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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
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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
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Weight Increase With Conventional Approach
Adapted from Lancet 1998;352:854-65
and Kahn SE et al. N Engl J Med 2006;355:2427-43
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)
Changeinweight(kg)
0
1
5
0 3 6 9 12
8
7
6
4
3
2
Years
0 1 2 3 4 5
96
92
88
0
100
Rosiglitazone
Metformin
Glibenclamide
UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years
UKPDS: United Kingdom Prospective Diabetes Study
ADOPT: A Diabetes Outcome Progression Trial
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Nurses’ Health Study: Risk for Type 2 Diabetes
0
1
2
3
4
5
6
7
<28 28-29 30-31 32-33 34-35 36-37 ≥38
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.
Relativerisk*
oftype2diabetes
Waist circumference (inches)
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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/m2
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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/m2
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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;365:1415-28.
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 b-cells by FFA
Insulin secretionSplanchnic
& systemic circulation
FFA







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Intra-Abdominal (Visceral) Fat or Just Ectopic Tissue Fat?
Reproduced with permission from Van Gaal LF et al. Nature 2006;444:875-80
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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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Vascular Disease and Hypertension According to Fat Distribution
in Type 2 Diabetes
Adapted from Van Gaal LF et al. Diabetes Care 1988;11:103-6.
0
10
20
30
40
50
60
10
42
37
30
50
47
5
42
47
Subjectswithdisease(%)
Nonobese
WHR<1
Nonobese
WHR>1
Obese
WHR>1
CHID: coronary heart ischemic disease
WHR: waist-to-hip ratio
Vascular disease
CIHD
Hypertension
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Intra-Abdominal (Visceral) Fat in Obese Diabetic Patients
From Van Gaal LF et al. unpublished data
Women
*p≤0.01
Women
Diabetic
(n=50)
Nondiabetic
(n=50)
Age (years) 57.8 56.8
Weight (kg) 83.2 82.0
Body mass index (kg/m2) 31.6 31.7
Fat mass (kg) 37.2 37.6
Total abdominal fat (cm2) 598 609
Visceral fat (cm2) 197 159*
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Abdominal Obesity – What to do About it?
Adapted from Van Gaal LF et al. Nature 2006;444:875-80
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
Additional risk factors
Metabolic syndrome
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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: www.myhealthywaist.orgSource: www.myhealthywaist.org
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Aerobic Exercise on Total and Intra-Abdominal
(Visceral) Fat
Adapted from Després JP et al. Am J Physiol 1991;261:E159-67
Changesinvisceralfatarea(cm2)
60
40
20
0
-40
-20
-15 -10 -5 0 5 10
Changes in fat mass (kg)
r=0.70
p<0.01
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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;133:92-103
0 1 2 3 4 5
Adipose tissue (kg)
Exercise without
weight loss
Exercise-induced
weight loss
Diet-induced
weight loss
Control
Subcutaneous adipose tissue
Visceral adipose tissue
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Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67
EXO DIO DEX
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
-40
-35
-30
-25
-20
-15
-10
-5
0
*
*
*
* p<0.01 – the relative reduction in visceral adipose tissue as
compared with the relative reduction in fat mass.
Δvisceraladiposetissue/Δfatmass
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Predictors of Intra-Abdominal (Visceral) Fat Loss With Lifestyle
Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67
Δvisceraladiposetissue/Δfatmass 0.7
0.2
0.3
0.0
Baseline visceral adipose tissue/fat mass
0.0
0.1
0.1 0.2 0.3 0.4 0.5
DIO: VLED-hypocaloric diet
DEX: VLED-hypocaloric diet and exercise
EXO: exercise only
VLED: very low energy diet
0.6
0.5
0.4
R2=0.72
p<0.01
EXO
DIO
DEX
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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;22:266-72
Δ Weight Δ BMI
Δ Fat
mass
Δ Waist Δ SAT Δ VAT
Δ BMI 0.98*
Δ Fat mass 0.78* 0.75*
Δ Waist 0.52* 0.50* 0.54*
Δ SAT 0.66* 0.66* 0.66* 0.31*
