di b t m llitdiabetes mellitus diagnosis and ...iacld.ir/dl/co/13/diabetes/diabetesmellitus... ·...

Di b t M llitDiabetes MellitusDiagnosis and classificationDiagnosis and classification

Ali reza Esteghamati MDAli reza Esteghamati MDAli reza Esteghamati, MDAli reza Esteghamati, MDProfessor of Endocrinology and Metabolism Professor of Endocrinology and Metabolism

Tehran University of Medical Tehran University of Medical SciencesSciencesSciencesSciences

DefinitionDefinition

Diabetes mellitusDiabetes mellitusA chronic disorder characterized by aA chronic disorder characterized by a deficiency ofdeficiency ofA chronic disorder characterized by a A chronic disorder characterized by a deficiency of deficiency of

insulin secretion and/or insulin effectinsulin secretion and/or insulin effect11 which causeswhich causes hyperglycemiahyperglycemia1.1. which causes which causes hyperglycemiahyperglycemia

22 Disturbances ofDisturbances of carbohydrate fat and protein metabolismcarbohydrate fat and protein metabolism2.2. Disturbances of Disturbances of carbohydrate, fat and protein metabolismcarbohydrate, fat and protein metabolism

3.3. constellation of chronic complications .constellation of chronic complications .

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pp

Importance

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Importance

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Global prevalence of diabetes.Estimates for the year 2000 and projections for 2030

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Diabetes Mellit sDiabetes Mellitus

Th “di b t llitTh “di b t llit t it iThe name “diabetes mellitus means The name “diabetes mellitus means sweet urine.sweet urine.

It stems from ancient times whenIt stems from ancient times when physiciansphysiciansIt stems from ancient times when It stems from ancient times when physicians physicians would taste a patients urine as a part of a would taste a patients urine as a part of a diagnosis.diagnosis.diagnosis.diagnosis.

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DIABETES MELLITUSDIABETES MELLITUS

Diabetes mellitus comprises a group of common metabolic disorders that share the phenotype of hyperglycemia.

Several distinct types of DM exist and are caused by a complex interaction of geneticsenvironmental factors

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life-style choices.

Trends in the prevalence of diabetes and impaired Trends in the prevalence of diabetes and impaired f i l i i i i h b i i If i l i i i i h b i i Ifasting glucose in association with obesity in Iran: fasting glucose in association with obesity in Iran: 20052005––20112011

Alireza Esteghamati , Alireza Esteghamati , EtemadEtemad, , KoohpayehzadehKoohpayehzadeh , , AbbasiAbbasi ,,MeysamieMeysamie , , NoshadNoshad , , AsgariAsgari , , MousavizadehMousavizadeh , , RafeiRafei ,,KhajehKhajeh , , NeishabouryNeishaboury ,,SheikhbahaeiSheikhbahaei ,,NakhjavaniNakhjavani

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Results

In In 20112011IFG and total DM prevalence rates wereIFG and total DM prevalence rates were 1414..6060%%IFG and total DM prevalence rates were IFG and total DM prevalence rates were 1414..6060%%

((9595%CI: %CI: 1212..4141––1616..7878) ) and and 1111..3737%% ((9595%CI: %CI: 99..8686––1212..8989) ) among among 2525––7070 years, respectively.years, respectively.2525 70 70 years, respectively. years, respectively.

DMDM i ldi ld (( 00 00010001))DM was more DM was more common in older age common in older age (p < (p < 00..00010001), ), in in womenwomen (p = (p = 00..02160216), and in ), and in urbanurban--dwellers dwellers (p (p

00 00010001))= = 00..00010001). ). 13

Burden of Diabetes in the U.S.Affects more than Affects more than 18 18 million personsmillion personsIncreases the risk of heart attack and stroke by Increases the risk of heart attack and stroke by at leastat least 33--foldfoldat least at least 33 fold fold

The leading cause of new blindness, end stage The leading cause of new blindness, end stage renal disease, and amputationrenal disease, and amputation

Accounts forAccounts for 1717% of all deaths after age% of all deaths after age 2525Accounts for Accounts for 1717% of all deaths after age % of all deaths after age 2525

Costs $Costs $132 132 billion per yearbillion per year

Diabetes Mellitus : Health Impact7th leading cause of death

Renal failure

Heart disease d t k

7th leading cause of death

Diabetes

failure and stroke: 2x to 4x increase

Diabetes

Blindness

Amputation

Nerve damage in 60% to 70% of patients

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AmputationDiabetes Statistics. March 1999. NIDDK publication NIH 99-3892.Harris MI et al. Diabetes Care. 1993;16:1446–1452.

Average para clinic cost per patient wasAverage para clinic cost per patient was 393.6 ± 47.8 and average inpatient cost per

ipatient was 1520.7 ± 104.5 USD.

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CLASSIFICATION OFCLASSIFICATION OF DIABETES MELLITUS

NDDG classification systemNDDG classification system was published was published in in 1979 1979 . .

The WHOThe WHO Expert Committee on Diabetes inExpert Committee on Diabetes inThe WHOThe WHO Expert Committee on Diabetes in Expert Committee on Diabetes in 19801980

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CLASSIFICATION OF DIABETES MELLITUS

These groups recognized two major forms ofThese groups recognized two major forms ofdiabetes, which they termeddiabetes, which they termed

IDDM, type IDDM, type 1 1 diabetes diabetes

NIDDM, type NIDDM, type 2 2 diabetesdiabetes

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Expert CommitteeExpert Committee considered the dataExpert Committee considered the data

and rationale for what was accepted in and rationale for what was accepted in pp19791979along with researchalong with research findings of the lastfindings of the lastalong with researchalong with research findings of the last findings of the last 18 18 years years proposed changesproposed changes to the NDDG/WHOto the NDDG/WHOproposed changesproposed changes to the NDDG/WHO to the NDDG/WHO classification scheme . classification scheme .

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CLASSIFICATION

Recent advances in the understanding ofRecent advances in the understanding of11 EtiologyEtiology1.1. Etiology Etiology 2.2. Pathogenesis Pathogenesis gghave led to a revised classification.have led to a revised classification.

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CLASSIFICATIONAlthough all forms of Although all forms of DMDM are are h t i d b h l ih t i d b h l icharacterized by hyperglycemiacharacterized by hyperglycemia

The pathogenic mechanisms by which The pathogenic mechanisms by which hyperglycemia hyperglycemia arises differ widely.arises differ widely.yp g yyp g y yy

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CLASSIFICATION

Some forms of DM are characterized bySome forms of DM are characterized by1.1. An absolute An absolute insulin deficiency insulin deficiency

22. Genetic defect leading to defective . Genetic defect leading to defective insulin secretion insulin secretion

33. . Insulin resistanceInsulin resistance as their underlying etiology. as their underlying etiology.

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CLASSIFICATIONAt present DM classification is on the basis of the At present DM classification is on the basis of the pathogenic processpathogenic process that leads to hyperglycemiathat leads to hyperglycemiapathogenic processpathogenic process that leads to hyperglycemiathat leads to hyperglycemia

As opposed to criteria such asAs opposed to criteria such asAgeAge of onsetof onsetAgeAge of onset of onset Type of therapyType of therapy

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CLASSIFICATION

The two broad categories of The two broad categories of DMDM are designatedare designated11type type 1 1

type type 22. .

Type Type 11A DM results fromA DM results fromautoimmune beta cell destructionautoimmune beta cell destructionautoimmune beta cell destructionautoimmune beta cell destructionusually leads to insulin deficiencyusually leads to insulin deficiency..

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CLASSIFICATIONCLASSIFICATION

TypeType 11B DM is alsoB DM is alsoThe mechanisms leading to The mechanisms leading to

Type Type 11B DM is also B DM is also characterized by characterized by

beta cell destruction are beta cell destruction are unknown.unknown.

Insulin deficiency Insulin deficiency Relatively few patients fall Relatively few patients fall into type into type 11B idiopathic B idiopathic

Tendency to develop ketosisTendency to develop ketosis

Lack immunologic markers of anLack immunologic markers of anMany of these are either Many of these are either Af iAf i A i A iA i A iLack immunologic markers of an Lack immunologic markers of an

autoimmune destructive process autoimmune destructive process of the beta cells.of the beta cells.

