Pathophysiology of type 2 diabetes mellitus

R. Leibel Naomi Berrie Diabetes Center 25 February 2008

Body Mass Index Chart

25-29.9 = overweight; 30-39.9= obese; >40= extreme obesity
Weight (lbs)
120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 5'0" 5'2" 5'4"

Height

5'6" 5'8" 5'10" 6'0" 6'2" 6'4"

Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and 2001

1986 -> 2000. BMI > 30 2x; >40 4x; > 50 6x.

Mokdad, A. H. et al. JAMA 2003;289:76-79

Relative Risk of Type 2 Diabetes in US Women According to BMI

Relative risk (age-adjusted)
100 80 60 40 20 0 Bars represent 95% confidence intervals <22.0 22.0 22.9 23.0 23.9 24.0 24.9 25.0 26.9 27.0 28.9 29.0 30.9 31.0 32.9 33.0 35.0 34.9

BMI (kg/m2)
Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7.

Plasma Glucose and Insulin Profiles After Oral Glucose Challenge

Reaven GM et al. Diabetologia. 1977;13:201-206.

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Nat ure Ma

Millions of Cases of Diabetes in 2000 and Projections for 2030, with Projected Percent Changes

Hossain P et al. N Engl J Med 2007;356:213-215

Clinical definition of diabetes

Plasma glucose > 200 mg/dl at any time or Fasting (post-absorptive) plasma glucose > 125 mg/dl or 2 hour post-75gm oral glucose load plasma glucose > 200 mg/dl
Diab. Care; 23:381, 2000

Clinical Definition Impaired Glucose Tolerance

Fasting (post-absorptive) plasma glucose: 100-125 mg/dl or 2 hr (OGTT) plasma glucose: 140 - 199 mg/dl
Diab. Care; 23:381, 2000

& update 4 04

Predisposing Genes Predisposing Environment

Predisposing Genes

Obesity

Type 2 Diabetes 80% diabetic are obese 50 % obese are diabetic

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Figure 1

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Nat ure Ma cmi llan Pu blis her s Ltd

Note: Figures may be difficult to render in a web browser.

In the absence of insulin, GLUT4 is localized to an intracellular compartment

GLUT1 GLUT1
Membrane

GLUT4

Nucleus

In the presence of insulin, GLUT4 translocates to the plasma membrane GLUT4 GLUT1
IRS

Membrane

PI 3-K

AKT ?

PKC

Translocation

GLUT4

Nucleus

Note: Figures may be difficult to render in a web browser. In such cases, we recommend downloading the PDF version of this document.

Nat ure Ma cmi llan Pu blis her s Ltd 200 1 Re gist ere d No. 785 998 En gla nd.

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Obici et al. Nature Medicine. 8:1396, 2002

Potential rate-controlling steps in insulin-mediated muscle glycogen synthesis

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Mechanisms FFA-induced insulin resistance in skeletal muscle

Randle

Shulman

Adipose tissue is an endocrine organ.

Lean adipose tissue
acrp30 TNF IL-6 leptin Brain IL-6 leptin Muscle acrp30

Obese adipose tissue

Liver

TNF

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In obese mice, adipose tissue macrophages have an unusual morphology: lipid vacuoles, multinucleated.
Lean 16week BL6 female, omental fat ob/ob 16week BL6 female, omental fat

Weisberg et al., JCI, Dec 2003

Adipose tissue macrophages

Perigonadal: r2 = 0.7, P < 104 Perirenal: r2 = 0.7, P < 104 Mesenteric: r2 = 0.9, P < 104 Subcutaneous: r2 = 0.39, P < 0.01

Weisberg et al., JCI, Dec 2003

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Improved insulin sensitivity in Ccr2-/mice

Insulin tolerance test Glucose tolerance test

= Ccr2 +/+ with dietary obesity; 44% body fat

= Ccr2 -/- with dietary obesity; 45% body fat

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Prospective Analysis
8 Year Cumulative Incidence (%) of Type 2 Diabetes in Pima Indians 317 NGT/62 Diabetics

50 40

(%)

30 20 10 0
Low Low Mid High

AIR

Mid

High

Diabetes Prevalence (%) in Offspring by Mothers Diabetes at Pregnancy

90 80 70 60 50 40 30 20 10 0

Nondiabetic Prediabetic Diabetic

5-9

10-14

15-19

20-24

25-29

Age (years)

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Kahn SE et al. Nature 2006

Longitudinal Study of the Transition from NGT to Type 2 Diabetes

Early Insulin Response vs Insulin Action
400
AIR (uU/ml)
NGT NGT N=3 1 NGT

300 200 100 0 0 1 2

IGT

NGT N=17 DIA

M-low (mg/kg-EMBS/min)
Adapted from Weyer et al, 1999

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DPPT

Nat ure Ma cmi llan Pu blis her s Ltd 200 1 Re gist ere d No. 785 998 En gla nd.

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Percentage of Weight Loss Achieved Over the 2-Year Study Period (n = 60) and Individual Weight Measures at Baseline and at 2 Years

Dixon, J. B. et al. JAMA 2008;299:316-323.

Copyright restrictions may apply.

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Kahn SE et al. Nature 2006

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Diabetes-susceptibility QTLs
Chr1 Chr2 Chr5 Chr8 Chr14 Chr17

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Do beta cells in D/D animals replicate as well as beta cells in B/B animals?
B/B: D/D:

60x

20x

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Zebrafish

prior candidates

TCF2, SLC30A8 not on this affy array

Frayling. Nature Reviews. Genetics. 8:657, 2007 from Zeggini et al. Science. 316:1336, 2007

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Cauchi S et al. Journal of Molecular Medicine 2007

[11C] DTBZ and PET visualizes the human pancreas

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