- DIABETES MELLITUS AND ITS COMPLICATIONS ARE NOW THE THIRD LEADING CAUSE OF MORTALITY IN THE UNITED STATES AND THE SECOND LEADING CAUSE OF BLINDNESS.

- DIABETES MELLITUS AND ITS COMPLICATIONS ARE NOW THE THIRD LEADING CAUSE OF MORTALITY IN THE UNITED STATES AND THE SECOND LEADING CAUSE OF BLINDNESS.

-ESTIMATED PREVALENCE IN

U.S.A 3 - 6 % AND INCREASING

RAPIDLY

-ESTIMATED PRVALENCE IN

SAUDI ARABIA to 2003

18-24%

-STROKE, M1 AND END – STAGE RENAL

DISEASE ARE FREQUENT CAUSES OF

MORTALITY.

-THE DISEASE IS FOUND THROUGHOUT THE WORLD AT VARYING PRVALENCE RATE.

- IN PIMA INDIANDS PREVALENEC RATE AT 50 %

NIDDM IS MAJOR CAUSE OF MORBIDITY AND MORTALITY PREVAILING FROM,MACROVASCULAR DISEASE , BUT ALSO FROM SPECIFIC COMPLICATIONS OF DISABETES , RETINOPATHY , NEPHROPATHY AND NEUROPATHY.

DIABETES MELLITUS IS ADISEASE

COMPLEX CHARACTERISED BY RELATIVE OR

ABSOLUTE INSUFFICIENCY OF INSULIN

SECRETION AND A CONCMMITANT

INTENSITIVITY OR RESISTANCE TO THE

METABOLIC ACTION INSULIN TARGET

TISSUE.

NON INSULIN DEPENDENT DABETES ( NIDDM ) IS by FAR THE MOST PREVALENT FORM OF DIABETES WORLD – WIDE , FORMING MORE THAN 95 % OF ALL DIABETES IN MANY DEVELOPING COUNTRIES .

Genetic Factors

HLA class 2 antigens in DR + DQ regions =

>90% Caucasian patients have either DR3 or DR4 , DR2 is protective.

Environmental Factors:

No Specific factors have been identified

Viruses

The risk greater for children born between February-September

IgM antibodies against conxsackievirus found in

25-30% of new cases suggesting recent infection

( cont . )

Coxsackievirus B RNA has been detected in 65% of children under the age of 7 years with newly diagnosed IDDM compared with 4% of controls which is consistent with recent Infection..

(CONT)

Dietary Factors

Cow,s mild feeding fist 4 months indicated risk of subsequent IDDM, whilst breast feeting appeared protective.

Case controlled studies in Sweden have indicated a positive association between IDDM ,high protein intake and frequency of consumption of foods containing nitrosamine.

(CONT)

Loss of first- phase insulin secretion in response to intravenous glucose is highly Predictive of early onset of diabetes .

Islet cell antibodies in ICA are present in 80% of children at the time of diagnosis and have been detected up to 15 years before diagnosis of IDDM.

Long- term follow up has shown that family members with ICA are at greatly increased risk of progression to diabetes and this risk is directly related to persistence and strength of the ICA reaction.

Other antibodies include:

insulin autoantibodies ( IAA)

antibodies to GAD ( Glutamate decarboxylase )

Protein tyrosine phosphatase IA-2

The presence of ICA together with 2 or more markers indicate a greater than 80% risk of progressing for insulin treatment in otherwise healthy family members .

( cont.)

0

50

100RELEASE

“HONEYMOON” PERIOD

OVERT DIABETES

PROGRESSIVE IMPAIRMENT IN INSULIN RELEASE

NORMAL INSUILN

TIME(YR)

BE

TA

-CE

LL

MA

SS

(%

OF

MA

X)

