1 Diabetes: The Burden of Disease Fall, 2007 NUR464.

1

Diabetes: The Burden of Disease

Fall, 2007

NUR464

2

Prevalence of Diabetes Is Escalating

2001

1990 1995

(Includes Gestational Diabetes)

Source: Mokdad A, et al. Diabetes Care. 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc. 2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79.

No Data < 4% 4%-6% 6%-8% 8%-10% > 10%

3

Diabetes Mortality Continues Unabated

YearFreid VM, et al. National Center for Health Statistics, 2003.

Age AdjustedDeath RateRelative to

1980

40

60

80

100

120

140

1980 1990 2000

Diseases of theHeartMalignantNeoplasmsCerebrovascularDiseasesDiabetes Mellitus

4

Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases• Type 2 diabetes

• About 90% of the diabetes population• Dual impairment: Insulin deficiency & Insulin resistance• No longer a disease of adults only• Obesity• Genetic link

• Type 1 diabetes• Approximately 10% of diabetes population• Absolute insulin requirement• Autoimmune mediated

CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

5

Link Between Obesity and Type 2 Diabetes: Harvard Nurses’ Health Study

Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

0

20

40

60

80

100

120

< 22 22 22.9

23 23.8

24 24.9

25 26.9

27 28.9

29 30.9

31 32.9

33 34.9

> 35

BMI (kg/m2)

Age Adjusted Relative Risk for Diabetes Mellitus

6

2002 — Total Per Capita Health Care Expenditures

$13,243

$2,560

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

Dollars

Diabetes Without Diabetes

ADA. Diabetes Care. Mar. 2003;26(3):917-932.

7

Physiologic Blood Insulin Secretion Profile

Plasma Plasma Insulin Insulin ((µU/mL) U/mL)

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

Breakfast Lunch Dinner

Time

8:008:00

Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

8

Normal Physiologic Insulin Sensitivity and Cell Function Produce Euglycemia

Pancreas

Normal Insulin Sensitivity

Liver

EuglycemiaEuglycemia

Islet Cell Degranulation;Insulin Released in Response to Elevated Plasma Glucose Muscle Adipose Tissue

Increased Glucose Transport

Decreased Lipolysis

↓ GlucoseProduction

↑ GlucoseUptake

Normal PhysiologicPlasma Insulin

Decreased Glucose Output

Normal Cell Function

Decreased Plasma FFADecreased Plasma FFA

9

Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes

Pancreas

Insulin Resistance

Liver

HyperglycemiaHyperglycemia

Islet Cell Degranulation;Reduced Insulin Content

Muscle Adipose Tissue

Decreased Glucose Transport & Activity

(expression) of GLUT4

Increased Lipolysis

↑GlucoseProduction

↓GlucoseUptake

ReducedPlasma Insulin

Increased Glucose Output

Cell Dysfunction

Elevated Plasma FFA

Elevated Plasma FFA

10

Frequent Symptoms of Type 2 Diabetes

• Usually slow onset

• May be asymptomatic

• 3 P’s: • polyuria,

• polydipsia,

• polyphagia

• Weakness/fatigue

• Glycosuria

• Dry, itchy skin

• Visual changes

• Skin and mucous membrane infections

11

Stages of Type 2 Diabetes Related to Beta-Cell Function

Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

2 12 2 10 6 0 6 10 14

Beta Cell Function

(%)

0

50

100

75

25

Type 2Phase 1IGT

Years from Diagnosis

Type 2Phase 2

Type 2Phase 3

Postprandial

Hyperglycemia

12

Significant Loss of Beta Cell Function at Diagnosis

• UKPDS• At the time diabetes was diagnosed, 50% of beta cell

function was lost

• Beta cell function continued to decline over the 10-year course of the study

• Correlated with loss of response to oral therapy

• Secondary failure (progressive loss of beta cell)

UKPDS 16. Diabetes. 1995;44:1249-1258 Turner RC, et al. JAMA. 1999 Jun 2;281(21):2005-2012.

13

Glucose Excursions in Type 2 Diabetes

Time of Day

400

300

200

100

00600 06001000 1400 1800 2200 0200

Glucose(mg/dL)

Diabetic

Normal

Polonsky KS, et al. NEJM. 1988;21;318(19):1237-1239.

Meal Meal Meal

14

Insulin Secretion in Type 2 Diabetes

Polonsky KS, et al. N Engl J Med. 1996 Mar 21;334(12):777-783.

