pathophysiology of type 2 diabetes mellitus
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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"
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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
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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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