1. Description of diabetes2. Classification base on etiopathogenesis of the disease3. Diagnostic criteria4. Testing for diabetes

Diabetes MellitusA group of metabolic diseasesCharacterized by hyperglycemiaResulting from defects in insulin secretion , insulin action, or both

Classification of Diabetes and Allied Categories of Glucose Intolerance (WHO, 1985; PERKENI, 1993)A. Clinical Classification 1. Diabetes Mellitus IDDM NIDDM Obese Non-obese Secondary Diabetes MRDM 2. Gestational Diabetes 3. Impaired Glucose Tolerance

B. Statistical Risk Classification

ETIOLOGIC CLASSIFIACTIONType 1 (-cell destruction leading to absolut deficiency) A. Immune mediated B. Idiopathic

II. Type 2 Predominantly insulin resistance + relative insulin deficiency Predominantly secretory defect + insulin resistance

III. Other specific types

IV. Gestasional diabetes mellitusThe Expert Committee,1997Type 1 + Type 2 = 70 95% of diabetes

Correlation between the therapeutic and etiological classification of diabetes (Slama, 2003)

Controversies in Classification = Controversies in ManagementType 1 diabetes = Insulin dependent DM (Dependency on insulin for life)Type 2 diabetes = Non Insulin Dependent DM = Not requiring insulin ??

Many diabetic individuals do not easily fit into a single class10 20 % of subjects with NIDDM show (+) ICA and/or anti GAD65Abs

Type 1 Diabetes(-cell destruction leading to absolut deficiency)

Hypothetical stages and loss of beta cells in an individual progressing to type 1A diabetes (Eisenbarth, NEJM, 1986) (16)

Clinical Subtypes of Type 1 DiabetesSlowly progressive Type 1 (SP type 1) diabetes (Diabetes Care 16: 780 788, 1993) 1. ICA and/or GAD ab (+) 2. Non-insulin dependent at onset 3. Non-insulin requiring period more than 13 months after the onset or diagnosisRegularFulminant Type 1 diabetes ( N Eng J Med 342: 301, 2000) 1. Ketosis/ketoasidosis within a week after the onset of hyperglycemic symptoms 2. Serum C-peptide < 0.3 ng/ml (fasting) and < 0.5 ng/ml (after meal or iv. Glucagon) 3. AIC < 5.5% on first visit

The destruction of -cells and the appearance of type 1 diabetes according to the age of onset and the putative pathogenetic mechanism (Paolo Pozzilli and Umberto Di Mario : Diabetes Care 2001 24: 1460-1467)

100%5-10%T-cell tests (+)T-cell tests ()-cell functionGAD65 antibodies ICA antibodiesIAA antibodies Clinical onsetTolerance reestablishedTime (months to years)IA2 and IA-2Abnormal -cell function testNatural History of Type 1 DM(Mehta,1996

Type 2 Diabetes

Pathogenesis of Type 2 DiabetesInsulin resistance vs -cell dysfunction??

Development of Type 2 DiabetesInsulin ResistanceInsulin Resistance and Hyperinsulinemia With Normal Glucose ToleranceInsulin Resistance and Declining Insulin Levels With Impaired Glucose ToleranceType 2 DiabetesImpaired b-Cell FunctionSaltiel & Olefsky. Diabetes 1996;45:16619

Natural History of Type 2 DiabetesGlucoseRelative to normal-10-5051015202530010020050150Post-prandial glucoseFasting glucoseInsulin resistanceInsulin levelYearsAt risk fordiabetesBeta-cell dysfunction250R.M. Bergenstal, International Diabetes Centermg/dL(%)

Insulin ResistanceNormal -cellsCompensatory HyperinsulinemiaIsulin Resistance SyndromeAbnormal -cellsInadequate Insulin ResponseType 2 DiabetesCVDHypertension Dyslipidemia ObesityRetinopathy Neuropathy Nephropaty

Pathogenesis of Type 2 DiabetesImpaired -Cell function Enzymatic defects Reduced mass Premature agingInsulin resistance Obesity (Genetic ?) Inactivity Hyperglycemia Hyperinsulinemia Drugs Genetic EnvironmentalSine qua none (and sufficients )Secondary and facilitative

