The Mediterranean Diet: HOW and WHY It Works So Well for T2DM

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1 The Mediterranean Diet: HOW and WHY It Works So Well for T2DM Susan L. Barlow, RD, CDE. Objectives 1. Discuss the effects of meal size on GLP-1 concentrations. 2. Compare and contrast the specific effects of macronutrients (carbohydrate, protein, fat) on GLP-1 concentrations, in healthy people and those with Type 2 diabetes. 3. Explain the physiologic mechanism of how MUFA specifically impacts L cells and the release of GLP List at least three other physiologic & pathophysiologic factors that affect GLP-1 concentrations. 5. Translate the effects of macronutrients on GLP-1 concentrations into practical advice for patient education (the Mediterranean Food Guide Pyramid). Hard to Swallow, But Studies Showed.. High-MUFA Diets Non-Inferior to ADA Diet Assumptions Decreased [GLP-1] are a consequence, NOT a cause, of T2DM Other factors, which contribute to the pathophysiology of DM, also influence the relative [GLP-1] These factors may impair the secretion of, and thus, relative [GLP-1], especially in the diabetic state Measurement of both Intact and total [GLP-1] is necessary Intact = active = reflects action (<) Total = reflects secretion only (>) How these are related to macronutrient ingestion was unknown Knop FK, et al. Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes 2007; 56(8):

2 Physiologic and Pathophysiologic Parameters Stimulating or Impairing GLP-1 Secretion STIMULATE GIP Fasting FFA Body Weight Age Glucagon Decrement FFA Decrement IMPAIR Acute hyperglycemia Insulin Resistance (IR) Glucagon Vollmer K, et al. Predictors of Incretin Concentrations in Subjects with Normal, Impaired, and Diabetic Glucose Tolerance. Diabetes 2008;57(3): Toft-Nielsen M-B, et al. Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients. JCEM 2001;86(8): Determinants of Impaired Secretion of GLP-1 in T2DM In a multiple regression analysis, 42% of variability of GLP-1 response was accounted for by: Diabetes BMI (+) Male Sex Insulin AUC (-) GIP AUC (-) Glucagon AUC (+) Toft-Nielsen M-B, et al. Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients. JCEM 2001;86(8): Dietary Factors Influencing [GLP-1] Meal Size: meal size = GLP-1 Macronutrient Composition of Diet (CHO/PRO/FAT) Breakdown of fats is an essential upstream event for GLP-1 secretion What Are the Effects of Meal Size on [GLP-1]?

3 GLP-1 Secretion in Relation to Meal Size + Body Weight in Healthy, T1DM and T2DM Objective: To investigate incretin secretion, in obesity, T1DM and T2DM and its dependence on the magnitude of the meal stimulus Methods: Plasma concentrations of intact and total GLP-1 were measured during two meal tests, 260 kcals and 520 kcals Meal composition = 33% FAT/ 48% CHO/ 19% PRO Subjects = 8 T1DM, 8 lean healthy, 8 obese T2DM, and 8 obese healthy Vilsboll T, et al. Incretin Secretion in Relation to Meal Size and Body Weight in Healthy Subjects and People with Type 1 and Type 2 Diabetes. JCEM 2003;88: Total and Intact GLP-1 in T2DM and Controls Following a Meal 4000 P=0.02 T2DM Control North P=0.07 AUC (pmol-l/min) 0 Total Intact Adapted from: Vilsboll T, et al. Reduced postprandial concentrations of intact biologically active glucagonlike peptide 1 in type 2 diabetic patients. Diabetes 2001;50: GLP-1 Secretion in Relation to Meal Size + Body Weight in Healthy, T1DM, and T2DM Results: GLP-1 with both meals in all subjects GLP-1 response with large vs. small meal, with corresponding C- peptide levels, in all subjects T2DM had GLP-1 response compared to obese healthy Conclusions: meal size = [GLP-1] Decreased GLP-1 secretion may contribute to impaired insulin secretion in T2DM GLP-1 secretion is normal in T1DM May modulate β-cell sensitivity in obese healthy subjects and T2DM by giving them a large meal? Vilsboll T, et al. Incretin Secretion in Relation to Meal Size and Body Weight in Healthy Subjects and People with Type 1 and Type 2 Diabetes. JCEM 2003;88: What are the Effects of Macronutrients on [GLP-1] in Animal Models, Healthy People and People with Diabetes?

