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Diabetes - diagnosis,complication and monitoring by Dr Prabhash

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Information about Diabetes - diagnosis,complication and monitoring by Dr Prabhash
Health & Medicine

Published on February 20, 2014

Author: Prabhashbhavsar

Source: slideshare.net

Description

pathophysiology of diabetes and its complications. monitoring of diabetes, newer modalities for assessing blood glucose
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Diabetes Mellitus Dr. Prabhash Bhavsar

Blood Glucose Regulation

Diabetes is a group of Metabolic Disorders characterized by Hyperglycemia resulting from defects in insulin secretion, insulin action, or both. -Diabetes Care Volume 37, Supplement 1, January 2014, S81

Etiological Classification of DM i Type 1 Diabetes Immune mediated β cell destruction, idiopathic ii Type 2 Diabetes Insulin resistance iii Genetic defect of β cell function MODY Genetic defect in insulin processing Defect in proinsulin conversion, insulinor action gene & receptor mutation etc. Exocrine pancreatic defect Other endocrinopathies Glucagonoma, hyperthyroidism, cushing syndrome etc. infections CMV, Coxsackie B etc. Drugs Steroids, thyroxin, β adrenergic etc. Genetic syndromes iv Pancreatitis, cystic fibrosis etc. Down, turner etc. Gestational Diabetes Mellitus Diabetic care 25, 2003

Pathogenesis of type1 DM Genetic susceptibility Environmental trigger Autoimmunity β cell destruction

Genetics • • • • • • • • Susceptibility of type1 DM is inherited. Mode of inheritance is complex. Concordance rate between identical twins is 30%. MHC on chromosome 6 Multigenic trait INS gene on chr 11 other loci on chr 9 HLA – DQ & DR are most important determinant. HLA – DQB1*0602 allele significantly reduces the risk of type1 DM. INS VNTR also increases the risk. Routine assessment of genetic markers is not recommended for Δx and Mx.

Environmental factors • Viruses such as rubella, mumps and coxsackie B have been implicated. • Autoimmunity to β cell is initiated by viral proteins. • Genetic susceptibility determines the progression of β cell destruction.

Autoimmunity • Type1 DM results from cell mediated autoimmune destruction of pancreatic β cell. • 80-90% destruction of β cell is required to induce symptomatic diabetes. • Marker of β cell autoimmunity are circulating antibodies. • They are present in the serum years before the onset of hyperglycemia.

• • • - Islet cell cytoplasmic antibodies (ICAs): Against sialoglycoconjugate antigen present in the cytoplasm of all endocrine cells of the pancreatic islets. Detectable in 75-80% of newly diagnosed DM type1 and 0.5% of normal subjects. Insulin autoantibody: detectable in >90% of type1 DM developing before age 5. <40% of type1 DM developing after age 12. 0.5 % of normal subjects. Antibodies to glutamic acid decarboxylase 65KDa isoform: 60% of newly diagnosed type1 DM. May be used to identify patients with apparent type2 DM who will subsequently progress to type1.

• Insulinoma associated antigen (IA-2A & IA-2βA): - Directed against tyrosin phosphatases - Detected in >50% of newly diagnosed type1 DM. • Zinc transporter (ZnT8): - It is recently identified major autoantigen in type1 DM - 60-80% of type1DM, <3% of type2 DM and <2% of controls.

Role of antibodies in Mx of Diabetes Initial fasting hyperglycemia detected Presence of multiple antibodies 85-90% of type1 DM 5-10% of type2 DM 1-2% of healthy subjects have single autoantibody Known as latent autoimmune diabetes of adulthood (LADA) No acceptable T/t available to prevent the clinical onset of diabetes in autoantibody +ve individuals. Immunosuppresant therapy under development to prevent auotoimmunity

Pathogenesis of type2 DM Genetic susceptibility Environmental factors Insulin Resistance Loss of β cell function

Genetic Susceptibility • Susceptibility of type2 DM is inherited. • Mode of inheritance is complex. • Concordance rate between identical twins • Multigenic trait. insulin receptor gene • Mutation in GLUT 4 genes glycogen synthase gene is ~100%.

• Genome wide association studies – 17 genetic loci for type2 diabetes identified. • Most of them are related to insulin secretion pathway and not the insulin resistance. • Despite the well known fact that type 2 DM has strong genetic association, only 5% of patients can be pinpointed with a genetic defect with available information on gene association studies. • So, genes causing common forms of type2 DM are still unknown.

Environmental factors • Diet : high fat diet, excessive intake of free sugars specially fructose. • Exercise : Sedentary life style increases the risk of diabetes. In a age, gender, BMI and family history matched study it is observed that for every 500 Kcal increase in energy expenditure there is 6% decrease in risk of type 2 DM. • BMI : BMI Relative risk of developing DM type2 30-34.9 20 23> 35≤ 38

Insulin resistance • • Insulin resistance is decreased biological response to normal concentration of Insulin. It is present in type2 DM and virtually all obese individuals.

