PATHOPHISIOLOGY OFPATHOPHISIOLOGY OF DIABETES MELLITUSDIABETES MELLITUS · Mt itMaturityy--onseonset di b t f th (MODY)t diabetes of the young (MODY) 22) Genetic Defects in Insulin

PATHOPHISIOLOGY OFPATHOPHISIOLOGY OFPATHOPHISIOLOGY OF PATHOPHISIOLOGY OF DIABETES MELLITUSDIABETES MELLITUSDIABETES MELLITUSDIABETES MELLITUS

R. R. MohammadiMohammadiBiochemist (Ph.D.)Biochemist (Ph.D.)Biochemist (Ph.D.)Biochemist (Ph.D.)

Faculty member of Medical FacultyFaculty member of Medical Faculty

BLOOD GLUCOSEBLOOD GLUCOSEBLOOD GLUCOSE BLOOD GLUCOSE REGULATIONREGULATIONREGULATIONREGULATION

METABOLIC FUELSMETABOLIC FUELSMETABOLIC FUELSMETABOLIC FUELS

GlucoseGlucoseF tt A idF tt A idFatty AcidsFatty AcidsKetone BodiesKetone BodiesAminoacidsAminoacids

ECONOMIC OF FUELSECONOMIC OF FUELSECONOMIC OF FUELSECONOMIC OF FUELS

Cellular CapacityCellular CapacityC ll N dC ll N dCell NeedsCell NeedsFuel AvailabilityFuel AvailabilityHormonal ConditionHormonal Condition

ROLE OF TISSUESROLE OF TISSUESROLE OF TISSUESROLE OF TISSUES

LiverLiverF tt TiF tt TiFatty TissueFatty TissueMuscleMuscle

ROLE OF HORMONESROLE OF HORMONESROLE OF HORMONESROLE OF HORMONES

InsulinInsulinInsulinInsulinGlucagonGlucagonE i h iE i h iEpinephrineEpinephrineCortisolCortisolThyroid HormoneThyroid HormoneGrowth HormoneGrowth HormoneGrowth HormoneGrowth Hormone

GLUCOSE TRANSPORTERSGLUCOSE TRANSPORTERSGLUCOSE TRANSPORTERSGLUCOSE TRANSPORTERS

GLUTGLUT11 All tissuesAll tissuesGLUTGLUT1 1 All tissuesAll tissuesGLUTGLUT2 2 Liver, Liver, ββ--cell, cell,

I t tiI t ti kidkidIntestine,Intestine, kidney kidney GLUTGLUT3 3 All TissuesAll TissuesGLUTGLUT4 4 Fatty Tissue, MuscleFatty Tissue, MuscleGLUTGLUT55 IntestineIntestine kidneykidneyGLUTGLUT5 5 Intestine,Intestine, kidneykidneyGLUTGLUT7 7 Endoplasmic ReticulumEndoplasmic Reticulum

BLOOD GLUCOSE BLOOD GLUCOSE G OG OREGULATIONREGULATION

FEEDING STATEFEEDING STATE

NONFEEDING STATENONFEEDING STATE

FEEDING STATEFEEDING STATE

ABSORPTION OF ABSORPTION OF O OS CC SO OS CC SMONOSACCHARIDESMONOSACCHARIDES

بل مكانيسم ها همين از كليه اپـي تليال سلول هاي .خونگردشبه داخلاپـي تليالسلولازانتقال)۲(واپـي تليالسلولبه داخلرودهمجرايازانتقال)۱(:مي پذيرد صورتمـرحلهدودرجذباين.رودهازمنوساكاريدهاجذب ۲۵-۳شكل ريج بينروزو يروررورج لروجريزل)(يپ لولب ي لولزل)(وپي ي لپي شب يونر لول ي مينزيپي ي .مي كنند استفاده گاالكـتوز و گلوكز بازجذب بـراي

HEXOKINASE & GLUCOKINASEHEXOKINASE & GLUCOKINASEHEXOKINASE & GLUCOKINASEHEXOKINASE & GLUCOKINASE

Glc + ATP GlcGlc + ATP Glc 66--p + ADPp + ADPGlc + ATP Glc Glc + ATP Glc 66--p + ADPp + ADP