AfricanAfrican--American or Asian American or Asian in heritagein heritage

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CLASSIFICATION

Type Type 2 2 DMDM is a heterogeneous group of disorders is a heterogeneous group of disorders usually characterized by variable degrees ofusually characterized by variable degrees of

Insulin resistance Insulin resistance I i d i li iI i d i li iImpaired insulin secretionImpaired insulin secretion

Increased glucose production.Increased glucose production.

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The 3 main pathophysiological defects of Type 2 diabetes

β-cell dysfunction

Insulin-resistance

the “triumvirate”t e t u ate

Increased hepatic glucose

production

CLASSIFICATION

Distinct genetic and metabolic defects inDistinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2common phenotype of hyperglycemia in type 2 DM. .

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CLASSIFICATIONTwo features of the current classification of Two features of the current classification of DMDM diverge from previous classifications.diverge from previous classifications.

First the termsFirst the terms insulininsulin dependent diabetesdependent diabetesFirst, the terms First, the terms insulininsulin--dependent diabetes dependent diabetes mellitusmellitus (IDDM) and (IDDM) and noninsulinnoninsulin--dependent dependent diabetes mellitusdiabetes mellitus (NIDDM) are obsolete(NIDDM) are obsoletediabetes mellitusdiabetes mellitus (NIDDM) are obsolete. (NIDDM) are obsolete.

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CLASSIFICATIONThese previous designations reflected the These previous designations reflected the

b i hb i h 11 DM ( i lDM ( i lobservation that most type observation that most type 1 1 DM (previously DM (previously IDDM) have an absolute requirement for insulin IDDM) have an absolute requirement for insulin treatmenttreatment

whereas many type whereas many type 2 2 DM (previously NIDDM) DM (previously NIDDM) do not require insulin therapy to prevent do not require insulin therapy to prevent q py pq py pketoacidosis.ketoacidosis.

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CLASSIFICATION

However, because many However, because many , y, yindividuals with type individuals with type 2 2 DM DM

t ll i i lit ll i i lieventually require insulin eventually require insulin treatment for control of glycemia, treatment for control of glycemia, g y ,g y ,the use of the latter term generated the use of the latter term generated

id bl f iid bl f iconsiderable confusionconsiderable confusion

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CLASSIFICATIONAAge is no longer used as a criterion in the new in the new classification systemclassification system

It is estimated that It is estimated that 5 5 --1010% of individuals who % of individuals who develop DM after agedevelop DM after age 3030classification system.classification system.

Although type Although type 1 1 DMDM most most

develop DM after age develop DM after age 30 30 have type have type 11A DM. A DM.

g ypg ypcommonly develops before commonly develops before the age of the age of 3030A t i b t llA t i b t ll

Although type Although type 2 2 DM more DM more typically develops with typically develops with increasing age it occurs inincreasing age it occurs inAn autoimmune beta cell An autoimmune beta cell

destructive process can destructive process can develop at any age.develop at any age.

increasing age, it occurs in increasing age, it occurs in children, particularly in children, particularly in obese adolescentsobese adolescents. .

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The major forms of diabetes

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The major forms of diabetes

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Type 1 or insulin-dependent diabetes mellitus

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Type 2 or non-insulin dependent diabetes mellitus

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Less common forms of diabetes mellitus

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Asia – the new center of the diabetes epidemic

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Risk of type 2 diabetes is increasingin children and adolescents

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Classification of Diabetes

Type Type 1 1 Diabetes MellitusDiabetes MellitusTypeType 22 Diabetes MellitusDiabetes MellitusType Type 2 2 Diabetes MellitusDiabetes MellitusOther Specific TypesOther Specific TypesG t ti l Di b t M llitG t ti l Di b t M llitGestational Diabetes MellitusGestational Diabetes Mellitus

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Diabetes Mellitus1010% % of diabetes is Type of diabetes is Type 11

G ti li k ( hG ti li k ( h 66HLA i )HLA i )Genetic link (chromosome Genetic link (chromosome 66HLA region)HLA region)Presence of islet cell Presence of islet cell autoantibodiesautoantibodiesA i d i f h b llA i d i f h b llAutoimmune destruction of the beta cellsAutoimmune destruction of the beta cells

9090%% f i if i i 229090% % of diabetes is Type of diabetes is Type 22

Genetic predispositionGenetic predispositionOb iOb iObesityObesityImpairment of insulin secretion and defects in Impairment of insulin secretion and defects in i li ti i Ti li ti i T 22 di b tdi b t

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insulin action in Type insulin action in Type 2 2 diabetesdiabetes

Differential DiagnosisType 1 and Type 2 DiabetesType 1 and Type 2 Diabetes

Type Type 1 1 DiabetesDiabetes Type Type 2 2 DiabetesDiabetes

Usual clinical courseUsual clinical course InsulinInsulin--dependentdependent Initially nonInitially non--insulininsulin--dependentdependent

Usual age of onsetUsual age of onset <<20 20 years (but ~years (but ~5050%% >>40 40 years butyears butUsua age o o setUsua age o o set 00 yea s (butyea s (but 5050%% 00 yea s butyea s butover over 20 20 years)years) increasingly earlierincreasingly earlier

Body weightBody weight Usually leanUsually lean Usually obeseUsually obese

Clinical onsetClinical onset Often ac teOften ac te S btle sloS btle sloClinical onsetClinical onset Often acuteOften acute Subtle, slowSubtle, slow

KetosisKetosis--proneprone YesYes NoNo

Family historyFamily history ≤≤1515% with % with 11°° relativerelative CommonCommon

Frequency of HLAFrequency of HLA--DRDR33,, IncreasedIncreased Not increasedNot increasedDRDR44, DQB, DQB11**02010201,, **03020302

IsletIslet autoantibodiesautoantibodies PresentPresent AbsentAbsentIslet Islet autoantibodiesautoantibodies PresentPresent AbsentAbsent((GADA, ICA,GADA, ICA, IAIA--22A, IAA)A, IAA)

Eti l i Cl ifi ti f DMEtiologic Classification of DM

II TypeType 11 diabetesdiabetes (b(b--cell destruction usually leading to absolutecell destruction usually leading to absoluteI. I. Type Type 1 1 diabetesdiabetes (b(b--cell destruction, usually leading to absolute cell destruction, usually leading to absolute insulin deficiency)insulin deficiency)A. ImmuneA. Immune--mediatedmediatedB. IdiopathicB. Idiopathic

IIII TypeType 22 diabetesdiabetes (may range from(may range from predominantly insulinpredominantly insulinII. II. Type Type 2 2 diabetesdiabetes (may range from (may range from predominantly insulin predominantly insulin resistanceresistance with relative insulin deficiency to a with relative insulin deficiency to a predominantly predominantly insulin insulin secretorysecretory defectdefect with insulin resistance)with insulin resistance)

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III Oth ifi t f di b tIII. Other specific types of diabetesA.A. Genetic defects of bGenetic defects of b--cell functioncell function characterized by mutations in:characterized by mutations in:yy

11. . HepatocyteHepatocyte nuclear transcription factor (HNF) nuclear transcription factor (HNF) 44a (MODY a (MODY 11))22. . GlucokinaseGlucokinase (MODY (MODY 22))33. HNF. HNF--11a (MODY a (MODY 33))44. Insulin promoter factor (IPF) . Insulin promoter factor (IPF) 1 1 (MODY (MODY 44))55. HNF. HNF--11b (MODY b (MODY 55))66 N DN D11 (MODY(MODY 66))66--NeuroDNeuroD1 1 (MODY (MODY 66))77-- Mitochondrial DNAMitochondrial DNA88-- ProinsulinProinsulin or insulin conversionor insulin conversion

Maturity onset diabetes of the young (MODY) :Maturity onset diabetes of the young (MODY) :characterized by characterized by AutosomalAutosomal dominant inheritancedominant inheritance

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Early onset of hyperglycemiaEarly onset of hyperglycemiaImpairment in insulin secretion . Impairment in insulin secretion .

