The Multisystemic Impact of Obesity

1
The Multisystemic Impact of Obesity
Excess Dietary Fat
Orlistat - Reduces Dietary Fat Absorption by 30
Obesity
Dyslipidaemia
Insulin resistance
Hypertension
Atherogenesis
Type 2 diabetes
CVD
2
Orlistat-Associated Weight Loss Reduces Multiple
Cardiovascular Risk Factors

• Total cholesterol
• LDL-cholesterol
• LDLHDL ratio
• Diastolic blood pressure
• Systolic blood pressure
• Fasting glucose
• Fasting insulin
• Insulin resistance

3
Pathophysiological Factors in Hyperglycaemia
Hyperglycaemia
4
Factors Involved in the Aetiology of Insulin
Resistance

• Genetics
• Physical inactivity
• Smoking
• Increased body weight
• Increased fat mass
• Visceral body fat distribution
• Dietary fat and fibre intake

5
Prevalence of Insulin Resistance Increases with
BMI
Prevalence ()
Insulin resistance
90
Insulin hypersecretion
80
70
60
50
40
30
20
10
0
25
28
35
gt35
BMI (kg/m2)
Ferrannini E, et al. J Clin Invest 1997 100
1166-73
6
Dietary Fat and Fibre Intake

• Epidemiological studies indicate
• High-fibre diets are associated with a lower
  risk for type 2 diabetes
• A diet high in saturated fat is a risk factor for
  type 2 diabetes
• High-fat intake is associated with increased BMI
• Fasting hyperinsulinaemia is related to high-fat
  intake independent of BMI

7
Relationship between Adipose Tissue and Skeletal
Muscle
Lipolysis ?
Free fatty acids ?
Lipid oxidation ? Glucose oxidation ? Glucose
uptake ? Glycogen synthesis ?
8
Fat-Weighted MR Imaging of the Human Calf
Insulin-sensitive
Insulin resistant
9
Skeletal Muscle Triglyceride Levels are Inversely
Related to Insulin Action
Insulin Sensitivity
r -0.53 plt0.0006
.9
.8
.7
.6
.5
.4
.3
.2
.1
1
2
3
4
6
7
8
9
5
10
Skeletal Muscle-Associated Triglyceride (?mol/g
wet weight of tissue)
Pan DA, et al. Diabetes 1997 46 983-8
10
Body Fat Compartments

• Subcutaneous fat
• Visceral fat
• Intramuscular fat
• Extramyocellular lipid (EMCL)(adipocytes between
  muscle fibres)
• Intramyocellular lipid (IMCL)(fat droplets
  within muscle fibres)

11
Lipolysis in Muscle is Tightly Regulated by
Physiological Doses of Insulin
Interstitial glycerol ( of basal)
GC I
GC II
GC III
100
80
60
40
20
0.1mU/kg?min
0.25mU/kg?min
1.0mU/kg?min
0
-40
0
60
120
180
240
300
360
Minutes
Jacob S, et al. Diabetologia 1999 42 1171-4
12
Anti-Lipolysis in Skeletal Muscle is Impaired in
Insulin Resistance
Insulin resistant
Insulin-sensitive
Interstitial glycerol in adipose tissue (mg/dL)
3
2
1
0
Basal
GC 1
GC 2
GC 3
Jacob S, et al. Diabetes 2000 abstract, in press
13
Trafficking of Dietary Fat in Rats - 24-hour
Detection of 14C-Oleate in Triglycerides
Dietary fat
Adipose tissue
40
40
Skeletalmuscle
Bessesen DH, et al. Obes Res 1995 3 191-203
14
Dietary Fat and Insulin Sensitivity

• A high-fat diet augments intramuscular lipids and
  decreases insulin sensitivity in rats
• A high-fat diet is associated with
  hyperinsulinaemia and insulin resistance in
  humans
• A low-fat diet improves insulin sensitivity
• Orlistat may improve insulin sensitivity
  independently of weight loss by reducing the
  absorption of dietary fat

15
Effect of Orlistat on Insulin Sensitivity

• Open-labeled pilot study of 6 obese male insulin
  resistant subjects (mean BMI 38 kg/m2, mean age
  29 years)
• Orlistat 120 mg tid for 3 months followed by 3
  months without orlistat
• Insulin sensitivity assessed by
  euglycaemic-hyperinsulinaemic clamp (MCR)
• Body weight maintenance mandatory during the
  study period

16
Constant Body Weight During Study
Weight (kg)
180
160
140
120
100
Orlistat 120 mg tid
80
0
3
6
Month
17
Orlistat Improves Glucose Tolerance
Placebo
of patients
Orlistat 120 mg
80
71.6
plt0.05
60
49.1
42.1
40
15.8
14.3
14.3
20
0
Diabetic
Diabetic
Impaired
Impaired
Normal
Normal
Heymsfield S et al. Arch Intern Med 2000 160
1361-9
18
Proton Spectra of the Tibialis Muscle
Insulin-sensitive
Insulin resistant
EMCL
EMCL
IMCL
IMCL
7
6
5
4
3
2
1
0
ppm
ppm
Jacob S, et al. Diabetes 1999 48 1113-9
19
IMCL is Correlated with Insulin Sensitivity -
Non-Diabetic Subjects
Insulin sensitivity
r -0.692 p lt 0.0017
90
75
60
45
30
15
0
1.2
1.6
2.0
2.4
2.8
3.2
IMCL ( of water resonance peak intensity)
Krssak M, et al. Diabetologia 1999 42 113-6
20
Association of IMCL Content with Insulin
Resistance

• Lean non-diabetic offspring of patients with type
  2 diabetes (mean BMI 23 kg/m2)
• Insulin-resistant (n13) and insulin sensitive
  (n13) subjects matched for age, gender, BMI,
  body fat, WHR and physical fitness
• IMCL in soleus and tibialis anterior was
  quantified by H-MRS

Jacob S, et al. Diabetes 1999 48 1113-9
21
IMCL Content is Increased in Insulin Resistant
Subjects
p0.008
IMCL
Insulin-sensitive
14
Insulin resistant
12
10
8
p0.017
6
4
2
0
Soleus
Tibialis anterior
Jacob S, et al. Diabetes 1999 48 1113-9
22
Effect of Orlistat on Insulin Sensitivity
50
40
30
changefrombaseline
20
10
0
3 months (with orlistat)
-10
3 monthslater (without orlistat)
-20
23
Conclusions

• Increased dietary fat intake is associated with
  insulin resistance and the development of type 2
  diabetes
• Intramuscular lipids represent an important
  compartment of fat distribution
• Increased IMCL is associated with impaired
  insulin-stimulated glucose uptake
• Low-fat diet improves insulin sensitivity
• Orlistat may improve insulin sensitivity
  independently of weight loss

24
Orlistat Improves Glucose Tolerance
Placebo
of patients
Orlistat 120 mg
80
71.6
plt0.05
60
49.1
42.1
40
15.8
14.3
14.3
20
0
Diabetic
Diabetic
Impaired
Impaired
Normal
Normal
Heymsfield S et al. Arch Intern Med 2000 160
1361-9