Whites

Hispan

ic

African

American

Native

American

02468

101214161820

Perc

ent o

f Pop

ulati

onPrevalence of Diabetes in Race & Ethnic Groups

General Population Native American0

5

10

15

20

25

30

35

40

45

50Pe

rcen

t Inc

reas

eIncrease in diabetes in 1990’s

Canadian All Native Americans Pima0

10

20

30

40

50

60Pr

eval

ence

per

100

0

The Prevalence of Diabetes in Native American Populations

Insulin comes from the Pancreas

$-Cells Produce and Secrete Insulin

Primary target tissue cites include:hepatic cells (liver)muscle cellsadipocytes (fat)

Insulin primarily released in response to a rise in blood glucose levels

Elongated tissue nestled within intestines and between kidneys/adrenals

Insulin

Insulin Receptor

Glucose

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

Glucose

Insulin

Insulin Receptor

PI3K

PIP3

AKT-1

AKT-2

AKT-3

IRS-1

IRS-2

IRS-3

IRS-4

Tyrosine Phosphorylation

HyperinsulinemiaProtein tyrosine phosphatases (PTPs)Serine PhosphorylationLigand-induced downregulation

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

Hyperinsulinemia → decreases expressionof IRS-1 and IRS-2Protein tyrosine phosphatases (PTPs) → dephophorylates important tyrosine residues → reducing activitySerine Phosphorylation → interaction with IRS Proteins → downregulates IR function

→modifies kinase activity of IRS proteinLigand-induced downregulation → internalization and degradation IR

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

PhosphatasePTENSHIP2

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

Phosphatase → dephosphrylates PIP3

PTEN → dephosphrylates PIP3

SHIP2 → dephosphrylates PIP3

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

AKT-1

AKT-2

AKT-3

Glucose Uptake

Cell Differentiation↑Protein

Synthesis↓Gluconeogenesis

↑Glucose Synthesis

GLUT4

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

AKT-1

AKT-2

AKT-3

Glucose Uptake

Cell Differentiation↑Protein

Synthesis↓Gluconeogenesis

↑Glucose Synthesis

GLUT4

Glucose

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

AKT-1

AKT-2

AKT-3

Glucose Uptake

Cell DifferentiationProtein

SynthesisGluconeogenesis

Glucose Synthesis

IRS-1

IRS-2

IRS-3

IRS-4

PI3K

PIP3

AKT-1

AKT-2

AKT-3

Glucose Uptake

Cell DifferentiationProtein

SynthesisGluconeogenesis

Glucose Synthesis

TNFα IL-6

FFA

CARBOHYDRATE METABOLISMLiver & Muscle Glycogenolysis

Hyperglycemia

Glucoseurea-Osmotic Diuresis

Fluid & Electrolyte Loss

Dehydration

CARBOHYDRATE METABOLISMHemoconcentration

Peripheral Circulatory FailureHypotension

Renal Blood FlowRenal Failure

ComaDeath

LIPID METABOLISMLipogenesis Lypolysis

LipemiaKetogenesisKetonemia

Metablic AcidosisKetonuria Hyperpena

Dehydration

LIPID METABOLISMHemoconcentration

Peripheral Circulatory FailureHypotension

Renal Blood FlowRenal Failure

ComaDeath

PROTEIN METABOLISM

Aminoacidemia

Gluconeogenesis

Urinary Nitrogen

Loss of cellular K+

Net loss of K+

Protein Catabolism

http://www.youtube.com/watch?v=CVUnzk40npw&NR=1

3 Years 5 years 10 years 15 years0

10

20

30

40

50

60

70

80

90

Prev

alen

ce (%

)

Fong, D.S., et al. Diabetes Care 27:S84, 2004

Prevalence of Diabetic Retinopathy after Diagnosis of Diabetes

• heart and blood vessels • digestive system • urinary tract • sex organs • sweat glands • eyes

AUTONOMIC NEUROPATHY

• Unawareness of Hypoglycemia • Postural Hypotension • Unresponsive Heart Rate • Maldistribution of Blood Flow • Alternating Constipation and Uncontrolled diarrhea • Gastroparesis (stomach to empty too slowly)

• persistent nausea and vomiting, bloating, and loss of appetite.