0

BIRTH

IMMUNOLOGIC ABNORMALITES

GENETIC PREDISPOSITION

NATURAL HISTORY OF BETA-CELL DEFECT

DUE TO BETA-CELL RESERVE

INSULIN REQUIREMENT DECREASED

LASTS FOR UP TO 1 YR

PATIENT ALWAYS RELAPSES

TREATMENT PROPOSED TO EXTEND HONEYMOON PERIOD STILL EXPERIMENTAL

RELATIONSHIPS OF TYPE I WITH OTHER AUTOIMMUNE DISEASES

ASSOCIATION BETWEEN HLA GENES AND DIABETES

PRESENCE OFANTI-ISULET AND/OR ANTI-INSULIN ANTIBIES

PRESENCE OF INFLAMMATORY CELLS AROUND ISLETS

EVIDENCE OF IMMUNE SYSTEM ACTIVATION

0 50

Slow B cell failure Less insulitis GAD antibodies/ ICA HLA associations+

Years

Acute B cell failure

Insulitis

1AA/1A-2 antibodies/1CA/GAD antibodies HLA

associations +++

The spectrum of autoimmune diabetes

0 50Years

? LADASlow type 1

Classic type 1

Type 1 in infancy

Clinical spectrum

The clinical and immunogenetic characteristics of insulin

dependent diabetes mellitus change according to age at

presentation

1AA,insulin auto-antibodies:1A-2,protein1A-2:GAD,glutamate decarboxylase;ICA,islet cell

antibodies,LADA, latent autoimmune diabetes in the adult

DR2

TYPE I DR3

DR4

A 2 ---------- BW51--------------- DR4

B8-------------B15 GENERALLY LOW IN POPULATION

W.H.O. CLASSIFICATION

TYPE I ( INSULIN DEPENDET DIABETES MLLITUS IDDM)

HAVE LITTLE OR NO ENDOGENOUS INSULIN

ONSET OF DISEASE IS CLNICALLYABRUPT WITH : MARKED POLYURIA, POLYDIPSIA POLYPHAGIA WEIGHT LOSS, FATIGUE.

THESE PATIENTS ARE HIGHLY PRONE TO KETOSTS

THEY FREQUENT ARE PRESNT IN AND INITIAL ATTACK OF KETOACIDOSIS

GENERALLY HAVE WEIGHT LOSS AND ARE FREQUENTLY AT OR BELOW IDEAL WEIGHT AND ARE THEREFORE PARTICULARY SENSITIVE TO INSULIN (ESPECIALLY REGULAR OR SOLUBLE INSULIN).

CAN OCCUR AT ANY AGE , BUT PEAKS IN THE

MIDDLE OF THE FIST DECADE AND AGAIN AT THE

TIME OF GROWTH ACCELERATION OF ADOLESCENCE.

OLD TERM – JUVENILE ONSET DIABETES MLLITUS .

TYPE I CONTD . .

A PRODOMAL PHAE OF POLYUREA , POLYDYPSIA AND WEIGH LOSS MAY PRECEDE THE DEVELOPMENT OF KETOACIDOSIS BY A PERIOD OF MONTHS ( MOST COMMONLY 2 - 4 WEEKS ).

GENETIC PREDISPOSISTION ( FAMILY HISTORY LESS STRONGLY ASSOCIATED THAN WITH TYPE II ).

ASSOCIATED WITH SOME HLA HITOCMPATIBILTY ANTIGENS EG . B8, B15, DW3, DW4.

TYPE I CONTD…

ASSOCIATED WITH ISLET CELL ANTIBODIES

VIRUS AETIOLOGY IS IMPLICATED ESPECIALLY COXACKIE B4 AND MUMPS.

SIGNIFICANT ASSOCIATION WITH CERTAIN AUTOIMMUNE DISORDERS - ADDISON ‘ S , HASHIMOTO’S TYROIDITS, HYPOPARATHYROIDISM, PERNICIOUS ANAEMIA

TYPE I CONTD .. .