Normal

Type 2 diabetes

Time (24 hour clock)

0600 1000 1400 1800 2200 0200

800

600

400

200

0

Insulin Secretion

(pmol/min)

Meal Meal Meal

15

A1C

PPG FPG+

=

Normal A1C < 6.0%

CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

16

2.4

2.0

1.6

1.2

1.0

Relative Risk of Death*

< 140

> 199

< 110 110-125 126- 139 >140

140-198

2-h Postprandial Glucose

(mg/dL)

Fasting Plasma Glucose (mg/dL)

Relative Risk for Death Increases with 2 hour Blood Glucose Regardless of the FPG Level

*Adjusted for age, sex, study center

Adapted from DECODE Study Group. Lancet. 1999;354:617-621.

17

As Patients Get Closer to A1C Goal, the Need to Manage PPG Significantly Increases

Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:881-885.

30%40% 45% 50%

70%

70%60% 55% 50%

30%

< 10.2 10.2 to 9.3 9.2 to 8.5 8.4 to 7.3 < 7.3

FPGPPG

Increasing Contribution of PPG as A1C Improves

% Contribution

0

20

40

60

80

100

A1C Range (%)

18

Blood Glucose Control Guidelines

American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50.American College of Endocrinology. Endocr Pract. 2002;8(suppl 1):40-82.

Preprandial blood glucose

90–130 mg/dL < 110 mg/dL

Postprandial blood glucose

< 180 mg/dL

(peak)

< 140 mg/dL

(2 hour)

A1C < 7% ≤ 6.5%

American Diabetes Association

(ADA)

American College of Endocrinology

(ACE)

19

UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin

Patients Requiring Additional Insulin (%)

Adapted from: Wright A, et al. Diabetes Care. 2002;25:330–336.

20

40

60

01 2 4 5

Years from Randomization

3 6

Chlorpropamide

Glipizide

20

Insulin is Associated with the Most Profound Effects on A1C

Diet & Exercise

SU & Glitinides

MetforminAlpha glycosidase Inhibitors

TZDs Insulin

TypicalChange in A1C

0.5 2.0 1.0 2.0 1.0 2.0 0.5 1.0 0.5 1.0 1.5 2.5

Max Dose

SU=

20 40 mg/day;

Glitinides:4 120 mg

Before meals

2550mg/day

100 mg w/ meals

16 45 mg/day

None

Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.

21

Human Insulins

• Regular

• Neutral Protamine Hagedorn (NPH)

• Premix 70/30 (70% NPH / 30% Regular)

22

Human Insulin Time-Action Patterns

Time (hours) SC injection

Normal insulin secretionat mealtime

Ch

an

ge

in s

eru

m in

su

lin

Baseline Level

Theoretical representation of expected insulin release in nondiabetic subjects

23




Regular insulin (human)

Baseline Level

Theoretical representation of profile associated with Regular Insulin (human)

Ch

an

ge

in s

eru

m in

su

lin

24




NPH insulin (human)

Baseline Level

Theoretical representation of profile associated with NPH Insulin

Ch

an

ge

in s

eru

m in

su

lin

25




Human Premix 70/30 (70% NPH & 30% Regular)

Baseline Level

Theoretical representation of profile associated with Human Premix 70/30

Ch

an

ge

in s

eru

m in

su

lin

26

Analog Insulins

• Rapid-acting

• Basal

• Premix

27

Analog Insulin Time-Action Patterns



Baseline Level

Theoretical representation of expected insulin release in nondiabetic subjects

Ch

an

ge

in s

eru

m in

su

lin

28




Baseline Level

Theoretical representation of profile associated with rapid-acting Insulin Analog

Ch

an

ge

in s

eru

m in

su

lin

Rapid-Acting Insulin Analog

29




QD (basal) Analog Insulin

Baseline Level

Theoretical representation of profile associated with Basal Analog Insulin

Ch

an

ge

in s

eru

m in

su

lin

30




Baseline Level

Theoretical representation of profile associated with Insulin Analog Premix

Ch

an

ge

in s

eru

m in

su

lin

Insulin Analog Premix

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“Although insulin therapy has not traditionally been implemented early

in the course of Type 2 diabetes, there is no reason why it should not be…”

Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.

1 Diabetes: The Burden of Disease Fall, 2007 NUR464.

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