BARIATRIC SURGERY AND TYPE 2 DIABETES MELLITUS

BARIATRIC SURGERY AND TYPE 2 DIABETES MELLITUS George Vl Valsamakis European Scope Fellow Obesity Visiting iti Associate Prof Warwick Medical School

Diabetes is an increasing healthcare epidemic throughout the world Global projections for the number of people with diabetes (20 79 age group), 2007 2025 (millions) 28.3 40.5 +43% 53.2 64.1 +21% Africa Eastern Mediterranean and Middle East Europe North America 10.4 South and Central America 16.2 18.7 32.7 +80% South-East Asia +102% Western Pacific 24.5 44.5 +81% 46.5 80.3 +73% Worldwide: 246 million people in 2007 380 million projected for 2025 67.0 99.4 +48% IDF. Diabetes Atlas 3rd Edition 2006

Diabesity

Early stages of T2DM and insulin secretion

Prediabetes to diabetes progression is not affected by postmeal glucose lowering

Influence of comorbidities on therapeutic progression of Diabetes treatment. (Vitry AI et al Plos One 2010) 20,000 patients

Obesity and cardiovascular risk

Obesity and cardiovascular risk <300 lbs >=300 lbs Prevale ence (%) 50 45 40 35 30 25 20 15 10 5 0 44,6 47 36,5 24,7 27,3 21,6 21 23,1 6,5 9 Smoking Hypertension Diabetes Low HDL High CRP

Glucose uptake and insulin secretion in obesity and T2DM

Plasma glucagon (upper panel), PP (middle panel), and GIP (lower panel) concentrations in T2DM patients ( ), NGT subjects ( ), and IGT subjects ( ) during a 240-min meal test. Toft-Nielsen M et al. JCEM 2001;86:3717-3723 2001 by Endocrine Society

Pories et al. rapid drop of glucose levels and insulin requirements after gastric bypass

Illustrations of bariatric procedures. Scott W R, and Batterham R L Am J Physiol Regul Integr Comp Physiol 2011;301:R15-R27 2011 by American Physiological Society

Bariatric surgery in obese and decreased incidence of T2DM

Bariatric surgery in T2DM and decreased incidence of cardiovascular events

Bariatric surgery and Diabetes remission

Schematic representation of the time course for putative diabetes remission (ύφεση) after various types of bariatric surgery. Vella A Diabetes 2013;62:3017-3018 Copyright 2011 American Diabetes Association, Inc.

T2DM remission rates after bariatric surgery (Diab Care) LAGB 48% VBG 68% RYGB 84% BPD 98%

Predictors of Diabetes remission after gastric bypass «surgery for severe obesity should be provided earlier» Diabetes es and Hypertension e in Severe e e Obesity and Effects of Gastric Bypass-Induced weight Loss (Sugerman HG et al.. Annals of Surgery 2003)

Effects of Gastric Bypass Surgery RYGB in Patients with Type 2 Diabetes and only Mild Obesity (BMI 30-35) 35) Cohen RV et al. Diab Care 2012

Cohen RV Diab Care 2012 (2)

Cohen RV Diab Care 2012 (3)

Diabetes Remission and Reduced Cardiovascular Risk After Gastric Bypass in Asian Indians with Body Mass Index <35 kg/m2, (mean BMI:28) Shashankh S et al. Surg Obes Relat Dis 2010

Shashank S Surg Obes Relat Dis 2010

Shashank S et al. Surg Obes Relat Dis 2010

Shashank S Surg Obes Relat Dis 2010

Physiologic effects of Bariatric surgery in Physiologic effects of Bariatric surgery in T2DM

Hypothetical model connecting increased appearance of meal glucose (RaOral) following RYGB and key regulatory steps for glucose metabolism. \ Ανεξαρτήτως απώλειας βάρους Salehi M, and D Alessio D A Diabetes 2013;62:3671-3673 Copyright 2011 American Diabetes Association, Inc.

Camastra S et al. Diabetes 2013;62:3709-3717 administered an Mixed meal to 12 obese T2D patients and 15 obese nondiabetic (ND) subjects before and 1 year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of β-cell

Plasma glucose (A) and insulin concentrations (B), ISRs (C), and insulin secretion dose response (D), RaO (E), and EGP (F) in the four groups of study subjects at baseline. Camastra S et al. Diabetes 2013;62:3709-3717 Copyright 2011 American Diabetes Association, Inc.

Plasma glucose and insulin concentrations in the patients (pts) before and after RYGB. The corresponding data for the obese control group are shown by the gray line. Camastra S et al. Diabetes 2013;62:3709-3717 Copyright 2011 American Diabetes Association, Inc.

Plasma glucagon, GLP-1, and GIP response to the meal in the patients (pts) before and after RYGB. The corresponding data for the obese control group are shown by the gray lines. Camastra S et al. Diabetes 2013;62:3709-3717 Copyright 2011 American Diabetes Association, Inc.