100

90

80

70

60

50

40

30

20

10

COMA 5%

WEIGHT LOSS

35%

DKA 25%

%

POLYURIA 75%

100

90

80

70

60

50

40

30

20

10

PH< 7.2

20%

HYPERGLYCEMIA AND/ OR

GLYCOSURIA 100%

KETONURIA 85%

HCO3<18 60%

%

NIDDM IS ALMOSTCERTAINLY A HETEOGENOUS MIXTURE OF CONDITIONS CHARACTERISEDBY HYPERGLYCAEMIA , OF INSULIN RESISTANCE AND INSULIN HYOP-SECRETION AND LACK OF DEPENDENCE ON EXOGENOUS INSULIN TO MAINTAIN LIFE

FOR MAJOR ABNORMLITIES APPEAR TO ACCOUNT

FOR THE INAPPROPRIATE HYPERGLYCMIA SEEM IN

TYPE II ( NIDDM) PATIENTS

1- DESCREASE IN QUANTITY INSULIN SECRETED

2- DELAY IN THE TIME OF RELEASE OF INSULIN

3- IMPAIRMET OF THE EFFCTS OF INSULIN ON THE PEREPHERAL TISSUES ( INSULIN RESISTANCE )

4- INCREASE IN HEPATIC GLUCOSE PRODUCTION

TYPE II ( NIDDM )

DIABETES MELLITUS

TYPE I ( IDDM )

TYPE II ( NIDDM)

- OBESE

- NONBESE

GESTATIONAL DIABETES

OTHER TYPES

IMPAIRED GLUCOSE TOLERANCE ( IGT)

Due primarily to a Beta cell defect resulting in inadequate insulin secretion for a given blood glucose level .

There is no significant increase in insulin resistance.

Various mutations in the giucokinase gene on

chromosomes 7p, probably account for 10-50% of cases of MODY .

Giucokinase – Mody is characterized by early onset ( often less than 18 months of age ) mild hyperglycaemia which is usually controIIed by diet alone until old age.

Autosmal Dominant

Diagnostic Criteria

• Diagnosis before 25 years of age in atleast 2 family member .

•No requirement of insulin treatment 5 years after diagnosis and/or C- Peptide positivity.

•Convincing vertical transmission of type II Diabetes mellitus through at least three generations.

•Accounts upto 1% of Diabetes Mellitus population.

1122334455Gene defectHNF4aGCKHNF1a1PF1HNF1B

Prevalence(%)51570<12

Glycaemia

Progressive deterioration in glycaemia

Mild stable hyperglycaemia

Progressive deterioration in glycaemia

Age of onset (years)

12-35Birth12-2814-4012-28

Other featuresLow glucose rise on OGTT

Sulphonylurea sensitivity

Cystic renal Chronic renal failure

ComplicationsYesVery rareCommon?Yes

Treatment

Progressive increase in requirements

Usually none except in pregnancy

Progressive increase in requirements Sulphonylurea first-line after diet failure

?

Progressive increase requirements

MODY

GENETICS :

( STRONG FAMILY AGGREGATES ALMOST 100% CONCORDANCE RATE IN IDENTICAL TWINS ( PYKE ET AL )

RACE :

( DIABETES IN MIGRANT INDIANS)

OBSITY :

(PIMA INDIANS NAURANS)

PHYSICAL INACTIVITY

LONGIVITY :

(DIABETES PREVALENCE INCREASES

WITH AGE E .G . PREVALENCE RATE > 30 % IN ELDERLY IN FINLAND)

Two genes have been implicated so far : NIDDM 1 and NIDDM2

MODY (Autosomal Dominant )

-MODY 1, (HNF-4) extremely uncommon)

-MODY 2, (Glucokinase gene-impairs B-cell glucose

sensing)

-MODY 3, ( Hepatocyte Nuclear factor 1- ( HNF-1) are more common

Maternally inherited diabetes with deafness ( MIDD) Late onset IDDM

SYNDROME CLINICAL FEATURES

Progressive cone dystrophy

Colour blindness Liver disease Deafiness Mental etardation

Turner,s 45,xo kayotype Short stature Gonadal dysgenesis

Thalassaemia Iron overland

Table 22.5

SYNDROMESYNDROMECLINICAL FEATURESCLINICAL FEATURES

Alstrom

• Retinitis pigmentosa

• Deafness

• Obesity

Laurence-Moon-Biedl

• Retinits pigmentosa

• Obesity

• Polydactyly

• Hypogonnadism

Pseudo-Refsum• Retinitis pigmentosa

• Ataxia

• Muscle wasting

Genetic syndromes associated with an early onset NIDDM

SYNDROMESYNDROMECLINICAL CLINICAL FEATURESFEATURES

Werner’s Premature senility Cataracts

Prader-Willi Obesity Short stature Mental retardation Micropenis

TYPE II CONTD . . . THE CLINICALPRESENTATION VARIES GREATLY:

I . THEY MAY MANIFEST DM AFTER THE

DEVELOPMENT OF COMPLICTIONS ( E .G.RE

TIOPATHY ) .

