increased visceral adipose production, increased IR, decreased vasoprotective and anti-atherosclerotic effects

15 © Pfutzner A, et al A Biomarker Concept for Assessment of Insulin Resistance, β-Cell Function and Chronic Systemic Inflammation in Type 2 Diabetes Mellitus. Clin Lab 2008; 54:

16 ©

17 PreD Guide

18 Inflammation is an underlying driver of the progression to diabetes. 1.Strongly Agree 2.Agree 3.Disagree 4.Strongly Disagree Answer Now Countdown 4

19 © 2008 © 2010 Inflammation: Driving the Progression 2 Diabetes

20 © Inflammation & Chronic Disease

21 © 2008 © 2010 AbdominalObesity Dysglycemia Dyslipidemia Hypertension Diabetes Mellitus Heart Disease

22 © 2008 © 2010 Insulin Resistance AbdominalObesity Dysglycemia Dyslipidemia Hypertension Diabetes Mellitus Heart Disease

23 © 2008 © 2010 Insulin Resistance AbdominalObesity Dysglycemia Dyslipidemia Hypertension Diabetes Mellitus Heart Disease InflammationInflammation

24 © Causes of Inflammation Diet –Sugar –Trans & saturated fats –Polyunsaturated omega 6 oils (except GLA) Allergens (food & environmental) Stress Lack of exercise Toxins (metals, petrochemicals) Infections (especially dental/gingivitis) Obesity & Insulin Resistance

25 © Inflammation: A Critical Underlying Driver Inflammation is a major driver of the progression to diabetes through each stage. Inflammation causes insulin resistance... – Jerrald M. Olefsky, MD The use of multiple inflammatory markers provides greater insight into the effects of inflammation -> one marker for inflammation may not provide a full clinical picture.

26 © Markers of Inflammation hs-CRP –Acute phase response protein/IR Interleukin IL-6 –Inflammatory cytokine/abdominal obesity Interleukin IL-8 –Inflammatory cytokine/abdominal obesity Tumor Necrosis Factor Alpha (TNFα) –Inflammatory cytokine/abdominal obesity Plasminogen Activator Inhibitor 1 (PAI-1) –Acute phase response protein/visceral obesity

27 © Kuller MRFIT 1996 CHD death Ridker PHS 1997 MI Ridker PHS 1997 Stroke Tracy CHS/RHPP 1997 CHD Ridker PHS 1998,2001 PAD Ridker WHS 1998,2000,2002 CVD Koenig MONICA 1999 CHD Roivainen HELSINKI 2000 CHD Mendall CAERPHILLY 2000 CHD Danesh BRITAIN 2000 CHD Gussekloo LEIDEN 2001 Fatal Stroke Lowe SPEEDWELL 2001 CHD Packard WOSCOPS 2001 CV Events Ridker AFCAPS 2001 CV Events Rost FHS 2001 Stroke Pradhan WHI 2002 MI, CVD death Albert PHS 2002 Sudden Death Relative Risk (upper versus lower quartile) Ridker PM. Circulation 2003;107: hs-CRP: Risk Factor for CVD

28 © C-Reactive Protein Marker of inflammation, infection and injury –Aspirins reduction of MI risk appears to be related to CRP levels –CRP activates complement which injures the inner layer of blood vessels constriction of vessels, arrhythmia Strong predictor of the risk of future MI JUPITER Study – November, % decrease in CAD end-points 20% decrease in all cause mortality 40% of participants had insulin resistance

29 © Inflammation & Risk of T2DM

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31 © 2008 © 2010 Stages of Progression 2 Diabetes

32 © Progression of Pre-Diabetes

33 © Optimal Function Intervention = Maintenance of healthy diet & lifestyle

34 © Stage 1: Early Insulin Resistance

35 © Adiponectin Protective adipose-derived protein Plays an important role in regulating glucose and lipid metabolism – Moderates fat tissue – Promotes insulin sensitivity – Is inversely related to glucose & insulin – Decreases hepatic glucose & lipid production – Protects against atherosclerosis by suppressing vascular inflammation (anti- inflammatory)

36 © Low Adiponectin associated with: Insulin resistance Glucose intolerance Dyslipidemia Increased risk of vascular injury & atherosclerosis Increased risk of diabetes mellitus Inflammation

37 © Pattern recognition: – LOW Adiponectin – Normal Glucose, HbA1C, Insulin, and Proinsulin – Normal or slightly high HOMA-IR Treat with diet, lifestyle, supplementation. Stage 1: Early Insulin Resistance Normal fasting blood sugar = < 100 mg/dL Blood sugar >87 mg/dL = progressive increase of type 2 DM. Blood sugar < 81 mg/dL = low risk of DM NEJM 2005;353:

