Diabetes Mellitus

Daozhan Yu dyu@medicine.umaryland.edu May 11th, 2005

Diabetes Mellitus
Diabetes Latin to flow through. high urine output (polydipsia)

MellitusLatin: honeylike Glucose in urine (glucosurea)

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What Are the Symptoms?

Glucosurea Frequent urination High blood glucose Increased thirst Increased hunger (especially after eating) Dry mouth
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Continued

Nausea and occasionally vomiting Hyperinsulinemia Fatigue (weak, tired feeling) Blurred vision Numbness or tingling of the hands or feet Frequent infections of the skin, urinary tract or vagina
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Other diseases related

Obesity Atherosclerosis Hypertension Pro-inflammatory state Pro-coagulant changes Dyslipidemia (hypertriglyceridemia and low HDL levels)
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Classification:

Insulin dependent (IDDM or type I) -No or little insulin Non-insulin dependent (NIDDM or type II) -High insulin Secondary diabetes -Pancreatitis, hormone therapy etc. Gestational diabetes -Initially limited to term of pregnancy
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Diagnosis

Fasting blood glucose 7.8mmol/L Oral glucose tolerance test (OGTT) 7.8mmol/L at 2h after 75g glucose Insulin levels Differentiate IDDM and NIDDM
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Diabesity Epidemic

Prevalence of diabetes worldwide was over 135 million people in 1995 Projected to be over 300 million by 2025 Over 80% of type 2 diabetic patients are overweight
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Obesity

Obesity is often diagnosed by using a body mass index (BMI). BMI = w h2

w = weight in kilograms h = height in meters

Healthy weight as BMI between 19 25. Obesity defined as BMI > 30.
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.
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TD2 and Obesity

Insulin resistance is a prominent feature of obesity and TD2 Glucose and FA concentrations in blood increase -affect insulin secretion - vicious cycle

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Bad News: The Epidemic Of Obesity And Diabetes Is Worsening In The USA

In 2000, the prevalence of obesity (BMI 30 kg/m2) was 19.8% 61% since 1991 Most adults are now overweight (BMI 25 kg/m2) -56.4% 25% since 1991 Each 1 kg weight - 4.5%-9% risk of diabetes
Mokdad et al. JAMA. 2001;286:1195-1200. 12

Actions of Insulin

Stimulates glucose uptake by muscle (GLUT-4)

Activates glycogen synthase and inactivates glycogen phosphorylase (liver and muscle) Stimulates storage of excess fuel as fat

FAs made in liver are converted to triacylglycerols (TGs) and transported in VLDLs to fat cells
In fat cells insulin stimulates TG synthesis
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Glucose Stimulates Insulin Secretion

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Insulin is stored in secretory granules contents released into blood stream upon stimulation

Electron micrograph showing release of insulin 16 from cell

Liver Glucagon stimulates glucose synthesis and export Muscle Insulin stimulates glucose uptake and consumption

High Blood Glucose

Pancreas Insulin Low Blood Glucose

Muscle
Glycogen Glucagon

Liver
Glycogen Glucose Pyruvate
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Glucose
Pyruvate CO2

What Happens When Insulin Reaches Cells ?

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 18 block the IRS function.

GLUT4 Is The Transporter Of Glucose In Muscle And Adipose Tissue

GLUT4 will be relocated from the cytoplasm to membrane
Blue: DNA Red: GLUT4 Green: Transferon

Foster et al, J. Biol. Chem., 2001

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What Will Happen If GLUT4 Doesnt move right?

Insulin Resistance: An impaired biological response to insulin
-Resistance to insulin-stimulated glucose uptake -Increased lipolysis/FFAs

McFarlane SI, et al. J Clin Endocrinol Metab. 2001

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The Metabolic Syndrome of Insulin Resistance

Complex Dyslipidemia
TG, sdLDL HDL

Endothelial Dysfunction

Systemic Inflammation

Disordered Fibrinolysis

Insulin Resistance
DM2/IGT/IFG

Atherosclerosis

Hypertension

Visceral Obesity
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Pradhan et al. JAMA. 2001

Insulin Resistance: Inherited and Acquired Influences

Inherited
Rare Mutations
Insulin receptor Glucose transporter Signaling proteins

Acquired
Inactivity Over eating Aging Medications Obesity Elevated FFAs

Common Forms
Largely unidentified

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A New View of the Adipocyte

The adipocyte is a metabolically active source of multiple proteins and cytokines that act via autocrine, paracrine and endocrine means The adipocyte, gut and brain communicate regarding the bodys state of energy balance and set the satiety thermostat
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Visceral vs. Subcutaneous fat

Visceral (abdominal, omental) fat correlates best with the co-morbidities of obesity including insulin resistance and diabetes

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Visceral Fat Distribution:

Normal vs Type 2 Diabetes

Normal

Type 2 Diabetes

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Insulin Sensitivity and Central Adiposity

Insulin sensitivity (mmol/min/kg lean mass) 100 90 80 70 60 50 40 30 20 20
Carey DG et al. Diabetes. 1996 27

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High risk for type 2

Low risk for type 2

30 35 40 45 25 % Central abdominal fat

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Chronic Inflammatory State Happens During Obesity

TNF alpha is a very important inflammatory mediator. It will be produced much during obesity.

