Insulin Resistance Syndrome

1. Insulin Resistance Syndrome Chou Chien-Wen MD. Endocrinology & Metabolism Division Chi-Mei Medical Center 9 July 2004

3. Differentiation between the IRS and T2 diabetes

4. Disease-related consequences of IRS/compensatory hyperinsulinemia Insulin resistance is not a disease but rather a physiological abnormality An association between CVD and plamsa uric acid cincentration, is not a very sensitive predictor of insulin resistanceInsulin resistance is not a disease but rather a physiological abnormality An association between CVD and plamsa uric acid cincentration, is not a very sensitive predictor of insulin resistance

5. Identification of individuals at risk for IRS Most powerful modurators of insulin action are differences in degree of obesity and physical activity Two variables were approimately equally powerfulMost powerful modurators of insulin action are differences in degree of obesity and physical activity Two variables were approimately equally powerful

6. Obesity and IRS Obesity is a physiological variable that decreases insulin-mediated glucose disposal BMI rather than abdominal circumference, be used to identify individuals at increased risk Abdominal circumference are neither routinely performed nor is its quantification as well standardized European Group for the Study of IR was not increased when abdominal circumference replaced BMI as the marker of obesity BMI and abdominal circumference were closely related r=0.9 in 15,271 participants in NHANES III

7. Criteria for predicting IRS 75-g oral glucose challenge, with a plasma glucose concentration 120 min after the glucose load > 140 mg/dl (and < 200 mg/dL) IRS excludes patients whose degrees of hyperglycemia fulfills the diagnostic criteria for type 2 diabetes75-g oral glucose challenge, with a plasma glucose concentration 120 min after the glucose load > 140 mg/dl (and < 200 mg/dL) IRS excludes patients whose degrees of hyperglycemia fulfills the diagnostic criteria for type 2 diabetes

8. 3-fold increase in identifying insulin resistant individuals by determining the plasma glucose concentration 2 hours after a standard oral glucose challenge3-fold increase in identifying insulin resistant individuals by determining the plasma glucose concentration 2 hours after a standard oral glucose challenge

9. Plasma insulin concentration and the IRS Plasma insulin concentrations are useful surrogate marker of IR Highly statistically significant correlations between measures of insulin-mediated glucose disposal and both fasting (r=0.6) and post-glucose challenge (r=0.8) plasma insulin concentrations Methods to quantify plasma insulin concentrations are not standardized Difficult to compare values measured in different clinical laboratories Has not been established that an increase in plasma insulin concentration, by itself, in the absence of any of changes listed in Table 3, can predict the development of CVD A research, not a clinical tool

10. Evaluation of the criteria (1) The prevalence of these 4 abnormalities in the 40-74 year-old age group in NHANES III database The prevalence of all 4 was reasonably similarThe prevalence of these 4 abnormalities in the 40-74 year-old age group in NHANES III database The prevalence of all 4 was reasonably similar

11. Evaluation of the criteria (2)

12. Evaluation of the criteria (3)

13. The 1st World Congress on the Insulin Resistance Syndrome was held in Los Angeles, 21-22 November 2003.

14. IRS (1) included insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, and increased risk of both diabetes and coronary heart disease. Other abnormalities associated with the IRS include glucose intolerance, small LDL particle size, postprandial accumulation of triglyceride-rich remnant lipoproteins, hypertriglyceridemia, and low HDL cholesterol. endothelial dysfunction: increased circulating cell adhesion molecules, increased asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), decreased endothelium-dependent vasodilation increased plasminogen activator inhibitor-1, fibrinogen, and inflammatory markers, including C-reactive protein (CRP) and leukocyte count.

15. IRS (2) The IRS is associated with decreased renal urate clearance, increased sympathetic nervous system activity and renal Na retention, increased ovarian testosterone secretion, and sleep-disordered breathing Associated illnesses include cardiovascular disease (CVD), type 2 diabetes, hypertension, the polycystic ovarian syndrome, nonalcoholic fatty liver disease (NAFLD) , malignancies including breast cancer, and sleep apnea.

