Dietary Interventions for Insulin Resistance and the Metabolic Syndrome

1. Dietary Interventions for Insulin Resistance and the Metabolic Syndrome Lisa M. Neff, MD Northwestern University Comprehensive Center on Obesity

2. “Dietary Interventions for Insulin Resistance and the Metabolic Syndrome” • Background • Metabolic Syndrome • Dietary Patterns and Insulin Sensitivity • Pilot Study Design and Data • Future Directions

3. The Metabolic Syndrome: NCEP/ATPIII/AHA Diagnostic Criteria Individuals must have 3 or more of the following: • Abdominal obesity • Waist circumference > 40” in men or > 35” in women • High triglycerides • ≥ 150 mg/dL • Low HDL cholesterol • < 40 mg/dL in men or < 50 mg/dL in women • High blood pressure • ≥ 130/85 mmHg • High fasting glucose • ≥ 100 mg/dL

4. DyslipidemiaHypertension DiabetesAbdominal Obesity Polycystic ovary disease Sleep apnea Non-alcoholic fatty liver disease Cancer Hyperuricemia & gout Insulin resistance Inflammation Prothrombotic state Endothelial dysfunction Cardiovascular disease

5. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006)

6. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006)

7. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006)

8. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006)

9. Is there an optimal dietary pattern for individuals with theMetabolic Syndrome?

10. Dietary Components Which May Affect Insulin Resistance • ↑ IR • Saturated fat • Salt (deficiency or excess) • Alcohol (>30g/day) ↓ IR • Whole grains • Fruits and vegetables • Low fat dairy products • Magnesium • Calcium • Dietary fiber • Omega-3 fatty acids • Low GI foods

11. Dietary Components Which May Affect Insulin Resistance DASH Diet ↓ IR • Whole grains • Fruits and vegetables • Low fat dairy products • Magnesium • Calcium • Dietary fiber • Omega-3 fatty acids • Low GI foods

12. The DASH Diet:Dietary Approaches to Stop Hypertension • Originally conceived as the optimal diet for hypertension • High in fruits and vegetables (typically 10 servings/day or more), whole grains, and low fat dairy products(2-3 servings/day or more) • Moderate amounts of nuts, beans, fish and poultry • Limited red meat, fried foods, and sweets • High in calcium, magnesium, potassium, vitamins, phytochemicals, and fiber • Low in cholesterol, saturated fat, sugars, and sodium

13. The DASH Diet: Epidemiologic Studies • Increased intake of fruits, vegetables, and low fat dairy products is associated with: • Increased insulin sensitivity • Reduced risk of metabolic syndrome • Reduced risk of Type 2 diabetes • Reduced risk of hypertension • High intakes of calcium and magnesium are associated with: • Increased insulin sensitivity • Reduced risk of metabolic syndrome • Reduced risk of Type 2 diabetes

14. The DASH Diet: Epidemiologic Studies • In the Nurses Health Study, adherence to a DASH-style diet is associated with: • A lower risk of CHD (fatal and non-fatal) (RR=0.76) • A lower risk of stroke (RR=0.82) • Lower plasma levels of CRP and IL-6 Fung et al. Arch Intern Med. 2008;168(7):713-20.

15. Magnesium and Metabolic Syndrome • Magnesium appears to play a role in: • carbohydrate metabolism • Mg++ is a cofactor for several glycolytic enzymes, including hexokinase, phosphofructokinase, and pyruvate kinase • insulin action • Low intracellular Mg++ impairs the tyrosine kinase activity of the insulin receptor • modulating vascular tone and blood pressure • Low intracellular Mg++ may affect calcium channel activity, raising intracellular Ca++, which has a vasoconstrictive effect • thrombosis • Magnesium may alter platelet reactivity or aggregation

16. Magnesium and Metabolic Syndrome • In healthy human subjects, experimental magnesium deficiency increases: (Nadler JL, Hypertension 1993, Nadler JL, Diabetes Care 1992) • Insulin resistance • Basal and angiotensin-II stimulated aldosterone levels • Thromboxane A2 levels • Platelet reactivity • In diabetics with hypomagnesemia, magnesium supplementation improves insulin sensitivity and reduces platelet reactivity (Rodriguez-Moran, Diabetes Care 2003; Nadler JL, Diabetes Care 1992) • In a canine model of stent thrombosis, IV magnesium administration reduced thrombus formation (Rukshin V, Circulation 2002)

