Source: TARGETING ABDOMINAL OBESITY IN DIABETOLOGY WHAT CAN WE DO ABOUT IT? Luc Van Gaal, MD, PhD Department of Endocrinology, Diabetology & Metabolism Antwerp University Hospital Antwerp, Belgium

Source: TARGETING ABDOMINAL OBESITY IN DIABETOLOGY WHAT CAN WE DO ABOUT IT? Luc Van Gaal, MD, PhD Department of Endocrinology, Diabetology & Metabolism Antwerp University Hospital Antwerp, Belgium

Source: Key Challenges of Type 2 Diabetes Diabetes is a progressive disease characterized by:  Declining β-cell function  Insulin resistance  Deterioration of glycemic control  Obesity, mainly abdominal fat accumulation  Increased prevalence of cardiovascular disease  Hypoglycemia risk  Complex treatment regimens

Source: Weight Increase With Conventional Approach Adapted from Lancet 1998;352: and Kahn SE et al. N Engl J Med 2006;355: Glibenclamide (n=277) Years from randomization Insulin (n=409) Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if fasting plasma glucose >15 mmol/l. Weight (kg) Change in weight (kg) Years Rosiglitazone Metformin Glibenclamide UKPDS: up to 8 kg in 12 yearsADOPT: up to 4.8 kg in 5 years UKPDS: United Kingdom Prospective Diabetes Study ADOPT: A Diabetes Outcome Progression Trial

Source: Nurses’ Health Study: Risk for Type 2 Diabetes Adapted from Carey VJ et al. Am J Epidemiol 1997;145:614-9 * Controlled for age, family history of diabetes, exercise, smoking, saturated fat intake, calcium, potassium, magnesium and glycemic index. Relative risk* of type 2 diabetes Waist circumference (inches)

Source: Not all Fat Is the Same… Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142-8 Intra-abdominal (visceral) adiposity Subcutaneous fat Maria's metabolic cardiovascular profile:  Cholesterol 188 mg/dl (4.87 mmol/l)  LDL cholesterol 106 mg/dl (2.75 mmol/l)  HDL cholesterol 56 mg/dl (1.45 mmol/l)  Glucose 84 mg/dl (4.7 mmol/l)  Blood pressure 125/78 mm Hg Maria Age: 58 years Weight: 92 kg BMI: 35.4 kg/m 2

Source: Not all Fat Is the Same… Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142-8 Intra-abdominal (visceral) adiposity Subcutaneous fat Claudine's metabolic cardiovascular profile:  Cholesterol 241 mg/dl (6.24 mmol/l)  LDL cholesterol 185 mg/dl (4.79 mmol/l)  HDL cholesterol 38 mg/dl (0.98 mmol/l)  Glucose 132 mg/dl (7.3 mmol/l)  Blood pressure 140/85 mm Hg Claudine Age: 58 years Weight: 92 kg BMI: 35.4 kg/m 2

Source: Intra-Abdominal (Visceral) Adiposity Promotes Insulin Resistance and β-Cell Dysfunction Adapted from Lam TK et al. Am J Physiol Endocrinol Metab 2003;284:E281-90: Carr MC et al. J Clin Endocrinol Metab 2004;89:2601-7: Eckel RH et al. Lancet 2005;365: CETP: cholesteryl ester transfer protein FFA: free fatty acids TG: triglycerides Intra-abdominal adiposity Portal circulation Hepatic glucose output Hepatic insulin resistance Systemic circulation TG-rich VLDL cholesterol Small, dense LDL Lipolysis Low HDL cholesterol CETP, Lipolysis Glucose utilization Insulin resistance Long-term damage to  -cells by FFA Insulin secretion Splanchnic & systemic circulation FFA        

Source: Intra-Abdominal (Visceral) Fat or Just Ectopic Tissue Fat? Reproduced with permission from Van Gaal LF et al. Nature 2006;444:875-80

Source: Intra-Abdominal (Visceral) Fat Excess – What Can We Do?  Assessment of problem and risk  Reduction of total and visceral fat by:  Lifestyle intervention  Pharmacotherapy  Bariatric surgery  Prevention  Other approaches

Source: Vascular Disease and Hypertension According to Fat Distribution in Type 2 Diabetes Adapted from Van Gaal LF et al. Diabetes Care 1988;11: Subjects with disease (%) Nonobese WHR<1 Nonobese WHR>1 Obese WHR>1 CHID: coronary heart ischemic disease WHR: waist-to-hip ratio Vascular disease CIHD Hypertension