FAMILYSTUDYFENOTYPEVSGENOTYPE

DISORDERS OF GLYCAEMIAEtiologic types and StagesStagesNormoglycemia Hyperglycemia TypesNormal glucoseregulationIGT orIFGDiabetes MellitusInsulin requiring No For control For survival

Type 1Type 2Other typesGestationaldiabetes

+++ +++++Insulin requirement

Many diabetic individuals do not easily fit into a single class10 20 % of subjects with NIDDM show (+) ICA and/or anti GAD65Abs

Hidden dangers of themetabolic syndrome icebergHyperglycemiaInsulin resistance + HyperinsulinaemiaPro-inflammatoryprofileAbdominal obesityHypertensionAtherogenic dyslipidemiaImpaired fibrinolysis

CASE Female 56 y.o, diagnosed as NIDDM 7 years ago, BMI 22 kg/m2, addhere to diet, routine exercise, Tx. Glibenclamide 15 mg/day + metformin 1500 kg, Blood sugar : fasting 230 mg ; 2 h pp 324 mg%Past medical history : good controlled with 2 mg glibenclamide but gradually needs higher dose and finally needs combined oral hypoglycemic drugs

OTHER SPECIFIC TYPESA. Genetic defects of -cell functionB. Genetic defects in insulin actionC. Diseases of the exocrine pancreasD. Endocrinopathies E. Drug or chemical inducedF. InfectionsG. Uncommon forms of immune mediated-diabetesH. Other genetic syndromes associated with diabetesThe Expert Committee,1997.

GENETIC DEFECTS OF -CELL FUNCTION1. Chromosome 12,HNF-1 (MODY3)2. Chromosome 7,glucokinase (MODY2)3. Chromosome 20,HNF-4 (MODY1)4. Mitochondrial DNA5. OthersThe Expert Committee,1997

GENETIC DEFECTS IN INSULIN ACTION1.Type A insulin resistance2.Leprechaunism3.Rabson-Mendenhall syndrome3.Lipoatriphic diabetes4.OthersThe Expert Committee. Diabetes Care 1997; 20:1183-1196

DRUG OR CHEMICAL INDUCED1. Vacor2. Pentamidine3. Nicotinic acid4. Glucocorticoid5. Thyroid hormone6. Diazoxide 7. -adrenergic agonist 8. Thiazides 9. Dilantin 10. -interferon 11. OthersThe Expert Committee,1997.

ENDOCRINOPATHIESAcromegalyCushings syndromeGlucagonomaPheochromocytomaHyperthyroidismSomatostatinomaAldosteronomaOthersThe Expert Committee,1997

INFECTIONSCongenital rubellaCytomegalo virusOthersThe Expert Committee,1997

UNCOMMON FORMS OF IMMUNE-MEDIATED DIABETESStiff-man syndromeAnti-insulin receptor anribodiesOthersThe Expert Committee,1997

OTHER GENETIC SYNDROME SOMETIMES ASSOCIATED WIH DIABETESDowns syndromeKlinefelters syndromeTuners syndromeWolframs syndromeFriedereichs ataxiaHuntungtons choreaLaurence-Moon-Biedl syndromeMyotonic dystrophyaPorphyriaPrader-Willy syndromeOthersThe Expert Committee,1997

DIAGNOSTIC CRITERIA

Criteria Diagnosis of Diabetes Mellitus1. Symptoms (+) & casual plasma glucose > 200 mg% (11.1 mmol/L)or2. FPG 126 mg% (7.0 mmol/L) or3. 2hPG 200 mg/dl during OGTT. Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss Glucose load described by WHO (75 g anhydrous glucose dissolved in water) In the absence of unequivocal hyperglycema with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day(The Expoert Committee,1997)