PATHWAYS OF PATHWAYS OF G COS O SG COS O SGLUCOSE METABOLISMGLUCOSE METABOLISM

Triacylglcerol GlycogenTriacylglcerol Glycogen

Glc Glc 66--pp

Glcolysis Pentose Uronic Glcolysis Pentose Uronic Phosphate AcidPhosphate Acid

INSULININSULININSULININSULIN

PrePreproproinsulininsulinPrePreproproinsulininsulin((100 100 aa)aa)

Signal PeptideSignal PeptideSignal PeptideSignal PeptideProProinsulininsulin

((8686 aa)aa)((86 86 aa)aa)

Peptide CPeptide CI liI liInsulinInsulin

((A Chain with A Chain with 21 21 aa & B Chain aa & B Chain 30 30 aa)aa)

ل۸۳۹شكل ازيكانا زالا طان كزت كزقت)۱(گل شگل شخگ قازاافزا لهاياGLUT2ط ال كزشانك طهگل ا ته ال ف فعاليت به واسطه گلوكز .مي شود پانكراسسلول هايواردGLUT2طريقازمي يابد،افزايشخونگردشدرگلوكزوقتي)۱(.گلوكز توسط انسولينازادسازيمكانيسممراحل ۳۹-۸شكل

ن نتيجه كه شده گليكوليز مسير وارد گلوكوكينازن نتيجه كه مي بندد را ATP بـه وابسته پتاسيمي كانالATP .)۲( مي باشد ATP غلظت افزايش ا

كلسيمي كانال بازشدن و غشاء دپوالريزاسيون ا

.)۵( مي شود تحريك انسولين حاوي ترشحي گرانول هاي اگزوسيتوز ،)۴( داخل سلولي كلسيم غلظت افزايش با .)۳( مي باشد ولتاژ به وابسته

NONFEEDINGNONFEEDINGNONFEEDING NONFEEDING STATESTATESTATESTATE

GLUCAGONGLUCAGONGLUCAGON GLUCAGON

Synthesis as ProglucagonSynthesis as Proglucagon2929 Amino AcidsAmino Acids29 29 Amino AcidsAmino AcidsAct on Liver & Fatty TissueAct on Liver & Fatty TissueIncreased GlycogenolysisIncreased GlycogenolysisIncreased Glycogenolysis, Increased Glycogenolysis, Gluconeogenesis, Lipolysis, Gluconeogenesis, Lipolysis, ββ--OxidationOxidation

EPINEPHRINEEPINEPHRINEEPINEPHRINEEPINEPHRINE

Synthesis from TyrosineSynthesis from TyrosineA t Li & M lA t Li & M lAct on Liver & MuscleAct on Liver & MuscleIncreased Glycogenolysis & Increased Glycogenolysis & GluconeogenesisGluconeogenesis

CORTISOLCORTISOLCORTISOLCORTISOL

Synthesis from CholesterolSynthesis from CholesterolI d Gl iI d Gl iIncreased GluconeogenesisIncreased GluconeogenesisIncreased ProteolysisIncreased ProteolysisIncreasesd or Decreased LipolysisIncreasesd or Decreased Lipolysis

THYROID HORMONETHYROID HORMONETHYROID HORMONETHYROID HORMONE

Sythesis from TyrosineSythesis from TyrosineI d Gl l iI d Gl l iIncreased Glycogenolysis Increased Glycogenolysis Increased Glucose AbsorptionIncreased Glucose Absorption

GROWTH HORMONEGROWTH HORMONEGROWTH HORMONEGROWTH HORMONE

191 191 Amino AcidsAmino AcidsI d Gl iI d Gl iIncreased GluconeogenesisIncreased GluconeogenesisInhibition of Glc UptakeInhibition of Glc UptakeIncreased Lipolysis Increased Lipolysis

DIABETES MELLITUSDIABETES MELLITUSDIABETES MELLITUS DIABETES MELLITUS (DM)(DM)(DM)(DM)

DEFINITION Of DMDEFINITION Of DMDEFINITION Of DMDEFINITION Of DMClinical DM Is A Syndrome ofClinical DM Is A Syndrome ofClinical DM Is A Syndrome of Clinical DM Is A Syndrome of Disordered Metabolism with Disordered Metabolism with Inappropriate Hyperglycemia Due to anInappropriate Hyperglycemia Due to anInappropriate Hyperglycemia Due to an Inappropriate Hyperglycemia Due to an Absolute or Relative Deficiency of Absolute or Relative Deficiency of InsulinInsulinInsulinInsulinIt May Be Due to Deficiency of Insulin It May Be Due to Deficiency of Insulin Secretion Defect in Insulin Action orSecretion Defect in Insulin Action orSecretion, Defect in Insulin Action or Secretion, Defect in Insulin Action or BothBoth