Δ VAT 0.30* 0.30* 0.19 0.30* 0.17
Δ SBP 0.17 0.18 0.16 0.06 0.06 0.09
Δ DBP 0.13 0.10 0.11 -0.09 0.09 0.07
Δ log FPG 0.07 0.10 -0.06 0.01 -0.03 0.25*
Δ log TG 0.05 0.12 -0.02 0.14 -0.02 0.37*
Δ HDL cholesterol 0.22 0.22 0.06 -0.03 0.01 -0.05
Δ Insulin 0.18 0.14 0.19 0.35* 0.04 0.15
Δ HOMA 0.14 0.11 0.16 0.37* -0.02 0.34*
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
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Twice-Weekly Progressive Resistance Training Decreases Abdominal Fat
and Improves Insulin Sensitivity in Older Men With Type 2 Diabetes
Adapted from Ibañez J et al. Diabetes Care 2005;28:662-7
Totalabominalfat(cm3)
400
600
0
300
Pretraining
1200
1000
800
1100
900
700
500
16-week Pretraining 16-week
1.5
2.5
0.0
1.0
5.5
4.5
3.5
5.0
4.0
3.0
2.0
0.5
*
**
Insulinsensitivityindex
(10-4xmin-1xμUxml-1)
* p<0.001vs. the pretraining value
** p<0.01 vs. the pretraining value
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Ectopic Fat Change vs. Metabolic Indices
Adapted from Durheim MT et al. Am J Physiol Endocrinol Metab;295:E407-12
HDLparticlesizechange(nm)
0.6
0.4
0.2
0.0
-5 -4 -3 -2 -1 0
Intermuscular adipose tissue
changes (cm2)
-6
-0.2
-0.4
r=-0.423
p=0.0065
1 2
LDLparticlesizechange(nm)
1.25
0.75
0.25
-0.25
Intermuscular adipose tissue
changes (cm2)
-0.75
-1.25
-6
r=-0.521
p=0.0006
-5 -4 -3 -2 -1 0 1 2
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
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
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SCOUT: Trial Population
Adapted from James WPT Eur Heart J; 2005;7:L44-8
Age:
 55 years old and older
BMI:
 ≥27 kg/m2 and <45 kg/m2
or
 ≥25 kg/m2 and <27 kg/m2 with a waist circumference of
≥102 cm (men) or ≥88 cm (women)
Three groups of patients:
 Type 2 diabetes with cardiovascular risk
 Previous cardiovascular event
 Type 2 diabetes with cardiovascular risk and previous
cardiovascular event
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
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GI lipase +
Xenical
TG
Intestinal lumen Mucosal cell Lymphatics
MicelleBile acids
MG
FA
MG
30%
Lipase Inhibition: Mechanism of Action
FFA
GI: gastrointestinal
FA: fatty acids
FFA: free fatty acids
MG: monoglyceride
TG: triglycerides
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8
7
6
5
4
3
2
1
0
Time (minutes)
-60 -30 0 30 60 90 120 150 180 210 240
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*
Glucoseutilization
(mg·min-1·kg-1fatfreemass)
Intervention + placebo 6 months
Intervention + orlistat baseline
Intervention + orlistat 6 months
* p<0.05 vs. intervention + placebo
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Effect of Lipase Inhibition on Fat Distribution
Adapted from Tiikkainen et al. Am J Clin Nutr 2004;79:22-30
0
500
1000
1500
2000
Intra-abdominal
(visceral)fat(cm3)
Orlistat Placebo
0
2000
4000
6000
8000
Subcutaneousfat(cm3)
Orlistat Placebo
0
10
20
30
Intra-abdominal
(visceral)fat/totalfat(%)
Orlistat Placebo
*
*
†
* p<0.0001
** p<0.001
† p<0.01
‡ p<0.05
‡
** **
Before After Before After Before After Before After
Before After Before After
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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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Changes in Intra-Abdominal (Visceral) and Ectopic Fat in
ADAGIO-Lipids
Adapted from Després JP et al. Arterioscler Thromb Vasc Biol 2009;29:416-23
-5.9
-16
-30
-20
-10
0
Changefrombaselinein
visceraladiposetissue(%)
Placebo
n=87
Rimonabant 20 mg
n=92
p=0.0003
-4.7
-9.7
-20
-15
-10
-5
0
Chhangefrombaselinein
subcutaneousadiposetissue(%)
Placebo
n=72
Rimonabant 20 mg
n=68
p=0.0043
0.05
0.16
0.00
0.10
0.20
0.30
Changefrombaseline
infattyliverindex*
Placebo
n=59
Rimonabant 20 mg
n=51
p=0.0017 * Fatty liver index:
liver/spleen attenuation ratio
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Endocannabinoids vs. Changes in Intra-Abdominal (Visceral)
Adipose Tissue
Adapted from Di Marzo V. et al. Diabetologia 2009;51:1356-67
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Baseline After 1 year
intervention
Anandamide
concentrations(pmol/ml)
0.0
0.5
1.0
1.5
2.0
Baseline After 1 year
intervention
2-AGconcentrations
(pmol/ml)
-140
-120
-100
-80
-60
-40
-20
0
-2.0
-1.5
-1.0
-0.5
0.0
*
*
(1) (2) (3)
Tertiles of changes in visceral
adipose tissue
Tertiles of changes in 2-AG
Visceraladipose
tissuevariation(cm2)
Triglyceridevariation
(mmol/l)
†
*Different from tertile 1, p<0.05
†Different from tertile 1 and 2, p<0.05
(1) (2) (3)
AG: arachidonoylglycerol
