2/24/2009

1

Pathophysiology of type 2 diabetes mellitus

R. LeibelR. LeibelNaomi Berrie Diabetes Center24 February 2009

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

obesity

5'4"

Weight (lbs)Weight (lbs)

5'2"

5'0"

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

5 4

HeightHeight

5'10"

5'8"

5'6"

6'0"

6'2"

6'4"

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

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

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

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

7.8 % of U.S. Population >20yo have diabetes.Diagnosed: 17.9 millionUndiagnosed: 5.7 million

20 yo. 23.5 Million60 yo. 12.2 Million

11 2 % M 10 2% F11.2 % M; 10.2% FNon-his white: 9.8%Non-his black: 14.7%

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

2/24/2009

2

Definition of Type 2 Diabetes (earlier NIDDM)

90 95% all diabetes

Beta cell diathesis exacerbated by obesity & inactivity

Relative hypoinsulinemia

Strong family Hx and Hx gestational diabetes

Race/ethnicity: American indians, Hispanic/Latino,

African-American, Asians/Pacific islanders:

These groups also showing increase in T2D in childhood

Overt Diabetes Mellitus

• Fasting plasma glucose ≥ 126 mg/dl

• Casual plasma glucose ≥ 200 mg/dl

• 2hr OGTT plasma glucose ≥ 200 mg/dl

Impaired Glucose Homeostasis

• Impaired Fasting Glucose: FPG 100‐125 mg/dl

• Impaired Glucose Tolerance:  OGTT 2hr plasma glucose 140‐199 mg/dl

Complications of Diabetes

Heart disease & stroke: 2-4x increaseHypertension: in 75% Blindness: leading cause 20-74 yoKidney disease: 44% all new casesKidney disease: 44% all new casesCNS/PNS: ~70%Amputations: 60% all non traumatic LLPeriodontal diseasePregnancy, fetal malformationPsychiatric

Predisposing Genes

Predisposing Environment

Predisposing Genes

Type 2 DiabetesObesity

80% diabetic are obese50 % obese are diabetic

Figure 1

2/24/2009

3

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

Membrane

GLUT4

IRS

PI 3-K

GLUT1

GLUT4

Nucleus

?

TranslocationAKT PKC

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

2/24/2009

4

Potential rate-controlling steps in insulin-mediated muscle glycogensynthesis

Randle

Mechanisms FFA-induced insulin resistance in skeletal muscle

Shulman

Adipose tissue is an endocrine organ.

acrp30

TNFα

acrp30

TNFα

Muscle

Liver

Lean adipose tissue

Obese adipose tissue

IL-6

leptin IL-6

leptin

Liver

Brain

In obese mice, adipose tissue macrophages have an unusual morphology: lipid vacuoles, multinucleated.

Lean 16-week BL6 female, omental fat

ob/ob 16-week BL6 female, 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

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

2/24/2009

5

C. J. R

hodes

A hypothetical model for postnatalpancreatic {beta}-cell growth in humans

Science 307, 380 -384 (2005)

Intrauterine Effects on Risk T2D

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

317 NGT/62 Diabetics

50

Prospective Analysis

0

10

20

30

40

50

(%)

Low Mid HighHigh

Mid Low

AIR

M

Diabetes Prevalence (%) in Offspring by Mother’s Diabetes at Pregnancy

5060708090

Nondiabetic

Prediabetic

Diabetic

010203040

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

Age (years)

Diabetic

Kahn SE et al. Nature 2006

2/24/2009

6

200

300

400

uU/m

l)

NGT

N=31

NGTNGTNGT

Longitudinal Study of the Transition from NGT to Type 2 Diabetes

Early Insulin Response vs Insulin Action

0

100

200

0 1 2 3 4

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

AIR

(u IGT

DIA

N=17

Adapted from Weyer et al, 1999

DPPT

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

Copyright restrictions may apply.

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

2/24/2009

7

prior candidates

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

TCF2, SLC30A8 not on this affy array

Florez. J. Clin Endocrin Metab. 2008

Cauchi S et al. Journal of Molecular Medicine 2007

Kahn SE et al. Nature 2006

END