Clinical Presentation of DMClinical Presentation of DMClinical Presentation of DMClinical Presentation of DM

DM Is Clinically Presented by ThreeDM Is Clinically Presented by ThreeDM Is Clinically Presented by Three DM Is Clinically Presented by Three PolysPolys which Are Due towhich Are Due to Glycosuria Glycosuria

PolyuriaPolyuriaPolydipsiaPolydipsiaPolyphagiaPolyphagiayp gyp g

COMPLICATIONS OF DMCOMPLICATIONS OF DMCOMPLICATIONS OF DMCOMPLICATIONS OF DM

AcuteAcute

ChronicChronic

ACUTE COMPLICATIONS OF DMACUTE COMPLICATIONS OF DMACUTE COMPLICATIONS OF DMACUTE COMPLICATIONS OF DM

Are Due to Reduced Insulin Activity andAre Due to Reduced Insulin Activity andAre Due to Reduced Insulin Activity and Are Due to Reduced Insulin Activity and Increased Counter Regulatory Increased Counter Regulatory HormenesHormenes, , specially glucagonspecially glucagonSeverity of Complications Are Dependent on Severity of Complications Are Dependent on Glucagon / Insulin RationGlucagon / Insulin RationAcute Complications Are Acute Complications Are 11) Hyperglycemia) Hyperglycemia22) Diabetic Ketoacidosis (DKA)) Diabetic Ketoacidosis (DKA)33) Hyperosmolar Coma) Hyperosmolar Coma) yp) yp44) Hypoglycemia) Hypoglycemia

HYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIAHYPERGLYCEMIA

Postprandial HyperglycemiaPostprandial HyperglycemiaPostprandial HyperglycemiaPostprandial HyperglycemiaFasting HyperglycemiaFasting HyperglycemiaGlucosuriaGlucosuria which results in Three Polys whichwhich results in Three Polys whichGlucosuriaGlucosuria which results in Three Polys which which results in Three Polys which are first presentations of overt DM:are first presentations of overt DM:11)) PolyuriaPolyuria (and(and NocturiaNocturia))11) ) PolyuriaPolyuria (and (and NocturiaNocturia))22) ) PolydipsiaPolydipsia33)) PolyphagiaPolyphagia (and(and weight lossweight loss))33) ) PolyphagiaPolyphagia (and (and weight lossweight loss))

DIABETIC KETOACIDOSIS (DKA)DIABETIC KETOACIDOSIS (DKA)DIABETIC KETOACIDOSIS (DKA)DIABETIC KETOACIDOSIS (DKA)

Is duo to increased lipolysis due to absence ofIs duo to increased lipolysis due to absence ofIs duo to increased lipolysis due to absence of Is duo to increased lipolysis due to absence of insulin activity, so it is more common in type insulin activity, so it is more common in type 1 1 DM and is uncommon in type DM and is uncommon in type 2 2 DMDMMay results in Coma due to May results in Coma due to hyperosmolalityhyperosmolality and and acidosisacidosisElectrolyte imbalance may occurs:Electrolyte imbalance may occurs:11) ) HyponatremiaHyponatremia occurs due to sodium excretion in urine and occurs due to sodium excretion in urine and

i di d l t b f i d l litl t b f i d l litincreased increased plasma water because of increased osmolalityplasma water because of increased osmolality22)) In In spite of potassium excretion, plasma potassium level spite of potassium excretion, plasma potassium level remains remains

normal normal because of a shift of Kbecause of a shift of K++ out of cells. But during insulin out of cells. But during insulin therapytherapy, K, K++ move back into cells and move back into cells and hypokalamiahypokalamia results.results.