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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: www.myhealthywaist.orgSource: www.myhealthywaist.org
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Inhibition of 11 b-Hydroxysteroid Dehydrogenase Type 1
Adapted from Berthiaume M et al. Endocrinology 2007;148:2391-7
0
1
2
3
4
mRNA(cprx10-3)
SCD1
*
0.0
1.0
2.0
3.0
mRNA(cprx10-3)
FAS
* 0
10
20
30
40
mRNA(cprx10-3)
DGAT1
*
0
200
400
600
800
mRNA(cprx10-3)
ATGL
*
0
20
40
60
80
mRNA(cprx10-3)
PEPCK
*
0.0
0.5
1.0
1.5
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
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Effect of Growth Hormone on Intra-Abdominal (Visceral) Fat
Adapted from Beauregard C et al. J Clin Endocrinol Metab 2008;93:2063-71
Changeinbodyfat(%)
Placebo
Growth
hormone
-10
-5
0
5
*
Changeinvisceral
adiposetissue(%)
Placebo
Growth
hormone
-20
-15
-10
-5
0
5
10
*
Changeinwaist-to-hipratio
(%)
Placebo
Growth
hormone
-4
-2
0
2
4
*
Changeinrestingenergy
expenditure(%)
Placebo
Growth
hormone
-5
0
5
10
15
20
*
* p<0.05
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Human Glucagon-Like Peptide-1 (GLP-1) Effects:
the Glucoregulatory Role of Incretins
Adapted from Nauck MA et al. Diabetologia 1996;39:1546-53
and Drucker DJ Diabetes1998;47:159-69
Promotes satiety and
reduces appetite
b-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
↑ b-cell
response
↓ b-cell
workload
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Liraglutide Lowers Weight in Subjects With Type 2 Diabetes
Adapted from Vilsbøll et al. Diabet Med 2008;25:152-6
-7
-6
-5
-4
-3
-2
-1
0
Weightchangefrombaseline(kg)
Placebo
Liraglutide
0.65 mg/day
Liraglutide
1.25 mg/day
Liraglutide
1.9 mg/day
Data are mean ±SEM
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Liraglutide Reduces Intra-Abdominal (Visceral) Body Fat:
Results From the LEAD-2 Substudy
Adapted from Jendle J et al. Diabetes Obes Metab 2009;11:1163-72
Change in body fat
DEXA scan
Changeinbodyfat(kg,(%))
Glimepiride + metformin
Liraglutide 1.2 mg + metformin
Liraglutide 1.8 mg + metformin
Visceral vs. subcutaneous fat
CT scan
Visceral Subcutaneous
Changeinpercentagefat(%)-4
-3
-2
-1
0
1
2
3
-1.6*
(-1.1%*) -2.4*
(-1.2%*)
+1.1 kg
(+0.4%)
-25
-20
-15
5
0
5
10
-10
-17.1
-16.4
-4.8 -7.8* -8.5*
+3.4
Two thirds of weight lost was fat tissue (liraglutide 1.8 mg).
* p<0.05 vs. glimepiride + metformin.
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Diabetes 2006;55:2025-31
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;356:2176-83
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Reproduced with permission from Klein S et al. N Engl J Med 2004;350:2549-57
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Reduction of Subcutaneous Fat Mass Does not Improve
Inflammatory Status
Adapted from Klein S et al. N Engl J Med 2004;350:2549-57
Normal glucose tolerance (n=8) Type 2 diabetes (n=7)
Variable Before
liposuction
After
liposuction
Change
(95% CI)
p
value
Before
liposuction
After
liposuction
Change
(95% CI)
p
value
Leptin (ng/ml) 31.7 12.0 23.5 5.4
-8.2
(-15.9 to -0.4)
0.05 35.7 13.5 30.2 12.6
-5.5
(-1.1 to -9.8)
0.05
Adiponectin
(ng/ml)
5.0 2.2 4.5 2.2
-0.5
(-0.8 to 0.1)
0.13 4.3 2.3 3.6 2.2
-0.7
(-1.5 to +0.1)
0.13
Tumor necrosis
factor-α (pg/ml)
3.5 5.8 2.8 3.3
-0.7
(-2.8 to +1.4)
0.54 7.6 8.3 7.7 7.8
+0.2
(-0.5 to +0.9)
0.60
Interleukin-6
(pg/ml)†
1.5 0.6 2.4 0.9
+0.9
(0 to +1.7)
0.10 3.8 3.8 3.2 2.5
-0.7
(-1.7 to +0.3)
0.24
C-reactive protein
(μg/ml)
6.9 6.7 6.7 6.5
-0.2
(-1.1 to +0.8)
0.74 8.2 7.2 7.7 6.9
-0.5
(-1.3 to +0.4)
0.30
* 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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Additional Omentectomy on Metabolic Features
Adapted from Thörne A et al. Int J Obes Relat Metab Disord 2002;26:193-9
Bodymassindex(kg/m2)
5
0
-5
-10
5 10 15 20 25
Time (months)
0
-15
Control
p=0.18
Glucose(mmol/l)
0.5
-0.5
-1.5
5 10 15 20 25
Time (months)
0
-2.5
0.0
-1.0
-2.0 p=0.03
Insulin(mU/l)
5
-5
5 10 15 20 25
Time (months)
0
-20
0
-10
-15
p=0.04
Omentectomy
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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;139:448-55
and Herrera MF et al. Diabetes Care 2010;33:1413-8
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Additional Omentectomy on Metabolic Features(1 of 2)
Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8
Before surgery 3 months
Omentectomy
+ LRYGB
LRYGB
Omentectomy
+ LRYGB
LRYGB
C-reactive protein (μg/ml) 64.5 ± 75.4 69.2 ± 57.2
-62.2
(-118.2 to -5.6)
-76.2
(-124.9 to -27.5)
Tumor necrosis factor-α
