DIABETES MELLITUS PATHOGENESIS, CLASSIFICATION, DIAGNOSIS

DIABETES MELLITUS

PATHOGENESIS, PATHOGENESIS, CLASSIFICATION, CLASSIFICATION,

DIAGNOSISDIAGNOSIS

DIABETES MELLITUS

A group of metabolic diseases characterized A group of metabolic diseases characterized by hyperglycemia by hyperglycemia andand: :

abnormal carbohydrate metabolism due abnormal carbohydrate metabolism due to absolute deficiency of insulin (type 1 to absolute deficiency of insulin (type 1 DM) or DM) or

a relative deficiency of insulin (type 2 a relative deficiency of insulin (type 2 DM)DM)

DIABETES MELLITUS

INCIDENCE: 600 000 INCIDENCE: 600 000 PER YEARPER YEAR IN U.S. IN U.S.

PREVPREVAALENCE: 8-10 MILLION IN U.S.LENCE: 8-10 MILLION IN U.S.

TYPE 1 DM: 10% OF ALL DIABETICSTYPE 1 DM: 10% OF ALL DIABETICS

TYPE 2 DM: 90% OF ALL DIABETICSTYPE 2 DM: 90% OF ALL DIABETICS

DIABETES MELLITUS

MORTALITY MORTALITY TYPE 1 DM: 11 TIMES GREATERTYPE 1 DM: 11 TIMES GREATER TYPE 2 DM: 2-3 TIMES GREATERTYPE 2 DM: 2-3 TIMES GREATER

ECONOMIC IMPACTECONOMIC IMPACT DIRECT HEALTH CARE: $7,9 DIRECT HEALTH CARE: $7,9

BILLIONBILLION DRUG TREATMENT: $380 MILLIONDRUG TREATMENT: $380 MILLION

DIABETES MELLITUSPATHOGENESIS OF TYPE 1 DM

CELLULAR-MEDIATED CELLULAR-MEDIATED AUTOIMMUNE AUTOIMMUNE DESTRUCTION DESTRUCTION OF OF --CELLS RESPONSIBLE FOR CELLS RESPONSIBLE FOR INSULIN PRODUCTION AND INSULIN PRODUCTION AND SECRETIONSECRETION


GENETIC SUSCEPTIBILITYGENETIC SUSCEPTIBILITY

ENVIROMENTAL FACTORSENVIROMENTAL FACTORS

AUTOIMMUNITYAUTOIMMUNITY

LYMPHOCYTIC INFILTRATIONLYMPHOCYTIC INFILTRATION

PANCREATIC AUTOANTIBODIESPANCREATIC AUTOANTIBODIES

HLA RegionHLA Region

Chromosome 6Chromosome 6

Class IIClass II Class IIIClass III Class IClass I

DP DQ DR 21 C4 B C2 TNF B C ADP DQ DR 21 C4 B C2 TNF B C A

Ring 3 Ring 4Ring 3 Ring 4

DPB2 DPA2 DPB1 DPA1 DNA DOB DQB2 DQA2 DQB1 DQA1 DRB1 DRB2 DRB3 DRB4 DRA1DPB2 DPA2 DPB1 DPA1 DNA DOB DQB2 DQA2 DQB1 DQA1 DRB1 DRB2 DRB3 DRB4 DRA1

Subregion DP Subregion DQ Subregion DRSubregion DP Subregion DQ Subregion DR

HLA-DR AND HLA-DQ: A RISK OF TYPE 1 DM

SusceptibilitySusceptibility DR3DR3 DR4DR4 DR (< DR3 or DR (< DR3 or

DR4)DR4) DQA1*0301DQA1*0301 DQA1*0501DQA1*0501 DQB1*0201DQB1*0201 DQB1*0302DQB1*0302

ResistanceResistance

DR2DR2 DR5 (<DR2)DR5 (<DR2) DQBI*0602DQBI*0602 DQBI*0301DQBI*0301

TYPE 1 DMENVIROMENTAL FACTORS

VirusesViruses Mumps, Coxackie B4, retroviruse, rubella, Mumps, Coxackie B4, retroviruse, rubella,

cytomegalovirus, Epstein-Barr viruscytomegalovirus, Epstein-Barr virus DietDiet

Cow’s milk (BSA)Cow’s milk (BSA) Nitrosamines (smoked and cured meat)Nitrosamines (smoked and cured meat) CoffeeCoffee Gluten and other proteins (experimental data)Gluten and other proteins (experimental data)

StressStress

PROPOSED PATHOGENESIS OF TYPE 1 DIABETES MELLITUS

Normal isletNormal islet

?Viral infection in pancreatic beta cells?Viral infection in pancreatic beta cells

Secretion of interferon-Secretion of interferon- by pancreatic by pancreatic -cells-cells

Hyperexpression of class I MHC antigen within isletsHyperexpression of class I MHC antigen within islets