HYPEOSMOLAR COMAHYPEOSMOLAR COMAHYPEOSMOLAR COMAHYPEOSMOLAR COMA

Is More Common in typeIs More Common in type 22 DMDMIs More Common in type Is More Common in type 2 2 DMDMResults from Sever Results from Sever hyperosmolalityhyperosmolality due to sever due to sever hyperglycemia ( >hyperglycemia ( >800 800 mg/mg/dLdL) and severe ) and severe yp g y (yp g y ( gg ))dehyratationdehyratation

HYPOGLYCEMIAHYPOGLYCEMIAHYPOGLYCEMIAHYPOGLYCEMIA

Is complication of insulin treatment in both typeIs complication of insulin treatment in both type 11Is complication of insulin treatment in both type Is complication of insulin treatment in both type 1 1 DM and type DM and type 2 2 DM, but may also occur with oral DM, but may also occur with oral oraloral hypoglycemic drugs, such as hypoglycemic drugs, such as sulfonyureassulfonyureasAcute response is mediated by counter Acute response is mediated by counter regulatory hormonesregulatory hormonesCommon symptoms are night sweats, Common symptoms are night sweats, nightmares, morning headachesnightmares, morning headaches

CHRONIC COMPLICATIONS OF DMCHRONIC COMPLICATIONS OF DMCHRONIC COMPLICATIONS OF DMCHRONIC COMPLICATIONS OF DM

MicrovascularMicrovascularM lM lMacrovascularMacrovascularOthersOthers


MicrovascularMicrovascularMicrovascularMicrovascularEye DiseaseEye DiseaseR ti th M l EdR ti th M l EdRetinopathy, Macular EdemaRetinopathy, Macular EdemaNeuropathyNeuropathySensory & Motor, AutonomicSensory & Motor, AutonomicNephropathyNephropathyNephropathyNephropathy


MacrovascularMacrovascularMacrovascularMacrovascularCoronary Artery DiseasesCoronary Artery DiseasesP i h l V l diP i h l V l diPeripheral Vascular diseasesPeripheral Vascular diseasesCerebrovascular DiseasesCerebrovascular Diseases


OthersOthersGastrointestinalGastrointestinalDiarrhea, GastroparesiaDiarrhea, Gastroparesia, p, pGenitourinaryGenitourinaryUropathy, Sexual DysfunctionUropathy, Sexual DysfunctionDermatologyDermatologyInfectionsInfectionsEyesEyesGlucoma, Cataract Glucoma, Cataract

CLASSIFICATION OF CLASSIFICATION OF DIABETES MELLITUSDIABETES MELLITUS

American Diabetes Association (ADA) American Diabetes Association (ADA) Classify DM into FourClassify DM into Four CalssCalss::Classify DM into Four Classify DM into Four CalssCalss::

Type Type 1 1 Type Type 22Other Specific TypesOther Specific Typesp ypp ypGDMGDM

DM Type DM Type 11 DM TypeDM Type 22ypeype55% % -- 1010% Frequency% FrequencyPrevioyslyPrevioysly NamedNamed

DM Type DM Type 229090% % -- 9595% Frequency% FrequencyPrevioyslyPrevioysly NamedNamed

JuvenileJuvenile--onset DM onset DM InsulinInsulin--dependent DMdependent DMAb t O tAb t O t

y yy yAdultAdult--onset onset DM DM NoninsulinNoninsulin--dependent dependent DMDM

Abrupt OnsetAbrupt OnsetNormal Body WeightNormal Body WeightFamily HistoryFamily History IsIs

GraduaIGraduaI OnsetOnsetObesityObesityFamily HistoryFamily History IsIsFamily History Family History Is Is

Less Less CommonCommonAutoimmuneAutoimmune

Family History Family History Is Is CommonCommonNo AutoimmuneNo Autoimmune

Often Ketones Present Often Ketones Present Total Total InsulinInsulin

No Ketones No Ketones Partial Partial Insulin Insulin D fi i / R i tD fi i / R i tDeficiencyDeficiency Deficiency / ResistanceDeficiency / Resistance

DIABETES MELLITUS TYPEDIABETES MELLITUS TYPE 11DIABETES MELLITUS TYPE DIABETES MELLITUS TYPE 11

Is anIs an autoimmuneautoimmune disease caused by selectivedisease caused by selectiveIs an Is an autoimmuneautoimmune disease caused by selective disease caused by selective destruction of pancreatic beta cellsdestruction of pancreatic beta cellsGenetic susceptibilityGenetic susceptibility is related, at is related, at leasetleaset in part, in part, p yp y ,, p ,p ,to the inheritance of specific immune response to the inheritance of specific immune response genes associated with HLAgenes associated with HLA--DR/DQ on DR/DQ on chromosome chromosome 66, as well as other genes and , as well as other genes and genetic markersgenetic markersI h h i d h i i iI h h i d h i i iIs hypothesized that a precipitating events Is hypothesized that a precipitating events occurs, such as occurs, such as viral infectionviral infection,, toxin exposuretoxin exposure, or , or other environmental influenceother environmental influence whichwhich trigerstrigers thetheother environmental influenceother environmental influence, which , which trigerstrigers the the autoimmune destruction of beta cells.autoimmune destruction of beta cells.


