12901990 Diabetes Mellitus Today

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DIABETES MELLITUS

TODAY

DIANA W. GUTHRIE RN, PhD

2006



DEFINITION & THE PROBLEM

• CRITERIA FOR DIAGNOSIS

• DEFINITION

• PATHOPHYSIOLOGY

• PREVALENCE

• OBESITY

•

METABOLIC SYNDROME



Glucose Tolerance Cate ories

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care.2002;25(suppl):S5

FP 2-hr PG on

100 and <126

<100

140 and

<

Glucos

Prediabet

Norm

Diabetes

Toleranc

Prediabet

Diabetes

Norm

mg/d mg/d



Etiologic Classification of

Type 1 -cell destruction withlack of

insulin

Type 2 Insulin resistance withinsulin

deficiency

Other specific Geneticdefects in -cell Types exocrine pancreasdiseases,

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-



Source: Mokdad et al., Diabetes Care 2000;23:1278-83;

Diabetes Trends* Among Adults in theU.S.,

19 19

20



Prevalence of Diabetes in



1 1

2

Obesity Trends* Among U.S. AdultsBRFSS, 1991-2002

No Data <10% 10%–14% 15%–19% 20%–24%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4”



DNPAGraphics:DNPA

Graphics:Diabetes Trends* Among Adults in theU.S.,

Source: Mokdad et al., J Am Med



Source: Behavioral Risk Factor Surveillance System, CDC

(*BMI 30, or ~ 30 lbs overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4”

Obesity Trends* Among U.S. AdultsBRFSS, 2002





• 20.8 million Americans have

diabetes• 1.5 million new cases in 2005

more than 3500 each day

•

Complications of diabetes area major cause of mortality andmorbidity (2002 statistics)

90% of patients with diabetes are

treated by primary care

Diabetes Today: An Epidemic

ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed April 11, 2005;ADA Diabetes Statistics. Available at http://www.diabetes.org/utils/printthispage.jsp?PageID=STATISTICS_233181. December 29,

2005.



Total Cost of Diabetes in the US, 2002Total Cost of Diabetes in the US, 2002

Indirect CostsIndirect Costs$39.8 billion$39.8 billionHealth Care ExpendituresHealth Care Expenditures

$91.8 billion$91.8 billion

DisabilityDisability$18.3 billion$18.3 billion

MortalityMortality$21.5 billion$21.5 billion

Inpatient careInpatient care

$40.3 billion$40.3 billion

Outpatient care/Outpatient care/home health &home health &medicationsmedications$37.1 billion$37.1 billion

Nursing home & hospiceNursing home & hospice$14.4 billion$14.4 billion

Total CostTotal Cost$132 billion$132 billion

American Diabetes Association. American Diabetes Association. Diabetes CareDiabetes Care. 2003;26(3):917-932.. 2003;26(3):917-932.



The Problem



Modern Life Has Both

Illustration taken from: Lambert C, Bing C. The Way We Eat Now. Harvard Magazine. May-June, 2004;50.



METABOLIC SYNDROME

• Obesity- high waist to hip ratio

• Hyperlipidemia

• Hyperinsulinemia

• Hypertension

• Hyperglycemia

•

Acanthosis Nigricans• PCOS



ACANTHOSIS NIGRICANS









Waist/Hip Ratio

High WHR

(

Low WHR

(

American Diabetes Association



Normal Type 2 Diabetes

Courtesy of Wilfred Y. Fujimoto, MD.

Visceral Fat DistributionNormal vs Type 2 Diabetes



And America Continues to Enjoy

Strong Economic Growth……………………………..



Glucose

50

100

150

200

250

300

350

050

100

150

200

250

-1 - 0 5 1 1 2 2 3

Years of Diabetes*IFG=impaired fasting glucose.

Burger HG, Loriaux DL, Marshall JC, Melmed S, Odell WD, Potts JT, Jr., Rubenstein AH. 2001. DiabetesMellitus, Carbohydrate Metabolism, and Lipid Disorders. Chap. in Endocrinology . 4th ed. Edited by Leslie J.

DeGroot and J. Larry Jameson. Vol. 1. Philadelphia: W.B. Saunders Co. Originally published in Type 2 Diabetes BASICS. (Minneapolis, International Diabetes Center, 2000).

