Diabetes MellitusDiabetes Mellitus

Sufyan Said, M.D.Staff Physician, CAVHS

Assistant Professor, UAMS

Definition of Diabetes Definition of Diabetes MellitusMellitus

Diabetes Mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both

The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially in the eyes, kidneys, nerves, heart and blood vessels.

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1998;21(suppl 1):S5-S19

1998 Criteria for the Diagnosis of Diabetes 1998 Criteria for the Diagnosis of Diabetes MellitusMellitus

(Each must be confirmed on a subsequent day.) Symptoms of Diabetes* plus casual† plasma

glucose concentration 200mg/dlOr

Fasting plasma glucose‡ 126 mg/dlOr

2-h plasma glucose 200 mg/dl during an OGTT§

* Classic Symptoms = polyuria, polydipsia, and unexplained weight loss.† Casual = any time of the day without regard to time since last meal.‡ Fasting = no calori intake for at least 8 h.§ Requires use of a glucose (75 gm) load.OGTT = oral glucose tolerance test.The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1998;21(suppl 1):S5-S19

Estimated Prevalence (20- 79 age Estimated Prevalence (20- 79 age group)group)

Country Prevalence

(%)

Country Prevalence

(%)

Papua New Guinea

15.5 Aruba, Bermuda, British Virgin

Islands, Cayman Islands, Grenada,

Hong Kong, St Kitts, Nevis

12.1Mauritius 15.0

Bahrain 14.8

Mexico 14.2

Trinidad

Tobago

14.1 Pakistan 11.8

Czech Republic 11.7

Barbados 13.2 Tonga 11.5

IDF D I A B E T E S 2000 executive summary page 10

Harris MI et al. Diabetes Care. 1998;21:518-524.

Incidence and Prevalence of Incidence and Prevalence of Diabetes (US)Diabetes (US)

15.7 million Americans have diabetes

Nearly 6% of the population 5.4 million of these people are unaware

they have diabetes Each year, >798,000 Americans

develop diabetes

>2,200 each day

0

5

10

15

20

25

30

35

20-39 40-49 50-59 60-74 75+

Undiagnosed Diabetes

Diagnosed Diabetes

Impaired Fasting Glucose

Age (yr)

Per

cen

t of

Pop

ula

tion

Prevalence of Diabetes and Impaired Prevalence of Diabetes and Impaired Fasting GlucoseFasting GlucoseUS, 1988-1994US, 1988-1994

Harris MI et al. Diabetes Care. 1998; 21:518-524.

1997 Per Capita Health Care Costs:1997 Per Capita Health Care Costs:Persons With and Without DiabetesPersons With and Without Diabetes

Data from American Diabetes Association. Diabetes Care. 1998;21:296-309.

An

nu

al C

ost

($10

00s)

0

5

10

15

20

25

OutpatientDrugs

OfficeVisits

EROutpatientServices

Inpatient

23.5

12.2

2.51.5

0.7 0.4 0.7 0.4 0.7 0.2

Diabetes

No diabetes

History of DiabetesHistory of Diabetes

1500 BCEarly healers notice that ants are attracted to the urine of people with a mysterious emaciating disease.

150 The Greek physician Aretaeus of Cappodocia writes about diabetes, which he says "melts the flesh."

1000 Greek physicians prescribe exercise, preferably on horseback, to relieve excess urination.

History of DiabetesHistory of Diabetes

1869Paul Langerhans discovers islet cells in the pancreas.

1889 Mehring and Minkowski produce DM in dogs by removing the pancreas.

1921Banting and Best find a pancreatic extract that lowers blood glucose in pancreatectomized dogs.

VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE

History of DiabetesHistory of Diabetes

1923The Nobel Prize for medicine goes to Banting and Macleod for the discovery of insulin.

1950-1980DNA technology allows development of genetically engineered "human" insulin.

1980-1989Blood glucose self- management gives patients greater control and flexibility in managing diabetes.

History of DiabetesHistory of Diabetes

1990-1997More sophisticated insulin analogues are introduced, and multiple injections and insulin pumps offer promise of closer control.

2000 and beyondResearch continues for ways to cure both type 1 and type 2 diabetes.