Monogenic Diabetes Syndromes

Monogenic defects that cause bMonogenic defects that cause b--cell dysfunction, cell dysfunction, such as such as neonatal diabetes and MODYneonatal diabetes and MODY, represent a , represent a small fraction of patients with small fraction of patients with diabetes(diabetes(55%). %).

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Monogenic Diabetes Syndromes

These forms of diabetes are frequently These forms of diabetes are frequently characterized by characterized by onset of hyperglycemia at onset of hyperglycemia at yy yp g yyp g yan early agean early age (generally before age (generally before age 25 25 years).years).

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Neonatal Diabetes

Diabetes diagnosed in Diabetes diagnosed in the first the first 66months of life months of life has been shown not to be typical autoimmune has been shown not to be typical autoimmune ypyptype type 1 1 diabetes. diabetes.

This soThis so--called neonatal diabetes can either be called neonatal diabetes can either be transient or permanenttransient or permanenttransient or permanenttransient or permanent

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N t l Di b tNeonatal DiabetesThe most common genetic defect causingThe most common genetic defect causingThe most common genetic defect causing The most common genetic defect causing transienttransient disease is a defect disease is a defect on ZAC/HYAMI on ZAC/HYAMI imprintingimprintingimprintingimprinting

PermanentPermanent neonatal diabetes is most commonly neonatal diabetes is most commonly a defect in the gene encoding a defect in the gene encoding the Kirthe Kir66..2 2 subunit subunit of the bof the b--cell KATP channel.cell KATP channel.

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N t l Di b tNeonatal DiabetesDiagnosing the latter has implications sinceDiagnosing the latter has implications sinceDiagnosing the latter has implications, since Diagnosing the latter has implications, since such children can be well managed with such children can be well managed with sulfonylureassulfonylureassulfonylureassulfonylureas..

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Maturity-Onset Diabetes of the YoungMaturity Onset Diabetes of the Young

MODY is characterized by MODY is characterized by impaired insulin impaired insulin secretion secretion with minimal or no defects in insulin with minimal or no defects in insulin action.action.

It is inherited in an It is inherited in an autosomalautosomal dominant pattern. dominant pattern. Abnormalities atAbnormalities at six geneticsix genetic loci on differentloci on differentAbnormalities at Abnormalities at six genetic six genetic loci on different loci on different chromosomes have been chromosomes have been identifiedidentified to date.to date.

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Maturity-Onset Diabetes of the YoungMaturity-Onset Diabetes of the Young

The most common form is associated with The most common form is associated with mutations on chromosome mutations on chromosome 12 12 in a hepatic in a hepatic pptranscription factor referred to as transcription factor referred to as hepatocytehepatocytenuclear factor nuclear factor (HNF)(HNF)--11a.a.( )( )

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A second form is associated with mutations inA second form is associated with mutations inA second form is associated with mutations in A second form is associated with mutations in the the glucokinaseglucokinase gene on chromosome gene on chromosome 77p and p and results in a defectiveresults in a defective glucokinaseglucokinase moleculemoleculeresults in a defective results in a defective glucokinaseglucokinase molecule.molecule.

GlucokinaseGlucokinase converts glucose to glucoseconverts glucose to glucose--66--phosphate, the metabolism of which, in turn, phosphate, the metabolism of which, in turn, stimulates insulin secretion by the bstimulates insulin secretion by the b--cell.cell.

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The less common forms of MODY result The less common forms of MODY result from mutations in other transcription from mutations in other transcription ppfactors, including HNFfactors, including HNF--44a,HNFa,HNF--11b, insulin b, insulin promoter factor (IPF)promoter factor (IPF)--11, and NeuroD, and NeuroD11p ( )p ( )

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MONOGENIC FORMS OF DIABETES MELLITUS

Six different variants of MODY, caused by Six different variants of MODY, caused by mutations mutations in genesin genes encodingencoding isletislet enriched transcription factorsenriched transcription factorsin genes in genes encoding encoding isletislet--enriched transcription factors enriched transcription factors or or glucokinaseglucokinase

MODY MODY 11, MODY , MODY 33, and MODY , and MODY 5 5 are caused by are caused by mutations in themutations in the hepatocytehepatocyte nuclear transcription factornuclear transcription factormutations in the mutations in the hepatocytehepatocyte nuclear transcription factor nuclear transcription factor (HNF) (HNF) 44αα , HNF, HNF--11αα , and HNF, and HNF--11 ββ , respectively, respectively

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MONOGENIC FORMS OF DIABETES MELLITUS

These These transcription factors transcription factors are expressed in the are expressed in the lili b l i h i i l di hb l i h i i l di hliver liver but also in other tissues, including the but also in other tissues, including the pancreatic islets and kidneypancreatic islets and kidney. .

These factors most likely affectThese factors most likely affectyyIIslet development slet development or or E i f i t tE i f i t t i li l ti l t dti l t dExpression of genes important Expression of genes important in glucosein glucose--stimulated stimulated insulin secretion insulin secretion or the maintenance or the maintenance of beta cell massof beta cell mass

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MODY 3MODY 3

Individuals with an HNFIndividuals with an HNF--11αα mutation mutation (MODY (MODY 33)) have a have a progressive decline in glycemic control but may progressive decline in glycemic control but may respond to respond to sulfonylureassulfonylureas. .

Some of these patients were initially thought to have Some of these patients were initially thought to have type type 1 1 DM but were later DM but were later shown to respond to a shown to respond to a

lf l d i li di ti dlf l d i li di ti dsulfonylurea, and insulin was discontinuedsulfonylurea, and insulin was discontinued. .

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MODY 5

Individuals with a HNFIndividuals with a HNF--11ββ mutation have progressive mutation have progressive impairment ofimpairment of insulin secretion hepatic insulininsulin secretion hepatic insulinimpairment of impairment of insulin secretion, hepatic insulin insulin secretion, hepatic insulin resistanceresistance, , and require insulin treatment (minimal and require insulin treatment (minimal response toresponse to sulfonylureassulfonylureas).).response to response to sulfonylureassulfonylureas).).

These individuals often have other abnormalities such These individuals often have other abnormalities such as as renal cystsrenal cystsrenal cystsrenal cystsmild pancreatic exocrine insufficiencymild pancreatic exocrine insufficiencyabnormal liver function testsabnormal liver function testsabnormal liver function tests. abnormal liver function tests.

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MODY 2MODY 2Mutations in the Mutations in the glucokinaseglucokinase genegeneMildMild tt d t h l i th t d t d OADd t h l i th t d t d OADMildMild--toto--moderate, hyperglycemia that does not respond OADmoderate, hyperglycemia that does not respond OAD..

Gl kiGl ki t l th f ti ft l th f ti f ll 66GlucokinaseGlucokinase catalyzes the formation of catalyzes the formation of glucoseglucose--66--phosphate from glucose,phosphate from glucose, is important for glucose is important for glucose sensing by the beta cells and for glucose utilization bysensing by the beta cells and for glucose utilization bysensing by the beta cells and for glucose utilization by sensing by the beta cells and for glucose utilization by the liver.the liver.

As a result of As a result of glucokinaseglucokinase mutations, higher glucose mutations, higher glucose are required to elicit insulinare required to elicit insulin secretorysecretory responses,responses, thusthusare required to elicit insulin are required to elicit insulin secretorysecretory responses, responses, thus thus altering the set point for insulin secretionaltering the set point for insulin secretion..

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MODY 4MODY 4Is a rare variant caused by mutations in the Is a rare variant caused by mutations in the insulin insulin promoter factor (IPF) promoter factor (IPF) 11, which is a transcription factor that , which is a transcription factor that regulates regulates pancreatic development pancreatic development and and insulin gene insulin gene t i tit i titranscription.transcription.

HH i i i ii i i i iiHomozygousHomozygous inactivating mutations cause inactivating mutations cause pancreatic pancreatic agenesisagenesis

Heterozygous Heterozygous mutations may mutations may result in DMresult in DM..

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Diagnosis

Readily available commercial genetic testing now Readily available commercial genetic testing now enables a true genetic diagnosisenables a true genetic diagnosisenables a true genetic diagnosis. enables a true genetic diagnosis.