InsulitisInsulitis

Selective destruction of Selective destruction of -cells-cells

Insulin-deficient isletInsulin-deficient islet


Markers of the immune destruction of the Markers of the immune destruction of the -cell-cell islet cell autoantibodies (icas)islet cell autoantibodies (icas) autoantibodies to insulin (iaas)autoantibodies to insulin (iaas) autoantibodies to glutamic acid autoantibodies to glutamic acid

decarboxylase (GADdecarboxylase (GAD6565))

autoantibodies to the tyrosine phosphatasesautoantibodies to the tyrosine phosphatasesOne and usually more of these autoantibodiesOne and usually more of these autoantibodies are present in 85–90% of individuals when are present in 85–90% of individuals when fasting hyperglycemia is initially detected.fasting hyperglycemia is initially detected.

DIABETES MELLITUSPHASES OF TYPE 1 DM DEVELOPMENT

Genetic Genetic

predispositionpredisposition

? Promoting? Promoting

factorfactor

Overt Overt

ImmunologicalImmunological

abnormalitiesabnormalities

Decrease in Decrease in

insulin secretioninsulin secretion

SymptomaticSymptomatic

diabetesdiabetes

Normal Normal

insulin secretioninsulin secretion

Normal Normal

glycemiaglycemia

C-peptideC-peptide

presentpresent

C-peptideC-peptide

absentabsent

Age (years)Age (years)

Be

ta c

ells

ma

ss

Be

ta c

ells

ma

ss


HYPERGLYCEMIA DUE TO A HYPERGLYCEMIA DUE TO A RELATIVE DEFICIENCY OF INSULIN RELATIVE DEFICIENCY OF INSULIN RELATED TO INSULIN RESISTANCE RELATED TO INSULIN RESISTANCE AND BETA CELL DYSFUNCTIONAND BETA CELL DYSFUNCTION


GENETIC PREDISPOSITIONGENETIC PREDISPOSITION

RELATIVE INSULIN DEFICIENCYRELATIVE INSULIN DEFICIENCY

LOSS OF FIRST PHASE SECRETIONLOSS OF FIRST PHASE SECRETION

DECREASED GLUT-2DECREASED GLUT-2

Insulin resistance genesInsulin resistance genes

Insulin secretion genesInsulin secretion genes

-cells number genes-cells number genes

Obesity genesObesity genes

ObesityObesity

DietDiet

Physical activityPhysical activity

AgeAge

TimeTime

Decreased insulin secretionDecreased insulin secretion

Desensitisation of Desensitisation of -cells for glucose-cells for glucose

Increased insulin secretionIncreased insulin secretion

Decreased insulin and glucose sensitivityDecreased insulin and glucose sensitivity

Genetic factorsGenetic factors Enviromental factorsEnviromental factors

DMDM

typetype

IIII

DIABETES MELLITUSMECHANISMS OF INSULIN RESISTANCE

DECDECREREASE IN INSULIN RECEPTORSASE IN INSULIN RECEPTORS

DECDECREREASE IN INSULIN BINDINGASE IN INSULIN BINDING

POST-RECEPTOR DEFECTSPOST-RECEPTOR DEFECTS

DECREASE IN GLUT-4DECREASE IN GLUT-4

INCREASED HEPATIC GLUCOSE INCREASED HEPATIC GLUCOSE PRODUCTIONPRODUCTION

DIABETES MELLITUS

CharacteristicsCharacteristics TYPE 1 DMTYPE 1 DM TYPE 2 DMTYPE 2 DM

Duration of symptomsDuration of symptoms weeksweeks months to yearsmonths to yearsComplications at diagnosisComplications at diagnosis NoNo 20%20%

Age at onsetAge at onset < 40 yrs< 40 yrs > 50 yrs> 50 yrs

AutoantibodiesAutoantibodies YesYes NoNo

Family HistoryFamily History ------ StrongStrong

ObesityObesity RarelyRarely OftenOften

History of DKAHistory of DKA CommonCommon RareRare

DIABETES MELLITUS OTHER SPECIFIC TYPES OF DIABETES

GGenetic defects of the enetic defects of the –cell–cellGenetic defects in insulin actionGenetic defects in insulin actionDiseases of the exocrine pancreasDiseases of the exocrine pancreasEndocrinopathieEndocrinopathiessDrug- or chemical-induced diabetesDrug- or chemical-induced diabetesInfectionsInfectionsUncommon forms of immune-mediated diabetesUncommon forms of immune-mediated diabetesOther genetic syndromes sometimes associated with Other genetic syndromes sometimes associated with diabetes. diabetes.

DIABETES MELLITUSGESTATIONAL DIABETES

any degree of glucose intolerance with onset or any degree of glucose intolerance with onset or first recognition during pregnancy. first recognition during pregnancy.