Relative

Functio

Fasting Glucose

Postmeal Glucose

Obesit I DiabetUncontrolledHyperglyce

Insulin

-cell Failure

Course of T e 2 Diabetes



*FFA=free fatty acids; TG=triglycerides.

Adapted from: Kahn SE. J Clin Endocrinol Metab. 2001;86(9):4047-4058. Adapted from: Ludwig DS. JAMA. 2002;287(18):2414-2423.

Factors That May Drive the

InsulinResistanc

Hyperglycemia(glucose

-

“Lipotoxicity”(elevated FFA*,



Progression to Type 2 Diabetes

Kruszynska Y, Olefsky JM.Kruszynska Y, Olefsky JM. J Invest Med J Invest Med ..1996;44:413-428.1996;44:413-428.Weyer C, et al.Weyer C, et al. J Clin Invest.J Clin Invest. 1999;104:787-794.1999;104:787-794.

Insulin

Hyperinsuline

Compensated insulinresistance

Impaired glucose

ß-cell

Type 2

Genetic Factors

Genetic Factors

Acquired:•Obesity

•Sedentary lifestyle•Aging

ß-cell

Glucose and/or fat toxicity



Over 90% of type 2 diabetics are Insulin Resistant

InsulinResistance

Hypertensi

Type 2

Disordered

ComplexDyslipidem

ia

TG,

Endothelial Systemic

Inflammati

Atheroscleros

Viscer al

Adapted from the Consensus Development Conference of the AmericanDiabetes Association.

-

The Importance of Targeting Insulin



ETIOLOGY OF T1DM

DQ* D C B A

SHORT ARM # 6 CHROMOSOME



IMPORTANCE OF GLUCOSECONTROL

• DCCT

• KUMAMOTO

• UKPDS

• IN-PATIENT CONTROL



BrainCerebrovascular disease

• Transient ischemicattack

• Cerebrovascular accident

• Cognitive impairment

Complications of Diabetes

HeartCoronary artery disease

• Coronary syndrome• Myocardial infarction• Congestive heart

ExtremitiesPeripheral vascular disease

• Ulceration• Gangrene• Amputation

Macrovascul Microvascul

EyeRetinopathyCataractsGlaucoma

KidneyNephropathy

• Microalbuminuria• Gross albuminuria• Kidney failure

NervesNeuropathy

• Peripheral• Autonomic



29

HbA1c

Retinopathy

Nephropathy

Neuropathy

Macrovascular disease

* not statistically significant

DCCT

63%

54%

60%

41%*

Kumamoto

69%

70%

–

–

UKPDS

17-21%

24-33%

–

16%*

Diabetes Control and Complications Trial (DCCT) Research Group.Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med N Engl J Med . 1993;329:977-986.. 1993;329:977-986.

Ohkubo Y et al.Ohkubo Y et al. Diabetes Res Clin Pract Diabetes Res Clin Pract . 1995;28:103-117.. 1995;28:103-117.UK Prospective Diabetes Study Group (UKPDS) 33:UK Prospective Diabetes Study Group (UKPDS) 33: Lancet Lancet .. 1998;352:837-853.1998;352:837-853.

Good Glycemic Control (Lower





Glycemic Goals For Diabetes



IN-HOSPITAL MANAGEMENT

• PREVALENCE

• SURGERY

• MI

• INFECTION

• ICU



Consensus:

• Intensive care unit

–110 mg/dL (6.1 mmol/L)

•

Medical/surgical floors –110 mg/dL (6.1 mmol/L) preprandial

–140 mg/dL (7.78 mmo/L) maximal

glucoseValues above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levelsmore frequently to determine the direction of any glucose trend and theneed for more intensive intervention. Achieving these targets may requireconsultation with an endocrinologist or diabetes specialist.

American Association of Clinical Endocrinologists. Available at:http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.



Diabetes in Hospitalized

• Fourth most common co-morbidcondition among hospitalizedpatients

• 10–12% of all hospital discharges

• 29% of all cardiac surgery patients

•

1–3 days longer hospital stay

Hogan P, et al. Diabetes Care. 2003;26:917–932. American Association of Clinical Endocrinologists. Available at:

http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.



