Diabetes Type 2: Tight Diabetes Type 2: Tight ControlControl

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 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

Estimated number in millions of people Estimated number in millions of people with diabetes (20- 79 age group)with diabetes (20- 79 age group)

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

country millionsIndia 32.7

China 22.6

USA 15.3

Pakistan 8.8

Japan 7.1

Indonesia 5.7

Mexico 4.4

Egypt 3.4

Brazil 3.3

Italy 3.1

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

History of DiabetesHistory of Diabetes

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

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

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

Diabetes is a wonderful affection, not Diabetes is a wonderful affection, not very frequent among men, being a very frequent among men, being a

melting down of the flesh and limbs melting down of the flesh and limbs into urineinto urine

Areteus the Cappadocian, sometime in the second to third century AD

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

Dr. F.G. Banting, Mr. C.H. Best, Mr. J.B. Collip and Prof. J.J.R. MacLeod discovered insulin in 1921 at the University of Toronto.

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 I and type II 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

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

Treatment to Goal:Treatment to Goal:The Levels of Glycemic ControlThe Levels of Glycemic Control

Biochemical Index Non-diabetic Goal

Additional action

suggested

Fasting glucose*

(mg/dl)

<110 80-120 <80

>140

Bedtime glucose

(mg/dl)

<120 100-140 <100

>160

Hemoglobin A1C

(%)

<6 <7 >8

*Capillary blood valuesHbA1C is referenced to non-diabetic range of 4% to 6%Diabetes Care. 1998;21(suppl 1):S23-S31

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

GlitazonesMetforminAcarbose

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

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.

lipoatrophylipoatrophy

CataractCataract

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%

DCCT: Reduction of Risk for Appearance or Progression of Diabetic DCCT: Reduction of Risk for Appearance or Progression of Diabetic Complications With Intensive Glycemic ControlComplications With Intensive Glycemic Control

Complications Risk Reduction

(%)

95%

confidence interval

Appearance of retinopathy

(primary prevention) 76 62-85

Progression of retinopathy

(secondary prevention) 54 39-66

Urinary albumin excretion

(mg/24 h)

40

300

39

54

21-52

19-74

Clinical neuropathy at 5 yr* 60 38-74

* Excluding patients with clinical neuropathy at base line.N = 1441 patientsHoowerf BJ et al. Cleve Clin J Med. 1994;61:34-37.

The EndThe End

The following was written by Areteus the Cappadocian, sometime in the The following was written by Areteus the Cappadocian, sometime in the second to third century AD. This is from Dorothy Clark's "Source Book of second to third century AD. This is from Dorothy Clark's "Source Book of Medical History," originally published in 1942, and republished in 1960 by Medical History," originally published in 1942, and republished in 1960 by Dover. She cites as her source a translation of a Greek version done by Dover. She cites as her source a translation of a Greek version done by

Francis Adams in 1856 for the Sydenham Society.Francis Adams in 1856 for the Sydenham Society.

Diabetes is a wonderful affection, not very frequent among men, being a melting down of the flesh and limbs into urine. Its cause is of a cold and humid nature as in dropsy. The course is a common one, namely the kidneys and bladder; for the patients never stop making water, but the flow is incessant, as if from the opening of aqueducts. The nature of the disease then is chronic, and it takes a long period to form, but the patient is short-lived if the constitution of the disease be completely established; for the melting is rapid, the death speedy. Moreover, life is disgusting and painful; thirst unquenchable; excessive drinking, which however is disproportionate to the large quantity of urine for more urine is passed; and one cannot stop them either from drinking or making water. Or if for a time they abstain from drinking, their mouth becomes parched and their body dry; the viscera seem as if scorched up; they are affected with nausea, restlessness, and a burning thirst; and at no distant term they expire. Thirst as if scorched by fire.

But by what method could they be restrained from making water? Or how can shame become more potent than pain? And even if they were to restrain themselves for a short time they become swelled in the loins, scrotum and hips; and when they give vent they discharge the collected urine, and the swellings subside for the overflow passes to the bladder. If the disease be fully established, it is strongly marked; but if it be merely coming on, the patients have the mouth parched, saliva white, frothy, as if from thirst (for the thirst is not yet confirmed), weight in the hypochondriac region. A sensation of heat or cold from the stomach to the bladder is, as it were, the advent of the approaching disease; they now make a little more water than usual and there is thirst but not yet great.