Source: Intra-Abdominal (Visceral) Fat in Obese Diabetic Patients From Van Gaal LF et al. unpublished data Women *p≤0.01

Source: Abdominal Obesity – What to do About it? Adapted from Van Gaal LF et al. Nature 2006;444: Visceral obesity Insulin resistance  Glucose intolerance  Dyslipidemia  Hypertension  Microalbuminuria  Low-grade inflammation  Disturbed adipokine secretion  Disturbances in hemostasis and fibrinolysis (PAI-1) Cardiovascular disease Type 2 diabetes Cardiovascular disease Type 2 diabetes Additional risk factors Metabolic syndrome

Source: Intra-Abdominal (Visceral) Fat and the Risk of Mortality Reproduced with permission from Kuk JL et al. Obesity (Silver Spring) 2006;14:336-41

Source: Intra-Abdominal (Visceral) Fat Excess – What Can We Do?  Assessment of problem and risk  Reduction of total and visceral fat by:  Lifestyle intervention  Pharmacotherapy  Bariatric surgery  Prevention  Other approaches

Source: Effect of Aerobic Exercise on Total and Intra-Abdominal (Visceral) Fat Adapted from Després JP et al. Am J Physiol 1991;261:E Changes in visceral fat area (cm 2 ) Changes in fat mass (kg) r=0.70 p<0.01

Source: Health Effects: Reduction in Subcutaneous and Intra-Abdominal (Visceral) Fat During a 3-Month Treatment Period Adapted from Ross R et al. Ann Intern Med 2000;133: Adipose tissue (kg) Exercise without weight loss Exercise-induced weight loss Diet-induced weight loss Control Subcutaneous adipose tissue Visceral adipose tissue

Source: Adapted from Christiansen T et al. Eur J Endocrinol 2009;160: EXODIODEX Changes in Intra-Abdominal (Visceral) Fat and Fat Mass After a Diet-Induced Weight Loss With or Without Aerobic Exercise in Obese Subjects: a 12-Week Randomized Intervention Study DIO: VLED-hypocaloric diet DEX: VLED-hypocaloric diet and exercise EXO: exercise only VLED: very low energy diet * * * * p<0.01 – the relative reduction in visceral adipose tissue as compared with the relative reduction in fat mass. Δ visceral adipose tissue/Δ fat mass

Source: Predictors of Intra-Abdominal (Visceral) Fat Loss With Lifestyle Adapted from Christiansen T et al. Eur J Endocrinol 2009;160: Δvisceral adipose tissue/Δ fat mass Baseline visceral adipose tissue/fat mass DIO: VLED-hypocaloric diet DEX: VLED-hypocaloric diet and exercise EXO: exercise only VLED: very low energy diet R 2 =0.72 p<0.01 EXO DIO DEX

Source: Correlations Between Changes in Anthropometric Measurements and Changes in Metabolic Variables Related to the Metabolic Syndrome Adapted from Park HS and Lee K Diabet Med 2005;22: HOMA: homeostasis model of assessment DBP: diastolic blood pressure FPG: fasting plasma glucose SAT: subcutaneous adipose tissue SBP: systolic blood pressure TG: triglycerides VAT: visceral adipose tissue * p<0.05 by Pearson’s correlation coefficient

Source: Twice-Weekly Progressive Resistance Training Decreases Abdominal Fat and Improves Insulin Sensitivity in Older Men With Type 2 Diabetes Adapted from Iba ñ ez J et al. Diabetes Care 2005;28:662-7 Total abominal fat (cm 3 ) Pretraining weekPretraining16-week * ** Insulin sensitivity index (10 -4 xmin -1 xμUxml -1 ) * p<0.001vs. the pretraining value ** p<0.01 vs. the pretraining value

Source: Ectopic Fat Change vs. Metabolic Indices Adapted from Durheim MT et al. Am J Physiol Endocrinol Metab;295:E HDL particle size change (nm) Intermuscular adipose tissue changes (cm 2 ) r= p= LDL particle size change (nm) Intermuscular adipose tissue changes (cm 2 ) r= p=

Source: Intra-Abdominal (Visceral) Fat Excess – What Can We Do?  Assessment of problem and risk  Reduction of total and visceral fat by:  Lifestyle intervention  Pharmacotherapy  Bariatric surgery  Prevention  Other approaches

Source: Recent Experience on Weight and Abdominal Fat With Anti-Obesity Drugs  Central active drugs  Sibutramine  Topiramate/phentermin combo  Pre-absorptive nutrient partitioning  Orlistat  Blockade of endocannabinoid system  Rimonabant

