prediction of diabetes mellitus type ii

PREDICTION OF DIABETES MELLITUS TYPE II -NEW DIAGNOSTIC PERSPECTIVESAdlija Jevric-Causevic Faculty of Pharmacy, University of Sarajevo I would like to thank to the members of the BCLF organizing commitee for giving me the opportunity to give this presentation I will try to describe current research efforts related to new diagnostic perspectives in DM type II Hopefully, I will be able to emphasize most important findings related to the possible early detection of disease DIABETES MELITUS TYPE II (T2D) * Costly healthcare burden and a major cause of morbidity and mortality due to coronary heart disease, cerebrovascular disease, peripheral vascular disease DIABETES MELLITUS TYPE II (T2D) • T2D –common endocrine disease strongly determined by inheritable factors, is likely polygenic • Develops from chronic and progressive loss of insulin secretion on a background of chronic and often progressive insulin resistance Hepatic glucose overproduction and diminished glucose uptake by muscle tissues • • Reduced insulin and increased glucagon secretion • Dyslipidemia • Reduced GLP-1 release, diminished incretin response MAJOR RISK FACTORS FOR T2D •Family history of diabetes (ie, parents or siblings with diabetes) •Obesity (>20% over desired body weight or body mass index >27 kg/m2) (Sedentary life style, active and passive smoking) •Race or ethnicity with high risk of diabetes (eg, African American, Hispanic American, Native American, Asian American, Pacific Islander) •Age >45 years •Previously identified impaired fasting glucose or impaired glucose tolerance • Hypertension (>140/90 mmHg) • Hyperlipidemia HDL cholesterol level < [0.90 mmol/L] or triglyceride level >[2.82 mmol/L], or both •History of gestational diabetes or delivery of a baby over (4.1 kg) FACTORS CONTRIBUTING TO THE LOSS OF BETA CELL FUNCTION AND INSULIN RESISTANCE • Separate genetic defects ( responsible for the predominance of one mechanism over the other) • Environmental factors • Glucose toxicity has been shown to contribute to the development of insulin resistance and impaired insulin secretion in animal models of diabetes • Hyperglycemia is responsible for some of the resistance and some of the impairment in beta-cell function • Lipotoxicity -A strong genetic basis for disease -Inheritance of ß-cell function suggested -Locus on chromosome 11 related to diabetes risk and linked with the DI -Inheritance of reduced DI, possible contributor to increased genetic DI risk for type diabetes OTHER TYPES OF MARKERS IN DETERMINING THE RISK OF DEVELOPMENT OF T2D Inflammatory and immunological markers (blood) • C-reactive protein (CRP) • serum amyloid A • interleukin-6 • RANTES • Macrophage migration inhibitory factor (MIF) • Soluble intercellular adhesion molecule • Low-grade inflammation and immunological activation may be elevated in patients at THE RATIONAL BEHIND USE OF IMMUNOLOGICAL MARKERS •Increased numbers of macrophages exist in the islets of type II diabetes patients •Associated with development of type II diabetes •Activation of the immune system in obesity is a risk factor for the development of type II diabetes GENETIC MARKERS IN T2D Clinical indications: Determine those at higher risk for T2D, above 140% RESULTS SO FAR: •Genes responsible for monogenic forms of diabetes (notably, maturityonset diabetes of the young), and, in patients presenting with early-onset diabetes, identified •Gene identification for more common, multifactorial forms of T2D slower Common variants in the PPARG, KCNJ11 and CAPN10 genes influence T2D-susceptibility (particularly in individuals with other risk factors) •Genes have been identified on chromosomes 1q, 12q, 20q, and 17q PPAR (Peroxisome proliferator-activated receptor gamma) ( G3p25,frequency of allele 85%., key regulator of adipocyte development and function KCNJ11 (Potassium inwardly rectifying channel, subfamily J, member 11) 11p15, E23K., 1.2 ,40% Component of the beta-cell KATP channel CAPN10 (Calpain 10) 2q37, 1.2., 10–25% (SNP44) Protease of uncertain function implicated in insulin secretion TCF1 (HNF1A) Hepatocyte nuclear factor 1-alpha; transcription factor 12q22-qter., 20%.,Transcription factor in beta-cell (and other tissues); HNF4 (Hepatocyte nuclear factor 4-alpha) A20q12?, ??????? I IRS1 (Insulin receptor substrate 1) 2q36., 1.25 , 7–10% GENES AND PREDICTION OF DIABETES TCF7L2 (transcription factor 7-like 2, linkage region on 10q) present in European, Chinese, USA population, highly replcated in Caucasian and African population •Associated with onset of diabetes condition in younger population •Increases the chances of diabetes in individuals with impaired glucose tolerance •Test for diabetes risk •TCF7L2 variants are associated with impaired beta-cell function but not with insulin resistance Chances of diabetes are increased by 50% if one gene variant If two copies of gene variant are carried/increase of 100 % Routine genetic testing for these variants still not recommended! OTHER GENES •KCNJ11 –Association T2D and hypertension (Korean population) •ARHGEF11 -chromosome 1q, associated with insulin resistance and T2D (Pima Indians) •Mutations in the NeuroD/BETA2 gene assocated with T2D •FABP2- 50% Americans FABP2 (FABP2 causes the food to be metabolized in a way that interferes with the body´s ability to get rid of the excess sugar in the blood stream, resulting in diabetes It is not yet the established cause of diabetes) •A minor role for some of the gene products involved in insulin secretion or insulin action, such as IRS-1, the glucagon receptor, the sulphonylurea receptor (SUR),the peroxisome proliferator activated receptor- (PPAR), and the MAPKBIP1 LIVER MARKERS AND RISK OF SUBSEQUENT DIABETES •Associations between these markers and diabetes risk were independent of directly measured insulin sensitivity •Raised liver markers in this context reflect hepatic IR •So far, no association between ALP concentrations and diabetes risk, (possible lack of specificity of ALK i indicating liver disease) •Five studies have assessed the diabetes risk associated with elevated GGT, and in four of these studies, the association with diabetes was statistically significant after adjustment for potential confounders •Markers of liver injury, including AST and ALT, were significantly associated with risk of incident type diabetes, independently of diabetes classical predictors, CRP, and the metabolic syndrome in middle-aged Caucasian men of average BMI (Adjustment for a broad spectrum of type diabetes risk factors, including directly measured insulin sensitivity and secretion was made) •Men with baseline ALT levels 29 units/l had more than three times the risk for diabetes than men with ALT