Diabetes mellitusDiabetes mellitus

Normal endocrine pancreasNormal endocrine pancreas

1 million microscopic clusters of cells1 million microscopic clusters of cells ΒΒ,,αα,,δδ,PP cells,PP cells ββ cells → insulin cells → insulin αα → glucagon → glucagon ΔΔ → somatostatin → somatostatin PP → VIPPP → VIP

Diabetes mellitusDiabetes mellitus Definition: group of metabolic Definition: group of metabolic

disorders sharing the common disorders sharing the common underlying feature of hyperglycemiaunderlying feature of hyperglycemia

Multisystem disease with biochemical Multisystem disease with biochemical and structural consequences.and structural consequences.

Defect of insulin secretion, insulin Defect of insulin secretion, insulin action or bothaction or both

Effect on carbohydrate, protein and Effect on carbohydrate, protein and fat metabolismfat metabolism

EpidemiologyEpidemiology 21 million people in US21 million people in US AsiansAsians Some tribals eg Pima indiansSome tribals eg Pima indians Complications- eye,renal,PNS,blood Complications- eye,renal,PNS,blood

vessels etc. vessels etc.

ClassificationClassification PRIMARYPRIMARY Type I- 10% ,absolute deficiency of Type I- 10% ,absolute deficiency of

insulininsulin Autoimmune disease,Autoimmune disease,ββ cell destruction cell destruction Type 2 - 80-90%Type 2 - 80-90% Peripheral resistance to insulin & Peripheral resistance to insulin &

inadequate insulin secretioninadequate insulin secretion Genetic defects of Genetic defects of ββ cell function (MODY) cell function (MODY) Genetic defects in insulin processing or Genetic defects in insulin processing or

insulin actioninsulin action

Classification (cont.)Classification (cont.) SECONDARYSECONDARY Exocrine pancreatic defectsExocrine pancreatic defects EndocrinopathiesEndocrinopathies Infections Infections Drugs –CS etcDrugs –CS etc Genetic syndrome associated with Genetic syndrome associated with

diabetes.diabetes. Gestational diabetes mellitusGestational diabetes mellitus

Role of insulinRole of insulin Glucose uptake & utilization in the Glucose uptake & utilization in the

peripheral tissues esp skeletal muscle, peripheral tissues esp skeletal muscle, adipocytesadipocytes

(brain independent of insulin)(brain independent of insulin) Anabolic action-Anabolic action-↑synthesis, ↓ ↑synthesis, ↓

degradation of glycogen, lipid & degradation of glycogen, lipid & protein. protein.

Mitogenic → ↑DNA, growth & Mitogenic → ↑DNA, growth & differentiationdifferentiation

Opposing actions of insulin and Opposing actions of insulin and glucagonglucagon

Metabolic actions of insulinMetabolic actions of insulin

Mechanism of insulin Mechanism of insulin releaserelease

Insulin release –Insulin release –Glucose, Intestinal Glucose, Intestinal hormoneshormones

Aminoacids: Aminoacids: leucine, arginineleucine, arginine

Insulin synthesisInsulin synthesis GlucoseGlucose

Mechanism of insulin actionMechanism of insulin action

Pathogenesis of Type 1 DMPathogenesis of Type 1 DM Organ specific autoimmune diseaseOrgan specific autoimmune disease Genetic susceptibility gene-HLA DR Genetic susceptibility gene-HLA DR

3,HLA DR4, both3,HLA DR4, both Environment- viral infections Environment- viral infections T lymphocytes against ill defined T lymphocytes against ill defined ββ cell cell

antigens ? epitopes on insulin hormoneantigens ? epitopes on insulin hormone Autoimmune antibodies against insulinAutoimmune antibodies against insulin

Glutamic acid decarboxylase (GAD)etc.Glutamic acid decarboxylase (GAD)etc.

Pathogenesis of Type 1 DM Pathogenesis of Type 1 DM (cont)(cont)

T lymphocytes TH-1, CD4+,Activate T lymphocytes TH-1, CD4+,Activate macrophagesmacrophages

CD 8+ directly cytotoxic, release CD 8+ directly cytotoxic, release cytokines that stimulate monocytescytokines that stimulate monocytes

Cytokines produced by T lymphocytes Cytokines produced by T lymphocytes & macrophages inc IFN & macrophages inc IFN γγ,TNF,IL-1,TNF,IL-1

InsulitisInsulitis ------overt diabetes >90% cells ------overt diabetes >90% cells

damageddamaged

Stages in the development of Stages in the development of type 1 DMtype 1 DM

MicroscopyMicroscopy

Type 1Type 1 Insulitis –lymphocytic inflitrate in Insulitis –lymphocytic inflitrate in

islets +/- macrophages , neutrophilsislets +/- macrophages , neutrophils Depletion of beta cells of islets Depletion of beta cells of islets Fibrosis of isletsFibrosis of islets NO AMYLOID DEPOSITIONNO AMYLOID DEPOSITION

Type 2 diabetes mellitusType 2 diabetes mellitus Heterogenous disorder characterized Heterogenous disorder characterized

by a combination of reduced tissue by a combination of reduced tissue sensitivity to insulin and inadequate sensitivity to insulin and inadequate secretion of insulin from the secretion of insulin from the pancreas.pancreas.

