EXERCISE PREVENTIONEXERCISE PREVENTION

<500 500-1999 >20000

5

10

15

20

25

30

35

40

45

50

Low Risk

High Risk

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

Inci

den

ce R

ate

s of

typ

e 2

(/ 1

0,0

00

ma

n-ye

ars

Regular Walking Decreases Morbidity Rates by 50% in Diabetics

Regular Walking Decreases Morbidity Rates by 50% in Diabetics

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

Gly

cosy

late

d H

b (%

)

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

110

Exercise Groups Control Groups

INSULIN SENSITIVITYINSULIN SENSITIVITY

Exercise Control0

50

100

150

200

250

300

350

Pre-

Post-

Glu

cose U

pta

ke

(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.

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 Differentiation↑Protein

Synthesis↓Gluconeogenesis

↑Glucose Synthesis

GLUT4

Glucose

AMPK

Table 1. Summary of clinical trials in diabetes and micro- and macro-vascular disease.Variable DCCT UKPDS Sterno-2 ADVANCE VADT ACCORDPurpose Micro/macrovascular

complications: Retinopathy neuropathy

Micro/macrovascularComplications in newly diagnosed type 2 diabetics

Macrovascular complications in microalbuminuric pts. Retinopathy Nephropathy Neuropathy Ischemic stress

tests

Vascular outcome in broad range of DM2

Cardiovascular complications

Cardiovascular events of DM2 with cardiovascular risk or disease

Years Recruit 1983-1989Follow-up 1993

Recruit 1997-1991Follow-up 2008

Recruit 1992-1993Follow-up 1996-7

2001-2003 Recruit 2000-?Follow-up 2008

Recruited 2001

Subject Number 1441 4075 160 11,140 1,791 10,251Type of Diabetes DM1 DM2 DM2 DM2 DM2 DM2Medications Metformin primary med.

Added OHA and insulins of goals were not achieved

Gliclazine primary med. Added OHA and insulins of goals were not achieved

Individualized therapeutic discretion of primary physician

Insulin C=Intermediate + rapid (BID)

I=Insulin pumps (TID)

“insulins” Conventional

therapy

NPH added to OHAs

Regular + NPH (BID) added to OHAs

Rapid @ meals “insulins” added last Insulin onlyInsulin + 4-5 OHAs

OHA Sulfonylurea + Metfomin

Metformin (BID) Gliclazide (BID)

added OHAs

Gliclazide Other OHAs

added

Metformin or Glimiperide Rosiglitazone

added

All OHAs in multiples – up to 5

Outcome ↓ 76% risk of retinopathy↓ 54% progression of

retinopathy↓ 47% development of

proliferative or severe non-prolif retinopathy

↓ 39% microalbuminuria↓ 54% albuminuria↓ 60% clinical neuropathy

↓ CV events Slows progression to

nephropathy progression of

retinopathy progression of

neuropathy↓ risk of CV death

↓ 21% nephropathy↔ retinopathy↔ CV events

↔ CV eventsTerminated early at 3.5 years because of CV mortality was 257 in I vs. 203 in C.

Key: DCCT Diabetes Control and Complication TrialUKPDS UK Prospective Diabetes StudySterno 2 Type 2 diabetes study at the Sterno Diabetes CenterADVANCE Action in Diabetes and Vascular Disease Preterax and Dlacmioron Modified Release Control EducationVADT Veterans Affairs Diabetes TrialACCORD Action to Control Cardiovascular Risk in Diabetes

OHA Oral Hypoglycemic AgentDM1 & DM2 Type 1 & Type 2 Diabetes MellitusC Control GroupI Intervention GroupNPH Intermediate Acting Insulin (Neutral Protamine Hagedorn)BID Twice a dayTID Three times a day

MUSCLE BLOOD FLOWMUSCLE BLOOD FLOW

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

0

2

4

6

8

10

12

14

Resitance Filtration Capacity

Control

Diabetes

Resis

tan

ce (

mm

Hg

/ml

min

/100 g

Filtr

ati

on

(d

l/m

in m

mH

g/1

00

g Cap

acit

y (

ml/

100

g)

MUSCLE BLOOD FLOWMUSCLE 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-

Cap

illa

ries/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

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