38 Medication considerations Supplement considerations Reduce excess weight; Increase physical activity; Reduce stress ; Treat inflammatory disorders (TNF-α inhibits adiponectin) Meds are not usually needed at this stage if dietary and lifestyle measures are followed. Stage 1 of metabolic dysglycemia represents early insulin resistance, with adequate pancreatic beta cell compensation to maintain normal glucose. Insulin level may be normal or high. Adiponectin, which provides protection against insulin resistance, diabetes and cardiovascular disease, is typically low. Dyslipidemia may or may not be present, including elevated triglycerides and LDL-C, and/or low HDL-C. At this stage, dietary and lifestyle measures are usually adequate for improving insulin sensitivity and preventing progression to Stage 2. Nutritional: B vitamins, vitamin D, biotin, magnesium, zinc, chromium, alpha-lipoic acid & other antioxidants, fish oils; Herbal: Green tea, cinnamon, fenugreek; Hormonal: DHEA (if low) Stage 1 – Early Insulin Resistance Lifestyle considerations Dietary considerations Minimize sugar and refined carbohydrates, fructose, soft drinks, and saturated fats. Avoid trans fats. Emphasize a low-saturated fat, Mediterranean-type diet (complex carbohydrates, fresh fruits and vegetables, nuts & other monounsaturates, foods rich in omega-3 fats, such as cold water fish). Treatment recommendations for Stage 1:

39 © Stage 2: Elevated Fasting Insulin

40 © Pattern recognition: – LOW Adiponectin – HIGH or high-normal HOMA-IR – HIGH Insulin, but normal Proinsulin – Mildly elevated glucose and/or HbA1C Fasting glucose mg/dl and/or 2-hr pp glucose mg/dl and/or HbA1C % Usually due to a combination of insulin resistance & early beta-cell impairment 24 million cases of type 2 DM in the U.S., but 57 million cases of pre-diabetes Treat with diet, lifestyle, supplementation, possible pharmacotherapy. Stage 2: Elevated Fasting Insulin

41 Stage 2 – Elevated Fasting Insulin Treatment recommendations for Stage 2 Stage 2 represents impaired glucose tolerance, usually due to combination of insulin resistance and early pancreatic beta-cell impairment. In most cases of insulin resistance, compensatory increased insulin secretion is sufficient to prevent hyperglycemia. However, in combination with beta- cell dysfunction, hyperglycemia can develop. 1 Adiponectin is usually low, and glucose and/or HbA1C are elevated, although not yet to a diabetic level. Insulin is usually elevated. Dyslipidemia may or may not be present, including elevated triglycerides and LDL-C, and/or low HDL-C. At this stage, diet and lifestyle measures, along with supplementation can help improve insulin sensitivity, restore proper glucose regulation, and prevent progression to diabetes (Stage 3). Medication considerations Supplement considerations Insulin sensitizers: Biguanides (e.g., metformin); Dual PPAR agonists (e.g., aleglitazar); Inhibitors of starch digestion: α-Glucosidase inhibitors (e.g., acarbose); Improvement of HbA1C: DPP-4 Inhibitors (e.g., sitagliptin) or Pramlintide Lifestyle considerations Dietary considerations Reduce weight; Increase physical activity (esp. aerobic); Reduce stress; Treat any inflammatory disorders Avoid sugar and refined carbohydrates, fructose, soft drinks, alcohol, and trans fats. Minimize saturated fats. Emphasize a high-fiber, low- saturated fat, Mediterranean-type diet (e.g., legumes and whole grains, fresh fruits and vegetables, nuts & other monounsaturates, foods rich in omega-3 fats, such as cold water fish). Nutritional: B vitamins, vitamin D, biotin, Mg, Zn, Cr, α-lipoic acid & other antioxidants, flavonoids (e.g., grape seed extract), fish oils, fiber supplement; Herbal: Gymnema sylvestre, green tea, cinnamon, fenugreek; Hormonal: DHEA (if low)

42 © Stage 3: Elevated Proinsulin

43 © Proinsulin Produced by pancreatic β-cells Precursor to insulin Serves as a marker of later stage β-cell dysfunction & insulin resistance Has been used in trials (proinsulin/insulin ratio) to describe improved β-cell function resulting from β-cell sensitizing meds (ie, biguanides/Metformin, TZDs/Actose)

44 © Proinsulin β-cell dysfunction impaired cleavage of proinsulin to insulin levels of proinsulin increase Higher circulating levels of circulating proinsulin (compared to insulin) indicate advancing β-cell dysfunction & increased risk or presence of diabetes. With advancing pre-diabetes, levels of both insulin & proinsulin decline.

