Diabetes Mellitus. Daozhan Yu firstname.lastname@example.org May 11th, 2005. Diabetes Mellitus. Diabetes – Latin “to flow through”. high urine output (polydipsia) Mellitus- Latin: “honeylike” Glucose in urine (glucosurea). What Are the Symptoms?. Glucosurea
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May 11th, 2005
Diabetes – Latin “to flow through”. high urine output (polydipsia)
Mellitus- Latin: “honeylike” Glucose in urine (glucosurea)
-No or little insulin
-Pancreatitis, hormone therapy etc.
-Initially limited to term of pregnancy
7.8mmol/L at 2h after 75g glucose
Differentiate IDDM and NIDDM
BMI = w h 2
w = weight in kilograms
h = height in meters
Obesity in childhood is due to an increase in both the size and the # of adipocytes.
Weight gains in adulthood is due to increase in adipocyte size in intra-abdominal fat.
-affect insulin secretion- vicious cycle
61% since 1991
25% since 1991
Mokdad et al. JAMA. 2001;286:1195-1200.
glycogen phosphorylase (liver and muscle)
Insulin is stored in secretory granules – contents released into blood stream upon stimulation
Electron micrograph showing release of insulin
Low Blood Glucose
LiverGlucagon stimulates glucose synthesis and export
MuscleInsulin stimulates glucose uptake and consumption
Insulin binding to IR will cause autophosphorylation and phosphorylation of IRS at Tyrosine, then IRS will be activated and bind to following components to activate the signal cascade.
Glucose will be transport from blood into cells.
Phosphorylation at Serine will block the IRS function.
GLUT4 will be relocated from the cytoplasm to membrane
Foster et al, J. Biol. Chem., 2001
An impaired biological response to insulin
-Resistance to insulin-stimulated glucose uptake
McFarlane SI, et al. J Clin Endocrinol Metab. 2001
TG, sdLDL HDL
Pradhan et al. JAMA. 2001
source of multiple proteins and cytokines
that act via autocrine, paracrine and
regarding the body’s state of energy balance
and set the “satiety” thermostat
Visceral (abdominal, omental) fat correlates
best with the co-morbidities of obesity
including insulin resistance and diabetes
Type 2 Diabetes
High risk for type 2
Low risk for type 2
Insulin sensitivity (mmol/min/kg lean mass)
% Central abdominal fat
Carey DG et al. Diabetes. 1996
TNF alpha is a very important inflammatory mediator. It will be produced much during obesity.
Hotamisligil, G.S., Science, 1993
TNFa activates IKK, which will phosphorylate IRS at serine. So IRS can’t bind to PI3K. HSL lipolysis will release FFA from fat into blood.
in Liver and Muscle
in Adipose Tissue
Ruan and Lodish, Cytokine & Growth Factor Reviews, 2003
Insulin resistance in adipose tissue
Glut 4 in
hormone-sensitive lipase (HSL)
phosphotidylinositide 3-kinase the (P13K)
free fatty acid (FFA)
Insulin receptor substrate(IRS)
Liver and Muscle
Too much information
LCCoA: Long chain acyl-CoA
Savage et al, Hypertention, 2005
Expression of Suppressors of Cytokine Signaling (SOCS)
Insulin Resistance in Adipose Tissue, Liver and Muscle
-SOCS-3 binds the insulin receptor (Tyr960), blocks interaction with IRS-1 and IRS-2.
-SOCS-1 bind the kinase domain of the insulin receptor, blocks phosphorylation of IRS-1 and IRS-2.
-Inhibition of SOCS activity in obese diabetic animals improves insulin sensitivity, normalizes SREBP-1c expression.
Ueki et al. Mol. Cell. Biol. 2003
Ueki et al. PNAS ,2004
state made exclusively in the adipocyte
women, and in CAD; rises with weight loss
oxidation of fatty acids in muscle
TNFa Also Modulates the Expression of Other Adipocyte-derived Hormones
Fatty Acid Oxidation
In Muscle, Adipose,
Other Adipose-derived Hormones May Play a Role in Mediating Insulin Resistance
Plasminogen Activator Inhibitor 1
Expression and secretion of these factors is increased during the development of type 2 diabetes/obesity
Weight loss causes decrease in circulating levels of these factors.
Kershaw and Flier, J. Clin. Endocrinol. Metab. 2004
Muoio et al, Science, 2004
sensitivity by acting at PPAR gamma. They
increase body weight but augment subcutaneous rather than visceral fat
Oh, sorry, not the end, just the beginning!