AdultAdult Central obesityCentral obesity

Pathogenesis of type 2 DMPathogenesis of type 2 DM

Predisposing factorsPredisposing factors

Environmental - sedentary, diet, Environmental - sedentary, diet, obesityobesity

Genetic predisposition-polygenicGenetic predisposition-polygenic

Insulin resistance in peripheral tissuesInsulin resistance in peripheral tissues

ΒΒ cell dysfunction (impaired insulin cell dysfunction (impaired insulin secretion in response to glucose)secretion in response to glucose)

Insulin resistanceInsulin resistance

Resistance to the effects of insulin on Resistance to the effects of insulin on glucose uptake, metabolism or storage. glucose uptake, metabolism or storage. (inability of tissues to respond to (inability of tissues to respond to insulin)insulin)

10-20 yrs before DM10-20 yrs before DM Predictor of subsequent progress to DMPredictor of subsequent progress to DM ↓ ↓ uptake of glucose in muscle and uptake of glucose in muscle and

adipose adipose Inability to supress hepatic Inability to supress hepatic

gluconeogeneisisgluconeogeneisis

Quantitative & qualitative abnormality Quantitative & qualitative abnormality of insulin signaling pathwayof insulin signaling pathway

Obesity and insulin resistanceObesity and insulin resistance

Obesity-central Obesity-central FFA levels inversely proportional to FFA levels inversely proportional to

insulin sensitivity insulin sensitivity → acquired insulin → acquired insulin resistance.resistance.

Adipocytokines dysregulationAdipocytokines dysregulation

Resistin- acquired insulin resistanceResistin- acquired insulin resistance

ΒΒ cell dysfunction cell dysfunction Inability of Inability of ββ cells to adapt to the long cells to adapt to the long

term demands of peripheral insulin term demands of peripheral insulin resistance and increased insulin resistance and increased insulin secretion.secretion.

Inadequate Inadequate ββ cell compensation -? cell compensation -? lipotoxic ? glucotoxiclipotoxic ? glucotoxic

Qualitative & quantitative dysfunction Qualitative & quantitative dysfunction of of

ββ cells cells Overt diabetesOvert diabetes

Morphology of type 2 DMMorphology of type 2 DM

NO morphological lesion in beta cells NO morphological lesion in beta cells or consistent reduction in their or consistent reduction in their numbers.numbers.

Fibrous tissue accumulation in some Fibrous tissue accumulation in some isletsislets

Amyloid deposit in islets (amylin)Amyloid deposit in islets (amylin)

An islet of Langerhans demonstrates amorphous pink An islet of Langerhans demonstrates amorphous pink deposition of amyloid in a patient with type II diabetes deposition of amyloid in a patient with type II diabetes mellitusmellitus

Monogenic forms of Monogenic forms of diabetesdiabetes

UncommonUncommon

Secondary to loss of function Secondary to loss of function mutations within a single gene.mutations within a single gene.

Primary defect in Primary defect in ββ cell function cell function (MODY)(MODY)

Defect in insulin /insulin receptor Defect in insulin /insulin receptor signalingsignaling

Clinical featuresClinical features Sir William OslerSir William Osler 3 P’s polydypsia,polyphagia,polyuria3 P’s polydypsia,polyphagia,polyuria Frequent infectionsFrequent infections Unexplained weight lossUnexplained weight loss

    HHigh fasting glucose or igh fasting glucose or impaired glucose toleranceimpaired glucose tolerance

(without diabetes, oral (without diabetes, oral glucose loads cause only slight glucose loads cause only slight rise in blood glucose due to rise in blood glucose due to brisk insulin response; with brisk insulin response; with diabetes, blood glucose rises diabetes, blood glucose rises markedly for a sustained markedly for a sustained period)period)

DiagnosisDiagnosis

Random Random glucoseglucose

(mg/dL )(mg/dL )

70-12070-120 >200>200

Fasting Fasting

Glucose Glucose

(mg/dL )(mg/dL )

<110<110 110-126110-126 >126>126

Abnormal Abnormal

OGTTOGTT<140 <140 140-200140-200 >200>200

DIAGNOSIDIAGNOSISS

EuglycemicEuglycemic Impaired Impaired glucose glucose

tolerancetolerance

Diabetes Diabetes

mellitusmellitus

DIAGNOSIS OF DIABETESDIAGNOSIS OF DIABETES

Glucose tolerance testGlucose tolerance test

Fasting overnight Fasting overnight Oral glucose 75 mgOral glucose 75 mg 2 hrs later2 hrs later Draw the graphDraw the graph

Glycosylated hemoglobinGlycosylated hemoglobin

(Hemoglobin A 1C)(Hemoglobin A 1C) Proportional to the average glucose Proportional to the average glucose

concentration and life span of RBCconcentration and life span of RBC Normal range 4.2-6.0 (< 6%)Normal range 4.2-6.0 (< 6%) Used as a monitor of good glucose Used as a monitor of good glucose

level control by patients.level control by patients.

SummarySummary

Normal glucose controlNormal glucose control Release &Action of insulinRelease &Action of insulin Definition of DiabetesDefinition of Diabetes Classification of DiabetesClassification of Diabetes Aetiology, pathogenesis morphology Aetiology, pathogenesis morphology

of Type 1 & type 2 DMof Type 1 & type 2 DM Lab diagnosis of DMLab diagnosis of DM