It i i t t t tl di f thIt i i t t t tl di f thIt is important to correctly diagnose one of the It is important to correctly diagnose one of the monogenic forms of diabetes because these children monogenic forms of diabetes because these children may be incorrectly diagnosed with typemay be incorrectly diagnosed with type 11 or typeor type 22may be incorrectly diagnosed with type may be incorrectly diagnosed with type 1 1 or type or type 2 2 diabetes, diabetes,

leading to suboptimal treatment regimens and delays leading to suboptimal treatment regimens and delays in diagnosing other family members.in diagnosing other family members.g g yg g y

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Diagnosis

The diagnosis of monogenic diabetes should be The diagnosis of monogenic diabetes should be considered in children with the following considered in children with the following ggfindingsfindings::

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Diagnosis

Diabetes diagnosed within the first Diabetes diagnosed within the first 6 6 months of months of lifelife

Strong family history of diabetes but without Strong family history of diabetes but without typical features of type typical features of type 2 2 diabetes (diabetes (nonobesenonobese, low, low--risk ethnic group)risk ethnic group)

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Diagnosis

Mild fasting hyperglycemia (Mild fasting hyperglycemia (100100––150 150 mg/mg/dLdL , , especially if young and especially if young and nonobesenonobesep y y gp y y g

Diabetes with negative Diabetes with negative autoantibodiesautoantibodies and and ith t i f b it i li i tith t i f b it i li i twithout signs of obesity or insulin resistancewithout signs of obesity or insulin resistance

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Genetic defects in insulin actionGenetic defects in insulin action

Mutations in the Mutations in the insulin receptorinsulin receptor cause a group of rare cause a group of rare disorders characterized by severe insulin resistancedisorders characterized by severe insulin resistance

11. . Type A insulin resistanceType A insulin resistance22. . LeprechaunismLeprechaunism33. . RabsonRabson--Mendenhall syndromeMendenhall syndrome44. . LipoatrophicLipoatrophic diabetesdiabetes

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Rabson Mendenhall syndromeRabson-Mendenhall syndrome Rare genetic disorder that was first described byRare genetic disorder that was first described by RabsonRabsonRare genetic disorder that was first described by Rare genetic disorder that was first described by RabsonRabson

et al in et al in 1956 1956 ..

It is characterized by:It is characterized by:growth retardationgrowth retardationgrowth retardationgrowth retardation

dysmorphismsdysmorphismslack of subcutaneous fatlack of subcutaneous fatlack of subcutaneous fat lack of subcutaneous fat acanthosisacanthosis nigricansnigricans, enlarged genitalia, , enlarged genitalia, hirsutismhirsutism, dysplastic , dysplastic dentition, coarse facial featuresdentition, coarse facial features

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Rabson Mendenhall syndromeRabson-Mendenhall syndrome

It is characterized by:It is characterized by:paradoxical fasting hypoglycemiaparadoxical fasting hypoglycemiaparadoxical fasting hypoglycemia paradoxical fasting hypoglycemia postprandial hyperglycemiapostprandial hyperglycemiaextremextrem hyperinsulinemiahyperinsulinemiaextremextrem hyperinsulinemiahyperinsulinemiasevere insulin resistance and hyperinsulinemiasevere insulin resistance and hyperinsulinemia

i li l h l ih l ipineal pineal hyperplasiaahyperplasiaa

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LeprechaunismLeprechaunism

Facial features indicative of Facial features indicative of Donohue syndrome include Donohue syndrome include protuberantprotuberant and lowand low setset earsearsprotuberant protuberant and lowand low--set set earsears, , flaring flaring nostrilsnostrils, and thick lips. , and thick lips. Physical features include stunted Physical features include stunted

h (i l di d ih (i l di d igrowth (including during growth (including during gestationgestation), an enlarged ), an enlarged clitorisclitorisand and breastsbreasts in affected in affected femalesfemales, , ,,and an enlarged and an enlarged penispenis in affected in affected males.males.

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OTHER TYPES OF DMDMDM can result from can result from pancreatic exocrine disease pancreatic exocrine disease when the majority ofwhen the majority of

C. C. Diseases of exocrine Diseases of exocrine pancreaspancreas pancreatitis, pancreatitis, pancreatectomypancreatectomy, , neoplasianeoplasia, , when the majority of when the majority of

pancreatic islets (pancreatic islets (>>8080%) are %) are destroyed.destroyed.

cystic fibrosis, cystic fibrosis, hemochromatosishemochromatosis, , fibrocalculousfibrocalculous pancreatopathypancreatopathy

Several Several endocrinopathiesendocrinopathies can can lead to DM as a result oflead to DM as a result of

D. D. EndocrinopathiesEndocrinopathiesacromegalyacromegaly, Cushing's syndrome, , Cushing's syndrome, lead to DM as a result of lead to DM as a result of

excessive secretion of excessive secretion of hormoneshormones that antagonize the that antagonize the

g yg y, g y ,, g y ,glucagonomaglucagonoma, , pheochromocytomapheochromocytoma, , hyperthyroidism, hyperthyroidism,

action of insulin.action of insulin. somatostatinomasomatostatinoma, , aldosteronomaaldosteronoma

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OTHER TYPES OF DM1.1. E. E. DrugDrug-- or chemicalor chemical--inducedinduced2.2. VacorVacor3.3. pentamidinepentamidine

F. F. InfectionsInfectionscongenital rubella, congenital rubella,

cytomegalovirus, cytomegalovirus, pp4.4. nicotinic acidnicotinic acid5.5. glucocorticoidsglucocorticoids66 thyroid hormonethyroid hormone

coxsackiecoxsackie

G. G. Uncommon forms Uncommon forms 6.6. thyroid hormonethyroid hormone7.7. diazoxidediazoxide, , thiazidesthiazides8.8. bb--adrenergic agonistsadrenergic agonists

h ih i

of immuneof immune--mediated mediated diabetesdiabetes

9.9. phenytoinphenytoin10.10. aa--interferoninterferon11.11. protease inhibitorsprotease inhibitors

"stiff"stiff--man" syndromeman" syndromeantianti--insulin receptor insulin receptor pp

12.12. clozapineclozapine antibodiesantibodies71

OTHER TYPES OF DMOTHER TYPES OF DMViral infectionsViral infections have been implicated in pancreatic islet have been implicated in pancreatic islet destruction, but are an extremely rare cause of DM.destruction, but are an extremely rare cause of DM.

Congenital rubella greatly increases the risk for Congenital rubella greatly increases the risk for DMDM

Most of these individuals also have immunologic Most of these individuals also have immunologic markers indicative of autoimmune beta cell markers indicative of autoimmune beta cell destruction.destruction.

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Etiologic Classification of DMEtiologic Classification of DM

H. H. Other genetic syndromes sometimes associated with Other genetic syndromes sometimes associated with diabetesdiabetesdiabetesdiabetesDown's syndromeDown's syndromeKlinefelter'sKlinefelter's syndrome syndrome Turner's syndromeTurner's syndromeWolfram's syndromeWolfram's syndromeFriedreich'sFriedreich's ataxiaataxiaFriedreich sFriedreich s ataxiaataxiaHuntington's chorea Huntington's chorea LaurenceLaurence--MoonMoon--BiedlBiedl syndromesyndromemyotonicmyotonic dystrophydystrophymyotonicmyotonic dystrophydystrophyporphyriaporphyria, , PraderPrader--WilliWilli syndromesyndrome

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DiagnosticGestational

Diagnostic criteria

DM Major complicationscomplications

Etiologic Classification of DM

IV. IV. Gestational diabetes Gestational diabetes mellitus (GDM)mellitus (GDM)

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GESTATIONAL DMGESTATIONAL DM Glucose intolerance may develop and Glucose intolerance may develop and first become recognized during first become recognized during pregnancy.pregnancy.

Insulin resistance related to the metabolic changes of Insulin resistance related to the metabolic changes of late pregnancylate pregnancyincreases insulin requirements and may lead to hyperglycemia or IGTincreases insulin requirements and may lead to hyperglycemia or IGT

Any degree of glucose intolerance with onsetAny degree of glucose intolerance with onset or first recognition or first recognition during pregnanduring pregnancy.cy.