II . MAY HAVE SIGNIFICANT POLYRIA ,

POLYDIPSIA ,EASY FATIGUABILITY ETC .

III . MAY BE FOUND BY CHANCE ON ROUTINE

examination

MILDTO AMRKED OBES IS PRESENT IN 80% TYPE II AT THE TIME OF DIAGNOSIS .

OBESITY IS A MAJOR RISK FACTOR RROBABLY DUE TO THE DECREASE INSULIN RECEPTOR DENSITY AND ABNORMAL COUPLING OF RECEPTOR TO METABOLIC PROCESS THAT OCCUR IN THE OBESE STATE

TYPE II CONTD. . .

MOSTPATIENTS ARE DIAGNOSED AFTER

THE AGE OF 40 YEARS

OLD NAME - MANTURIY ONSET D.M .

A GTT IS DOME FOR THOSE IN THE IMPAIRED TOLERANCE RANGE COMMON CAUSES OF TRANSIENT

CARBOHYDRTE INTOLERANCES :

PHYSICAL OR EMOTIONAL STRESS

INFECTION

UNDER NUTRITION

BED REST

TRAUMA

NONOREGNANT ADULITS

PLASMA OTHER CRITERIA

GLUCOSE ( mg/dI)

RANDOM > 200 CLASSIC SIGNS AND SYMPTOMS

OR

FASTING >126 ON AT

LEST 2 OCCASIONS

OR

FASTING < 126 SUSTAINED ELEVATED LASMA GLUCOSE DURING AT LEAST 2OGTTs

OGTT SAMPLE PLASMA GLUCOSE VALUES ( mg/dI)

FASTING < 126

2 HOUR 126- 199

INTERVENING >200

*NONPREGANT

Dx OF IMPAIRED GLUCOSE

TOLERANCE IN ADULTS*

WHO

DIABETICDIABETIC IMPAIRED GTIMPAIRED GTASTING ASTING >> 8 MMOL 8 MMOL/ / LL

HRS HRS >>11 MMOL11 MMOL / / LL

6- 8 MMOL / L6- 8 MMOL / L

8 – 11 MMOL / 8 – 11 MMOL / LL

Diabetes mellitus in older adults is the commonest metabolic disorder in mainstream clinical practice

The disorder present an interplay between metabolic dysfunction, vasculopathy and the ageing process

Key Points

cardinal features with enable clinicians to focus diabetes risk associated with functional decline, visual cognitive disorder depression, and vulnerability to hypoglycemia

Interventions based on both vascular and rehabilitation models complement the metabolic approach to restructuring diabetes care for elderly

Diabetes is suspected

Measure FPG or RPG

If FPG >7.8 or RPG > 11.1

If FPG 5.5-7.7 or RPG 7.8-11.0

If FPG < 5.5or RPG< 7.8

Perform OGTT ( 75g)

If FPG >7.8 and/or2hPG > 11.1

If FPG <7.8 and 2hPG 7.8-11.0

If FPG <7.8 and 2hPG< 7.8

Normal Impaired glucose tolerance

Diabetes

20

18

16

14

12

10

8

6

4

2

0

Fasting 0.5 1.0 1.5 2.0

Diabetic

Impaired

glucose tolerance

Normal

Time after oral glucose ( hours)

Pla

sma

glu

c os e

(m

mo l

/lit

re)

Examples of the oral glucose tolerance test curve

GLUCOSE INTOLERANCE DEVELOPS

DURING PREGNANCY

OCCURS IN 2% OF PRENGNANT WOMEN

ONSET USUALLY IN 2nd OR 3rd

TRIMESTER

INCREASED FEATAL SIZE AND MORBIDITY

GTT USUALLY RETURNS TO NORMAL AFTER PARTURITION

Dx TEST INDICATED

CRIERION FOR POSITIVE SCREEN

1 HOUR PLASMA GLUCOSE > 140 mg / dI

If POSITIVE SCREEN

1.DISEASES PRODUCING ANTI – INSULIN HOSRMONES.