Comparison of clinical, genetic and immunologic Comparison of clinical, genetic and immunologic features of type 1 and type 2 diabetesfeatures of type 1 and type 2 diabetes

Characteristic Type 1 Type 2

Onset Abrupt Progressive

Endogenous insulin Low to absent Normal, elevated or depressed

Ketosis Common Rare

Age at onset Any age Vast majority Adults

Body mass Usually non-obese Obese or nonobese

Family history 10-15% 30%

Twin concordance 30-50% 70-90%

HLA HLA-DR, HLA-DQ Unrelated

Autoantibodies >85% Rare

Insulin Resistance & Impaired Insulin Resistance & Impaired -Cell -Cell FunctionFunction

InsulinInsulinresistanceresistance

CompensatoryCompensatoryHyperinsulinemiaHyperinsulinemia

NormoglycemiaNormoglycemia

Normal Normal -cell -cell functionfunction

Relative insulin deficiencyRelative insulin deficiency

HyperglycemiaHyperglycemia

Type 2 diabetesType 2 diabetes

Abnormal Abnormal --cell functioncell function

Visceral Fat Distribution:Visceral Fat Distribution:Normal vs Type 2 DiabetesNormal vs Type 2 Diabetes

Normal Type 2 Diabetes

050

100150200250

Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes

50100150200250300350

Obesity IFG* Diabetes Uncontrolled hyperglycemia

Postmeal glucose

Fasting glucose

Insulin resistance

Insulin level-cell failure

Glucose(mg/dL)

Relative function

(%)

Years of diabetes*IFG=impaired fasting glucose.

-10 -5 0 5 10 15 20 25 30

Adapted from International Diabetes Center (Minneapolis, Minn).

Approach to Treatment of Type 2 Approach to Treatment of Type 2 DiabetesDiabetes

Diet Exercise Weight reduction Oral agents Insulin Careful attention to cardiovascular risk

factors; hypertension, smoking, dyslipidemia and family history

Diabetes Care. 1998;21(suppl 1):S23-S31

Goals of Diet Therapy: Metabolic Control Goals of Diet Therapy: Metabolic Control and Balanceand Balance

Maintenance of as near-normal blood glucose levels as possible

Prevention of acute and long term complications of diabetes

Improvement of overall health through optimal nutrition Adequate calories for maintaining/attaining reasonable

weights for adults, normal growth and development in children and adolescents, increased metabolic needs during pregnancy and lactation, or recovery from catabolic illnesses

Diabetes Care. 1998;21(suppl 1):S32-S35

Antihyperglycemic Agents:Antihyperglycemic Agents:Major Sites of ActionMajor Sites of Action

Liver

Plasma glucose

GI tract

+

Pancreas

Muscle/Fat

–

Injected Insulin

(–)

(+)

-GlucosidaseInhibitors

(–)Carbohydrat

eAbsorption

Metformin (–)

GlucoseProduction

Glitazones

(+)Glucos

eUptake

InsulinSecretion

SulfonylureasMeglitinides

(+)Insulin

Secretion

Pharmacological approaches to Pharmacological approaches to Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes

Sulfonylureas Glyburide Diabeta,

Micronase, Glynase Glipizide Glucotrol Glimepiride Amaryl

Meglitinides Neteglinide Starlix Rapeglinide Prandin

Biguanides Metformin Glucophage

Thiazolidinediones Pioglitazone Actos Rosiglitazone Avandia

α-Glucosidase Inhibitors

Acarbose Precose Miglitol Glycet

Insulin Several

The The -Glucosidase Inhibitors:-Glucosidase Inhibitors:Basic Characteristics of Acarbose and MiglitolBasic Characteristics of Acarbose and Miglitol

Mechanism of action Delays carbohydrate absorptionDepends upon Postprandial hyperglycemia

Power Decreases HbA1c 0.5% to 1%Dosing Three times dailySide effects FlatulenceMain risk Liver enzyme elevation (rare)

Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

The Thiazolidinediones The Thiazolidinediones (Glitazones):(Glitazones):