But, if it increase still more, the heat is small indeed, but pungent, and seated in the intestines; the abdomen shrivelled, veins protuberant, general emaciation when the quantity of urine and thirst have already increased; and when, at the same time, the sensation appears in the extremity of the member, the patients immediately make water. Hence the disease appears to me to have got the name diabetes, as if from the Greek word which signifies a siphon, because the fluid does not remain in the body, but uses the man¼s body as a bladder whereby to leave it. They stand out for a certain time, though not for very long for they pass urine with pain, and the emaciation is dreadful; nor does any great portion of the drink get into the system, and many parts of the flesh pass out along with the urine.

The cause of it may be that some of the acute diseases may have terminated in this; and during the crisis of the disease may have left some malignity lurking in the part. It is not improbable also, that something pernicious, derived from other diseases which attack the bladder and kidneys, may sometimes prove the cause of this affection. But if anyone is bit by the dipsas [a species of viper] the affection induced by the wound is of this nature; for the reptile, the dipsas, if it bite one, kindles up an unquenchable thirst. For they drink copiously, not as a remedy for thirst, but so as to produce repletion of the bowels, by the insatiable desire of drink. But if one be pained by the distention of the bowels and feel uncomfortable, and abstain from drink for a little, he again drinks copiously from thirst, and thus the evils alternate; for the thirst and the drink conspire together. Others do no pass urine, nor is their any relief from what is drank. Wherefore, what from insatiable thirst, an overflow of liquids, and distention of the belly, the patients have suddenly burst.

TREATMENT The affection of diabetes is a species of dropsy, both in cause and

condition, differing only in the place by which the humour runs. For, indeed, in ascites the receptacle is the peritoneum, and it has no outlet, but remains there and accumulates. But in diabetes, the flow of the humour from the affected part and the melting are the same, but the defluction is determined to the kidneys and the bladder; and in dropsical cases this is the outlet when the disease takes a favorable turn; and it is good when it proves a solution to the cause, and not merely a lightening of the burden. In the latter disease the thirst is greater; for the fluid running off dries the body.

But the remedies for the stoppage of the melting are the same as those for dropsy. For the thirst there is need for a powerful remedy for in kind it is the greatest of all sufferings; and when a fluid is drunk it stimulates the discharge of urine; and sometimes as it flows off it melts and carries away with it particles of the body. Medicines then which cure thirst are required, for the thirst is great with an insatiable desire of drink, so that no amount of fluid would be sufficient to cure the thirst. We must, then, by all means strengthen the stomach, which is the fountain of the thirst. When, therefore, you have purged with the hiera, use as Epithemes the nard, mastich, dates, and raw quinces; the juice of these with nard and rose oil is very good for lotions; their pulp with mastich and dates, form a cataplasm....

But the water used as drink is to be boiled with autumn fruit. The food is to be milk, and with it cereals, starch, groats of spelt, gruels. Astringent wines to give tone to the stomach, and these but little diluted, in order to dissipate and clear away the other humours; for thirst is engendered by saltish things.

But the water used as drink is to be boiled with autumn fruit. The food is to be milk, and with it cereals, starch, groats of spelt, gruels. Astringent wines to give tone to the stomach, and these but little diluted, in order to dissipate and clear away the other humours; for thirst is engendered by saltish things.

The following are excerpts from a letter written in 1894 to the Mayor of New The following are excerpts from a letter written in 1894 to the Mayor of New York City by Cyrus Edson, the Commissioner of Health. It was published in a York City by Cyrus Edson, the Commissioner of Health. It was published in a popular journal called Overland Monthly and Out West Magazine. Most of the popular journal called Overland Monthly and Out West Magazine. Most of the

letter discusses the "wholesomeness" of glucose (grape sugar) compared letter discusses the "wholesomeness" of glucose (grape sugar) compared with sugar derived from cane sugar, apparently a major issue in the late 19th with sugar derived from cane sugar, apparently a major issue in the late 19th

century. I have included only that part that describes diabetes and its two century. I have included only that part that describes diabetes and its two types as then recognized. types as then recognized.

...In addition to certain nervous varieties, due solely to disturbed nerve functions, diabetes is divided into two classes, of which one is due to excessive sugar formation in the blood and the other to diseased digestion, which prevents sugar from entering the circulation in the condition to be utilized by the system. The first of these classes is caused by disease of the liver; the second by disease of the pancreas. The latter form is by far the most dangerous and rapidly fatal. The former variety, on the other hand, may last many years.