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Module IEpidemiology, Pathogenesis, Classification & Diagnosis of Diabetes Mellitus (DM)

ObjectivesDefinition of type 2 diabetes mellitus (type 2 DM)Epidemiology of diabetes mellitusClassification and diagnosis of diabetes mellitusGlucose homeostasis and pathogenesis

Definition The term diabetes mellitus describes a metabolic disorder of multiple etiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defect in insulin secretion, insulin action, or both.

The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organsWorld Health Organization., http://www.who.int/ncd/dia/

Epidemiology ofType 2 Diabetes Mellitus

Global projections for diabetesDiabetes Atlas, 3rd editionIDF 2006. www.eatlas.idf.org/index2983.html

20072025DiabetesComparative prevalence (%)6.07.3No. people with diabetes (millions)246380

Predicted diabetes epidemic greatest prevalence in AP (Asia Pacific) countries vs. rest of worldWild S, et al. Diabetes Care 2004;27:104753

Ranking20002030CountryPeople with diabetes (millions)CountryPeople with diabetes (millions)1India31.7India79.42China20.8China42.33U.S.A.17.7U.S.A.30.34Indonesia8.4Indonesia21.35Japan6.8Pakistan13.96Pakistan5.2Brazil11.37Russian Fed.4.6Bangladesh11.18Brazil4.6Japan8.99Italy4.3Philippines7.810Bangladesh3.2Egypt6.7

Indonesia prevalence= 5.7%Riskesdas ,2007Indonesia prevalence = 5.7%

Prevalence of Known Diabetes, Newly Diagnosed Diabetes and IGT9Data from capital city of 33 provinces in Indonesia ,Riskesdas ,2007

Number of adults with diabetes in developed and developing countries in 2010 and prediction in 2030, according to age-groupDiabetes Research and Clinical Practice 87 (2010) 4-14

Prevalence DM based on agePrevalence (%)Age RISKESDAS 2007

Risk factors Age > 45 years oldObesityPhysical inactivity First -degree relative with diabetesWomen who delivered a baby weighing 4 kg or were diagnosed with gestasional DMHypertension ( blood pressure 140/90mmHg)Dyslipidemia ( TG> 250, HDL < 35mg/dL)IFG (impaired fasting glucose) or IGT (impaired glucose tolerance) on previous testingHistory with coronary heart diseaseHistory of polycystic ovarial syndrome (PCOS)

How To Diagnose?

Criteria for the Diagnosis Classic symptoms* of DM + random plasma glucose 200 mg/dL or

Classic symptoms of DM + Fasting plasma glucose 126 mg/dL or(Fasting is defined as no caloric intake for at least 8 h)

2-h plasma glucose >200 mg/dL) 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 glucose dissolved in 200 cc water .

*Classic Symptoms of DM : polyuria, polydipsia,polyphagia, weight loss without any causes

Criteria for the Diagnosis * OGTT : post load 75 g

NormalPrediabetes DMIFGIGTFPG (mg/dL)< 100100-125 1262-h PG (mg/dL)< 140< 140140-199*> 200

Classification of Diabetes

Glucose Homeostasis And Pathogenesis

Glucose Homeostasis SkeletalMuscleFatBrainInsulin-independent Glucose UptakePlasma GlucoseInsulin-dependent Glucose UptakeInsulinLiverInsulinGlucagonPancreasJoslins Diabetes Mellitus,2005

The natural progression of type 2 diabetesAdapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.Years-10-505101520253035030025020015010050InsulinlevelInsulin resistance-cell failure250200150100500Relative -cellfunction (%)Fasting BGPost-meal BGGlucose (mg/dL)DIAGNOSISClinicalfeatures ObesityIGTDiabetes Uncontrolled hyperglycaemia

Mechanisms of HyperglycemiaGLP-1 GIPGLP-1, GIP DPP-4 enzyme LipolysisGluconeogenesis Glucagon Glucose Uptake Insulin

The ominous octetH Y P E R G L Y C E M I ADecreased Incretin EffectDeFronzo Ralph A Diabetes 2009; 58:773

Hyperglycemia in Type 2 DiabetesAdapted from Yki-Jarvinen H. Textbook of Diabetes 1, third edition; 2003Gluco- lipotoxicity Glucose production in the liverOverweight, inactivity(inherited/acquired) FFAInherited/acquired factors Glucose uptakeFFA=free fatty acid

Summary Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia with resulting from defect in insulin secretion, insulin action, or both.Prevalence of type 2 DM tend to increase from 6% (2007) to 7.3% (2025)National Data of the prevalence diabetes: 5.7% , whereas 74% of them are newly diagnosed.Most of the cases are type 2 diabetes.The main factors of type 2 diabetes are insulin resistance and insulin deficiency