3% of pregnancies3% of pregnancies

onset: 24-28onset: 24-28thth week of gestation week of gestation

risk factorsrisk factorsprevious gestational dmprevious gestational dm

obesityobesity

previous macrosomiaprevious macrosomia

DIABETES MELLITUSGESTATIONAL DIABETES

CONSEQUENCESCONSEQUENCES::increased perinatal mortalityincreased perinatal mortalitymacrosomiamacrosomianeonatal hyperbilirubinaemianeonatal hyperbilirubinaemiahypocalcemiahypocalcemiahypoglycemiahypoglycemiaobesity in childrenobesity in children

DIABETES MELLITUS

GLUCOSE INTOLERANCEGLUCOSE INTOLERANCE IMPAIRED GLUCOSE TOLERANCEIMPAIRED GLUCOSE TOLERANCE IMPAIRED FASTING GLUCOSEIMPAIRED FASTING GLUCOSE

DIABETES MELLITUSCLINICAL MANIFESTATIONS

HYPERGLYCEMIAHYPERGLYCEMIA

NormalNormal F Fastingasting GlucoseGlucose: 70: 70--110 mg/dL110 mg/dL

Absolute/relative deficiency of insulinAbsolute/relative deficiency of insulin

Impaired glucose uptakeImpaired glucose uptake

Increased produIncreased producctiontion


HYPERGLYCEMIAHYPERGLYCEMIA

Assessment of severityAssessment of severityMild: 126-200 mg/dLMild: 126-200 mg/dLModerate: 200-300 mg/dLModerate: 200-300 mg/dLSevere: 300-500 mg/dLSevere: 300-500 mg/dLVery severe: > 500 mg/dLVery severe: > 500 mg/dL

Also evaluate symptomsAlso evaluate symptoms


GLUCOSURIAGLUCOSURIAWhen ability of kidney to reabsorb When ability of kidney to reabsorb

glucose is exceededglucose is exceededPOLYURIAPOLYURIADue to osmotic diuresis from glucose Due to osmotic diuresis from glucose

not reabsorbednot reabsorbedPOLYDIPSIAPOLYDIPSIAResponse to increase fluid lossResponse to increase fluid loss


POLYPHAGIAPOLYPHAGIADue to proteolysis/gluconeogenesisDue to proteolysis/gluconeogenesis

WEIGHT LOSSWEIGHT LOSSExcretion of ingested caloriesExcretion of ingested caloriesMetabolism of fat/proteinsMetabolism of fat/proteinsFluid lossFluid loss

WEAKNESS, FATIGUEWEAKNESS, FATIGUEDecreased ATP productionDecreased ATP production


OTHER SYMPTOMSOTHER SYMPTOMSacetone breathacetone breathnausea, vomitingnausea, vomitingabdominal painabdominal painKKussmaul respirationsussmaul respirations

DIABETES MELLITUS DIAGNOSIS

3 CRITERIA BY WHICH DIAGNOSIS IS 3 CRITERIA BY WHICH DIAGNOSIS IS MADE:MADE:

casual PG > 200 mg/dL + symptomscasual PG > 200 mg/dL + symptoms

FPG FPG 126 mg/dL 126 mg/dL

2-Hr PG 2-Hr PG 200 mg/dL during OGTT 200 mg/dL during OGTT

confirm on a subsequent dayconfirm on a subsequent day


ORAL GLUCOSE TOLERANCE TESTORAL GLUCOSE TOLERANCE TEST

(OGTT)(OGTT)SHOULD BE PERFORMED IN ASHOULD BE PERFORMED IN A MORNINGMORNING

USE A GLUCOSE LOAD CONTAININGUSE A GLUCOSE LOAD CONTAINING THETHE EQUIVALENT OF 75 GEQUIVALENT OF 75 G ANHYDROUSANHYDROUS GLUCOSE DISSOLVED INGLUCOSE DISSOLVED IN 250-300 ML OF 250-300 ML OF WATER.WATER.


IMPAIRED GLUCOSE TOLERANCEIMPAIRED GLUCOSE TOLERANCE

2-hr PG: 140-200 mg/dL2-hr PG: 140-200 mg/dL

IMPAIRED FASTING GLUCOSEIMPAIRED FASTING GLUCOSE

FPG = 110 –125 mg/dLFPG = 110 –125 mg/dL


GESTATIONAL DIABETESGESTATIONAL DIABETES

Screening test during 24-28Screening test during 24-28 thth week of week of pregnancypregnancy

DIABETES MELLITUS

56 year-old male in office56 year-old male in office feeling tired, less energy x 6 monthsfeeling tired, less energy x 6 months UA: 2+ glucoseUA: 2+ glucose FPG = 140 mg/dLFPG = 140 mg/dL Fulfill the criteria for diabetes?Fulfill the criteria for diabetes? Why or Why not?Why or Why not? Type of diabetesType of diabetes

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DIABETES MELLITUS PATHOGENESIS, CLASSIFICATION, DIAGNOSIS