The definition appliesThe definition applies regardless of whether insulin or only diet modification regardless of whether insulin or only diet modification is usedis used for treatment or whether the condition persists after pregnancyfor treatment or whether the condition persists after pregnancy

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is usedis used for treatment or whether the condition persists after pregnancyfor treatment or whether the condition persists after pregnancy

Gestational diabetes mellitus

GDM complicates GDM complicates 77% of all pregnancies% of all pregnancies in the in the U.S., resultingU.S., resulting in in 200200,,000 000 cases annually .cases annually .

The prevalence may range The prevalence may range fromfrom 1 1 to to 1414%% ofofpregnancies, depending on the population studiedpregnancies, depending on the population studied . . GDM represents nearly GDM represents nearly 9090% of all pregnancies% of all pregnanciescomplicatedcomplicated by diabetes.by diabetes.

77

Gestational diabetes mellitusGestational diabetes mellitus

MaternalMaternal complications related to GDM complications related to GDM also includealso includealso include also include

Increased rateIncreased rate of of cesarean deliverycesarean delivery

Chronic hypertension .Chronic hypertension .

78

Risks of pre GDMRisks of pre GDMRisks of pre GDMRisks of pre GDMTo mother:To mother:To mother:To mother:

HypoglycemiaHypoglycemiayp g yyp g yKetoacidosis (type Ketoacidosis (type 1 1 only)only)Retinopathy Retinopathy NephropathyNephropathyPre eclampsia Pre eclampsia U i i f iU i i f iUrinary tract infectionsUrinary tract infectionsHydramniosHydramnios

79

Ri k fRi k f GDMGDMRisks of Risks of preGDMpreGDM

To Fetus:To Fetus:

Congenital abnormalitiesCongenital abnormalitiesMacrosomiaMacrosomiaSpontaneous abortionSpontaneous abortionIntrauterine growth retardationIntrauterine growth retardationIntrauterine growth retardationIntrauterine growth retardationFetal death in Fetal death in uteroutero

80

Increased incidence of :

Neonatal metabolic complications Neonatal metabolic complications HyperbilirubinemiaHyperbilirubinemiaHyperbilirubinemiaHyperbilirubinemiaHypocalcemiaHypocalcemiaP l th iP l th iPolycythemiaPolycythemiaPerinatal mortalityPerinatal mortalityHypoglycemiaHypoglycemia

83

Increased incidence due to poor control:

Congenital malformations (Congenital malformations (4 4 fold)fold)caudal regressioncaudal regressionggspina bifidaspina bifidaanencephalusanencephalusanencephalusanencephalusheart anomaliesheart anomaliesrectal atresiarectal atresiarectal atresiarectal atresiarenal agenesisrenal agenesisit iit i

84

situs inversussitus inversus

P t t lP t t lPost natalPost natalRi k t b bRi k t b bRisks to baby:Risks to baby:

prematurityprematurityR i diR i diRespiratory distressRespiratory distressBirth traumaBirth traumaHypoglycemiaHypoglycemia

Risks to mother:Risks to mother:Hypoglycemia (if on insulin therapy)Hypoglycemia (if on insulin therapy)

85


Deterioration of glucose tolerance occurs Deterioration of glucose tolerance occurs normally during pregnancy,normally during pregnancy, particularly particularly in the in the 33rd trimester.rd trimester.

The criteria for abnormalThe criteria for abnormal GTT in GTT in pregnancy, were proposed bypregnancy, were proposed by O’SullivanO’Sullivanpregnancy, were proposed by pregnancy, were proposed by O Sullivan O Sullivan and Mahanand Mahan in in 19641964 and were based on data and were based on data from OGTTs on from OGTTs on 752752 pregnant womenpregnant women

86


oneone--step approachstep approachPerform a diagnostic OGTT without prior Perform a diagnostic OGTT without prior g pg pplasma or serum glucoseplasma or serum glucose screening. screening.

The oneThe one--step approach may be coststep approach may be cost--effective ineffective inThe oneThe one step approach may be coststep approach may be cost effective in effective in highhigh--riskrisk patients or populations patients or populations

87

GDM screening high risk group

88

Low risk group

89

Two-step approach

Perform an initial screening by measuring Perform an initial screening by measuring the plasma or serumthe plasma or serum glucose concentration glucose concentration 1 1 h fh f l l l d ( ll l l d ( lh after a h after a 5050--g oral glucose load (glucoseg oral glucose load (glucosechallenge test [GCT]) challenge test [GCT])

Perform a diagnostic OGTT on thatPerform a diagnostic OGTT on that subset subset f di h l h h ldf di h l h h ldof women exceeding the glucose threshold of women exceeding the glucose threshold

value on thevalue on the GCT. GCT.

93

Two-step approach

When the twoWhen the two--step approach is employedstep approach is employed

A glucose thresholdA glucose threshold value >value >140 140 mg/dl (mg/dl (77..8 8 mmol/l) identifies approximately mmol/l) identifies approximately 8080%% of of ) pp y) pp ywomen with GDMwomen with GDM

The yield is further increased to The yield is further increased to 9090%% by by using a cutoff of >using a cutoff of >130 130 mg/dl (mg/dl (77..2 2 mmol/l).mmol/l).

94

gg g (g ( ))

Diagnosis of GDM

With either approach, the diagnosis of With either approach, the diagnosis of GDM is based on an OGTTGDM is based on an OGTTGDM is based on an OGTT.GDM is based on an OGTT.

Diagnostic criteria for theDiagnostic criteria for the 100100 g OGTTg OGTTDiagnostic criteria for the Diagnostic criteria for the 100100--g OGTT g OGTT are derived from theare derived from the original work of original work of O’S lli d M h difi d bO’S lli d M h difi d bO’Sullivan and Mahan, modified by O’Sullivan and Mahan, modified by CarpenterCarpenter and Coustan,. and Coustan,.

95

gestational diabetes is presentIf If two or moretwo or more of the following serum glucose of the following serum glucose

values are exceeded:values are exceeded:

1.1. Fasting serum glucose >Fasting serum glucose >95 95 mg/dLmg/dL22 OneOne hour serum glucose >hour serum glucose >180180 mg/dLmg/dL2.2. OneOne--hour serum glucose >hour serum glucose >180 180 mg/dL mg/dL 3.3. TwoTwo--hour serum glucose >hour serum glucose >155 155 mg/dL mg/dL 44 ThreeThree hour serum glucose >hour serum glucose >140140 mg/dLmg/dL4.4. ThreeThree--hour serum glucose >hour serum glucose >140 140 mg/dL mg/dL

96

Gestational diabetes mellitusmost women revert to normal glucose tolerance postmost women revert to normal glucose tolerance post--partum partum substantial risk (substantial risk (30 30 to to 6060%) of developing %) of developing DMDM later in lifelater in life..

Six weeks or more after pregnancy ends, the, the woman should be woman should be reclassified, into one of the following categories:reclassified, into one of the following categories:11) diabetes) diabetes))22) IFG) IFG33) IGT) IGT44) normoglycemia. ) normoglycemia. ) g y) g yIn the majorityIn the majority of cases of GDM, glucose regulation will return to of cases of GDM, glucose regulation will return to normal afternormal after delivery.delivery.

97

Symptoms of marked hyperglycemia

Polyuria, polydipsiaPolyuria, polydipsiaWeight loss, sometimes with polyphagiaWeight loss, sometimes with polyphagiaWeight loss, sometimes with polyphagiaWeight loss, sometimes with polyphagiaBlurred vision.Blurred vision.I i t f thI i t f thImpairment of growth Impairment of growth Susceptibility to certain infectionsSusceptibility to certain infections may also may also accompany chronic hyperglycemia.accompany chronic hyperglycemia.

98

EPIDEMIOLOGYEPIDEMIOLOGYThe worldwide prevalence of The worldwide prevalence of DMDM has risen has risen dramatically over the past two decadesdramatically over the past two decades. .

DM will continue to increase in the near future.DM will continue to increase in the near future.

Between Between 1976 1976 -- 19941994, the prevalence of DM in the, the prevalence of DM in theU S U S increased from increased from 88..99% to % to 1212..33%.%.