4 Macronutrient Effects on GLP-1 Secretion and Concentrations Macronutrients may have selective effects on potentiation of incretin secretion and incretin degradation Carbohydrate Protein (whey) Fat (oleic acid) Specific macronutrients may serve as exogenous regulators of secretion and inactivation of the incretin hormones (both GLP-1 and GIP) with beneficial influence on glucose metabolism Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147(7): Modulated by OOral Fat and Protein in Mice. Endocrinology 2006;147(7): Carbohydrate and [GLP-1] Most studies have focused on responses to an OGTT GIP, GLP-1, insulin glucagon Thus, GIP and GLP-1 regulate islet function AFTER carbohydrate ingestion Less is known regarding relationships between incretin responses and changes in islet hormones (insulin & glucagon) after a mixed meal or non-carbohydrate macronutrient ingestion Carr RD, et al. Incretin and islet hormone responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab 2008;295:E779-E784. Protein, Fat and [GLP-1] in Mice Objective: To explore the effects of MUFA and milk proteins (whey protein) insulinotropic effects by examining the relationship to GLP-1 and GIP Methods: Measured total and intact GLP-1 and GIP after administration of glucose w/ or w/o oleic acid (OA) or whey protein (WP) Through gastric gavage in anesthetized C57BL/6J mice Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147 (7): Modulated by Oral Fat and Protein in Mice. Endocrinology 2006;147(7): Protein, Fat and [GLP-1] in Mice Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147(7): Modulated by OOral Fat and Protein in Mice. Endocrinology 2006;147(7):

5 Protein, Fat and [GLP-1] in Mice Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147(7): Modulated by Oral Fat and Protein in Mice. Endocrinology 2006;147(7): Protein, Fat and [GLP-1] in Mice Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147(7): Modulated by OOral Fat and Protein in Mice. Endocrinology 2006;147(7): Protein and [GLP-1] in Mice Similar earlier work was published in both mice and human subjects (Frid AH, et al. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 2005:82:69-75.) Drucker DJ. Enhancing the Action of Incretin Hormones: A New Whey Forward? Endocrinology 2006;147(7): Modulated by OOral Fat and Protein in Mice. Endocrinology 2006;147(7): What Physiologic Mechanism Explains the Effects of MUFA on [GLP-1]?

6 MUFA Diets Improve Glucose Tolerance Through Increased Secretion of GLP-1 Objectives: To determine whether MUFA-induced glucose tolerance in vivo is due to increased GLP-1 release To determine the total contribution of GLP-1 to the enhanced glycemic tolerance in OO-fed rats To probe the mechanism by which the OO diet enhances GLP-1 secretion MUFA Diets Improve Glucose Tolerance Through Increased Secretion of GLP-1 Methods: Lean Zucker rats were pair-fed a synthetic diet containing the following rat chow, differing only by type of fat (total fat = 5%) Composition of Rat Chow = 75% CHO, 20% Protein, 5% of EITHER Coconut Oil (palmitic acid; 87% SAT) OR Olive Oil (oleic acid; 74% MUFA) GLP-1 receptor antagonist, exendin (9-39) was infused 3 min, before a duodenal glucose tolerance test in the OO-fed rats A GLP-1-secreting L cell line was incubated for 24 h with either 100µM oleic acid (MUFA) or 100µM palmitic acid (SFA) and subsequently challenged with GIP, a known stimulator of the L cell Oral Glucose Tolerance Test: Effect of 2-Week Fat Feeding in Lean Zucker Rats Duodenal Glucose Tolerance Test: Effect of 2- Week Fat Feeding in Lean Zucker Rats

7 Effects of Exendin (9-39) on Duodenal Glucose Tolerance Tests in Lean Zucker Rats Effects of 24 Hour Pre-Exposure of GLUTag Cells to MUFA or SFA Mechanism of MUFA-Stimulated Secretion of GLP-1: Summary Benefit in glycemic tolerance obtained with MUFA diets occurs in association with increased GLP-1 secretion Mechanism is enhanced L-cell sensitivity Chronic exposure to MUFAs enhances L cell sensitivity to subsequent stimulation, resulting in greater levels of GLP-1 secretion SFAs suppress the secretory response to the same stimulus Intracellular mechanism(s) underlying response are unknown PKC (protein kinase-c) preferentially activated by unsaturated vs. saturated fatty acids and is a known intracellular mediator of GLP-1 secretion expressed in L cells I-FABP (Intestinal fatty acid binding protein) altered membrane fluidity Dietary therapy with MUFAs may be useful for treatment of patients with IGT and/or T2DM via increased GLP-1 secretion How Does the Scientific Data of Effects of Macronutrients on [GLP-1] Translate Into Practical Advice for Patients and Practitioners?