Symptoms and signs of diabetesLinked to osmotic diuresis Polyuria Increased thirst and polydipsia Blurred vision Drowsiness, dehydrationLinked to lacked of insulin Hyperglyceaemia with massiveglucosuria Extreme fatigue Muscle wasting Weight loss Ketosis, ketoasidosisSymtoms of decreased resistance to infections Skin infection Genital pruritusLinked to caloric depletion Increased appetite Weight lossSlama, 2003

CATEGORIES WHEN THE OGTT IS USEDGlucose load described by WHO (75 g anhydrous glucose dissolved in water)

Categories of 2 hours after glucose loading (2 hPG) valuesNormal: 2 hPG 140 mg%

IGT : 2 hPG 140 mg% and 200 mg%

DM : 2 hPG 200 mg%* The Expert Committee,1997Provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).

Categories of FPG values FPG

Diagnostic Criteria for epidemiological studies estimates of prevalence and incidence should be based on FPG 126 mg%The Expert Committee,1997

CRITERIA FOR TESTING FOR DIABETES (SCREENING) 1. All individuals at age 45 - repeat every 3 years2. Considered at a younger age or be carried more frequently : - Obese > 120% or BMI 27kg/m2 - First degree relative with diabetes (+) - Members of a high-risk ethnic population - Delivered a baby weighing 9 lb (Indonesia ?) or have been diagnosed with GDM - Hypertensive ( 140/90) - HDL-chol < 35 mg% and/or TG > 250 mg% - On previous testing had IGT or IFG

The Low-risk GroupAge < 25Normal weightNo family history of diabetesNot members of and ethnic/racial group with a high prevalence of diabetesThe Expert Committee,1997

GESTATIONAL DIABETES

SCREENING AND DIAGNOSTIC SCHEME FOR GDM (24 28 week of gestation)The Expert Committee,1997

Plasma glucose

50-g

screening test

100-g

diagnostic test

Fasting

1-h

2-h

3-h

-

140 mg/dl

-

-

105 mg/dl

190 mg/dl

165 mg/dl

145 mg/dl

Diagnosis of GDM with a 100-g or 75-g glucose loadTwo or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis

mg/dlmmol/l100-g Glucose loadFasting1-h2-h3-h

75-g Glucose loadFasting1-h2-h95180155140

951801555.310.08.67.8

5.310.08.6

Hospital Admission Guidelines For Diabetes MellitusLife-threatening acute metabolic complications of diabetesNewly diagnosis diabetes in children and adolescentsSubstantial poor metabolic control (Etiology of control problems ? Modification of therapy ?)Severe chronic complications that require intensive treatmentSevere condition unrelated to diabetes that significantly affects its control or complicated by diabetesUncontrolled or newly discovered insulin-requiring diabetes during pregnancyInstitution of intensive insulin regimens

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Insulin resistance and impaired beta-cell function are primary defects that occur early in the course of development of type 2 diabetes. Insulin resistance leads to an obligatory hyperinsulinemia in order to maintain normal glucose tolerance. In most cases of type 2 diabetes, beta-cell dysfunction develops subsequent to the development of insulin resistance and it is not until such beta-cell dysfunction develops that any abnormality in glucose tolerance is seen. The condition which results is termed impaired glucose tolerance. In some cases individuals may develop beta-cell dysfunction in the absence of early insulin resistance. However, exposure of tissues to hyperglycemia in the face of beta-cell dysfunction adds resistance to the effects of insulin whether or not insulin resistance was present to begin with. Ultimately, type 2 diabetes is the result of worsening beta-cell function, either in the most common situation of chronic pre-existing insulin resistance or, in the less common scenario of decreased beta-cell function without pre-existing insulin resistance. It is interesting to note that animal studies have demonstrated that the beta-cell dysfunction that occurs most commonly following pre-existing insulin resistance may actually be a function of the pre-existing insulin resistance itself.

Prior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and post-prandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. However, at some point in time, either due to early beta-cell dysfunction or due to a natural limit of beta-cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, post-prandial glucose levels become abnormal as a limitation in insulin response is reached. Following the onset of beta-cell dysfunction, insulin levels can no longer keep up in overcoming the insulin resistance, and fasting and post-prandial glucose levels increase progressively over time.