Diabetes Mellitus

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Diabetes Mellitus

• Daozhan Yu
• dyu_at_medicine.umaryland.edu
• May 11th, 2005

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Diabetes Mellitus
Diabetes Latin to flow through. high
urine output (polydipsia) Mellitus- Latin
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
  
  h 2
• w weight in kilograms
• h height in meters
• Healthy weight as BMI between 19 25.
• Obesity defined as BMI gt 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. 20012861195-1200.
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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
from ? cell
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LiverGlucagon stimulates glucose synthesis and
export
MuscleInsulin stimulates glucose uptake and
consumption
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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 block
the IRS function.
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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
SystemicInflammation
ComplexDyslipidemia ? TG, sdLDL? HDL
EndothelialDysfunction
Insulin Resistance
DisorderedFibrinolysis
Atherosclerosis
Hypertension
DM2/IGT/IFG
VisceralObesity
Pradhan et al. JAMA. 2001
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Insulin Resistance Inherited and Acquired
Influences
Inherited
Acquired

• Rare Mutations
• Insulin receptor
• Glucose transporter
• Signaling proteins
• Common Forms
• Largely unidentified

• Inactivity
• Over eating
• Aging
• Medications
• Obesity
• Elevated FFAs

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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 DistributionNormal vs Type 2
Diabetes
Normal
Type 2 Diabetes
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Insulin Sensitivity and Central Adiposity
100
110
High risk for type 2 Low risk for type 2
90
80
70
60
Insulin sensitivity (mmol/min/kg lean mass)
50
40
30
20
20
25
30
35
40
45
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Central abdominal fat
Carey DG et al. Diabetes. 1996
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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 insulinsensitivity

• 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

Lean obesity
Hotamisligil, G.S., Science, 1993
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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 kb Kinase (IKK),
Initiating Event ?
IRS-1 Ser 307
HSL Lipolysis
TNFa
FFA
PI3K
Insulin Resistance in Adipose Tissue
Ruan and Lodish, Cytokine Growth Factor
Reviews, 2003
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The Lipotoxic Hypothesis of Insulin Resistance
Diacyl- glycerol
PKCq PKCe JNK1
FA-CoA
Insulin resistance in adipose tissue
HSL
insulin receptor
allosteric
Lipolysis
IRS-1/2
Glucokinase
P13K
Triglycerides
PKB
Ceramide
FFA
FFA
FOXO
GSK3
LPL
FA-CoA
PEPCK G6Pase
transcription
Overnutrition
Triacylglycerols in Chylomicrons
Glycogen Synthase
b-oxidation
Glucose
Acetyl-CoA NADH ATP
Glut 4 in muscle
hormone-sensitive lipase (HSL) phosphotidylinosit
ide 3-kinase the (P13K) free fatty acid (FFA)
Insulin receptor substrate(IRS) Lipoprotein
lipase(LPL)
Gluconeogenesis in Liver
Liver and Muscle
Too much information
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Lipotoxic Hypothesis of Insulin Resistance
LCCoA Long chain acyl-CoA DAG diacylglycerol
Savage et al, Hypertention, 2005
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Other Pathways That Link TNFa Signaling to
Insulin Resistance
Expression of Suppressors of Cytokine Signaling
(SOCS)
IRS-1 Tyr P
Insulin Resistance in Adipose Tissue, Liver and
Muscle
Inhibitor kb Kinase (IKK)
TNFa
NF-kB
Glut 4 PPARg IRS-1 Perilipin
Expression of
-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
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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!