Have Have 2 2 subtypessubtypes11) ) IaIa including including 9595% % 00f patients who have f patients who have

autoantibodiesautoantibodies22) ) IbIb including including 55% of patients who have not % of patients who have not

autoantibodiesautoantibodiesAutoantibodies includesAutoantibodies includes

Islet cell antibodies (ICA)Islet cell antibodies (ICA)Islet cell antibodies (ICA)Islet cell antibodies (ICA)glutamic acid decarboxylase (GAD) glutamic acid decarboxylase (GAD) tyrosine phosphatasetyrosine phosphatase--22 protein (IAprotein (IA22))tyrosine phosphatasetyrosine phosphatase 2 2 protein (IAprotein (IA22))Insulin Autoantibodies (IAA) Insulin Autoantibodies (IAA)


Is More common in Children Whom have rapid Is More common in Children Whom have rapid onsetonsetAlso, may be seen in adults who often have slow Also, may be seen in adults who often have slow progression which may results in Wrong progression which may results in Wrong Diagnosis as type Diagnosis as type 2 2 , so they are called , so they are called Latent Latent Autoimmune Diabetes of Adulthood (LADA)Autoimmune Diabetes of Adulthood (LADA)Autoimmune Diabetes of Adulthood (LADA)Autoimmune Diabetes of Adulthood (LADA)

OBESITY ,OBESITY ,OBESITY ,OBESITY ,METABOLIC SYNDROMEMETABOLIC SYNDROME

& TYPE & TYPE 2 2 DIABETESDIABETES

OBESITY IS LIFE THREATENINGOBESITY IS LIFE THREATENINGOBESITY IS LIFE THREATENINGOBESITY IS LIFE THREATENING

Obesity Increases the Chance of DevelopingObesity Increases the Chance of DevelopingObesity Increases the Chance of DevelopingObesity Increases the Chance of Developing

T pe II DiabetesT pe II DiabetesType II DiabetesType II DiabetesAtherosclerosisAtherosclerosisCancers of Colon, Breast, Prostate & Cancers of Colon, Breast, Prostate & EndometriumEndometrium

BODY MASS INDEX (BMI)BODY MASS INDEX (BMI)BODY MASS INDEX (BMI)BODY MASS INDEX (BMI)Obesity Is Defined in Terms of BMIObesity Is Defined in Terms of BMIyy

Weight in KgBMI =

(Height in m)2

BMI < BMI < 1818..5 5 UnderweightUnderweightBMI = BMI = 1818..5 5 –– 2424..9 9 NormalNormalBMI = BMI = 25 25 –– 2929..9 9 OverweightOverweightBMI = BMI = 30 30 –– 40 40 ObeseObeseBMI > BMI > 40 40 Morbidly ObeseMorbidly Obese

FATTY TISSUE IS AN FATTY TISSUE IS AN OC O GOC O GENDOCRINE ORGANENDOCRINE ORGAN

Adipocytes Secrets Different Adipocytes Secrets Different AdipokinsAdipokins::

LeptinLeptinAdiponectinAdiponectinResistinResistinCytokines such as Cytokines such as TNFTNF