45 © Stage 3: Elevated Proinsulin Pattern recognition: – LOW Adiponectin – HIGH Insulin & Elevated Proinsulin – HIGH HOMA-IR – HIGH Glucose & HbA1C May or may not meet ADA definition for Type 2 Diabetes Mellitus – Fasting Glucose > 125 mg/dL – HgbA1c > 6.5% Treat with diet, lifestyle, supplementation, and pharmacotherapy.

46 Stage 3 – Elevated Pro-Insulin Treatment recommendations for Stage 3 Stage 3 represents the development of diabetes, with insulin resistance and progressive pancreatic beta-cell impairment. Beta- cell dysfunction can result from glucose toxicity, inflammatory cytokines, oxidative stress, and/or lipotoxicity in the presence of excess glucose. 1,2 Glucose and HbA1C are significantly elevated, and insulin may or may not be elevated, depending on beta-cell capacity to produce adequate insulin. Sequential measurements can help reveal the degree of beta-cell dysfunction; declining insulin along with increasing proinsulin signifies late-stage impairment. The most important therapeutic goal at this stage is to normalize and maintain normal blood glucose levels. 3 At this stage, a comprehensive approach is essential, including diet and lifestyle measures, supplementation, and targeted pharmaceuticals, based on the degree of beta-cell impairment. Medication considerations Supplement considerations Insulin sensitizers: Thiazolidinediones (e.g., pioglitazone); Biguanides (e.g., metformin); Dual PPAR agonists (e.g., aleglitazar); Inhibitors of starch digestion: α-Glucosidase inhibitors (e.g., acarbose); Improvement of HbA1C: DPP-4 Inhibitors (e.g., sitagliptin) or Pramlintide; AGE Inhibitor: Aminoguanidine; Insulin secretagogues: Sulfonylureas (e.g., glipizide); Meglitinides; exanatide; Insulin & K channel openers Lifestyle considerations Dietary considerations Reduce weight; Increase physical activity (esp. aerobic); Reduce stress; Treat any inflammatory disorders Avoid sugar and refined carbohydrates, fructose, soft drinks, alcohol, and trans fats. Minimize saturated fats. Emphasize a high-fiber, low- saturated fat, Mediterranean-type diet (e.g., legumes and whole grains, fresh fruits and veggies, nuts & other monounsaturates, foods rich in omega-3 fats, such as cold water fish). Nutritional: B vitamins (esp. niacinamide, B6, B12, folate), vitamin D, biotin, Mg, Zn, Cr, V, antioxidants (e.g., NAC, vitamins C, E, α-lipoic acid, Se), flavonoids (e.g., grape seed, bilberry), fish oils, fiber supplement, carnosine; Herbal: Gymnema, green tea, cinnamon, fenugreek, maitake, American or Panax ginseng, rehmannia, scutellaria

47 © 2008 © 2010 Metabolic Markers

48 © PreD Guide

49 © Hemoglobin A1c (HbA1c) Measures the amount of hemoglobin in a red blood cell (RBC) that has been glycated by excess glucose. Reflects average glucose concentration during the previous 3 month period ~ the life cycle of the RBC.

50 © HOMA-IR Homeostatic Model Assessment- Insulin Resistance Calculation based on plasma levels of: –Fasting Glucose & Insulin –Non-invasive, mathematical estimate insulin resistance

51 © C-Peptide C-peptide is produced when proinsulin is cleaved to form insulin and C-peptide. Increased levels of C-peptide reflect insulin resistance.

52 © ©2007 by National Academy of Sciences Conversion of Proinsulin to Insulin (cleavag e)

53 © Leptin Leptin is an adipocyte-derived hormone that regulates appetite. In a healthy body, overeating induces leptin production which suppresses appetite and controls weight gain. Leptin is protective against obesity.

54 © Elevation of Leptin Indicates leptin resistance (interference with leptin signaling) Associated with: –High BMI & abdominal obesity –Pancreatic beta-cell damage –High triglycerides & Low HDL-C

55 © 2008 © 2010 Case Study

56 ©

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58 © Key Points on Progression to Diabetes Can be prevented Can be reversed Can be treated effectively Metabolic processes may be present when the patient is not yet symptomatic.

59 © Obesity: Final Considerations Obesity remains a major clinical concern. Insulin resistance is a major cause of obesity (at least 70%). Diabetes Prevention Program trial showed 58% reduction in incidence of T2DM with lifestyle modifications. 5-10% reduction in body weight improves insulin sensitivity, lipid profiles, endothelial function, reduces thrombosis and inflammatory markers. There is a 3-fold increase in the odds that a patient will attempt weight loss if it is recommended by a trusted health care professional.

60 © 2008 © 2010 The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH PAFP 9 March 2012


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