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How the adipocyte affects insulin sensitivity

Lean obesity

TNF alpha Levels rise with increasing adiposity Lowers insulin stimulated glucose uptake in fat and muscle via paracrine effects Reduces Glut-4 gene expression Reduces insulin stimulated IR autophosphorylation and IRS-l phosphorylation Interferes with pancreatic beta cell insulin secretion
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Hotamisligil, G.S., Science, 1993

What Causes Insulin Resistance in Adipose Tissue?

TNFa activates IKK, which will phosphorylate IRS at serine. So IRS cant bind to PI3K. HSL lipolysis will release FFA from fat into blood.

Insulin Resistance in Liver and Muscle Inhibitor k Kinase (IKK),

Initiating Event ?

TNFa

IRS-1 Ser 307

PI3K

HSL Lipolysis

FFA

Insulin Resistance in Adipose Tissue Ruan and Lodish, Cytokine & Growth Factor Reviews, 2003 30

The Lipotoxic Hypothesis of Insulin Resistance

Diacylglycerol PKCq PKCe JNK1 P13K

Insulin resistance in adipose tissue

HSL

FA-CoA Lipolysis

allosteric

Glucokinase Triglycerides

IRS-1/2

insulin receptor

FFA
LPL

FFA
FA-CoA

Ceramide GSK3 Glycogen Synthase

PKB
FOXO PEPCK transcription G6Pase

Overnutrition

Triacylglycerols in Chylomicrons

Acetyl-CoA NADH ATP

Glucose
Glut 4 in muscle

hormone-sensitive lipase (HSL) phosphotidylinositide 3-kinase the (P13K) free fatty acid (FFA) Insulin receptor substrate(IRS) Too Lipoprotein lipase(LPL)

Gluconeogenesis in Liver

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much information

Liver and Muscle

Lipotoxic Hypothesis of Insulin Resistance

LCCoA: Long chain acyl-CoA

DAG: diacylglycerol

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Savage et al, Hypertention, 2005

Other Pathways That Link TNFa Signaling to Insulin Resistance

Expression of Suppressors of Cytokine Signaling (SOCS) IRS-1 Tyr P

TNFa

Inhibitor k Kinase (IKK)

NF-kB

Insulin Resistance in Adipose Tissue, Liver and Muscle

Expression of

Glut 4 PPARg IRS-1 Perilipin

-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, 33 normalizes SREBP-1c expression. Ueki et al. Mol. Cell. Biol. 2003
Ueki et al. PNAS ,2004

Adiponectin

An anti-atherogenic and anti-inflammatory Adipokine entrained to the insulin sensitivity state made exclusively in the adipocyte Levels reduced in obesity, T2D, in men vs. women, and in CAD; rises with weight loss Increases insulin sensitivity by promoting beta oxidation of fatty acids in muscle
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TNFa Also Modulates the Expression of Other Adipocyte-derived Hormones

TNFa Adiponectin/Acrp30/AdipoQ AMPK Fatty Acid Oxidation FFA Insulin Sensitivity gluconeogenesis In Muscle, Adipose, and/or Liver

Adiponectin knockout animals develop insulin resistance, increased serum NEFAs. PPARg agonists (thiazolidinediones) stimulate adiponectin expression and increase insulin sensitivity. Pharmacological potential of adiponectin appears high.

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Other Adipose-derived Hormones May Play a Role in Mediating Insulin Resistance

Resistin IL-6 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

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New Point of view

Muoio et al, Science, 2004

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Approach to modifying insulin resistance

Weight control

Diet Exercise Body composition Weight loss medications

Medications

Insulin sensitizers: metformin, thiazolidinediones

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Diabetes therapies and body weight

Metformin (biguanide) inhibits hepatic glucose release and promotes mild weight loss. Thiazolidinediones (TZDs) increase insulin sensitivity by acting at PPAR gamma. They increase body weight but augment subcutaneous rather than visceral fat

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The END! Thank You!

Oh, sorry, not the end, just the beginning!

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