TNFTNF INCDUCES DYSLIPIDEMIAINCDUCES DYSLIPIDEMIATNFTNF INCDUCES DYSLIPIDEMIAINCDUCES DYSLIPIDEMIATNF

Lipoprtein Lipase Hormone-sensitveLipase

Release of FFAs Into Circulation

Clearance of VLDLfrom Circulation

Hepatic Synthesis of TAGs

Hepatic Uptakef

from Circulation

Blood VLDL

of TAGs

of FFAs

Hepatic Synthesisof VLDL

TNFTNF INDUCES DYSLIPIDEMIAINDUCES DYSLIPIDEMIATNFTNF INDUCES DYSLIPIDEMIAINDUCES DYSLIPIDEMIATNF

Expression & Activityof LCAT

Expression ofABC Transporters

Expression ofAPo A-I & Apo-A-IVof LCAT ABC Transporters APo A I & Apo A IV

Blood HDL

FFAs INDUCE HYPERGLYCEMIAFFAs INDUCE HYPERGLYCEMIAFFAs INDUCE HYPERGLYCEMIAFFAs INDUCE HYPERGLYCEMIAFFAs

Activation of PKC Competitive Inhibition of

GLUT2 & GLUT4

Phosphorylation of IRS-1 & IRS-2

GLUT4 TranslocationIn MuscleIRS 1 & IRS 2

Blood Glucose

In Muscle

Interfering with

Down-Regulation ofGluconeogenesis

In Liver

Interfering with

In Liver

PANCREATIC COMPENSATIONPANCREATIC COMPENSATIONPANCREATIC COMPENSATIONPANCREATIC COMPENSATION

Hyperinsulinemia

Increased Cell Proliferation

Stimulation of SympattheticNervous System

yp

Cell Proliferation

Normal or Near NormalBlood Glucose

Increased Risk ofDifferent Types

Blood Glucose

Na & Water RetentionVasoconstriction

Of Cancers

Hypertension

DECOMPENSATION PROCESSDECOMPENSATION PROCESSDECOMPENSATION PROCESSDECOMPENSATION PROCESS

Increased FFAs and/or CytokinesIncreased FFAs and/or Cytokines

Gradual Loss of the Abilityof the Pancreas to Overproduce Insulin

Increased Blood Glucose

Type 2 Diabetes Begins

MTABOLIC SYNDROMEMTABOLIC SYNDROMEMTABOLIC SYNDROMEMTABOLIC SYNDROME

The insulin resistance associated with obesity The insulin resistance associated with obesity yyincreases the risk of developing increases the risk of developing type type 2 2 diabetesdiabetes, , heart diseaseheart disease, , hypertensionhypertension, and several types , and several types ofof cancerscancersof of cancerscancers..

Increased risk of some of these diseases mayIncreased risk of some of these diseases mayIncreased risk of some of these diseases may Increased risk of some of these diseases may occur long before the patient becomes diabetic, occur long before the patient becomes diabetic, so the condition between the onset of insulin so the condition between the onset of insulin resistance and development of type resistance and development of type 2 2 diabetes diabetes is referred as is referred as metabolic syndromemetabolic syndrome

METABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROME

WHO Defines Metabolic Syndrome as Two or WHO Defines Metabolic Syndrome as Two or More of the Following Conditions:More of the Following Conditions:More of the Following Conditions:More of the Following Conditions:

Abd i l b itAbd i l b itAbdominal obesityAbdominal obesityDyslipidemia Dyslipidemia (Increased VLDL and Decreased HDL)(Increased VLDL and Decreased HDL)

HypertenstionHypertenstionInsulin ResistantInsulin Resistant (Modest increase in FBS)(Modest increase in FBS)Insulin Resistant Insulin Resistant (Modest increase in FBS)(Modest increase in FBS)

METABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROME

Defining criteria according to theDefining criteria according to the Third Report ofThird Report ofDefining criteria according to the Defining criteria according to the Third Report of Third Report of NCEP Expert panel on Detection, Evaluation, and NCEP Expert panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Treatment of High Blood Cholesterol in Adults i l d th f Th M f thi l d th f Th M f thinclude the presence of Three or More of the include the presence of Three or More of the following conditions:following conditions:Impaired Fasting GlucoseImpaired Fasting Glucosep gp gBlood Pressure ≥ Blood Pressure ≥ 135 135 / / 85 85 mmHgmmHgWaist circumference > Waist circumference > 102 102 cm in men and >cm in men and >88 88 cm in cm in womenwomenSerum TG ≥ Serum TG ≥ 150 150 mg/mg/dLdLHDLHDL C <C < 4040 mg/mg/dLdL in men and <in men and < 5050 mg/mg/dLdL in womenin womenHDLHDL--C < C < 40 40 mg/mg/dLdL in men and < in men and < 50 50 mg/mg/dLdL in womenin women