17. Calcium and Metabolic Syndrome • Calcium appears to play a role in: • insulin action • High levels of intracellular Ca++ may impair insulin signaling • modulating vascular tone and blood pressure • High levels of intracellular Ca++ may have a vasoconstrictive effect

18. Calcium and Metabolic Syndrome • In hypertensive patients, oral calcium supplementation: • reduces intracellular calcium levels and may improve insulin sensitivity (Sanchez M, Hypertension 1997) • may produce modest improvements in systolic blood pressure (Allender PS, Ann Intern Med 1996; Bucher HC, JAMA 1996) • Amlodipine therapy reduces intracellular Ca++, improves glycemic control, and increases insulin sensitivity (Beer NA, J Clin Endo Metab 1993, Ueshiba, Horm Metab Res 2003)

19. The DASH Diet: Clinical Trials The DASH Diet: • Lowers blood pressure in normotensive and hypertensive adults (Appel, NEJM 1997, Sacks, NEJM 2001) • Reduces LDL cholesterol(Obarzanek, AJCN 2001) • Reduces Framingham risk score(Maruther, Circulation 2009)

20. The DASH Diet: Clinical Trials The DASH Diet: • May produce greaterweight loss than standard low-fat diets (Azadbakht, Diabetes Care 2005, Ard, Diabetes Care 2004) • May reduce fasting glucose and improveinsulin sensitivity more than standard weight loss diets (Azadbakht, Diabetes Care 2005, Ard, Diabetes Care 2004) To our knowledge, no studies have examined the effects of the DASH diet on insulin sensitivity and glucose metabolism under controlled feeding conditions or during weight stability.

21. The DASH Diet:Clinical Trials The DASH Diet: • May increase antioxidant capacityand reduce oxidative stress(Lopes, Hypertension, 2003) • May increase levels of adiponectin, the anti-inflammatory and insulin-sensitizing adipokine(Lien, Obesity, 2006) • May reduce inflammatory markers such as C-reactive protein(Lien, Obesity, 2006)

22. The DASH Diet: Caveats • The DASH diet may also • reduce HDL cholesterol, like other low-fat diets (Obarzanek, AJCN, 2001) • Increase TG (mean of 18 mg/dL), like other high carbohydrate diets (Erlinger, Circulation, 2003)

23. Glycemic Index Foods with similar carbohydrate content can affect blood glucose levels differently Ludwig, D. S. JAMA 2002;287:2414-2423.

24. Potato • Instant oatmeal • White bread • Watermelon • Basmati rice • Stoneground whole wheat bread • Raisins • Pineapple • Kidney beans • Chocolate ice cream • Oatmeal made with steel-cut oats • Spaghetti, al dente

25. Glycemic Index and Obesity High Glycemic Index Meal Postprandial Hyperglycemia Hyperinsulinemia Relative Lipogenesis Reactive Hypoglycemia OBESITY Counterregulatory Hunger ↑ Food Intake Hormones

26. Glycemic Index and Diabetes High Glycemic Index Meal Postprandial Hyperglycemia ↑ FFA Hyperinsulinemia Glucotoxicity Lipotoxicity Relative INSULIN Reactive RESISTANCE Hypoglycemia BETA CELL FAILURE Counterregulatory Hormones

27. The Low Glycemic Index Diet:Epidemiologic Studies • In some but not all studies, low GI diets are associated with: • Increased insulin sensitivity • Reduced adiposity • Reduced risk of metabolic syndrome • Reduced risk of type 2 diabetes

28. The Low Glycemic Index Diet:Clinical Trials • Low GI diets: • Reduce postprandial glucose levels in normal individuals and people with diabetes (Ludwig, JAMA, 2002) • Produce modest improvements in HbA1c in patients with diabetes (Brand-Miller, Diabetes Care, 2003) • May or may not affect insulin sensitivity (improvements noted in 2 of 7 studies)