99

EPIDEMIOLOGYEPIDEMIOLOGY

Prevalence of IFG increased from Prevalence of IFG increased from 66..55% to % to 99..77%% over the over the same period. same period.

Although the prevalence of both type Although the prevalence of both type 1 1 and type and type 2 2 DM is DM is increasingincreasing

Prevalence of type Prevalence of type 2 2 DM is expected to rise more DM is expected to rise more rapidly because of increasing rapidly because of increasing obesity and reduced obesity and reduced

i i l li i l l100

activity levelactivity level

EPIDEMIOLOGYEPIDEMIOLOGYThere is considerableThere is considerable geographic variationgeographic variation in thein theThere is considerable There is considerable geographic variationgeographic variation in the in the incidence of both type incidence of both type 1 1 and type and type 2 2 DMDM. .

Scandinavia has the highest rate of type Scandinavia has the highest rate of type 1 1 DM (in DM (in Finland, incidence is Finland, incidence is 3535//100100,,000 000 per year). per year). ,, ,, p y )p y )

The Pacific Rim has a much lower rate (in Japan and The Pacific Rim has a much lower rate (in Japan and e c c s uc owe e ( J p de c c s uc owe e ( J p dChina, incidence is China, incidence is 1 1 to to 33//100100,,000000 per year) of type per year) of type 1 1 DMDM

101

EPIDEMIOLOGYEPIDEMIOLOGY

Northern Europe and the U S shareNorthern Europe and the U S shareNorthern Europe and the U S share Northern Europe and the U S share an intermediate rate (an intermediate rate (8 8 to to ((1717//100100,,000 000 per year). per year).

102

EPIDEMIOLOGYIn In 19981998, approximately , approximately 16 16 million in the million in the U S( ~U S( ~66% of the population) met the % of the population) met the diagnostic criteria for diagnostic criteria for DMDM. . gg

About About 800800,,000 000 in the U S develop DM in the U S develop DM ,, ppeach year. each year.

103

EPIDEMIOLOGYThe vast majority (The vast majority (>>9090%) have type %) have type 2 2 DM. DM.

The number of people with DM increases The number of people with DM increases e u be o peop e w t c easese u be o peop e w t c easeswith the age with the age

Incidence ~Incidence ~11..55% in % in 20 20 to to 39 39 years to years to 2020% f i di id l% f i di id l 7575~~2020% of individuals % of individuals >>75 75

years.years.

104

Diagnostic criteria

FBS 2hpp OGTFBS 2hpp OGT

Criteria for the Diagnosis of D M

Symptoms of diabetes plus random Symptoms of diabetes plus random blood glucose ≥ (blood glucose ≥ (200 200 mg/mg/dLdL) ) oror

Random is defined as without Random is defined as without regard to time since the last regard to time since the last meal. meal.

Fasting plasma glucose ≥ (Fasting plasma glucose ≥ (126 126 mg/mg/dLdL) ) oror Fasting is defined as no caloric Fasting is defined as no caloric

intake for at least intake for at least 8 8 hhTwoTwo--hour plasma glucose ≥ hour plasma glucose ≥ 200 200 mg/mg/dLdL during an OGTT In the absence during an OGTT In the absence of unequivocal hyperglycemia and of unequivocal hyperglycemia and acute metabolicacute metabolic decompensationdecompensation

The test should be performed The test should be performed using a glucose load containingusing a glucose load containingacute metabolic acute metabolic decompensationdecompensation

these criteria should be confirmed by these criteria should be confirmed by repeat testing on a different dayrepeat testing on a different day

using a glucose load containing using a glucose load containing 75 75 g anhydrous glucose g anhydrous glucose dissolved in water; dissolved in water; not not recommended for routine recommended for routine p g yp g yclinical use.clinical use.

106

DM diagnosis

107

A1C

The AThe A11C test should be performed using a C test should be performed using a method that is method that is certifiedcertified by the NGSP and by the NGSP and yystandardized or traceable to the Diabetes Control standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference and Complications Trial (DCCT) reference p ( )p ( )assay. assay.

109

A1C

Although pointAlthough point--ofof--care (POC) Acare (POC) A11C assays may C assays may be NGSP be NGSP certifiedcertified, , proficiencyproficiency testing is not testing is not ,, p yp y ggmandated for performing the testmandated for performing the test, so use of POC , so use of POC assays for diagnostic purposes may be assays for diagnostic purposes may be y g p p yy g p p yproblematic and is not recommendedproblematic and is not recommended

110

A1C

The AThe A11C has several advantages to the FPG C has several advantages to the FPG and OGTT, includingand OGTT, including, g, ggreater convenience (fasting not required)greater convenience (fasting not required)greatergreater preanalyticalpreanalytical stabilitystabilitygreater greater preanalyticalpreanalytical stabilitystabilityless dayless day--toto--day perturbations during stress and day perturbations during stress and illillillness. illness.

111

A1CA1C

These advantages must be balanced byThese advantages must be balanced byThese advantages must be balanced by These advantages must be balanced by greater costgreater costthe limited availability of Athe limited availability of A11C testing in certain C testing in certain regions of the developing worldregions of the developing world

the incomplete correlation between Athe incomplete correlation between A11C andC andthe incomplete correlation between Athe incomplete correlation between A11C and C and average glucose in certain individualsaverage glucose in certain individuals

112

A1CIt i i t t t t kIt i i t t t t kIt is important to take :It is important to take :

ageagerace/ ethnicityrace/ ethnicityanemia/anemia/hemoglobinopathieshemoglobinopathiesanemia/anemia/hemoglobinopathieshemoglobinopathies

Into consideration when using the AInto consideration when using the A11C to C to diagnose diabetesdiagnose diabetesdiagnose diabetes.diagnose diabetes.

113

Age

The epidemiological studies that formed the framework The epidemiological studies that formed the framework p gp gfor recommending Afor recommending A11C to diagnose diabetes C to diagnose diabetes only only included adult populations.included adult populations.

Therefore, it remains Therefore, it remains unclearunclear if Aif A11C and the same C and the same AA11C cut point should be used to diagnose diabetes C cut point should be used to diagnose diabetes in in children and adolescentschildren and adolescents..

114

Race/EthnicityRace/Ethnicity

AA11C may vary with patients’ race/ ethnicityC may vary with patients’ race/ ethnicityAA11C may vary with patients race/ ethnicity. C may vary with patients race/ ethnicity.

F lF l Af i A iAf i A i h hi hh hi hFor example, For example, African Americans African Americans may have higher may have higher AA11C than nonC than non--Hispanic whites despite similar fasting Hispanic whites despite similar fasting andand postglucosepostglucose load glucose levelsload glucose levelsand and postglucosepostglucose load glucose levels.load glucose levels.

115

Race/EthnicityA recent epidemiological study found that, when matched for A recent epidemiological study found that, when matched for FPGFPG African AmericansAfrican Americans (with and without diabetes) had(with and without diabetes) had higherhigherFPG, FPG, African Americans African Americans (with and without diabetes) had (with and without diabetes) had higher higher AA11C C than nonthan non--Hispanic whitesHispanic whites

But also had But also had higher fructosamine and glycated albumin higher fructosamine and glycated albumin and and lower lower 11,,55--anhydroglucitolanhydroglucitol

Suggesting that theirSuggesting that their glycemic burdenglycemic burden (particularly(particularlySuggesting that their Suggesting that their glycemic burden glycemic burden (particularly (particularly postprandiallypostprandially) may be higher.) may be higher.

116

Hemoglobinopathies/AnemiasHemoglobinopathies/Anemias

Interpreting AInterpreting A11C in the presence of certain C in the presence of certain hemoglobinopathies and anemia may be problematic.hemoglobinopathies and anemia may be problematic.

For patients with an abnormal hemoglobin but normal redFor patients with an abnormal hemoglobin but normal redFor patients with an abnormal hemoglobin but normal red For patients with an abnormal hemoglobin but normal red cell turnover, such as those with the cell turnover, such as those with the sickle cell traitsickle cell trait, an A, an A11C C assay without interference from abnormal assay without interference from abnormal hemoglobinshemoglobinsh ld b dh ld b dshould be used. should be used.