Basic Characteristics of GlitazonesBasic Characteristics of Glitazones

Mechanism of action Enhance muscle and adiposetissue response to insulin

Depends upon Presence of insulin and resistance to its action

Power Decreases HbA1c 0.5% to 1.5%Dosing Once or twice dailySide effects Edema, weight gain, anemia Main risk Liver failure (? troglitazone only)

The Biguanides:The Biguanides:Basic Characteristics of MetforminBasic Characteristics of Metformin

Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537; De Fronzo, et al. N Engl J Med. 1995;333:541-549; Bailey & Turner. N Engl J Med. 1996;334:574-579; Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

Mechanism of action Decreases hepatic glucoseproduction

Depends upon Presence of insulin

Power Decreases HbA1c 1% to 2%Dosing One to three times dailySide effects Diarrhea, nausea Main risk Lactic acidosis

The Insulin Secretagogues:The Insulin Secretagogues:Basic Characteristics of the Sulfonylureas and Basic Characteristics of the Sulfonylureas and

the Meglitinidesthe Meglitinides

Mechanism of action Increase basal and postprandialinsulin secretion

Depends upon Functioning -cells

Power Decreases HbA1c 1% to 2%

Dosing Once or twice daily (sulfonylureas);three times daily (meglitinides)

Side effects Weight gain

Main risk Hypoglycemia

Practical Management of Type 2 Diabetes Practical Management of Type 2 Diabetes MellitusMellitusFBG >126 mg/dL

Diet and Exercise

126-140 mg/dL 140-200 mg/dL 200-240 mg/dL 240-300 mg/dL >300 mg/dL

SulfonylureaMetforminAcarbose

Sx

Insulin

No Sx

Sulfonylurea

No Sx/Sx

Sulfonylurea

Evolving criteria If FBG >140 mg/dL (126 mg/dL) HbA1c >8% (7%?)

Add second oral agent and titrate to maximum dose

If no improvement: Try triple therapy? Or continue oral agent(s)

+ insulin Rx at PM or HS

Sx

Sulfonylurea

No Sx

SulfonylureaMetformin

Acarbose

Glitazones

Sulfonylurea

Repaglinide

Metformin

Oral Combination Triple Therapy

Monotherapy

Insulin StructureInsulin Structure

Insulin PreparationsInsulin PreparationsClass Agents

Human insulins Regular, NPH, lente,

ultralente

Insulin analogues Aspart, glulisine, lispro, glargine

Premixed insulins Human 70/30, 50/50Humalog mix 75/25Novolog mix 70/30

Human InsulinHuman InsulinA-chain

B-chain

Zn++

Zn++

Self-aggregationin solution

Monomers

Dimers

Hexamers

21 amino acids

30 amino acids

Modified Human InsulinModified Human Insulin

Regular Insulin Short actingHexamers in Zn2+ buffer

Neutral Protamine Hagedorn (NPH) Insulin Intermediate actingMedium-sized crystals in protamine-Zn2+ buffer

Lente and Ultralente Insulin Intermediate andLarge crystals in acetate-Zn2+ buffer long acting

Insulin AnaloguesInsulin AnaloguesHuman InsulinDimers and hexamers

in solution

A-chain

B-chain

Lys Pro

Gly

Arg Arg

Asp

LisproLimited self-aggregation

Monomers in solution

AspartLimited self-aggregation

Monomers in solution

GlargineSoluble at low pH

Precipitates atneutral (subcutaneous) pH

GluGlulisine

Limited self-aggregationMonomers in solution

Lys

Insulin GlargineInsulin GlargineA-chain

Phe

1

Val

2

Asn

3

Gin

4

His

5

Leu

6

Cys

7

Gly

8

Ser

9

His

10

Leu

11

Val

12

Glu

13

Ala

14

Leu

15

Tyr

16

Leu

17

Val

18

Cys

19

Glu

21

Arg

22

Gly

23

Phe

24

Phe

25

Tyr

26

Thr

27

Pro

28

Lys

29

Thr

30

Gly

20

Gly

1

Ile

2

Val

3

Glu

4

Gin

5

Cys

6

Cys

7

Thr

8

Ser

9

Ile

10

Cys

11

Ser

12

Leu

13

Tyr

14

Gin

15

Leu

16

Glu

17

Asn

18

Tyr

19

Cys

20

Asn

21

S

S S

S

S S

B-chain

Arg

31

Arg

32

GlyGly

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

Lantus® Prescribing Information. Please see accompanying prescribing information

Insulin Glargine: AbsorptionInsulin Glargine: Absorption

Clear Solution pH 4.0

pH 7.4

Precipitation

Dissolution

Capillary Membrane

Insulin in Blood

Hexamers Dimers Monomers

10-3 M 10-5M 10-8 M

Injection of an acidic solution (pH 4.0)