Source: SCOUT: Trial Population Adapted from James WPT Eur Heart J; 2005;7:L44-8 Type 2 diabetes with cardiovascular risk:  Controlled hypertension (≤160/≤90 mmHg)  Dyslipidemia  Current smoker  Diabetic nephropathy Previous cardiovascular event:  Myocardial infarction  Coronary artery bypass graft  Percutaneous transluminal coronary angioplasty  Coronary artery disease

Source: GI lipase + Xenical TG Intestinal lumenMucosal cellLymphatics Micelle Bile acids MG FA MG 30% Lipase Inhibition: Mechanism of Action FFA GI: gastrointestinal FA: fatty acids FFA: free fatty acids MG: monoglyceride TG: triglycerides

Source: Time (minutes) Intervention + placebo baseline Δ1.20 Improvement in Glucose Utilization With Orlistat Compared With Placebo at 6 Months Adapted from Kelley DE et al. Diabetes Care 2004;27:33-40 Δ 2.15* Glucose utilization (mg·min -1 ·kg -1 fat free mass) Intervention + placebo 6 months Intervention + orlistat baseline Intervention + orlistat 6 months * p<0.05 vs. intervention + placebo

Source: Effect of Lipase Inhibition on Fat Distribution Adapted from Tiikkainen et al. Am J Clin Nutr 2004;79:22-30 Intra-abdominal (visceral) fat (cm 3 ) OrlistatPlacebo Subcutaneous fat (cm 3 ) OrlistatPlacebo Intra-abdominal (visceral) fat/total fat (%) OrlistatPlacebo * * † * p< ** p<0.001 † p<0.01 ‡ p<0.05 ‡ ** BeforeAfter BeforeAfter BeforeAfter BeforeAfter BeforeAfter BeforeAfter

Source: Recent Experience on Weight and Abdominal Fat With Anti- Obesity Drugs  Central active drugs  Sibutramine  Pre-absorptive nutrient partitioning  Orlistat  Blockade of endocannabinoid system  Rimonabant

Source: Changes in Intra-Abdominal (Visceral) and Ectopic Fat in ADAGIO-Lipids Adapted from Després JP et al. Arterioscler Thromb Vasc Biol 2009;29: Change from baseline in visceral adipose tissue (%) Placebo n=87 Rimonabant 20 mg n=92 p= Chhange from baseline in subcutaneous adipose tissue (%) Placebo n=72 Rimonabant 20 mg n=68 p= Change from baseline in fatty liver index* Placebo n=59 Rimonabant 20 mg n=51 p= * Fatty liver index: liver/spleen attenuation ratio

Source: Endocannabinoids vs. Changes in Intra-Abdominal (Visceral) Adipose Tissue Adapted from Di Marzo V. et al. Diabetologia 2009;51: Baseline After 1 year intervention Anandamide concentrations (pmol/ml) Baseline After 1 year intervention 2-AG concentrations (pmol/ml) * * (1)(2)(3) Tertiles of changes in visceral adipose tissue Tertiles of changes in 2-AG Visceral adipose tissue variation (cm 2 ) Triglyceride variation (mmol/l) † *Different from tertile 1, p<0.05 † Different from tertile 1 and 2, p<0.05 (1)(2)(3) AG: arachidonoylglycerol

Source: Future – What Is Lacking?  Long-term trial with anti-obesity drugs in patients with early onset diabetes.  Maintenance studies in patients with metabolic syndrome and type 2 diabetes.  Safe combination studies.  Outcome trials with hard cardiovascular endpoints.

Source: Future Drug Options: A Search to Break the 10% Weight Loss Target  Second generation peripheral CB1 antagonists  11 β-hydroxysteroid dehydrogenase inhibitor  Growth hormone in lipodystrophy?  GLP-1 analogues/mimetics  Leptin – Pramlintide combination

Source: Effect of Inhibition of 11  -Hydroxysteroid Dehydrogenase Type 1 Adapted from Berthiaume M et al. Endocrinology 2007;148: mRNA (cprx10 -3 ) SCD1 * mRNA (cprx10 -3 ) FAS * mRNA (cprx10 -3 ) DGAT1 * mRNA (cprx10 -3 ) ATGL * mRNA (cprx10 -3 ) PEPCK * Activity (nkat/g) CPT1 * Control Compound A * p<0.05 vs. control ATGL: adipose triglyceride lipase CPT1: carnitine palmitoyltransferase 1 DGAT1: diacylglycerol acyltransferase 1 FAS: fatty acid synthase mRNA: messenger of ribonucleic acid PEPCK: phosphoenolpyruvate carboxykinase SCD1: stearoyl-CoA desaturase Mesenteric adipose depot

