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Pathophysiology of type 2 diabetes mellitus

R. LeibelNaomi Berrie Diabetes Center25 February 2008

Body Mass Index Chart25-29.9 = overweight; 30-39.9= obese; >40= extreme obesity

5'4"

HeightHeight

Weight (lbs)Weight (lbs)

5'2"

5'0"

5'10"

5'8"

5'6"

6'0"

6'2"

120120 130 150 160 170 180 190 200 210 220 230 240 250140 260 270 280 290 300

6'4"

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Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and2001

Mokdad, A. H. et al. JAMA 2003;289:76-791986 -> 2000. BMI > 30 2x; >40 4x; > 50 6x.

Relative Risk of Type 2 Diabetes inUS Women According to BMI

Relative riskRelative risk(age-adjusted)(age-adjusted)

100

60

80

40

20

0<22.0 22.0–

22.923.0–23.9

24.0–24.9

25.0–26.9

27.0–28.9

29.0–30.9

31.0–32.9

33.0–34.9

³35.0

BMI (kg/mBMI (kg/m22))

Bars represent 95%Bars represent 95%confidence intervalsconfidence intervals

Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7.

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Plasma Glucose and Insulin Profiles After Oral Glucose Challenge

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

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Nature©MacmillanPublishersLtd2001RegisteredNo.785998England.

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

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

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Clinical definition of diabetes

Plasma glucose > 200 mg/dl at any timeor

Fasting (post-absorptive) plasmaglucose > 125 mg/dl

or 2 hour post-75gm oral glucose load plasma

glucose > 200 mg/dl

Diab. Care; 23:381, 2000

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Clinical Definition Impaired GlucoseTolerance

Fasting (post-absorptive) plasma glucose: 100-125 mg/dlor

2 hr (OGTT) plasma glucose: 140 - 199 mg/dl

Diab. Care; 23:381, 2000 & update 4 04

Predisposing Genes

Predisposing Environment

Predisposing Genes

Type 2 DiabetesObesity

80% diabetic are obese50 % obese are diabetic

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Figure 1

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

Nature©MacmillanPublishersLtd2001RegisteredNo.785998England.

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

Nature©MacmillanPublishersLtd2001RegisteredNo.785998England.

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

GLUT4

GLUT1

GLUT1

Nucleus

Membrane

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

GLUT4

Nucleus

Membrane

?

Translocation

GLUT4

IRS

PI 3-K

AKT PKC

GLUT1

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

Nature©MacmillanPublishersLtd2001RegisteredNo.785998England.

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

Potential rate-controlling steps in insulin-mediated muscle glycogensynthesis

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Randle

Shulman

Mechanisms FFA-induced insulin resistance in skeletal muscle

Adipose tissue is an endocrine organ.

acrp30

TNFα

IL-6

leptin

acrp30

TNFα

IL-6

leptin

Muscle

Liver

Brain

Lean adiposetissue

Obese adiposetissue

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In obese mice, adipose tissue macrophageshave an unusual morphology: lipidvacuoles, multinucleated.

Lean 16-week BL6female,omental fat

ob/ob 16-week BL6female,omental fat

Weisberg et al., JCI, Dec 2003

Adipose tissue macrophages

Perigonadal:r2 = 0.7, P < 10–4

Perirenal:r2 = 0.7, P < 10–4

Mesenteric:r2 = 0.9, P < 10–4

Subcutaneous:r2 = 0.39, P < 0.01

Weisberg et al., JCI, Dec 2003

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Improved insulin sensitivity in Ccr2-/-

mice

= Ccr2 +/+ with dietaryobesity; 44% body fat

= Ccr2 -/- with dietaryobesity; 45% body fat

Insulin tolerance test Glucose tolerance test

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8 Year Cumulative Incidence (%) of Type 2Diabetes in Pima Indians

317 NGT/62 Diabetics

0

10

20

30

40

50

(%)

Low Mid High

High

Mid

Low

AIR

M

Prospective Analysis

Diabetes Prevalence (%) in Offspring byMother’s Diabetes at Pregnancy

0

10

20

30

40

50

60

70

80

90

5-9 10-14 15-19 20-24 25-29

Age (years)

Nondiabetic

Prediabetic

Diabetic

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Kahn SE et al. Nature 2006

0

100

200

300

400

0 1 2 3 4

M-low (mg/kg-EMBS/min)

AIR

(u

U/m

l)

NGTIGT

DIA

N=17

N=31

Adapted from Weyer et al, 1999

NGTNGTNGT

Longitudinal Study of the Transitionfrom NGT to Type 2 Diabetes

Early Insulin Response vs Insulin Action

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DPPT

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Copyright restrictions mayapply.

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

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

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Kahn SE et al. Nature 2006

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Diabetes-susceptibility QTLsChr1 Chr2 Chr5 Chr8 Chr14 Chr17

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Do beta cells in D/D animals replicate aswell as beta cells in B/B animals?

B/B: D/D:

60x

20x

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Zebrafish

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

TCF2, SLC30A8 not on this affy array

prior candidates

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Cauchi S et al. Journal of Molecular Medicine 2007

[11C] DTBZ and PET visualizes thehuman pancreas

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