117

Hemoglobinopathies/Anemiasg pAn updated list of interferences is available at An updated list of interferences is available at www ngsp org/interf aspwww ngsp org/interf aspwww.ngsp.org/interf.aspwww.ngsp.org/interf.asp..

I diti i t d ith i d d ll tI diti i t d ith i d d ll tIn conditions associated with increased red cell turnover, In conditions associated with increased red cell turnover, such assuch asPregnancy (second and third trimesters)Pregnancy (second and third trimesters)Pregnancy (second and third trimesters) Pregnancy (second and third trimesters) Recent blood loss or transfusion Recent blood loss or transfusion Erythropoietin therapyErythropoietin therapyy p pyy p pyHemolysisHemolysis

only only blood glucose criteria blood glucose criteria should be used to should be used to diagnose diagnose yy gg ggdiabetesdiabetes..

118

Recognize pitfalls of A1C: Conditions that ffcan Affect Value

Factors affecting A1C

Increased A1C Decreased A1C Variable Change in A1CA1C A1C

Erythropoiesis B12/Fe deficiency Decreased erythropoiesis

Use of EPO, Fe, or B12Reticulocytosis Chronic liver Dx

Altered hemoglobin

Fetal hemoglobin Hemoglobinopathies Methemoglobin

Altered glycation Chronic renal failure th t H

ASA, vitamin C/E H l bi thi↓↓erythrocyte pH Hemoglobinopathies ↑ erythrocyte pH

Erythrocyte destruction

Splenectomy HemoglobinopathiesChronic renal failureSplenomegalySplenomegalyRheumatoid arthritisHAART meds, RibavirinDapsone

Assays Hyperbilirubinemia HypertriglyceridemiaAssays HyperbilirubinemiaCarbamylated HbETOHChronic opiates

Hypertriglyceridemia

HbA1c for Diagnosisseveral prospective studies used Aseveral prospective studies used A11C to predict the C to predict the progression to diabetes demonstratedprogression to diabetes demonstrated a strong,a strong,progression to diabetes demonstrated progression to diabetes demonstrated a strong, a strong, continuous association between Acontinuous association between A11C and subsequentC and subsequentdiabetes.diabetes.

120

HbA1c for DiagnosisHbA1c for Diagnosis

In a systematic review ofIn a systematic review ofIn a systematic review ofIn a systematic review of44203 44203 individuals individuals fromfrom 1616 cohort studiescohort studiesfrom from 16 16 cohort studiescohort studiesfollowfollow--up averaging up averaging 55..6 6 years (range years (range 22..88––12 12 ))

those with anthose with anthose with anthose with an

AA11C betweenC between 55 55 andand 66 00% had a substantially increased risk of% had a substantially increased risk ofAA11C between C between 55..5 5 and and 66..00% had a substantially increased risk of % had a substantially increased risk of diabetes withdiabetes with55--year incidences ranging from year incidences ranging from 99––2525%.%.

121

HbA1c for DiagnosisHbA1c for Diagnosis

An AAn A11C range of C range of 66..00––66..55% had a % had a 55--yearyeari k f d l i di b t b ti k f d l i di b t b t 2525 5050%%risk of developing diabetes between risk of developing diabetes between 2525––5050%%

l i i kl i i k i hi h d i hi hi h d i hRelative risk Relative risk 20 20 times higher compared with an Atimes higher compared with an A11C C of of 55..00%%

122

HbA1cHbA1cThe biological variability of The biological variability of AA11C within an individual is C within an individual is

h ll h h f f i l (h ll h h f f i l (CVCV 33 66 55 77%)%)somewhat smaller than that of fasting glucose (somewhat smaller than that of fasting glucose (CV CV 33..6 6 vs. vs. 55..77%) %)

considerably less than that ofconsiderably less than that of 22 h glucose (h glucose (CVCV 1616 66%)%)considerably less than that of considerably less than that of 22--h glucose (h glucose (CV CV 1616..66%) , %) , suggesting suggesting that repeated measurements would be more consistent that repeated measurements would be more consistent using Ausing A11C.C.

Fasting glucose varies with the time of day, with acute stress and Fasting glucose varies with the time of day, with acute stress and with many other factors;“with many other factors;“AA11C being an integrated measurementC being an integrated measurementwith many other factors;with many other factors; AA11C being an integrated measurement C being an integrated measurement of average glucose is relatively resilient.of average glucose is relatively resilient.

123

Fasting and 2-Hour Plasma Glucose

In addition to the AIn addition to the A11C test, the FPG and C test, the FPG and 22--h PG may h PG may also be used to diagnose diabetes. also be used to diagnose diabetes.

The The concordanceconcordance between the FPG and between the FPG and 22--h PG tests is h PG tests is i f ti f timperfectimperfect

A i hA i h dd b Ab A11C d i hC d i h llAs is the As is the concordanceconcordance between Abetween A11C and either C and either glucoseglucose--based test. based test.

124

Fasting and 2-Hour Plasma GlucoseFasting and 2 Hour Plasma Glucose

National Health and Nutrition Examination Survey (NHANES) National Health and Nutrition Examination Survey (NHANES) data indicate that andata indicate that an AA11C cut point of >C cut point of >66 55% identifies one% identifies one thirdthirddata indicate that an data indicate that an AA11C cut point of >C cut point of >66..55% identifies one% identifies one--third third fewer fewer cases of undiagnosed diabetes cases of undiagnosed diabetes than a fasting glucose cut than a fasting glucose cut point of >point of >126 126 mg/Dlmg/Dl..pp gg

125

Fasting and 2-Hour Plasma Glucoseg

di hdi h fi dfi d h d i hh d i hNumerous studies have Numerous studies have confirmedconfirmed that, compared with that, compared with these Athese A11C and FPG cut points, C and FPG cut points, the the 22--h PG value h PG value diagnoses more people with diabetesdiagnoses more people with diabetesdiagnoses more people with diabetesdiagnoses more people with diabetes. .

Of note, Of note, the lower sensitivity of Athe lower sensitivity of A11C C at the designated at the designated cut point may be offset by the test’scut point may be offset by the test’s ease of use andease of use andcut point may be offset by the test s cut point may be offset by the test s ease of use and ease of use and facilitation facilitation of more widespread testing.of more widespread testing.

126

Fasting and 2-Hour Plasma Glucoseg

Unless there is a clear clinical diagnosis (e.g., a patient Unless there is a clear clinical diagnosis (e.g., a patient g ( g , pg ( g , pin a hyperglycemic crisis or with classic symptoms of in a hyperglycemic crisis or with classic symptoms of hyperglycemia and a random plasma glucose >hyperglycemia and a random plasma glucose >200 200 mg/mg/dLdL))

It is recommended that It is recommended that the same test be repeated the same test be repeated immediately using a new blood sample for immediately using a new blood sample for confirmationconfirmation because there will be a greater likelihood because there will be a greater likelihood of concurrenceof concurrenceof concurrence.of concurrence.

127


For example, if the AFor example, if the A11C is C is 77..00% and a repeat result is % and a repeat result is 66..88%, the diagnosis of diabetes is %, the diagnosis of diabetes is confirmedconfirmed..

If two different tests (such as AIf two different tests (such as A11C and FPG) are both C and FPG) are both above the diagnostic threshold, this also above the diagnostic threshold, this also confirmsconfirms the the diagnosisdiagnosis

128


On the other hand, if a patient has On the other hand, if a patient has discordantdiscordantresults from two different tests, then the test results from two different tests, then the test ,,result that is above result that is above the diagnostic cut point the diagnostic cut point should be repeated.should be repeated.pp

The diagnosis is made on the basis of theThe diagnosis is made on the basis of theThe diagnosis is made on the basis of the The diagnosis is made on the basis of the confirmedconfirmed testtest. .

129


For example, if a patient meets the diabetes For example, if a patient meets the diabetes criterion of the Acriterion of the A11C C (two results >(two results >66..55%), %), (( ),),but not FPG >but not FPG >126 126 mg/mg/dLdL , that person , that person should nevertheless be considered to have should nevertheless be considered to have diabetes.diabetes.