(pg/ml)
5.2 ± 3.3 5.7 ± 2.7
-1.9
(-40.4 to 36.5)
-12.3
(-36.8 to 10.5)
Interleukin-6 (pg/ml) 4.8 ± 9.5 8.9 ± 16.9
+247.9
(-264.6 to 762.5)
+24.7
(-20.2 to 70.8)
Leptin (ng/ml) 55.4 ± 30 103.6 ± 153.1
-18.2
(-57 to 20.6)
-56.9
(-129.8 to 36.1)
Adiponectin (ng/ml) 10.7 ± 5.1 9.5 ± 4.8
+42.1
(8.4 to 76.6)
+66.3
(32.6 to 101.1)
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Additional Omentectomy on Metabolic Features(2 of 2)
Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8
6 months 12 months
Omentectomy
+ LRYGB
LRYGB
Omentectomy
+ LRYGB
LRYGB
C-reactive protein (μg/ml)
-65.6
(-152.1 to -20.8)
-75.9
(-127.7 to -23.8)
-80.0
(-196.7 to 36.7)
-86.27
(-143.4 to -23.8)
Tumor necrosis factor α
(pg/ml)
-51.9
(-98.1 to -5.8)
-17.5
(-40.4 to 3.5)
+11.05
(-80.8 to 107.7)
-14.0
(-75.4 to 43.9)
Interleukin-6 (pg/ml)
+104.2
(-285.4 to 493.8)
-23.6
(-93.3 to 46.1)
+35.4
(-43.8 to 116.7)
-34.8
(-132.6 to 62.9)
Leptin (ng/ml)
-9.7
(-40.1 to 20.6)
-36.5
(-137.0 to 64.0)
+16.8
(-30.9 to 64.4)
-21.8
(-145.8 to 102.0)
Adiponectin (ng/ml)
+74.8
(40.2 to 109.3)
+87.4
(46.3 to 127.4)
+80.4
(30.8 to 129.0)
+69.5
(-3.2 to 144.2)
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Effect of Additional Omentectomy on Metabolic Features
Adapted from Fabbrini E et al. Gastroenterology 2010;139:448-55
Insulin-mediatedincrease
inglucosedisposal
(%abovebasal)
0
300
900
600
LRYGB alone
LRYGB + omentectomy
1200
* * *
*
Hepaticinsulin
sensitivityindex
(103·min·l/mg·mU)
0
1
3
2
*
*
*
*
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<0.00002 vs. value before surgery
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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
Visceraladipose
tissue(kg)
3
2
25 30 35 40 45
Total adipose tissue (kg)
20
1
0
r=0.36
p=0.43
Band Bypass
Visceraladipose
tissue(kg)
3
2
Total adipose tissue (kg)
1
0
Visceraladipose
tissue(kg)
3
2
20 30 40 50
Weight loss (%)
10
1
0
r=-0.28
p=0.53
30 40 50 6020
r=0.81
p=0.005
Visceraladipose
tissue(kg)
3
2
20 30 40 50
Weight loss (%)
1
-1
0
r=-0.73
p=0.016
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Percentage of Patients With Resolution or Improvement of
Major Comorbidities*
Adapted from Kral JG and Näslund E Nat Clin Pract Endocrinol Metab 2007;3:574-83
Operations
Major
comorbidity
Adjustable
gastric banding
Vertical banded
gastroplasty
Gastric
bypass
Biliopancreatic
bypass
Diabetes 48 (9; 29–67) 72 (11; 55–88) 84 (26; 77–90) 99 (9; 87–100)
Dyslipidemia 59 (6; 82–89) 74 (7; 61–86) 97 (6; 94–100) 99 (3; 98–100)
Hypertension 43 (12; 30–56) 69 (20; 57–79) 68 (20; 58–77) 83 (7; 73–94)
Sleep apnea 95 (5; 89–100) 78 (10; 54–100) 80 (13; 68–92) 92 (6; 82–100)
* The table shows the mean percentage of patients (with number of studies; and 95% CI).
Data were compiled by Buchwald et al. JAMA 2004;292:1724-37 from separate studies.
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
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: www.myhealthywaist.orgSource: www.myhealthywaist.org
Intra-Abdominal (Visceral) Fat Excess – Preventive Measures
 Special lifestyle approaches (smoking).
 Avoidance trans fats & fructose
beverages.
 Avoidance selective, atypical
neuroleptics.
 Selection safe medication.
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Body Fat Responses to Consumption of Glucose- and
Fructose-Sweetened Beverages
Adapted from Stanhope KL et al. J Clin Invest 2009;119:1322-34
(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.
Δinbodyweight(kg)
0.8
1.2
2.0
1.6
2.4
-0.4
0.0
0.4
Changefrombaseline
(cm3)
30
40
60
50
70
0
10
20
**
****
*
*
**
Glucose
Total SAT VAT
Fructose
Total SAT VAT
SAT: subcutaneous adipose tissue
VAT: visceral adipose tissue
Glucose
Fructose
A B
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Intra-Abdominal (Visceral) Fat Excess – Other Approaches
 Dehydroepiandrosterone (DHEA)
supplements.
 Nicotinic acid & receptor pathway.
 Continuous positive airway pressure.
Source: www.myhealthywaist.orgSource: www.myhealthywaist.org
Niacin Acts Through Nicotinic Acid Receptors on Multiple
Tissues
Adapted from Pike NB. J Clin Invest 2005;115:3400-3
Adipocytes
Immune cells
(spleen, lymphoid
cells, lung)
Epidermal
Langerhans
cells
Niacin
Antilipolytic
effects
Probable
anti-inflammatory
effect
PLA2
Arachidonic acid
PGD2
GPR109A
Flushing
Niacin Niacin
GPR109A: G protein-coupled receptor 109A
PLA2: phospholipase A2
PGD2: prostaglandin D2
Source: www.myhealthywaist.org

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Targeting abdominal obesity in diabetology: What can we do about it?

