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Diabetes Mellitus. Daozhan Yu dyu@medicine.umaryland.edu 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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diabetes mellitus

Diabetes Mellitus

Daozhan Yu

dyu@medicine.umaryland.edu

May 11th, 2005

diabetes mellitus2
Diabetes Mellitus

Diabetes – Latin “to flow through”. high urine output (polydipsia)

Mellitus- Latin: “honeylike” Glucose in urine (glucosurea)

what are the symptoms
What Are the Symptoms?
  • Glucosurea
  • Frequent urination
  • High blood glucose
  • Increased thirst
  • Increased hunger (especially after eating)
  • Dry mouth
continued
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
other diseases related
Other diseases related
  • Obesity
  • Atherosclerosis
  • Hypertension
  • Pro-inflammatory state
  • Pro-coagulant changes
  • Dyslipidemia (hypertriglyceridemia and low HDL levels)
slide6

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

diagnosis
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

diabesity epidemic
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

obesity
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 > 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.

td2 and obesity
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

bad news the epidemic of obesity and diabetes is worsening in the usa
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.

slide14

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
slide16

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

Electron micrograph showing release of insulin

from  cell

slide17

High Blood Glucose

Pancreas

Low Blood Glucose

Insulin

Muscle

Liver

Glycogen

Glycogen

Glucagon

Glucose

Glucose

Pyruvate

Pyruvate

CO2

LiverGlucagon stimulates glucose synthesis and export

MuscleInsulin stimulates glucose uptake and consumption

what happens when insulin reaches cells
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.

glut4 is the transporter of glucose in muscle and adipose tissue
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

what will happen if glut4 doesn t move right
What Will Happen If GLUT4 Doesn’t 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

the metabolic syndrome of insulin resistance
The Metabolic Syndrome of Insulin Resistance

SystemicInflammation

EndothelialDysfunction

ComplexDyslipidemia

 TG, sdLDL HDL

Insulin Resistance

DisorderedFibrinolysis

Atherosclerosis

Hypertension

DM2/IGT/IFG

VisceralObesity

Pradhan et al. JAMA. 2001

insulin resistance inherited and acquired influences
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
a new view of the adipocyte
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 body’s state of energy balance

and set the “satiety” thermostat

visceral vs subcutaneous fat
Visceral vs. Subcutaneous fat

Visceral (abdominal, omental) fat correlates

best with the co-morbidities of obesity

including insulin resistance and diabetes

insulin sensitivity and central adiposity
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

30

35

40

45

25

50

% Central abdominal fat

Carey DG et al. Diabetes. 1996

slide28

Chronic Inflammatory State Happens During Obesity

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

how the adipocyte affects insulin sensitivity
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

slide30

What Causes Insulin Resistance in Adipose Tissue?

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.

Insulin Resistance

in Liver and Muscle

Inhibitor kb

Kinase

(IKK),

Initiating

Event ?

IRS-1

Ser 307

HSL

Lipolysis

TNFa

PI3K

FFA

Insulin Resistance

in Adipose Tissue

Ruan and Lodish, Cytokine & Growth Factor Reviews, 2003

slide31

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

Triacylglycerols in

Chylomicrons

Overnutrition

Glycogen

Synthase

b-oxidation

Glucose

Acetyl-CoA

NADH

ATP

Glut 4 in

muscle

hormone-sensitive lipase (HSL)

phosphotidylinositide 3-kinase the (P13K)

free fatty acid (FFA)

Insulin receptor substrate(IRS)

Lipoprotein lipase(LPL)

Gluconeogenesis

in Liver

Liver and Muscle

Too much information

slide32

Lipotoxic Hypothesis of Insulin Resistance

LCCoA: Long chain acyl-CoA

DAG: diacylglycerol

Savage et al, Hypertention, 2005

slide33

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

adiponectin
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

slide35

TNFa Also Modulates the Expression of Other Adipocyte-derived Hormones

TNFa

Adiponectin/Acrp30/AdipoQ

Fatty Acid Oxidation

AMPK

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.
slide36

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

slide37

New Point of view

Muoio et al, Science, 2004

approach to modifying insulin resistance
Approach to modifying insulin resistance
  • Weight control
    • Diet
    • Exercise
    • Body composition
    • Weight loss medications
  • Medications
    • Insulin sensitizers: metformin, thiazolidinediones
diabetes therapies and body weight
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

the end thank you
The END!Thank You!

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