RISK FACTORS OF TYPERISK FACTORS OF TYPE 22 DMDMRISK FACTORS OF TYPE RISK FACTORS OF TYPE 2 2 DMDM

Family History Of DiabetesFamily History Of Diabetesy yy yObesityObesityInactivityInactivityHi h Bl d PHi h Bl d PHigh Blood PressureHigh Blood PressureLow HDL or High TGLow HDL or High TGHistory of GDM or Child Birth >History of GDM or Child Birth > 44 kgkgHistory of GDM or Child Birth History of GDM or Child Birth 4 4 kgkgHistory of Impaired GTTHistory of Impaired GTTRace : Americans, AfricansRace : Americans, AfricansPolycystic Ovary Syndrome or Polycystic Ovary Syndrome or AcanthosisAcanthosis NigricansNigricansHistory of Vascular DiseasesHistory of Vascular DiseasesHistory of Vascular DiseasesHistory of Vascular Diseases

OTHER SPECIFIC TYPESOTHER SPECIFIC TYPESOTHER SPECIFIC TYPESOTHER SPECIFIC TYPES11) Genetic Defects of Beta Cell Function) Genetic Defects of Beta Cell Function

M t itM t it t di b t f th (MODY)t di b t f th (MODY)MaturityMaturity--onset diabetes of the young (MODY)onset diabetes of the young (MODY)22) Genetic Defects in Insulin Action) Genetic Defects in Insulin Action

LeperchaunismLeperchaunism syndromesyndrome33) ) PacntreaticPacntreatic DiseasesDiseases))

Pancreatitis, Cystic Fibrosis, Hemochromatosis, NeoplasmsPancreatitis, Cystic Fibrosis, Hemochromatosis, Neoplasms44) ) EndocrinopathiesEndocrinopathies

Hyperthyroidism, Cushing, Hyperthyroidism, Cushing, PheochromocytomaPheochromocytoma, , GlucagonomaGlucagonoma, , AldostronomaAldostronomaAldostronomaAldostronoma

55) Drugs) DrugsGlucocorticoidesGlucocorticoides, Nicotinic Acid, Thyroid Hormones, , Nicotinic Acid, Thyroid Hormones, PhenytoeinPhenytoein, ,

Thiazides, Thiazides, αα--Interferon, BetaInterferon, Beta--BlockersBlockers44) Infections) Infections44) Infections) Infections

Congenital Rubella, Congenital Rubella, CoxsakieCoxsakie, CMV, CMV55) Genetic Defect of B Cell Function ) Genetic Defect of B Cell Function 66) Other Genetic Syndromes) Other Genetic Syndromes

Down, Down, KlinfelterKlinfelter, Turner, Chorea, Porphyria, Turner, Chorea, Porphyria

GESTATIONAL DIABETES GESTATIONAL DIABETES S (G )S (G )MELLITUS (GDM)MELLITUS (GDM)

Is defined as glucose intolerance Is defined as glucose intolerance that develops or is first recognized that develops or is first recognized p gp gduring pregnancyduring pregnancyDevelops during approximatelyDevelops during approximately 77%%Develops during approximately Develops during approximately 77% % of all pregnanciesof all pregnanciesThere is both insulin insensitivityThere is both insulin insensitivityThere is both insulin insensitivity There is both insulin insensitivity and failure to increase insulin and failure to increase insulin secretionsecretionsecretion secretion

LowLow--Risk WomenRisk WomenLowLow Risk WomenRisk Women

Less thanLess than 2525 yearsyearsLess than Less than 25 25 yearsyearsNormal weight before pregnancyNormal weight before pregnancyRRRaceRaceAbsence of DM in first relatedAbsence of DM in first relatedAbsence of abnormal glucose Absence of abnormal glucose intoleranceintoleranceintoleranceintoleranceAbsence of complicated pregnancyAbsence of complicated pregnancy

HighHigh--Risk WomenRisk WomenHighHigh Risk WomenRisk Women

More thanMore than 3737 yearsyearsMore than More than 37 37 yearsyearsPregnancy weight > Pregnancy weight > 80 80 kgkgRRRaceRaceFamily history of DMFamily history of DMy yy yPolycystic ovary syndromePolycystic ovary syndromePrevious macrosomiaPrevious macrosomiaPrevious macrosomiaPrevious macrosomiaPrevious unexplained stillbirthPrevious unexplained stillbirth

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PATHOPHISIOLOGY OFPATHOPHISIOLOGY OF DIABETES MELLITUSDIABETES MELLITUS · Mt itMaturityy--onseonset di b t f th (MODY)t diabetes of the young (MODY) 22) Genetic Defects in Insulin