DIABETES MELLITUS PATHOGENESIS, CLASSIFICATION, DIAGNOSIS

DIABETES MELLITUS A group of metabolic diseases characterized by hyperglycemia and: abnormal carbohydrate metabolism due to absolute deficiency of insulin (type 1 DM) or a relative deficiency of insulin (type 2 DM)

DIABETES MELLITUS INCIDENCE: PER YEAR IN U.S. PREVALENCE: 8-10 MILLION IN U.S. TYPE 1 DM: 10% OF ALL DIABETICS TYPE 2 DM: 90% OF ALL DIABETICS

DIABETES MELLITUS MORTALITY  TYPE 1 DM: 11 TIMES GREATER  TYPE 2 DM: 2-3 TIMES GREATER ECONOMIC IMPACT  DIRECT HEALTH CARE: $7,9 BILLION  DRUG TREATMENT: $380 MILLION

DIABETES MELLITUS PATHOGENESIS OF TYPE 1 DM CELLULAR-MEDIATED AUTOIMMUNE DESTRUCTION OF  -CELLS RESPONSIBLE FOR INSULIN PRODUCTION AND SECRETION

DIABETES MELLITUS PATHOGENESIS OF TYPE 1 DM GENETIC SUSCEPTIBILITY ENVIROMENTAL FACTORS AUTOIMMUNITY LYMPHOCYTIC INFILTRATION PANCREATIC AUTOANTIBODIES

HLA Region Chromosome 6 Class II Class III Class I DP DQ DR 21 C4 B C2 TNF B C A Ring 3 Ring 4 DPB2 DPA2 DPB1 DPA1 DNA DOB DQB2 DQA2 DQB1 DQA1 DRB1 DRB2 DRB3 DRB4 DRA1 Subregion DP Subregion DQ Subregion DR

HLA-DR AND HLA-DQ: A RISK OF TYPE 1 DM Susceptibility Susceptibility  DR3  DR4  DR (< DR3 or DR4)  DQA1*0301  DQA1*0501  DQB1*0201  DQB1*0302 Resistance  DR2  DR5 (<DR2)  DQBI*0602  DQBI*0301

TYPE 1 DM ENVIROMENTAL FACTORS Viruses Viruses  Mumps, Coxackie B4, retroviruse, rubella, cytomegalovirus, Epstein-Barr virus Diet Diet  Cow’s milk (BSA)  Nitrosamines (smoked and cured meat)  Coffee  Gluten and other proteins (experimental data) Stress Stress

PROPOSED PATHOGENESIS OF TYPE 1 DIABETES MELLITUS Normal islet ?Viral infection in pancreatic beta cells Secretion of interferon-  by pancreatic  -cells Hyperexpression of class I MHC antigen within islets Insulitis Selective destruction of  -cells Insulin-deficient islet

DIABETES MELLITUS PATHOGENESIS OF TYPE 1 DM Markers of the immune destruction of the  -cell  islet cell autoantibodies (icas)  autoantibodies to insulin (iaas)  autoantibodies to glutamic acid decarboxylase (GAD 65 )  autoantibodies to the tyrosine phosphatases One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected.

DIABETES MELLITUS PHASES OF TYPE 1 DM DEVELOPMENT Geneticpredisposition ? Promoting factor factor OvertImmunologicalabnormalities Decrease in insulin secretion Symptomaticdiabetes Normal NormalglycemiaC-peptidepresentC-peptideabsent Age (years) Beta cells mass

DIABETES MELLITUS PATHOGENESIS OF TYPE 2 DM HYPERGLYCEMIA DUE TO A RELATIVE DEFICIENCY OF INSULIN RELATED TO INSULIN RESISTANCE AND BETA CELL DYSFUNCTION

DIABETES MELLITUS PATHOGENESIS OF TYPE 2 DM GENETIC PREDISPOSITION RELATIVE INSULIN DEFICIENCY LOSS OF FIRST PHASE SECRETION DECREASED GLUT-2