130


Since all the tests have Since all the tests have preanalyticpreanalytic and and analytic variability,analytic variability, it is possible that an it is possible that an y y,y y, ppabnormal result (i.e., above the diagnostic abnormal result (i.e., above the diagnostic threshold), threshold), when repeated,when repeated, will produce a will produce a )) pp ppvalue below the diagnostic cut pointvalue below the diagnostic cut point

131


This scenario is This scenario is least likely for Aleast likely for A11CCmore likely for FPGmore likely for FPGmore likely for FPGmore likely for FPGmost likely for the most likely for the 22--hPG hPG

i ll if th l l ll t d ti ll if th l l ll t d tespecially if the glucose samples are collected at especially if the glucose samples are collected at room temperature and not centrifuged promptly. room temperature and not centrifuged promptly.

132

Fasting and 2-Hour Plasma GlucoseFasting and 2-Hour Plasma Glucose

B i l b t h ti t ill lik lB i l b t h ti t ill lik lBarring laboratory error, such patients will likely Barring laboratory error, such patients will likely have test results near the margins of the have test results near the margins of the di ti th h lddi ti th h lddiagnostic threshold.diagnostic threshold.

The health care professional should follow the The health care professional should follow the patient closely patient closely and repeat the test in and repeat the test in 33––66monthsmonths..p yp y pp

133

DIAGNOSISGlucose tolerance is classified Glucose tolerance is classified into three categories based on into three categories based on the the FPGFPG: :

It is analogous to It is analogous to IGTIGT, which , which is defined as plasma glucose is defined as plasma glucose levels between levels between 140 140 and and 200 200 mg/dmg/d 22 h after ah after a 7575 g oralg oral

11--FPG FPG << 100 100 mg/mg/dLdL is normalis normal

22-- FPGFPG ≥≥ 100100 mg/mg/dLdL butbut <<

mg/d mg/d 2 2 h after a h after a 7575--g oral g oral glucose load . glucose load .

22 FPG FPG ≥≥ 100 100 mg/mg/dLdL but but <<126 126 mg/mg/dLdL is is IFGIFG

33 FPGFPG ≥≥ 126126 mg/mg/dLdL

Individuals with IFG or IGT Individuals with IFG or IGT are at substantial risk for are at substantial risk for developing type developing type 2 2 DM and DM and 33-- FPG FPG ≥≥ 126 126 mg/mg/dLdL

diagnosis of diagnosis of DMDM..

p g ypp g ypcardiovascular disease in the cardiovascular disease in the futurefuture

134

Criteria for the Diagnosis of DiabetesCriteria for the Diagnosis of Diabetes

A1C ≥6.5%OR

Fasting plasma glucose (FPG)≥126 mg/dl (7.0 mmol/l)

ORTwo-hour plasma glucose ≥200 mg/dl (11.1

mmol/l) during an OGTTOR

A random plasma glucose ≥200 mg/dl (11.1l/l)mmol/l)

ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2.


A1C ≥6.5%

The test should be performed in a laboratory using ifi d h d d di d han NGSP-certified method standardized to the

DCCT assay*

*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.



Fasting plasma glucose (FPG)g p g ( )≥126 mg/dl (7.0 mmol/l)

i l i i k fFasting: no caloric intake forat least 8 h*

*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.



Two-hour plasma glucose ≥200 mg/dl (11.1 p g g (mmol/l) during an OGTT

The test should be performed as described by the World Health Organization, using a glucose load

containing the equivalent of 75 g anhydrous glucosecontaining the equivalent of 75 g anhydrous glucose dissolved in water*

*n the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.



In a patient with classic symptoms of p y phyperglycemia or hyperglycemic crisis,

a random plasma glucose ≥200 mg/dl (11.1 mmol/l)


Prediabetes: IFG, IGT, Increased APrediabetes: IFG, IGT, Increased A11CC

Categories of increased risk for diabetes (Prediabetes)*

FPG 100 125 /dl (5 6 6 9 l/l) IFGFPG 100-125 mg/dl (5.6-6.9 mmol/l): IFGor

2-h plasma glucose in the 75-g OGTT140-199 mg/dl (7.8-11.0 mmol/l): IGT

or

A1C 5.7-6.4%

*For all three tests risk is continuous extending below the lower limit of a range and becoming For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.


Diagnostic Criteria AssociatedDiagnostic Criteria Associated with Glucose Abnormalities

FPG 2-Hour PG on OGTT

Diabetes MellitusDiabetes Mellitus Diabetes MellitusDiabetes Mellitus

126 mg/dL

100 mg/dL

7.0 mmol/L

5.6 mmol/LPrediabetes

200 mg/dL

140 mg/dL

11.1 mmol/L

7.8 mmol/L

be es e usbe es e us

Impaired Glucose Tolerance

abe es e usabe es e us

g

NormalNormal

g

NormalNormal

Diagnosis of DiabetesDiagnosis of DiabetesADA Expert Committee

NORMALNORMAL IMPAIREDIMPAIRED DIABETESDIABETES

FASTINGFASTING < < 100100 mg%mg% 100100--125125 >= >= 126126 mg%mg%((55..6 6 mM)mM) ((7 7 mM)mM)

ORAL GTTORAL GTT <<140140 %% 140140 199199 >> 200200 %%ORAL GTTORAL GTT <<140140 mg%mg%((77..8 8 mM)mM)

140140--199199 >=>=200200 mg%mg%((1111..1 1 mM)mM)

143Diabetes Care 2004, 27: S5-S10

DIAGNOSISThe revised criteria for the diagnosis of The revised criteria for the diagnosis of DMDM emphasize theemphasize the

FPGFPG asas the most reliable and convenient test for the most reliable and convenient test for diagnosing DM in asymptomatic individualsdiagnosing DM in asymptomatic individuals..g g y pg g y p

Oral glucose tolerance testing, Oral glucose tolerance testing, although a valid mechanism for although a valid mechanism for g g,g g, ggdiagnosing DMdiagnosing DM

is not recommended as part of routine screening.is not recommended as part of routine screening.

144

Why& Whom should be screened

screening

High riskNormal >45 yearsyea s

SCREENINGSCREENINGWidespread use of the Widespread use of the FPGFPG as a screening test for type as a screening test for type 2 2 DMDM is strongly is strongly encouraged because:encouraged because:

((11) A large number of individuals with DM are unaware) A large number of individuals with DM are unaware(( ) g) g

(2)(2) Type Type 2 2 DM may be present for up to a decade before diagnosisDM may be present for up to a decade before diagnosis

((33) ) as many as as many as 5050% of individuals with type % of individuals with type 2 2 DM have one or more diabetesDM have one or more diabetes--specific complications at the time of their diagnosisspecific complications at the time of their diagnosisspecific complications at the time of their diagnosis.specific complications at the time of their diagnosis.

((44) treatment of type ) treatment of type 2 2 DM may favorably alter the natural history of DM. DM may favorably alter the natural history of DM.

146

Screening

147

Risk factors for type 2 DM

Family history of DMFamily history of DMObesity AcanthosisObesity Acanthosis nigricansnigricansObesity, Acanthosis Obesity, Acanthosis nigricansnigricansAge > Age > 45 45 yearsyearsRace/ethnicityRace/ethnicityPrevious IFG or IGT or HbAPrevious IFG or IGT or HbA11C>C>55 77%%Previous IFG or IGT or HbAPrevious IFG or IGT or HbA11C>C>55..77%%History of vascular diseaseHistory of vascular disease

148

Risk factors for type 2 DM

History of GDM or delivery of baby History of GDM or delivery of baby >>99lbslbs>>99lbslbsHypertension >Hypertension >140140//9090HDL <HDL <3535mg/dl and or TG> mg/dl and or TG> 250 250 mg/dlmg/dlPCOSPCOS oror acanthosisacanthosis nigricansnigricansPCOS PCOS or or acanthosisacanthosis nigricansnigricansHabitual physical inactivityHabitual physical inactivity

149

di b t m llitdiabetes mellitus diagnosis and ...iacld.ir/dl/co/13/diabetes/diabetesmellitus... ·...

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