Hyperglycemia in Patients

• Hyperglycemia occurred in 38% of patientsadmitted to the hospital – 26% had known history of diabetes

–

12% had no history of diabetes• Newly discovered hyperglycemia was associated

with:

– Higher in-hospital mortality rate (16%) compared with

patients with a history of diabetes (3%) and patientswith normoglycemia (1.7%; both P < 0.01)

Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–



Higher Costs:Higher Costs:

• Higher rate of hospitalizationHigher rate of hospitalization

• Longer staysLonger stays

• More procedures, meds.More procedures, meds.

• Chronic complicationsChronic complications

• More arteriosclerotic disease-More arteriosclerotic disease-• More infectionMore infection



Hyperglycemia Is an Independent Marker of

Adapted from Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–

In-hospitalMortality Rate

(%)

NewlyDiscovered

Hyperglycemia

PatientsWith Historyof Diabetes

PatientsWith

Normoglycemia

P < 0.01

P < 0.01



Hospital Mortality Rate and

MortalityRate (%)

Mean Glucose Value (mg/dL)

Retrospective review of 1,826 consecutive intensive care unitpatients

at The Stamford Hospital in Stamford, Connecticut.



Intensive Insulin Therapy in

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

Copyright ©2001 Massachusetts Medical Society. All rights reserved.

Conventional: insulin when blood glucose > 215 mg/dL.Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110

Survival

in ICU (%)

100

96

92

88

80

0

84

0 20 40 60 80 100 120 140 160

Intensive treatment

Conventional treatment

Days After Admission



Intensive Insulin Therapy in Critically

• Intensive therapy to achieve blood glucose levels of 80–110 mg/dL reduced mortality (-34%), sepsis (-46%),dialysis (-41%), blood transfusion (-50%), andpolyneuropathy (-44%)

van den Berghe G, et al. N Engl J Med . 2001;345:1359–1367.

Reduction(%)

Mortality Sepsis Dialysis neuropathy

Blood

Transfusion

34%

46%41%

44%

50%



Hyperglycemia and Risk of

• Glucose > 220 mg/dL onpostoperative day 1 is

– A sensitive predictor of nosocomialinfection

– Associated with•

2.7 times higher rate of infection• 5.9 times higher rate of severe infection

Pomposelli JJ, et al. J Parenter Enteral Nutr. 1998;22:77–





Glucose Control Lowers Risk of Wound

Reprinted from Zerr KJ, et al. Ann Thorac Surg . 1997;63:356–361 with permission from

Society of Thoracic Surgeons.

Deep WoundInfectionRate (%)

13%16%

25%

67%

Day 1 Blood Glucose

P = 0.002



Portland Diabetic Project:Incidence of DSWI and Impact of

CII

DSWI = deep sternal wound infection; CII = continuous insulin infusion.

4.0

3.0

2.0

1.0

0.0

DSWI(%)

87 88 89 90 91 92 93 94 95 96 97

Year

Patients with diabetes

Patientsdiabetes

Reprinted from Furnary AP, et al. Ann Thorac Surg . 1999;67:352–362 with permission

from Society of Thoracic Surgeons.



Cost-Effectiveness in First

For every 9 patients treated withintensive insulin regimen, one life was

saved

Almbrand B, et al. Eur Heart J. 2000;21:733–739.

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.



Indications for Intravenous

• Diabetic ketoacidosis• Nonketotic

hyperosmolar state

•

Critical care illness(surgical, medical)• Postcardiac surgery• Myocardial infarction

or cardiogenic shock• NPO status in Type 1

diabetes

• Labor and delivery

• Glucose exacerbatedby high-dose

glucocorticoidtherapy

• Perioperative period

• After organ

transplant

American Association of Clinical Endocrinologists. Available at:

http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.



Yale Insulin Infusion Protocol

Insulin infusion: Mix 1 U regular human insulin per 1 mL0.9% NaCl Administer via infusion pump inincrements of 0.5 U/h

START INSULIN AT O.O5 U/KG/HR

Subsequent rate adjustments:Changes in infusion rate are determined by the current infusion

rateand the hourly rate of change from the prior BG level; see table

for instructionsOR ORDER-TITRATE TO KEEP BG 70-140 MG/DL

Goldberg PA, et al. Diabetes Care. 2004;27:461–



Insulin Requirements in Health

Copyright © 2004 American Diabetes Association. From Clement S, et al. Diabetes Care.

