diabetes mellitus pathogenesis, classification, diagnosis
TRANSCRIPT
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
DIABETES MELLITUSPATHOGENESIS OF TYPE 1 DM
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
DIABETES MELLITUSPATHOGENESIS OF TYPE 1 DM
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
DIABETES MELLITUSPATHOGENESIS OF TYPE 2 DM
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
DIABETES MELLITUSPATHOGENESIS OF TYPE 2 DM
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
DIABETES MELLITUSCLINICAL MANIFESTATIONS
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
DIABETES MELLITUSCLINICAL MANIFESTATIONS
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
DIABETES MELLITUSCLINICAL MANIFESTATIONS
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
DIABETES MELLITUSCLINICAL MANIFESTATIONS
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
DIABETES MELLITUS DIAGNOSIS
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.
DIABETES MELLITUS DIAGNOSIS
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
DIABETES MELLITUS DIAGNOSIS
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