Dari ke 33 provinsi prevalensi yang tertinggi adalah Maluku Utara dan Kalimantan Barat (11.1%) selanjutntnya Riau 10.4%, NAD dan Bangka Belitung 8.5% dan prevalensi terendah adalah provinsi Bali 3%Dari prevalensi DM 5.7% tersebut yang telah mengetahui menderita DM sebelumnya sebesar 26%, sedangkan sebagian besar yg terdiagnosis DM 74 % tidak mengetahui menderita DM sebelumnya .Artinya bahwa sebagian besar penderita tidak menyadari bahwa telah menderita DMJumlah populasi penderita DM menurut umur pada negara maju jumlah terbanyak pada th 2010 usia antara 60-79 th demikian juga nanti pada th 2030, sedangkan pada negara berkembang jumlah populasi DM terbanyak pada th 2010 pada usia 40-59 th dan diperkirakan pada th 2030 populasi terbanyak pada kelompok umur 40-59 thData Riskesdas 2007 (Riset Kesehatan Dasar yg dikerjakan oleh Depkes th 2007), populasi DM yg terbanyak pada kelompok umur55-64 th dan usia 65-74 th sedangkan populasi IGT terbanyak pada kelompok usia 75 tahun keatasFaktor risiko DM menurut Perkeni 2006 dan ADA ,2009Glukosa dalam darah dipertahankan dalam batas normal oleh hormon insulin dan glukagon. Pada saat puasa glukosa dalam darah turun maka keluarlah hormon glukagon merangsang produksi glukosa hepar melalui proses glukoneogesis dan sekresi insulin dihambat sehingga ambilan glukosa di jaringan otot ,adiposa dan hepar dihambat sehingga glukosa dalam darah tetap normal untuk memenuhi kebutuhan glukosa di otak . Bila glukosa didalam darah tinggi karena ada asupan makan maka sel beta pankreas akan mensekresi insulin untuk meningkatan ambilan glukosa di jaringan otot, lemak dan hepar , menekan lipolisis dan glukoneogenesis, sehingga mencegah hiperglikemi postmealT2DM is a progressive disease characterised by declining pancreatic -cell function leading to increasing insulin resistance and insulin deficiency. Typically, by the time of diagnosis of T2DM, 50% of -cell function has already been lost.1 When the secretion of insulin cannot keep pace with the underlying insulin resistance, impaired glucose tolerance (IGT) and T2DM develop.Initially, the increased blood glucose is attributable to postprandial blood (PPBG) glucose, but as the disease progresses, the role of fasting blood glucose (FBG) becomes more important.The natural progression of T2DM is prolonged and many key features such as insulin resistance and macrovascular changes occur before hyperglycaemia develops and therefore before diagnosis. Exposure to metabolic dysregulation, even before diagnosis, substantially increases the risk of developing macrovascular (e.g. stroke, ischaemic heart disease and peripheral vascular disease) and microvascular (e.g retinopathy, nephropathy and neuropathy) complications at a later date.

Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215.Akibat dari faktor keturunan maupun faktor lingkungan ( kegemukan maupun inaktivitas) menyebabkan insulin resisten di jar adipose, terjadilah lipolisis meningkat terjadilah lipotoksisitas yg berakibat sekresi insulin oleh pankreas menurun. Hiperglikemi terjadi melalui mekanisme resistensi insulin di jaringan otot dan menurunnya sekresi insulin maka ambilan glukosa di jaringan otot menurun,menurunnya sekresi insulin selain melalui mekanisme lipotoksisitas juga melalui mekanisme menurunnya GLP1 akibat dipecah oleh enzim DPP4 , GLP1 menurun menyebabkan juga glukagon meningkat. Akibat glukagon tinggi dan resistensi insulin dihepar menyebabkan proses glukoneogenesis meningkat terjadilah hiperglikemi. Sebagai ringkasan hiperglikemi terjadi akibat rsistensi insulin di jar otot, adipose dan jaringan hepar serta menurunnya sekresi insulin akibat lipotoksisitas dan glukotoksisitas dan menurunnya kadar GLP1 dan meningkatnya sekresi glukagon sebagai dampak dari kurangnya kadar GLP1, dan absorpsi langsung glukosa oleh usus. The liver, being the major site for production and degradation of glucose, plays a pivotal role in glucose homeostasis. Liver glucose production plays the major role in determining the levels of blood glucose. When glucose is released from the liver into the circulation, the concentration of blood glucose increases and promotes the release of insulin from the pancreas. The net effect of insulin is to lower blood glucose. In patients with T2DM, there is a reduction in the amount of insulin released from the pancreas. This results in less conversion of excess glucose to glycogen, reduced glucose uptake and, hence, increased blood glucose levels. Insulin resistance impairs the ability of insulin to inhibit glucose production and stimulate glucose uptake, leading to hyperglycaemia.Insulin resistance also results in increased concentrations of circulating free fatty acids (FFAs) because insulin fails to suppress lipolysis in adipose tissue. FFAs stimulate gluconeogenesis, triglyceride synthesis and glucose production in the liver, and further impair glucose utilisation by skeletal muscle.Excess circulating glucose and FFAs act on cells and tissues, including the pancreatic -cell, to inhibit both insulin secretion and action. This is referred to as gluco-lipotoxicity.

Postic C, et al. Diabetes Metab. 2004;30:398408.Yki-Jrvinen H. In: Textbook of Diabetes 1, third edition. Oxford, UK: Blackwell; 2003: p22.122.19.