Insulin resistance genes Insulin secretion genes  -cells number genes Obesity genes ObesityDiet Physical activity Age Time Decreased insulin secretion Desensitisation of  -cells for glucose Increased insulin secretion Increased insulin secretion Decreased insulin and glucose sensitivity Decreased insulin and glucose sensitivity Genetic factors Enviromental factors DMtype II II

DIABETES MELLITUS MECHANISMS OF INSULIN RESISTANCE DECREASE IN INSULIN RECEPTORS DECREASE IN INSULIN BINDING POST-RECEPTOR DEFECTS DECREASE IN GLUT-4 INCREASED HEPATIC GLUCOSE PRODUCTION

DIABETES MELLITUS Characteristics TYPE 1 DM TYPE 2 DM Duration of symptoms weeks months to years Complications at diagnosis No20% Age at onset < 40 yrs > 50 yrs AutoantibodiesYesNo Family History ---Strong ObesityRarelyOften History of DKA CommonRare

DIABETES MELLITUS OTHER SPECIFIC TYPES OF DIABETES Genetic defects of the  –cell Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced diabetes Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes.

DIABETES MELLITUS GESTATIONAL DIABETES any degree of glucose intolerance with onset or first recognition during pregnancy. 3% of pregnancies onset: th week of gestation risk factors previous gestational dm obesity previous macrosomia

DIABETES MELLITUS GESTATIONAL DIABETES CONSEQUENCES: increased perinatal mortality macrosomia neonatal hyperbilirubinaemia hypocalcemiahypoglycemia obesity in children

DIABETES MELLITUS GLUCOSE INTOLERANCE  IMPAIRED GLUCOSE TOLERANCE  IMPAIRED FASTING GLUCOSE

DIABETES MELLITUS CLINICAL MANIFESTATIONS HYPERGLYCEMIA Normal Fasting Glucose: mg/dL Absolute/relative deficiency of insulin Impaired glucose uptake Increased production

DIABETES MELLITUS CLINICAL MANIFESTATIONS HYPERGLYCEMIA Assessment of severity  Mild: mg/dL  Moderate: mg/dL  Severe: mg/dL  Very severe: > 500 mg/dL Also evaluate symptoms

DIABETES MELLITUS CLINICAL MANIFESTATIONS GLUCOSURIA  When ability of kidney to reabsorb glucose is exceeded POLYURIA  Due to osmotic diuresis from glucose not reabsorbed POLYDIPSIA  Response to increase fluid loss

DIABETES MELLITUS CLINICAL MANIFESTATIONS POLYPHAGIA  Due to proteolysis/gluconeogenesis WEIGHT LOSS  Excretion of ingested calories  Metabolism of fat/proteins  Fluid loss WEAKNESS, FATIGUE  Decreased ATP production

DIABETES MELLITUS CLINICAL MANIFESTATIONS OTHER SYMPTOMS  acetone breath  nausea, vomiting  abdominal pain  Kussmaul respirations

DIABETES MELLITUS DIAGNOSIS 3 CRITERIA BY WHICH DIAGNOSIS IS MADE: casual PG > 200 mg/dL + symptoms FPG  126 mg/dL 2-Hr PG  200 mg/dL during OGTT confirm on a subsequent day confirm on a subsequent day

DIABETES MELLITUS DIAGNOSIS ORAL GLUCOSE TOLERANCE TEST (OGTT) SHOULD BE PERFORMED IN A MORNING USE A GLUCOSE LOAD CONTAINING THE EQUIVALENT OF 75 G ANHYDROUS GLUCOSE DISSOLVED IN ML OF WATER.

DIABETES MELLITUS DIAGNOSIS IMPAIRED GLUCOSE TOLERANCE 2-hr PG: mg/dL 2-hr PG: mg/dL IMPAIRED FASTING GLUCOSE FPG = 110 –125 mg/dL FPG = 110 –125 mg/dL

DIABETES MELLITUS DIAGNOSIS GESTATIONAL DIABETES Screening test during th week of pregnancy

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