Precipitation of glargine in SC tissue (pH 7.4)

Slow dissolution of free glargine hexamers from precipitated glargine (stabilized aggregates)

Protracted action

Adapted with permission from Kramer W. Exp Clin Endocrinol Diabetes.1999;107(suppl 2): S52-S61.

Please see accompanying prescribing informationPlease see accompanying prescribing information

Insulin Profiles Insulin Profiles

Rosenstock J. Clin Cornerstone. 2001;4:50-61.Please see accompanying prescribing information

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sm

a I

nsu

lin

Levels

Regular (6–10 hr)

NPH (10–20 hr)

Ultralente (~16–20 hr )

Time (hr)

Glargine (~24 hr)

Aspart, Lispro (4–5 hr)

Comparison of Human Insulins and Comparison of Human Insulins and AnaloguesAnalogues

Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours

Human Regular 30-60 minutes 2-4 hours 6-10 hours

Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours

HumanUltralente 2-4 hours Unpredictable 16-20 hours

Glargine 1-2 hours Flat ~24 hours

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

Insulin Preparations

Onset of Action Peak

Duration of Action

Moderate intensive therapyModerate intensive therapy

Intensive TherapyIntensive Therapy

Insulin PenInsulin Pen

5-21

1 Pump moves insulin...

2 ...into the Subcutaneous tissue

where it eventually diffuses...

3 ...to the Bloodstream, which slowly

carries the insulin...

4 ...to the Cells where it combines

 with the insulin receptors, which

      use it to allow glucose to enter

  the cell and be metabolized.

GluControl® GC300 by Arthomed Last updated 8-2000 not FDA approved Uses Near-Infrared Quantitative Chemical Analysis.

SugarTrac® NONINVASIVE GLUCOSE MONITOR LifeTrac Systems, Inc. Uses Near-Infrared Quantitative Chemical Analysis. Clinical Trials being conducted in conjunction with Harvard University http://www.sugartrac.com

The Diasensor 2000 available in Europe Biocontrol Technology, Inc FDA is reviewing at this time Uses Near-Infrared Quantitative Chemical Analysis.

Relationship of A1C* to Risk of Microvascular Complications

Adapted with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243

RetinopathyNephropathyNeuropathyMicroalbuminuria

Re

lati

ve

Ris

k

A1C (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

*Based on DCCT data

DCCTDCCT

Microvascular Risk Reduction Microvascular Risk Reduction With Intensive TreatmentWith Intensive Treatment

Data from the Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.

Reduction inComplication Relative Risk

Retinopathy 63%

Nephropathy 54%

Neuropathy 60%

Results of Intensive Glycemic Control in Type 2 Results of Intensive Glycemic Control in Type 2 Diabetes: Kumamoto University StudyDiabetes: Kumamoto University Study

Intensive glycemic control reduced the risk of:

Retinopathy (65%) Severe retinopathy (40%) Worsening of nephropathy (70%) Microalbuminuria (57%)

Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117

Blood Glucose Control GuidelinesBlood Glucose Control Guidelines

American Diabetes Association (ADA)

American College of Endocrinology

Preprandial blood glucose

90-130 mg/dl <110 mg/dl

Postprandial blood glucose

<180 mg/dl (peak) <140 mg/dl (2 hour)

HBA1C <7 <6.5

American Diabetes Association. Diabetes Care. 2004; 27(suppl 1):S1 .S150American College of Endocrinology. EndocrPract. 2002;8(suppl 1):40.82.

lipoatrophylipoatrophy

CataractCataract

The EndThe End