8 The Role of Diet in the Prevention of Type 2 Diabetes The conclusion is that there is no universal dietary strategy to prevent diabetes, or delay its onset. Together with the maintenance of ideal body weight, the promotion of the socalled prudent diet (characterized by a higher intake of food groups that are generally recommended for health promotion, particularly plant-based foods, and a lower intake of red meat, meat products, sweets, high-fat dairy and refined grains) or a Mediterranean dietary pattern rich in olive oil, fruits and vegetables, including whole grains, pulses and nuts, low-fat dairy, and moderate alcohol consumption (mainly red wine) appears as the best strategy to decrease diabetes risk, especially if dietary recommendations take into account individual preferences, thus enabling long-time adherence. Salas-Salvado J, et al. The role of diet in the prevention of type 2 diabetes. Nutrition, Metabolism and Cardiovascular Disease 2011; doi: /j.numecd Rationale for the Use of a Mediterranean Diet in Diabetes Management A Mediterranean diet, based on a centuries-old eating pattern, is proposed as an eating plan that integrates key elements from nutrition therapy recommended to treat each of these three risk factors: blood glucose, blood pressure and blood cholesterol This article discusses the national guidelines for treatment of BG, BP, and cholesterol, including similarities and differences, but proposes the Mediterranean diet as a common thread to meet all of these guidelines. Benson G, Pereira RF and Boucher JL. Rationale for the Use of a Mediterranean Diet in Diabetes Management. Diabetes Spectrum 2011; 24:1: The Mediterranean Food Guide Pyramid Downloaded from on 12/8/11 Mediterranean Foods Table Downloaded from on 12/8/11

9 What Makes the Mediterranean Diet Work? Objective: Prospective cohort study Greek segment of the European Prospective Investigation into Cancer and Nutrition (EPIC) Methods: Subjects = 23,349 Greeks; years old Subjects completed food surveys and were followed for ~8.5 years Controlled for age, sex, smoking status, amount of exercise and BMI Results: Main outcome measure = All-cause mortality Confirmed those who ate the Mediterranean Diet were healthier (4% mortality rate) versus those who did not (5% mortality rate) Trichipoulou A, Barnia C, Trichipoulos D. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study. BMJ 2009;338:b2337 What Makes the Mediterranean Diet Work? Food/Dietary Component % Contribution to Total Benefit (predictor of lower mortality) Alcohol (wine with meals) 23.5 Low Meat Consumption 16.6 High Vegetables Consumption 16.2 High Fruits and Nuts Consumption 11.2 Olive Oil (MUFA/SAT lipid ratio) 10.6 High Legume Consumption 9.7 High Cereal Consumption Low Dairy Products Consumption Seafood Trichipoulou A, Barnia C, Trichipoulos D. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study. BMJ 2009;338:b2337 Effects of Two Different Hypocaloric Diets on [GLP-1] in Obesity Objective: Compare effect of low carbohydrate diet (Diet I) to low fat diet (Diet II) on circulating GLP-1 levels and relation to insulin response after weight loss Methods: Evaluable population = 118 (52 on Diet I and 66 on Diet II) Biochemical and anthropometric variables were measured at baseline and after 3 months of hypocaloric diet De Luis DA, et al. The effects of two different hypocaloric diets on glucagon-like peptide 1 in obese adults, relation with insulin response after weight loss. Journal of Diabetes and Its Complications 2009;23: Effects of Two Different Hypocaloric Diets on [GLP-1] in Obesity Results: In Diet 1 group, basal GLP-1 levels did not change after treatment In Diet II, GLP-1 levels decreased significantly by 8.4% Only insulin levels were an independent predictor of [GLP-1] in a multivariate model (Δ +0.6 ng/ml [GLP-1] with Δ +1 mui/ml of insulin) Conclusions: A hypocaloric diet with a low fat percentage decreased GLP-1 levels with a direct correlation with insulin levels A hypocaloric diet with a low carbohydrate percentage did not change GLP-1 levels Dietary macronutrient manipulation on GLP-1 response could be useful in an obesity nutrition program De Luis DA, et al. The effects of two different hypocaloric diets on glucagon-like peptide 1 in obese adults, relation with insulin response after weight loss. Journal of Diabetes and Its Complications 2009;23:

10 Summary: Macronutrients and [GLP-1] [GLP-1] IS affected by dietary macronutrient composition In particular, MUFA stimulates GLP-1 secretion through a mechanism of enhanced L cell sensitivity Whey protein increases [GLP-1] via significant DPP-IV inhibition There is now an explanation for the established proven success of MUFA-rich diets in the treatment of CVD and DM Dietary manipulation (Mediterranean Diet or MUFA-rich diets) may be a potent lifestyle tool for people predisposed to diabetes and/or CVD or those already diagnosed Further studies are needed to control for the multiple physiologic factors and environmental influences regulating expression and activity of [GLP-1] and DPP-IV Michael Pollan s Food Rules Eat foods; mostly plants; not too much + Rule #43: Have a glass of wine with dinner Pollan, Michael: Food Rules: An Eater s Manual. Published by the Penguin Group, New York, NY; Resources Cooking Light Superfast Mediterranean Recipes iid=cmnewsletter nl2&promkey=xet? fpa_acxiomfindernumber=