PHAEOCHROMOCYTOMA

CUSHING ‘S

ACHROMEGALY

GLUCAGONOMA

THROTOXICOSIS

2. DRUGS

THIAZIDE DIURETICS

FRUSOMIDE ( LASIX )

STEROIDS

THYROID HORMONES

ORAL CONTRACETIVES

COMPLICATIONS OF MANAGEMENT

-HYPOGLYCAEMIA

-KETOACIDOSIS

-LACTICACIDOSIS OTHER COMPLICATIONS

-INFECTIONS

-SOCIAL ETC

TREATEMENT

-DIET

-ORAL HYPOGLYCAEMICS

-INSULIN

3.ASSOCIATED WITH MANY OTHER DISEASES

EG . MUSLAR DYSTROPHIES

DOWN ‘S

KLEINFELTER’S

TURNER ‘S

FREDERICK’ S ATAXIA

GLYCOGEN STORAGE DISEASE

CLINICALFEATURES

TYPE IJUVENILE ONST

TYPE IIMATURITY ONSET

KETOSISOBESITYONSET

USUALUNCOMMON

ACUTE OR SUB ACUTE

RAREFREOUENT OFTEN INSIDOUS

EPIDEMIOLOGYINCIDENCE

AGE AT ONSET

PATHOLOGYISLETMASSBETACELLMASS INSULITIS ATONSET

PEAK AGE 12 - 14

MOSTLY < 40 YRS

< 10 % < 10 %

FREQUENT

RISES UNTIL 8TH

DECADE MOSTLY > 40 YRS

MODERATE RED.MODERATE RED.

PROBABLY ABSENT

IMMUNOLOGYANTIPANCRETICCELL MEDIATEDIMMUNITYANTIPANCREATICCELL HUMORALIMMUNITY

35– 50 % AT ONSET

60 – 85 %

< 5 %

APPROX . 5 %

GENETICSCONCRODANCE WITH IDENTICAL TWITNSASSOCIATED EITHHLA

< 50 %

PRESENT

MOSTLY INVAR

PRESENT

THE PRESENCE OF COMMONLY

ASSOCIATAED CONDITIONS SHOULD

BE EVALUATED EG:

-

•OBESITY

• HYPERTENSION

• HYPERLIPIDAEMIA

• MACROVASCULARDISEASE

AT DIAGNOSIS , A COMPLETE HISTORY AND PHYSICAL EXAMINATION ARE ANDATORY AS MACROVASCLUAR ISEASE , AND SOMETIONS MICROVASCULAR COMPLICATIONS ARE RESENT AT DIAGNSIS OF NIDDM

HETEROGENEOUS DISORDER

CHARACTERIZED BY :

DEFICIENT INSULIN SECRETION

INSULIN RESISTANCE

•* Mature onset diabetes of the young is inherited in an autsomal dominant manner and associated with 8 cell dysfunction.

* Environmental factors important for NIDDM include physical inactivity, excessive consumption of food leading to obesity stress and some drugs

•* Non-insulin dependent diabetes mellitus ( NIDDM ) is a heterogeneous disease in which a number of genetic and environmental factors interact to cause diabetes

•* Maternally inhented diabetes and deafness is a distinct subtype of NIDDM

Practice points

Fasting plasma glucose(mM)

4

6 8 10 12

0

60

80

100

40

20

Mea

n p

iasm

a in

suli

n r

esp

onse

gu

rin

g O

GT

T (

U/m

l)Relationship between fasting glucose and insulin secretion

HETEROGENEOUS DISORDER

CHARACTERIZED BY :

DEFICIENT INSULIN SECRETION

INSULIN RESISTANCE

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10

1 marker2 markers>3 markers

Follow – up(years)

IDD

M-f

ree

surv

ival

(%)