Source: Effect of Growth Hormone on Intra-Abdominal (Visceral) Fat Adapted from Beauregard C et al. J Clin Endocrinol Metab 2008;93: Change in body fat (%) Placebo Growth hormone * Change in visceral adipose tissue (%) Placebo Growth hormone * Change in waist-to-hip ratio (%) Placebo Growth hormone * Change in resting energy expenditure (%) Placebo Growth hormone * * p<0.05

Source: Human Glucagon-Like Peptide-1 (GLP-1) Effects: the Glucoregulatory Role of Incretins Adapted from Nauck MA et al. Diabetologia 1996;39: and Drucker DJ Diabetes1998;47: Promotes satiety and reduces appetite  -cells: Enhances glucose- dependent insulin secretion Liver: ↓ Glucagon reduces hepatic glucose output ɑ -cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying GLP-1 secreted upon the ingestion of food ↑  -cell response ↓  -cell workload

Source: Liraglutide Lowers Weight in Subjects With Type 2 Diabetes Adapted from Vilsbøll et al. Diabet Med 2008;25:152-6 Weight change from baseline (kg) Placebo Liraglutide 0.65 mg/day Liraglutide 1.25 mg/day Liraglutide 1.9 mg/day Data are mean ±SEM

Source: Liraglutide Reduces Intra-Abdominal (Visceral) Body Fat: Results From the LEAD-2 Substudy Adapted from Jendle J et al. Diabetes Obes Metab 2009;11: Change in body fat DEXA scan Change in body fat (kg, (%)) Glimepiride + metformin Liraglutide 1.2 mg + metformin Liraglutide 1.8 mg + metformin Visceral vs. subcutaneous fat CT scan VisceralSubcutaneous Change in percentage fat (%) * (-1.1%*) -2.4* (-1.2%*) +1.1 kg (+0.4%) * -8.5* +3.4 Two thirds of weight lost was fat tissue (liraglutide 1.8 mg). * p<0.05 vs. glimepiride + metformin.

Source: Intra-Abdominal (Visceral) Fat Excess – What Can We Do?  Assessment of problem and risk  Reduction of total and visceral fat by:  Lifestyle intervention  Pharmacotherapy  Bariatric surgery  Prevention  Other approaches

Source: Diabetes 2006;55: Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Guidone C, Manco M, Valera-Mora E, laconelli, A Gniuli D, Mari A, Nanni G, Castagneto M, Calvani M, Mingrone G Reproduced with permission from DeMaria EJ N Engl J Med 2007;356:

Source: Reproduced with permission from Klein S et al. N Engl J Med 2004;350: Intra-Abdominal Obesity or Fat Mass? Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease Photographs and abdominal magnetic resonance images obtained before and after liposuction. The photographs of one study subject and images of another show the large amount of subcutaneous abdominal fat removed by liposuction. Before liposuction After liposuction

Source: Reduction of Subcutaneous Fat Mass Does not Improve Inflammatory Status Adapted from Klein S et al. N Engl J Med 2004;350: * Plus–minus values are means ±SD. The measurements were made within 9 days before liposuction and again 10 to 12 weeks after liposuction. † Values were obtained from six subjects in each group. Effects of liposuction on mediators of inflammation in obese women with normal glucose tolerance or type 2 diabetes*

Source: Effect of Additional Omentectomy on Metabolic Features Adapted from Thörne A et al. Int J Obes Relat Metab Disord 2002;26:193-9 Body mass index (kg/m 2 ) Time (months) Control p=0.18 Glucose (mmol/l) Time (months) p=0.03 Insulin (mU/l) Time (months) p=0.04 Omentectomy

Source: Surgical Removal of Omental Fat Does Not Improve Insulin Sensitivity and Cardiovascular Risk Factors in Obese Adults Fabbrini E, Tamboli RA, Magkos F, Marks-Shulman PA, Eckhauser AW, Richards WO, Klein S, Abumrad NN Potential Additional Effect of Omentectomy on Metabolic Syndrome, Acute- Phase Reactants, and Inflammatory Mediators in Grade III Obese Patients Undergoing Laparoscopic Roux-en-Y Gastric Bypass: A Randomized Trial Herrera MF, Pantoja JP, Velázquez-Fernández D, Cabiedes J, Aguilar-Salinas C, García- García E, Rivas A, Villeda C, Hernández-Ramírez DF, Dávila A, Zaraín A Adapted from Fabbrini E et al. Gastroenterology 2010;139: and Herrera MF et al. Diabetes Care 2010;33:1413-8