  • 1. Source: www.myhealthywaist.org 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
  • 2. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 3. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Weight Increase With Conventional Approach Adapted from Lancet 1998;352:854-65 and Kahn SE et al. N Engl J Med 2006;355:2427-43 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) Changeinweight(kg) 0 1 5 0 3 6 9 12 8 7 6 4 3 2 Years 0 1 2 3 4 5 96 92 88 0 100 Rosiglitazone Metformin Glibenclamide UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years UKPDS: United Kingdom Prospective Diabetes Study ADOPT: A Diabetes Outcome Progression Trial
  • 4. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Nurses’ Health Study: Risk for Type 2 Diabetes 0 1 2 3 4 5 6 7 <28 28-29 30-31 32-33 34-35 36-37 ≥38 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. Relativerisk* oftype2diabetes Waist circumference (inches)
  • 5. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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/m2
  • 6. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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/m2
  • 7. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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;365:1415-28. 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 b-cells by FFA Insulin secretionSplanchnic & systemic circulation FFA       
  • 8. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Intra-Abdominal (Visceral) Fat or Just Ectopic Tissue Fat? Reproduced with permission from Van Gaal LF et al. Nature 2006;444:875-80
  • 9. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 10. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Vascular Disease and Hypertension According to Fat Distribution in Type 2 Diabetes Adapted from Van Gaal LF et al. Diabetes Care 1988;11:103-6. 0 10 20 30 40 50 60 10 42 37 30 50 47 5 42 47 Subjectswithdisease(%) Nonobese WHR<1 Nonobese WHR>1 Obese WHR>1 CHID: coronary heart ischemic disease WHR: waist-to-hip ratio Vascular disease CIHD Hypertension
  • 11. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Intra-Abdominal (Visceral) Fat in Obese Diabetic Patients From Van Gaal LF et al. unpublished data Women *p≤0.01 Women Diabetic (n=50) Nondiabetic (n=50) Age (years) 57.8 56.8 Weight (kg) 83.2 82.0 Body mass index (kg/m2) 31.6 31.7 Fat mass (kg) 37.2 37.6 Total abdominal fat (cm2) 598 609 Visceral fat (cm2) 197 159*
  • 12. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Abdominal Obesity – What to do About it? Adapted from Van Gaal LF et al. Nature 2006;444:875-80 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 Additional risk factors Metabolic syndrome
  • 13. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Intra-Abdominal (Visceral) Fat and the Risk of Mortality Reproduced with permission from Kuk JL et al. Obesity (Silver Spring) 2006;14:336-41
  • 14. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 15. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Aerobic Exercise on Total and Intra-Abdominal (Visceral) Fat Adapted from Després JP et al. Am J Physiol 1991;261:E159-67 Changesinvisceralfatarea(cm2) 60 40 20 0 -40 -20 -15 -10 -5 0 5 10 Changes in fat mass (kg) r=0.70 p<0.01
  • 16. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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;133:92-103 0 1 2 3 4 5 Adipose tissue (kg) Exercise without weight loss Exercise-induced weight loss Diet-induced weight loss Control Subcutaneous adipose tissue Visceral adipose tissue
  • 17. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67 EXO DIO DEX 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 -40 -35 -30 -25 -20 -15 -10 -5 0 * * * * p<0.01 – the relative reduction in visceral adipose tissue as compared with the relative reduction in fat mass. Δvisceraladiposetissue/Δfatmass
  • 18. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Predictors of Intra-Abdominal (Visceral) Fat Loss With Lifestyle Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67 Δvisceraladiposetissue/Δfatmass 0.7 0.2 0.3 0.0 Baseline visceral adipose tissue/fat mass 0.0 0.1 0.1 0.2 0.3 0.4 0.5 DIO: VLED-hypocaloric diet DEX: VLED-hypocaloric diet and exercise EXO: exercise only VLED: very low energy diet 0.6 0.5 0.4 R2=0.72 p<0.01 EXO DIO DEX