Rate of appearance of oral glucose (RaO), endogenous glucose (EGP), and glucose clearance rate in the patients (pts) before and after RYGB. The corresponding data for the obese control group are shown by the shaded areas. Camastra S et al. Diabetes 2013;62:3709-3717 Copyright 2011 American Diabetes Association, Inc.

ISR and dose-response function in the patients (pts) before and after RYGB. The corresponding data for the obese control group are shown by the shaded areas. Camastra S et al. Diabetes 2013;62:3709-3717 Copyright 2011 American Diabetes Association, Inc.

GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. (Jiménez A et al. Diab Care 2013;36:2062-2069) Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucosedependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9-39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. Infusion of exendin-(9-39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dl compared with exendin-(9-39) 116.5 ± 223mg/dL; 22.3 P < 0.001]. 001] The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement

GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. (Jiménez A et al. Diab Care 2013;36:2062-2069) Insulin and C-peptide response to a standardized meal test with saline infusion (open squares) or exendin-glp1 antagonist (9 39) (black squares) in control (A, B) and RYGBP (C, D) subjects. Copyright 2011 American Diabetes Association, Inc.

Blood glucose response to a standardized meal test with saline infusion (open squares) or exendin-(9 39) (black squares) in control (A) and RYGBP (B) subjects. Jiménez A et al. Dia Care 2013;36:2062-2069 Copyright 2011 American Diabetes Association, Inc.

Glucagon, GLP-1, and GIP response to a standardized meal test with saline infusion (open squares) or exendin-(9 39) (black squares) in control (A C) and RYGBP (D F) subjects. Jiménez A et al. Dia Care 2013;36:2062-2069 Copyright 2011 American Diabetes Association, Inc.

Very Low Calorie Diet Mimics the Early Beneficial Effect of Roux-en-Y Gastric Bypass on Insulin Sensitivity and b-cell Function in Type 2 Diabetic Patients Graphic representation of the relationship between insulin sensitivity and insulin secretion before and after interventions. Jackness C et al. Diabetes 2013;62:3027-3032 Copyright 2011 American Diabetes Association, Inc.

Laferrère B et al. JCEM 2008;93:2479-2485 to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. Obese women with T2DM studied before and 1 month after GBP (n 9), or after a diet-induced equivalent weight loss (n10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes. Glucose, insulin, C peptide, glucagon, total and active GLP-1 and GIP levels during the OGTT in patients before (diamond) and after (square) GBP, and before (triangle) and after (circle) diet. Laferrère B et al. JCEM 2008;93:2479-2485 2008 by Endocrine Society

Time course of plasma glucose concentrations (top panel) and insulin secretion rates (bottom panel) in nondiabetic control subjects and diabetic patients before and 2 and 12 months after biliopancreatic diversion. Astiarraga B et al. JCEM 2013;98:2765-2773 2013 by Endocrine Society

Time course of plasma glucagon, GLP-1, and FFA concentrations during the mixed meal in nondiabetic control subjects and diabetic patients before and 2 and 12 months after biliopancreatic diversion. Astiarraga B et al. JCEM 2013;98:2765-2773 2013 by Endocrine Society

Insulin secretion rates as a function of concomitant plasma glucose concentrations during the mixed meal in nondiabetic control subjects and diabetic patients before and 2 and 12 months after biliopancreatic diversion. Astiarraga B et al. JCEM 2013;98:2765-2773 2013 by Endocrine Society

Insulin sensitivity (M value from the euglycemic clamp) in nondiabetic control subjects and diabetic patients before and 2 and 12 months after biliopancreatic diversion. Astiarraga B et al. JCEM 2013;98:2765-2773 2013 by Endocrine Society

Beneficial effects of bariatric surgery in Beneficial effects of bariatric surgery in T2DM antidiabetic treatments

Schauer PR Annals of Surgery 2003 RYGB in DM

Metabolic effects of bariatric surgery in T2DM and diabetes remission

Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes (S. R. KASHYAP et al. Diab Care 2013) To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on b-cell function and body composition a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 %) and moderate obesity (BMI 36. 6 kg/m2) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy Assessment of b-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months

(S. R. KASHYAP et al. Diab Care 2013) cont (2) Post op mean HbA1c of 6.76±1.2% for gastric bypass, 7.16±0.8% for sleeve gastrectomy, and 8.46±2.3% for IMT Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P 5 0.004) and did not change in sleeve gastrectomy or IMT b-cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P 5 0.001), and was not different between sleeve gastrectomy versus IMT

Glucose (A) and C-peptide (B) during the mixed-meal tolerance test performed at time of randomization (baseline) and at 24 months after randomization for IMT, sleeve gastrectomy, and gastric bypass. Copyright 2011 American Diabetes Association, Inc. Kashyap S R et al. Diab Care 2013;36:2175-2182

Bariatric surgery in diabetes and cost effectiveness

Cost-Effectiveness of Bariatric Surgery for Severely Obese Adults With Diabetes Hoerger TJ et al. (Diab Care 2010)

Bariatric surgery: IDF guidelines