16. Factors that increase the likelihood of IRS include having CVD Hypertension polycystic ovarian syndrome acanthosis nigricans a family history of type 2 diabetes, hypertension, or CVD a history of gestational diabetes or glucose intolerance non-Caucasian ethnicity sedentary lifestyle obesity

17. Table of content Determinants of insulin sensitivity Mechanisms of insulin resistance Endothelial dysfunction and insulin resistance Nonalcoholic fatty liver disease Lifestyle approaches for the IRS Low-carbohydrate diet for atherogenic dyslipidemia Relationship between obesity and the IRS Adipocyte hormones and insulin action Inflammation and the IRS

18. Determinants of insulin sensitivity (1) Reaven suggested that adiposity and physical fitness each account for ~25% of the variability in insulin sensitivity with genetic factors, responsible for an additional 50% of this variation illustrated with the differences in insulin sensitivity between persons of European and persons of South Asian or Mexican ancestry and with the similarity in insulin sensitivity of related persons in a familyillustrated with the differences in insulin sensitivity between persons of European and persons of South Asian or Mexican ancestry and with the similarity in insulin sensitivity of related persons in a family

19. Determinants of insulin sensitivity (2) Surrogate measures of insulin sensitivity (based on comparison with the SSPG) include fasting insulin or homeostasis model Glucose tolerance per se: (IFG) has sensitivity 0.10 and specificity 0.97, impaired glucose tolerance (IGT) 0.26 and 0.95, fasting insulin in the highest tertile 0.66 and 0.83, and insulin 2 h after oral glucose 0.71 and 0.86, respectively Overweight is another strong predictor. Reaven suggested that triglyceride >130 mg/dl, triglyceride-to-HDL ratio >3, and insulin >15 �U/ml are considerably stronger markers of insulin resistance

20. Determinants of insulin sensitivity (3) In a group of 208 persons without diabetes who underwent SSPG measurement, measuring waist circumference with a tape measure held horizontally at the superior iliac crest while standing, the BMI and waist circumference showed identical correlation to SSPG with R = 0.6 for both measures. Using a BMI cutoff of 25 kg/m2, 60% had insulin resistance, whereas with waist >88 cm in women or 102 cm in men, 68% had insulin resistance

21. Mechanisms of insulin resistance (1) Carbon NMR studies with a profound defect in muscle glycogen synthesis in persons with type 2 diabetes Phosphorus NMR studies suggest transport defects at the level of hexokinase or GLUT4 to be primary offspring of persons with type 2 diabetes suggest this abnormality to precede the onset of the disease Further 13C NMR spectroscopy has suggested that the defect is at the level of GLUT4. The abnormality in GLUT4 is strongly predicted by the free fatty acid (FFA) level and, even more strongly, by intramyocellular triglyceride levels.

22. Mechanisms of insulin resistance (2) A potential mechanism by which fatty acid metabolites inhibit glucose transport activity appears to involve the insulin signaling cascade, with decreased phosphatidylinositol 3-kinase caused by activation of a serine kinase cascade via protein kinase C-[theta] decreasing the translocation of GLUT4 to the cell membrane. peroxisome proliferator-activated receptor [gamma] agonists act by increasing adipose tissue fat stores and preventing the increase in fatty acid metabolites in liver and muscle.

23. Endothelial dysfunction and insulin resistance Exercise increases eNOS, improving vasodilation, whereas obesity and insulin resistance are associated with deficiency of NO leading to endothelial dysfunction Insulin resistance is associated with elevations in circulating ADMA. ADMA acts as a competitive inhibitor of eNOS, and the enzyme dimethylarginine dimethylaminohydrolase (DDAH) increases ADMA metabolism, with insulin resistance decreasing DDAH levels and activity by increasing oxidative stress TZDs, metformin, ACEI, ARB, statins, and antioxidants all have been shown to decrease plasma ADMA levels, to improving vessel wall NO synthesis and decreasing superoxide anion levels.