Source: Effect of Additional Omentectomy on Metabolic Features (1 of 2) Adapted from Herrera MF et al. Diabetes Care 2010;33: Data after surgery are means ± SD or percent of change from basal (95% CI). Minus signs denote decreases and plus signs increases. All comparisons p=ns. LRYGB: laparoscopic Roux-en-Y gastric bypass

Source: Effect of Additional Omentectomy on Metabolic Features (2 of 2) Adapted from Herrera MF et al. Diabetes Care 2010;33: LRYGB: laparoscopic Roux-en-Y gastric bypass Data after surgery are means ± SD or percent of change from basal (95% CI). Minus signs denote decreases and plus signs increases. All comparisons p=ns.

Source: Effect of Additional Omentectomy on Metabolic Features Adapted from Fabbrini E et al. Gastroenterology 2010;139: Insulin-mediated increase in glucose disposal (% above basal) LRYGB alone LRYGB + omentectomy 1200 * * * * Hepatic insulin sensitivity index (10 3 ·min·l/mg·mU) * * * * Before surgery 6 months after surgery 12 months after surgery LRYGB: laparoscopic Roux-en-Y gastric bypass Before surgery 6 months after surgery 12 months after surgery * p< vs. value before surgery

Source: Type of Surgery vs. Effect on Intra-Abdominal (Visceral) Adipose Tissue Adapted from Korner J et al. Int J Body Compos Res 2008;6:93-9 Visceral adipose tissue (kg) Total adipose tissue (kg) r=0.36 p=0.43 BandBypass Visceral adipose tissue (kg) 3 2 Total adipose tissue (kg) 1 0 Visceral adipose tissue (kg) Weight loss (%) r=-0.28 p= r=0.81 p=0.005 Visceral adipose tissue (kg) Weight loss (%) 1 0 r=-0.73 p=0.016

Source: Percentage of Patients With Resolution or Improvement of Major Comorbidities* Adapted from Kral JG and Näslund E Nat Clin Pract Endocrinol Metab 2007;3: * The table shows the mean percentage of patients (with number of studies; and 95% CI). Data were compiled by Buchwald et al. JAMA 2004;292: from separate studies.

Source: Intra-Abdominal (Visceral) Fat Excess – What Can We Do?  Assessment of problem and risk  Reduction of total and visceral fat by:  Lifestyle intervention  Pharmacotherapy  Bariatric surgery  Prevention  Other approaches

Source: Intra-Abdominal (Visceral) Fat Excess – Preventive Measures  Special lifestyle approaches (smoking).  Avoidance trans fats & fructose beverages.  Avoidance selective, atypical neuroleptics.  Selection safe medication.

Source: Body Fat Responses to Consumption of Glucose- and Fructose-Sweetened Beverages Adapted from Stanhope KL et al. J Clin Invest 2009;119: (A) Changes of body weight during the 2-week inpatient baseline, 8-week outpatient intervention, and 2-week inpatient intervention periods. **p<0.01; ****p<0.0001, day 56 outpatient:intervention vs. day 1 outpatient:intervention; paired Student’s t test. Glucose, n=15; fructose, n=17. (B) Changes of total abdominal adipose tissue, SAT, and VAT volume in subjects after consuming glucose- or fructose-sweetened beverages for 10 weeks. *p<0.05; **p<0.01, 10 weeks vs. 0 weeks; paired Student’s t test. Glucose, n=14; fructose, n=17. Data represent mean ± SEM. Δ in body weight (kg) Inpatient: baselineOutpatient: interventionInpatient: interventionInpatient: baselineOutpatient: interventionInpatient: intervention Change from baseline (cm 3 ) ** **** * * ** Glucose TotalSATVAT Fructose TotalSATVAT SAT: subcutaneous adipose tissue VAT: visceral adipose tissue Glucose Fructose AB

Source: Intra-Abdominal (Visceral) Fat Excess – Other Approaches  Dehydroepiandrosterone (DHEA) supplements.  Nicotinic acid & receptor pathway.  Continuous positive airway pressure.

Source: Niacin Acts Through Nicotinic Acid Receptors on Multiple Tissues Adapted from Pike NB. J Clin Invest 2005;115: Adipocytes Immune cells (spleen, lymphoid cells, lung) Epidermal Langerhans cells Niacin Antilipolytic effects Probable anti-inflammatory effect PLA 2 Arachidonic acid PGD 2 GPR109A Flushing Niacin GPR109A: G protein-coupled receptor 109A PLA 2 : phospholipase A 2 PGD 2 : prostaglandin D 2

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