• fluctuations in blood glucose levels • Swallowing difficulties • Incomplete bladder emptying

• bacteria to grow in the bladder and kidneys and causing urinary tract infections.

• Urinary incontinence • Decrease sexual response in men and women • Lack of or perfuse sweating • pupils less responsive to changes in light

AUTONOMIC NEUROPATHY

• toes • feet • legs • hands • arms

PERIPHERAL NEUROPATHY

• numbness or insensitivity to pain or temperature

• a tingling, burning, or prickling sensation

• sharp pains or cramps • extreme sensitivity to touch, even a

light touch • loss of balance and coordination

PERIPHERAL NEUROPATHY

• eyes • facial muscles • ears • pelvis and lower back • thighs • abdomen

FOCAL NEUROPATHY

• inability to focus the eye • double vision • aching behind one eye • paralysis on one side of the face (Bell's palsy) • severe pain in the lower back or pelvis • pain in the front of a thigh • pain in the chest, stomach, or flank • pain on the outside of the shin or inside the foot • chest or abdominal pain that is sometimes mistaken

for heart disease, heart attack, or appendicitis

FOCAL NEUROPATHY

• thighs • hips • buttocks

PROXIMAL NEUROPATHY

• pain in either the thighs, hips, buttocks, or legs, usually on one side of the body

• weakness in the legs, manifested by an inability to go from a sitting to a standing position without help

PROXIMAL NEUROPATHY

ANHYDROSIS

EXERCISE PREVENTION

<500 500-1999 >200005

101520253035404550

Low RiskHigh Risk

Helmich, S.P. et al. New England J Medicine 325:147-152, 199

Inci

denc

e R

ates

of t

ype

2

(/ 10

,000

man

-yea

rs

Regular Walking Decreases Morbidity Rates by 50% in Diabetics

Gregg, E.W., Arch Intern Med 163:1440-1447, 2003

0 <1 1-1.9 2-2.9 3-3.9 >40

0.2

0.4

0.6

0.8

1

1.2

Hours Walking per Week

Risk

of A

ll-Ca

use

Mor

talit

y

Pre Post5

6

7

8

9

10

11

12

13

Glyc

osyl

ated

Hb

(%)

Boule, N.G. et al JAMA 286:1218-1227, 2001.

Pre Post5

6

7

8

9

10

11

12

13Exercise Groups Control Groups

Pre Post50

60

70

80

90

100

110

Body

Wei

ght (

kg)

Boule, N.G. et al JAMA 286:1218-1227, 2001.

Pre Post50

60

70

80

90

100

110Exercise Groups Control Groups

INSULIN SENSITIVITY

Exercise Control0

50

100

150

200

250

300

350

Pre-Post-

Glu

cose

Upt

ake

(mg/

m2 /m

in)

*

Landt, et al, Diabetes Care 8:461-465, 1985Wallberg-Henriksson et al., Am J Clinical Nutrition 249:C233-C237, 1985Yki-Jarvinen et al, Diabetes Care 7:520-527, 1984.

MUSCLE BLOOD FLOW

Katz, M. and N. Janjan. Diabetes 27:726-731, 1978

0

2

4

6

8

10

12

14

Resitance Filtration Capacity

ControlDiabetes

Resi

stan

ce (

mm

Hg/

ml

min

/100

gFi

ltra

tion

(dl

/min

mm

Hg/

100

g Capa

city

(m

l/100

g)

MUSCLE BLOOD FLOW

Wallberg-Henriksson et al., Am J Clinical Nutrition 249:C233-C237, 1985Wallberg-Henriksson, et al, Diabetes 33:851-857, 1984

1.45

1.5

1.55

1.6

1.65

1.7

1.75

1.8

Exercise Control

Pre-Post-

Capi

llari

es/F

iber

SIGNS AND SYMPTOMS OF HYPOGLYCEMIAApathy Sweating Excessive Hunger

Drowsy Fainting Convulsions

Dizziness Fatigue Crying

Hand Tremors Irritability Blurred Vision

Confusion Delusion Double Vision

Headache Slurred Speech Unsteady Gait

Nervousness Poor Coordination

Inability to concentrate Loss of Consciousness