24. Nonalcoholic fatty liver disease (1) NAFLD and nonalcoholic steatohepatitis (NASH), which he described as "the hepatic manifestation of the IRS" Approximately 40% of persons with NASH have diabetes, and an additional 20% have impaired glucose tolerance whereas ~50% of persons with diabetes have NAFLD, of whom 20% have NASH, with perhaps 20% of these persons ultimately developing cirrhosis.

25. Nonalcoholic fatty liver disease (2) Pathologically, in fatty liver, replacement of the hepatocyte by small or large fat globules. Steatohepatitis includes evidence of cytologic ballooning and pericellular fibrosis. pathogenesis is that increased fatty acid delivery to the liver, in a setting of increased fatty acid oxidation causing oxidative injury and de novo triglyceride synthesis, causes the development of fatty liver, which is associated with mitochondrial paracrystalline inclusions both mitochondrial and peroxisomal fatty acid oxidation cause an increase in reactive oxygen species (ROS), one consequence of which is depletion of mitochondrial DNA

26. Lifestyle approaches for the IRS (1) body weight has increased ~15% over the past century, with BMI >25 and 30 kg/m2 in 46 and 14%, respectively, of the population in 1980 and 65 and 31% in 2000. One of the major approaches to management of the IRS is lifestyle change, with 7% weight loss and 150 min/week exercise in the Diabetes Prevention Program reducing diabetes by 58%. Realistic goals are a 5-10% weight loss

27. Lifestyle approaches for the IRS (2) Keeping a food diary, typical patients underreport calories by one-third and over-report exercise by one-half. structure eating and exercise patterns (for example, putting out exercise clothes before going to bed). small changes is the "100/100" plan: eliminating 100 cal by diet and increasing activity by 100 cal, which should lead to a 20-lb annual weight loss. participate longer in treatment, and increase physical activity to at least 1 h/day are most likely to succeed. Strength training is as good as aerobic exercise Multiple short periods of exercise may be as good as one continuous bout of exercise

28. Lifestyle approaches for the IRS (3) Pharmacotherapy, very-low-calorie diet, residential diets, and "meal replacements" allow structured eating and are effective in producing sustained weight loss Sibutramine Trial on Obesity Reduction and Maintenance XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study: with orlistat, with 4-year data showing new diabetes in persons with IGT decreased 37%. BMI exceeds 40 kg/m2, bariatric surgery should be strongly considered.

29. Low-carbohydrate diet for atherogenic dyslipidemia either weight loss or carbohydrate restriction can be effective in improving the atherogenic lipid phenotype

30. Relationship between obesity and the IRS (1) almost 5% of the population has BMI >40 kg/m2. Insulin resistance is linearly associated with the BMI, although with wide scatter at any given level, so that 25-30% of the variance in insulin sensitivity is explained by BMI. In a study of 50 obese persons, 29 insulin resistant with mean SSPG 232 mg/dl and 21 insulin sensitive with mean SSPG 84 mg/dl, with similar age and BMI, the 2-h glucose was 144 vs. 112, triglyceride 199 vs. 125, and HDL 42 vs. 54 mg/dl, with a triglyceride-to-HDL ratio 5.4 vs. 2.5, suggesting that insulin resistance contributes to CVD risk independent of obesity.

31. Relationship between obesity and the IRS (2) Using the Stamford database of ~500 persons whose SSPG had been measured, its correlation coefficients were 0.33 for fasting glucose, 0.56 for insulin, 0.42 for triglyceride, and 0.41 for the triglyceride-to-HDL ratio. The best cut point for the triglyceride-to-HDL ratio was 3.0, with sensitivity 72% and specificity 63% for insulin resistance the optimal triglyceride cut point of 131 mg/dl showed similar sensitivity and specificity. The ATP III criteria had sensitivity 55% and specificity 85%.