  • 19. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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;22:266-72 Δ Weight Δ BMI Δ Fat mass Δ Waist Δ SAT Δ VAT Δ BMI 0.98* Δ Fat mass 0.78* 0.75* Δ Waist 0.52* 0.50* 0.54* Δ SAT 0.66* 0.66* 0.66* 0.31* Δ VAT 0.30* 0.30* 0.19 0.30* 0.17 Δ SBP 0.17 0.18 0.16 0.06 0.06 0.09 Δ DBP 0.13 0.10 0.11 -0.09 0.09 0.07 Δ log FPG 0.07 0.10 -0.06 0.01 -0.03 0.25* Δ log TG 0.05 0.12 -0.02 0.14 -0.02 0.37* Δ HDL cholesterol 0.22 0.22 0.06 -0.03 0.01 -0.05 Δ Insulin 0.18 0.14 0.19 0.35* 0.04 0.15 Δ HOMA 0.14 0.11 0.16 0.37* -0.02 0.34* 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
  • 20. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Twice-Weekly Progressive Resistance Training Decreases Abdominal Fat and Improves Insulin Sensitivity in Older Men With Type 2 Diabetes Adapted from Ibañez J et al. Diabetes Care 2005;28:662-7 Totalabominalfat(cm3) 400 600 0 300 Pretraining 1200 1000 800 1100 900 700 500 16-week Pretraining 16-week 1.5 2.5 0.0 1.0 5.5 4.5 3.5 5.0 4.0 3.0 2.0 0.5 * ** Insulinsensitivityindex (10-4xmin-1xμUxml-1) * p<0.001vs. the pretraining value ** p<0.01 vs. the pretraining value
  • 21. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Ectopic Fat Change vs. Metabolic Indices Adapted from Durheim MT et al. Am J Physiol Endocrinol Metab;295:E407-12 HDLparticlesizechange(nm) 0.6 0.4 0.2 0.0 -5 -4 -3 -2 -1 0 Intermuscular adipose tissue changes (cm2) -6 -0.2 -0.4 r=-0.423 p=0.0065 1 2 LDLparticlesizechange(nm) 1.25 0.75 0.25 -0.25 Intermuscular adipose tissue changes (cm2) -0.75 -1.25 -6 r=-0.521 p=0.0006 -5 -4 -3 -2 -1 0 1 2
  • 22. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 23. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 24. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org SCOUT: Trial Population Adapted from James WPT Eur Heart J; 2005;7:L44-8 Age:  55 years old and older BMI:  ≥27 kg/m2 and <45 kg/m2 or  ≥25 kg/m2 and <27 kg/m2 with a waist circumference of ≥102 cm (men) or ≥88 cm (women) Three groups of patients:  Type 2 diabetes with cardiovascular risk  Previous cardiovascular event  Type 2 diabetes with cardiovascular risk and previous cardiovascular event 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
  • 25. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org GI lipase + Xenical TG Intestinal lumen Mucosal cell Lymphatics MicelleBile acids MG FA MG 30% Lipase Inhibition: Mechanism of Action FFA GI: gastrointestinal FA: fatty acids FFA: free fatty acids MG: monoglyceride TG: triglycerides
  • 26. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 8 7 6 5 4 3 2 1 0 Time (minutes) -60 -30 0 30 60 90 120 150 180 210 240 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* Glucoseutilization (mg·min-1·kg-1fatfreemass) Intervention + placebo 6 months Intervention + orlistat baseline Intervention + orlistat 6 months * p<0.05 vs. intervention + placebo
  • 27. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Lipase Inhibition on Fat Distribution Adapted from Tiikkainen et al. Am J Clin Nutr 2004;79:22-30 0 500 1000 1500 2000 Intra-abdominal (visceral)fat(cm3) Orlistat Placebo 0 2000 4000 6000 8000 Subcutaneousfat(cm3) Orlistat Placebo 0 10 20 30 Intra-abdominal (visceral)fat/totalfat(%) Orlistat Placebo * * † * p<0.0001 ** p<0.001 † p<0.01 ‡ p<0.05 ‡ ** ** Before After Before After Before After Before After Before After Before After
  • 28. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 29. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Changes in Intra-Abdominal (Visceral) and Ectopic Fat in ADAGIO-Lipids Adapted from Després JP et al. Arterioscler Thromb Vasc Biol 2009;29:416-23 -5.9 -16 -30 -20 -10 0 Changefrombaselinein visceraladiposetissue(%) Placebo n=87 Rimonabant 20 mg n=92 p=0.0003 -4.7 -9.7 -20 -15 -10 -5 0 Chhangefrombaselinein subcutaneousadiposetissue(%) Placebo n=72 Rimonabant 20 mg n=68 p=0.0043 0.05 0.16 0.00 0.10 0.20 0.30 Changefrombaseline infattyliverindex* Placebo n=59 Rimonabant 20 mg n=51 p=0.0017 * Fatty liver index: liver/spleen attenuation ratio
  • 30. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Endocannabinoids vs. Changes in Intra-Abdominal (Visceral) Adipose Tissue Adapted from Di Marzo V. et al. Diabetologia 2009;51:1356-67 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Baseline After 1 year intervention Anandamide concentrations(pmol/ml) 0.0 0.5 1.0 1.5 2.0 Baseline After 1 year intervention 2-AGconcentrations (pmol/ml) -140 -120 -100 -80 -60 -40 -20 0 -2.0 -1.5 -1.0 -0.5 0.0 * * (1) (2) (3) Tertiles of changes in visceral adipose tissue Tertiles of changes in 2-AG Visceraladipose tissuevariation(cm2) Triglyceridevariation (mmol/l) † *Different from tertile 1, p<0.05 †Different from tertile 1 and 2, p<0.05 (1) (2) (3) AG: arachidonoylglycerol
  • 31. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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.