29. The Low Glycemic Index Diet:Clinical Trials • Low GI diets: • May be beneficial for weight management, particularly in individuals with features of the metabolic syndrome (Pittas, Diabetes Care, 2005) • May reduce LDL cholesterol and TG and increase HDL(Luscombe, EJCN, 1999 and Pereira, JAMA, 2004) • May reduce inflammatory markers such as C-reactive protein (Pereira, JAMA, 2004) and IL-6 (Kallio, AJCN, 2008) • May increase antioxidant capacity(Botero, Obesity, 2009)

30. Questions • Does the DASH diet or the low GI improve insulin sensitivity, in the absence of weight loss? • Does the DASH diet or the low GI diet improve other features of the metabolic syndrome (such as dyslipidemia and inflammation), in the absence of weight loss? • Do these dietary patterns and weight loss have synergistic effects?

31. Pilot Study Overview • 15-week feasibility study with 18 volunteers • Three different study diets • DASH Diet • Low Glycemic Index Diet • American-Style Diet • All food provided by Bionutrition for 13 weeks

32. Pilot Study Overview • Inclusion criteria: ages 18-45, BMI ≥27, with: • fasting insulin ≥ 9 uIU/mL • OR fasting glucose ≥ 100 mg/dl • OR 2-hour OGTT ≥ 140 mg/dl AND • ≥2 other features of the metabolic syndrome • Abdominal obesity • High triglycerides • Low HDL • Prehypertension or hypertension

33. 2 weeks Outpatient Study Overview Run-in Phase on Usual Diet Testing #1 on American Diet 3-4 days Inpatient Wt Stable on American Diet Wt Stable on DASH Diet Wt Stable on Low GI Diet 2 weeks Inpatient Testing #2 Testing #2 Testing #2 8 weeks Outpatient Weight loss phase 50% kcal reduction Wt Stable on American Diet Wt Stable on DASH Diet Wt Stable on Low GI Diet 2 weeks Inpatient Testing #3 Testing #3 Testing #3

34. Measures of Insulin Sensitivity • HOMA – • Used to assess hepatic insulin sensitivity • a lower score indicates better insulin sensitivity • OGTT – • Used to assess whole body insulin sensitivity • Frequent blood sampling for 3 hours following the consumption of 75 grams of glucose • The Area Under the Curve (AUC) was calculated for glucose and insulin using the trapezoidal method • Hyperinsulinemic Euglycemic Clamp– • A measure of peripheral insulin sensitivity • High insulin infusion rate: 80 mU/m2 body surface area • Variable infusion rate of dextrose to keep blood glucose levels in the range of 90-100 mg/dl. • A higher glucose infusion rate (GIR) indicates better insulin sensitivity

35. Other Testing

36. Composition of the Study Diets

37. Composition of the Study Diets

38. Composition of the Study Diets

39. Composition of the Study Diets * predominantly juice and juice drinks

40. Baseline Characteristicsof 18 Enrolled Volunteers who Completed ≥ 2 Testing Periods

41. 100% had elevated fasting insulin levels and abdominal obesity. 28% had fasting hyperglycemia. 67% had low HDL levels. 44% had hypertriglyceridemia. 39% had prehypertension or hypertension. 50% had elevated CRP levels. Baseline Metabolic Characteristics of 18 Enrolled Volunteers who Completed ≥ 2 Testing Periods

42. Baseline Parameters by Study Diet Assignment: Median (range)

43. Baseline Metabolic Parameters by Study Diet Assignment: Median(range)

44. Baseline Metabolic Parameters by Study Diet Assignment: Median(range)

45. Baseline Metabolic Parameters by Study Diet Assignment: Median(range) Mean IL-6 level in healthy volunteers is 1.77 pg/mL.

46. Subjects’ Baseline Diets vs American Diet

47. Comparison of Baseline and American Diets

48. Comparison of Baseline and American Diets

49. Comparison of 3200 kcal American Diet and Average US Intake * predominantly juice and juice drinks

50. Weight Stability Phase Data • Subjects consumed the study diet for two weeks prior to testing. • Our goal for weight stability was +/-1% of initial weight. • Volunteers wore pedometers for 1 week in each phase and were asked to keep activity levels constant. • For this phase, reliable data were available for 5 volunteers in each group.