32. Adipocyte hormones and insulin action the role of adipocyte hormones in regulating insulin action, lipid metabolism, and energy homeostasis. Adipocytes produce many cytokines, including leptin, with effects on food intake leptin deficiency in humans in association with severe hyperphagia, suggesting lack of satiety response. Partial leptin deficiency is also associated with increased body fat insulin increases leptin production Adiponectin is produced by adipocytes, but levels are inversely proportional to total adipocyte mass and therefore are lower in obesity.

33. Inflammation and the IRS (1) The initiating steps of atherosclerosis may involve inflammation due to lipoproteins, phospholipids, and other substances modified by oxidation or glycation, with subsequent expression by endothelial cells of chemoattractant molecules leading monocyte uptake into the arterial wall and activation into macrophages, which in turn produce proinflammatory molecules including TNF-[alpha] and interleukin (IL)-6. IL-6 acts as a messenger cytokine in the liver, leading to CRP and serum amyloid A production, further mediating atherosclerotic processes. CRP activates complement, stimulates cytokine secretion, increases endothelial cell adhesion molecule expression, decreases eNOS expression and bioactivity, increases plasminogen activator inhibitor-1 levels and activity, increases LDL uptake by macrophages, increases monocyte chemoattraction, increases expression of the angiotensin II type 1 receptor, and has many additional inflammatory effects. CRP is strongly associated with obesity

34. Inflammation and the IRS (2) levels should be measured twice, 2 weeks apart, to avoid effects of intercurrent illness, particularly if baseline levels exceed 10 mg/l. CRP elevation predicts future events in studies of both high- and low-risk populations Low-risk levels are <1 mg/l, average-risk levels are 1-3 mg/l, and high-risk levels are >3 mg/l and are associated with the doubling of CVD risk. CRP levels increase with age, are higher in women, and are associated with coronary disease and type 2 diabetes. Modifiable causes of CRP elevation include obesity, cigarette use, estrogen treatment, and chronic bronchial or periodontal inflammation. CRP decreases during treatment with statins, fibrates, antibiotics, metformin, and TZDs and with alcohol ingestion

35. Definitions of the Insulin Resistance Syndrome The Adult Treatment Panel III WHO Clinical Criteria AACE Clinical Criteria EGIR

39. Table of content IRS and CVD IRS and HT IRS and PCOSIRS in childhood IRS and malignancy

40. The Adult Treatment Panel III: metabolic syndrome (1) propose a new definition of the metabolic syndrome heightening awareness of the insulin resistance syndrome (IRS) not recommend routine measurement of insulin sensitivity or of inflammatory markers The 2-h glucose was not included Not calling the metabolic syndrome a CHD equivalent Accentuate the risk accompanying elevated LDL cholesterol Reverse its root causes of obesity and physical inactivity likely to be present in younger persons with CHD

41. The Adult Treatment Panel III: metabolic syndrome (2) metabolic syndrome is present in ~10% of children. 52% of persons with but 23% of those without metabolic syndrome have increased carotid intima-media thickness (IMT) association of C-reactive protein with atherosclerotic risk Usefulness of measurement of ankle brachial systolic pressure ratio

42. The American Association of Clinical Endocrinologists: IRS (1) Differences from the ATP III included focus on the IRS rather than on CVD, a decision to specifically exclude persons with type 2 diabetes, and recognition of the limitations of the fasting glucose and the usefulness of the 2-h postchallenge glucose in assessing insulin resistance. the IRS was felt to be a continuum of risk based on the number and severity of components. early recognition of the IRS Close follow-up

43. AACE: IRS (2) Obesity, based on either BMI or waist circumference, was seen as a risk factor rather than a criterion for the syndrome Measures of obesity must be ethnically based, and one must recognize that in certain Asian populations, both BMI and waist circumference criteria must be reduced by 15-20%. many obese persons do not have the syndrome and many with the syndrome are not obese.many obese persons do not have the syndrome and many with the syndrome are not obese.