Units

Healthy Sick/Eatin Sick/NPO

Correction

Nutritional

PrandialBasal



TREATMENT OF DIABETES

• IV INSULIN THERAPY

• ORAL HYPOGLYCMIC AGENTS

• INSULINS

• NEW AGENTS – SYMLIN

– BYETTA

– DPP-IV INHIBITORS

– ALPHA-GAMMA TZD



GlucosGlucos

RelativeRelativeFunctionFunction

© International Diabetes Center. From Kendall D, Bergenstal R. © International Diabetes Center. From Kendall D, Bergenstal R.

0

5

10

15

20

25

-1 - 0 5 1 1 2 2 3

5

10

15

20

25

30

35

Years of Diabetes Years of Diabetes

InsulinInsulin

InsulinInsulin

FastingFasting

Beta cellBeta cell

Post MealPost Meal

At riskAt riskfor for

Timeline for Utilization of

LifestyleLifestyle InsulinInsulin

Metformin, TZD, AGIMetformin, TZD, AGI

SUMeglitinide



Oral Agents

Drug Class

Sulfonylureas

Examples

GlimepirideGlipizideGlyburide

RepaglinideMeglitol

Principal Mode of Action

Stimulate insulinsecretion frompancreatic ß-cells

Stimulate insulinsecretion frompancreatic ß-cells

Key Issues

HypoglycemiaWeight gain

HypoglycemiaWeight gain



Examples

Metformin

RosiglitazonePioglitazone

AcarboseMi litol

Principal Mode of ActionDecreases hepaticglucose

Improve peripheral

insulin sensitivity

Dela carboh drate

Key Issues

GI upsetRenal dis.

Liver enzymes

Weight gain

Flatulence

Oral Agents•

•Drug Class

•

•Biguanides

•

•

•TZD

•

• Alpha-lucosidase

Mi i ki N t With I li



Mimicking Nature With Insulin

Ph siolo ic Insulin Secretion

I n

s u l i n

U / m L

G l u c

o s e

( m g

/ d L )

9

B L D

15

10

5

0

7 8 9 1 11 1 1 2 3 4 5 6 7 8A PTime of Day

§ Suppresses glucose productionbetween meals and overnight

§ Nearly constant levels

§ 50% of daily needs

Basal

5

2

0

24-hr

Basal insulin

Adapted with permission from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology.



Comparison of Human Insulins

Onset of Duration of Insulin Preparations Action Peak Action

Lispro,Asparte,Apidra 5 to 15 min 1 to 2 hr 4 to 6 hr

Human Regular 30 to 60 min 2 to 4 hr 6 to 10 hr

Human NPH 1 to 2 hr 4 to 6 hr 10 to 16 hr

Glargine 2 hr none 22 to 24 hr

* The time course of action of any insulin may vary in different individuals, or at different times in the same individual.

Because of thisvariation, time periods indicated here should be considered as general guidelines only.



I n s u l i n

B DL H

Bolus

Basal

Endogenous

Adapted with permission from McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY:

Marcel Dekker, Inc; 2002:193

Short Acting Insulin Analogs:



Short-Acting Insulin Analogs:

1

5

1

2

2

3

1

51 1

2

Human InsulinHuman Insulin

S S

S

S

S

S

PrLy

Insulin aspart

Aspartate at positionB28 instead of proline

Insulin lispro

Positions of proline andlysine reversed at B28 and

1

Cy

Cy

Cy

Cy

CyCy

Adapted with permission from Barnett A, Owens D.Lancet. 1997;349:47

Bolli G et al. Diabetologia. 1999;42:1151



GLULISINE-APIDRA

GLULISINE APIDRA VS



GLULISINE-APIDRA VS

APIDRA VS HUMALOG VS



APIDRA VS HUMALOG VS







Insulin Glargine

A-

Phe

Val

As

n

Gi

n

His

Leu

Cys

Gly

Ser

His

Leu

Val

Glu

Ala

Leu

Tyr

Leu

Val

Cys

Glu

Ar g

Gly

Phe

Phe

Tyr

Thr

Pr o

Lys

Thr

Gly

Gly

Ile

Val

Glu

Gin

Cys

Cys

Thr

Ser

Ile

Cys

Ser

Leu

Tyr

Gin

Leu

Glu

Asn

Tyr

Cys

Asn

21

B-

Ar g

Ar g

GlGl

Bolli GB, Owens DR. Lancet.