  • 32. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 33. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Inhibition of 11 b-Hydroxysteroid Dehydrogenase Type 1 Adapted from Berthiaume M et al. Endocrinology 2007;148:2391-7 0 1 2 3 4 mRNA(cprx10-3) SCD1 * 0.0 1.0 2.0 3.0 mRNA(cprx10-3) FAS * 0 10 20 30 40 mRNA(cprx10-3) DGAT1 * 0 200 400 600 800 mRNA(cprx10-3) ATGL * 0 20 40 60 80 mRNA(cprx10-3) PEPCK * 0.0 0.5 1.0 1.5 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
  • 34. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Growth Hormone on Intra-Abdominal (Visceral) Fat Adapted from Beauregard C et al. J Clin Endocrinol Metab 2008;93:2063-71 Changeinbodyfat(%) Placebo Growth hormone -10 -5 0 5 * Changeinvisceral adiposetissue(%) Placebo Growth hormone -20 -15 -10 -5 0 5 10 * Changeinwaist-to-hipratio (%) Placebo Growth hormone -4 -2 0 2 4 * Changeinrestingenergy expenditure(%) Placebo Growth hormone -5 0 5 10 15 20 * * p<0.05
  • 35. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Human Glucagon-Like Peptide-1 (GLP-1) Effects: the Glucoregulatory Role of Incretins Adapted from Nauck MA et al. Diabetologia 1996;39:1546-53 and Drucker DJ Diabetes1998;47:159-69 Promotes satiety and reduces appetite b-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 ↑ b-cell response ↓ b-cell workload
  • 36. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Liraglutide Lowers Weight in Subjects With Type 2 Diabetes Adapted from Vilsbøll et al. Diabet Med 2008;25:152-6 -7 -6 -5 -4 -3 -2 -1 0 Weightchangefrombaseline(kg) Placebo Liraglutide 0.65 mg/day Liraglutide 1.25 mg/day Liraglutide 1.9 mg/day Data are mean ±SEM
  • 37. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Liraglutide Reduces Intra-Abdominal (Visceral) Body Fat: Results From the LEAD-2 Substudy Adapted from Jendle J et al. Diabetes Obes Metab 2009;11:1163-72 Change in body fat DEXA scan Changeinbodyfat(kg,(%)) Glimepiride + metformin Liraglutide 1.2 mg + metformin Liraglutide 1.8 mg + metformin Visceral vs. subcutaneous fat CT scan Visceral Subcutaneous Changeinpercentagefat(%)-4 -3 -2 -1 0 1 2 3 -1.6* (-1.1%*) -2.4* (-1.2%*) +1.1 kg (+0.4%) -25 -20 -15 5 0 5 10 -10 -17.1 -16.4 -4.8 -7.8* -8.5* +3.4 Two thirds of weight lost was fat tissue (liraglutide 1.8 mg). * p<0.05 vs. glimepiride + metformin.
  • 38. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 39. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Diabetes 2006;55:2025-31 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;356:2176-83
  • 40. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Reproduced with permission from Klein S et al. N Engl J Med 2004;350:2549-57 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
  • 41. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Reduction of Subcutaneous Fat Mass Does not Improve Inflammatory Status Adapted from Klein S et al. N Engl J Med 2004;350:2549-57 Normal glucose tolerance (n=8) Type 2 diabetes (n=7) Variable Before liposuction After liposuction Change (95% CI) p value Before liposuction After liposuction Change (95% CI) p value Leptin (ng/ml) 31.7 12.0 23.5 5.4 -8.2 (-15.9 to -0.4) 0.05 35.7 13.5 30.2 12.6 -5.5 (-1.1 to -9.8) 0.05 Adiponectin (ng/ml) 5.0 2.2 4.5 2.2 -0.5 (-0.8 to 0.1) 0.13 4.3 2.3 3.6 2.2 -0.7 (-1.5 to +0.1) 0.13 Tumor necrosis factor-α (pg/ml) 3.5 5.8 2.8 3.3 -0.7 (-2.8 to +1.4) 0.54 7.6 8.3 7.7 7.8 +0.2 (-0.5 to +0.9) 0.60 Interleukin-6 (pg/ml)† 1.5 0.6 2.4 0.9 +0.9 (0 to +1.7) 0.10 3.8 3.8 3.2 2.5 -0.7 (-1.7 to +0.3) 0.24 C-reactive protein (μg/ml) 6.9 6.7 6.7 6.5 -0.2 (-1.1 to +0.8) 0.74 8.2 7.2 7.7 6.9 -0.5 (-1.3 to +0.4) 0.30 * 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*
  • 42. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Additional Omentectomy on Metabolic Features Adapted from Thörne A et al. Int J Obes Relat Metab Disord 2002;26:193-9 Bodymassindex(kg/m2) 5 0 -5 -10 5 10 15 20 25 Time (months) 0 -15 Control p=0.18 Glucose(mmol/l) 0.5 -0.5 -1.5 5 10 15 20 25 Time (months) 0 -2.5 0.0 -1.0 -2.0 p=0.03 Insulin(mU/l) 5 -5 5 10 15 20 25 Time (months) 0 -20 0 -10 -15 p=0.04 Omentectomy
  • 43. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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;139:448-55 and Herrera MF et al. Diabetes Care 2010;33:1413-8
  • 44. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Additional Omentectomy on Metabolic Features(1 of 2) Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8 Before surgery 3 months Omentectomy + LRYGB LRYGB Omentectomy + LRYGB LRYGB C-reactive protein (μg/ml) 64.5 ± 75.4 69.2 ± 57.2 -62.2 (-118.2 to -5.6) -76.2 (-124.9 to -27.5) Tumor necrosis factor-α (pg/ml) 5.2 ± 3.3 5.7 ± 2.7 -1.9 (-40.4 to 36.5) -12.3 (-36.8 to 10.5) Interleukin-6 (pg/ml) 4.8 ± 9.5 8.9 ± 16.9 +247.9 (-264.6 to 762.5) +24.7 (-20.2 to 70.8) Leptin (ng/ml) 55.4 ± 30 103.6 ± 153.1 -18.2 (-57 to 20.6) -56.9 (-129.8 to 36.1) Adiponectin (ng/ml) 10.7 ± 5.1 9.5 ± 4.8 +42.1 (8.4 to 76.6) +66.3 (32.6 to 101.1) 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
  • 45. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Additional Omentectomy on Metabolic Features(2 of 2) Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8 6 months 12 months Omentectomy + LRYGB LRYGB Omentectomy + LRYGB LRYGB C-reactive protein (μg/ml) -65.6 (-152.1 to -20.8) -75.9 (-127.7 to -23.8) -80.0 (-196.7 to 36.7) -86.27 (-143.4 to -23.8) Tumor necrosis factor α (pg/ml) -51.9 (-98.1 to -5.8) -17.5 (-40.4 to 3.5) +11.05 (-80.8 to 107.7) -14.0 (-75.4 to 43.9) Interleukin-6 (pg/ml) +104.2 (-285.4 to 493.8) -23.6 (-93.3 to 46.1) +35.4 (-43.8 to 116.7) -34.8 (-132.6 to 62.9) Leptin (ng/ml) -9.7 (-40.1 to 20.6) -36.5 (-137.0 to 64.0) +16.8 (-30.9 to 64.4) -21.8 (-145.8 to 102.0) Adiponectin (ng/ml) +74.8 (40.2 to 109.3) +87.4 (46.3 to 127.4) +80.4 (30.8 to 129.0) +69.5 (-3.2 to 144.2) 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.