44. The IRS and CVD In 1,209 Finnish men aged 42-60 years, the 10-year CVD risk was increased 2.1- and 2.5-fold with the ATP III and WHO IRS definitions, respectively In the Botnia study, there was a 1.8-fold increase in risk in persons satisfying the WHO IRS criteria Using the Hoorn Study data among men, high insulin predicted a 1.5-fold increase in CVD, increased waist circumference predicted a doubling, and hypertension predicted a two- to threefold increase in risk. Among women, high insulin and waist circumference predicted risk of nonfatal but not fatal CVD, and both low HDL and high triglyceride were significant factors predicting both total and fatal CVD.

45. The IRS and hypertension comparing persons with normal and increased blood pressure, with 50% of the hypertensive patients but 10% of those with normal blood pressure having evidence of hyperinsulinemia. Insulin does cause sodium retention

46. Association between the IRS and the PCOS (1) PCOS may be the most common endocrinopathy among young women and is a syndrome of chronic anovulation and hyperandrogenism that affects 6-10% of women of childbearing age and accounts for ~50-60% of female infertility due to anovulation. metformin monotherapy improved the ovulation rate 3.9-fold over placebo and the combination of metformin and clomiphene improved both the ovulation and pregnancy rates 4.4-fold compared with clomiphene alone. PCOS is associated with a 30-50% rate of early pregnancy loss and that hyperinsulinemia is also a risk factor for miscarriage.

47. Association between the IRS and the PCOS (2) Women with PCOS have 30 and 10% prevalence of impaired glucose tolerance and diabetes, respectively Nurses' Health Study (NHS) of 101,073 women followed for 8 years, oligomenorrheic women had a twofold higher rate of conversion to type 2 diabetes. Conversely, 25-28% of women with type 2 diabetes have evidence of PCOS, and 80% of women with type 2 diabetes may have polycystic ovaries in the NHS, women with irregular menses had a doubled risk of fatal myocardial infarction

48. The IRS in childhood Type 2 diabetes is increasing in children Abnormal glucose tolerance is frequently seen among obese children, although it is noteworthy that fasting glucose is rarely abnormal significant correlation between parents and children in both weight and insulin sensitivity Using the ATP III criteria, the prevalence of metabolic syndrome was 2, 4, and 8% at ages 13, 15, and 19, respectively.

49. Figure 1. Effect of Insulin Resistance on the Prevalence of the Metabolic Syndrome in White Subjects (Panel A), Hispanic Subjects (Panel B), and Black Subjects (Panel C), According to the Degree of Obesity.

50. Figure 2. C-Reactive Protein and Adiponectin Levels According to the Degree of Obesity and the Insulin-Resistance Category.

51. The IRS and malignancy link between insulin resistance, hyperinsulinemia, and cancer. association of breast cancer with hyperinsulinemia and diabetes.

52. Lifestyle and insulin resistance in cancer lifestyle factors, such as obesity, caloric intake, and physical activity, that may affect insulin resistance in cancer. Women's Health Initiative regarding the effects of energy intake and physical activity, suggesting that both physical activity and less food intake can reduce hyperinsulinemia.

53. Breast cancer a relationship between insulin resistance and breast cancer. Meta-analysis has shown a 1.56-fold increase in breast cancer associated with obesity Insulin resistance is also associated with worse breast cancer prognosis, with overweight women having a 1.8- to 1.9-fold increased rate of recurrence and a 1.4- to 1.6-fold increased mortality a study of 535 women with early-stage breast cancer, ~15% of whom were obese, in which BMI was an important adverse prognostic factor for distant recurrence and death, with insulin levels also predictive of death and distant recurrence in both overweight and normal-weight women

54. Colorectal cancer an inverse association between physical activity and colon cancer, with a 30-50% risk reduction related to high activity. an association between BMI and colon cancer, with a 1.3- to 2-fold increased risk associated with BMI >30 kg/m2 type 2 diabetes is associated with a 1.5-fold increased risk of colon cancer. The risk of colon cancer is greatest in persons with type 2 diabetes at 11-15 years after diagnosis, suggesting a role of longstanding hyperinsulinemia