Produced by recombinant DNA technology; 2 modifications in amino acid sequence of insulinmolecule create stable molecule



Clear solution pH

Microprecipitati

Dissolutio

Capillary

pH

Injectionacidic solution (pH

Microprecipitation of

glargine in SC(pH

Slow dissolutionstabilized

Protracted

Seipke G et al. Diabetologia. 1992;35:A4; Hilgenfeld R et al. Diabetologia. 1992;35:A193

Mechanism of Action

Insulin in

INSULIN TACTICS

Gl i NPH I li i T



Glargine vs NPH Insulin in Type

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

6

5

4

3

2

1

00 1

Time (h) After SC

End of observation

2 3

Glargin

P

G l u c o s e U t i l i z a t i o n R a t e

m

/ k / h

Insulin detemir



LysB29(N -tetradecanoyl)des(B30)human insulin

Insulin detemir

B

A2

A

B2



INSULIN IN DIABETES

• INSULIN REQUIREMENTS – 1-2 UNITS/KG/DAY FOR CHILDREN-1/2-

1UNITS/KG/DAY FOR ADULTS DEPENDINGON DEGREE OF KETOSIS &/OR GROWTHRATE

– DISTRIBUTION FOR INJECTABLE INSULIN• BREAKFAST 20% OF TOTAL AS FAST ACTING

• LUNCH 13% OF TOTAL AS FAST ACTING

• SUPPER 17% OF TOTAL AS FAST ACTING• BEDTIME 50% OF TOTAL AS LONG ACTING



EXAMPLE – 24 Units/day



CASE K.M.



EXUBERA INHALABLE INSULIN



Photograph reproduced with permission of

Continuous Glucose Monitoring SystemContinuous Glucose Monitoring System



Continuous Glucose Monitoring SystemContinuous Glucose Monitoring System(CGMS)(CGMS)



3 Interstitial fluid

glucose(G2) is ?comparable with

Interstitial Fluid Measurement



Adapted from Unger RH, Foster DW. Williams Textbook of Endo (8th edition) 1992; 1273-1275

Amide

S SA

YT

N

SG

V NT

T TT

N

AA

A

LI

KS

SC

CQ

RL N

NNF

G

FL

VH

Amylin the Hormone

• Reported in 1987

• 37-amino acid peptide

• Co-located and co-secreted with insulin

from pancreatic β-cells• Neuroendocrine hormone

• Deficient in diabetes



GILA MONSTER ORIGINAL



GILA MONSTER-ORIGINAL



Prescribing Consideration



Prescribing Consideration

•2 fixed-dose prefilled pens – 60 doses per pen (30-day supply)

– Ready to use, easy to teach

See Important Safety Information included in this presentation

S



Summary

• The evidence is overwhelming that goodcontrol does count

• Morbidity and mortality can be reduced

• There is nothing inevitable about thecomplications of diabetes

S ( t)



Summary (cont)

• The cost of diabetes is in its complications

• Any expense paid up front in better management will pay off handsomely in

the long run• The tools for good diabetes care already

exist

•No tool is more important than theservices of a certified diabetes educator

S ( t)



Summary (cont)

• Assessment tools include Self Monitoringof Blood Glucose and HbA1C

• Targets should be established for each of

these for each patients within the nationalguidelines

• When targets are not reached the help of

a specialist should be sought• Christopher D. Saudek MD. Pres. ADA

2002

S



Summary

• Insulin administration should mimic nature

• Natures way is basal insulin 24 hrs. a day

• And bolus insulin with every feeding

• Insulin lispro, asparte or glulisine cansupply bolus

• Insulin glargine or detemir can supply the

basal with one injection per day• Control of blood sugar will prevent the

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12901990 Diabetes Mellitus Today