  • 46. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Effect of Additional Omentectomy on Metabolic Features Adapted from Fabbrini E et al. Gastroenterology 2010;139:448-55 Insulin-mediatedincrease inglucosedisposal (%abovebasal) 0 300 900 600 LRYGB alone LRYGB + omentectomy 1200 * * * * Hepaticinsulin sensitivityindex (103·min·l/mg·mU) 0 1 3 2 * * * * 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<0.00002 vs. value before surgery
  • 47. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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 Visceraladipose tissue(kg) 3 2 25 30 35 40 45 Total adipose tissue (kg) 20 1 0 r=0.36 p=0.43 Band Bypass Visceraladipose tissue(kg) 3 2 Total adipose tissue (kg) 1 0 Visceraladipose tissue(kg) 3 2 20 30 40 50 Weight loss (%) 10 1 0 r=-0.28 p=0.53 30 40 50 6020 r=0.81 p=0.005 Visceraladipose tissue(kg) 3 2 20 30 40 50 Weight loss (%) 1 -1 0 r=-0.73 p=0.016
  • 48. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Percentage of Patients With Resolution or Improvement of Major Comorbidities* Adapted from Kral JG and Näslund E Nat Clin Pract Endocrinol Metab 2007;3:574-83 Operations Major comorbidity Adjustable gastric banding Vertical banded gastroplasty Gastric bypass Biliopancreatic bypass Diabetes 48 (9; 29–67) 72 (11; 55–88) 84 (26; 77–90) 99 (9; 87–100) Dyslipidemia 59 (6; 82–89) 74 (7; 61–86) 97 (6; 94–100) 99 (3; 98–100) Hypertension 43 (12; 30–56) 69 (20; 57–79) 68 (20; 58–77) 83 (7; 73–94) Sleep apnea 95 (5; 89–100) 78 (10; 54–100) 80 (13; 68–92) 92 (6; 82–100) * The table shows the mean percentage of patients (with number of studies; and 95% CI). Data were compiled by Buchwald et al. JAMA 2004;292:1724-37 from separate studies.
  • 49. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 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
  • 50. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Intra-Abdominal (Visceral) Fat Excess – Preventive Measures  Special lifestyle approaches (smoking).  Avoidance trans fats & fructose beverages.  Avoidance selective, atypical neuroleptics.  Selection safe medication.
  • 51. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Body Fat Responses to Consumption of Glucose- and Fructose-Sweetened Beverages Adapted from Stanhope KL et al. J Clin Invest 2009;119:1322-34 (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. Δinbodyweight(kg) 0.8 1.2 2.0 1.6 2.4 -0.4 0.0 0.4 Changefrombaseline (cm3) 30 40 60 50 70 0 10 20 ** **** * * ** Glucose Total SAT VAT Fructose Total SAT VAT SAT: subcutaneous adipose tissue VAT: visceral adipose tissue Glucose Fructose A B
  • 52. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Intra-Abdominal (Visceral) Fat Excess – Other Approaches  Dehydroepiandrosterone (DHEA) supplements.  Nicotinic acid & receptor pathway.  Continuous positive airway pressure.
  • 53. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Niacin Acts Through Nicotinic Acid Receptors on Multiple Tissues Adapted from Pike NB. J Clin Invest 2005;115:3400-3 Adipocytes Immune cells (spleen, lymphoid cells, lung) Epidermal Langerhans cells Niacin Antilipolytic effects Probable anti-inflammatory effect PLA2 Arachidonic acid PGD2 GPR109A Flushing Niacin Niacin GPR109A: G protein-coupled receptor 109A PLA2: phospholipase A2 PGD2: prostaglandin D2

Editor's Notes

  1. Liraglutide reduces intra-abdominal (visceral) body fat.Liraglutide, a once-daily human glucagon-like peptide-1 (GLP-1) analogue:Reduced body weight with concomitant improvement in HbA1cHad a more pronounced effect on fat tissue than on lean tissueReduced body fat percentage with marked reductions in intra-abdominal adipose tissue and subcutaneous adipose tissueReduced hepatic steatosis