Factors causing insulin resistance Pre-receptor Insulin autoantibodies Primary defect in insulin signaling Insulin receptor mutations Leprechaunism (complete) Ataxia telangectasia syndrome Secondary to other endocrine disorders Cushing syndrome Acromegaly Pheochromocytoma Glucagonoma Hyperthyroidism Secondary to other disorders Visceral obesity Stress (infection, surgery, etc) Cytogenetic disorders (Down,Turner, Klinefelter) Secondary to normal physiologic states Puberty Pregnancy Starvation Secondary to medications Glucocorticoids Thiazide diuretics Oral contraceptive Progesterone blockers

• The insulin resistance syndrome (aka Syndrome X or metabolic syndrome) is a constellation of clinical and lab findings including hyperinsulinemia, insulin resistance, dyslipidemia, obesity and hypertension. • WHO criteria for diagnosis of metabolic syndrome isAny one of the following Any two of the following DM Blood pressure: ≥ 140/90 Impaired fasting glucose TG >150 and HDL <35 M & < 40F Impaired glucose tolerance WHR >0.9 M & >0.85 F or BMI >30 Insulin resistance urinary albumin excretion ≥ 20 µg/min or albumin : creatinine ratio ≥ 30 mg/g

Type1 Normal or increased No (if +ve LADA) Ketoacidosis is common Hyperosmolar state common 30% concordance in twins ~100% HLA linked Not linked Autoimmunity Insulin resistance Severe insulin deficiency Islet cell histology Obese mostly Autoantibodies +ve pathogenesis >30 years ↓ blood insulin levels Genetics Onset < 20 year Normal or underweight Clinical Type2 Relative insulin deficiency Insulitis NO Marked atrophy and fibrosis Focal atrophy with amyloidosis Severe beta cell depletion Mild beta cell depletion Dr. Prabhash

Complications of Diabetes Mellitus

Effect of insulin on metabolism • Carbohydrate metabolism: - ↑ glucose uptake in muscle and adipose tissues - In liver : ↑ glycogenesis ↓ glycogenolysis & gluconeogenesis • Fat metabolism: - ↓ TG degradation by inhibiting lipoprotein lipase - ↑ TAG synthesis in adipose tissues. • Protein metabolism: - ↑ AA entry into the cells - ↑ protein synthesis by activating translational factors

Meal absorbed Plasma glucose Plasma fatty acid Plasma amino acid No insulin released Fat breakdown Fat storage Plasma fatty acid Glucose uptake Glucose utilization Aminoacid uptake Plasma amino acid Liver Ketones glycogenolysis gluconeogenesis Tissue loss Brain interpret as starvation ventilation Metabolic acidosis Protein breakdown Tissue loss hyperglycemia polyphagia Osmotic diuresis Lactic acidosis Anaerobic metabolism thirst Coma and death dehydration Hypovolemia & Hypotension Circulatory failure polydipsia

Long term complications

Diagnostic criteria for DM Any one of the following is diagnostic A. Glucose 1. Fasting plasma glucose ≥126 mg% or 2. Symptoms of hyperglycemia and casual plasma glucose ≥200mg% or 3. During an OGTT 2 hour plasma glucose ≥ 200mg% B. HbA1c ≥ 6.5 mg% Point of care assay should not be used for diagnosis.

Pre clinical screening of DM • Type1 DM: - Screening is not recommended other than clinical studies. - Islet cell autoantibody detection may be useful in- (1) identifying LADA (2) to screen non diabetic family member who wish to donate kidney or part of pancreas fir transplantation (3) screening of women with GDM to identify those at high risk of progression to type1 DM (4) distinguishing type1 from type2 in children to institute insulin at the time of diagnosis. - HLA typing is not recommended. - Glucose induced insulin secretion test is also not recommended for routine clinical use.

• Type 2 DM - All asymptomatic individuals over 45 years of age - Overweight children with any of the two following risk factors- (i) type2 DM in of 1st or 2nd degree relative (ii) high risk race/ethnic group (iii) have conditions associated with insulin resistance (iv) maternal history of GDM……. Testing should be done every 3 years starting at the age of 10. - Screening can be done using fasting glucose, 2 hour OGTT or HbA1c.

Monitoring of blood glucose • SMBG: - With glucometer - Indications (1) patient under intense insulin therapy- 4-5 times a day. (2) prevention and detection of hypoglycemia, especially in those who are not able to recognize the early warning signs. (3) avoidance of severe hyperglycemia especially when having medication that alter insulin secretion and action (4) adjusting the dose in response to life style modification, exercise, food taken etc. (5) determination of necessity for initiating insulin therapy in GDM - Should not be used for diagnosis.

Minimally invasive monitoring of blood glucose: • Implanted sensors: - CGMS- needle type of sensor, monitors glucose 1 to 5 minute from interstitial tissue fluid. - Glucoday- microdialysis, every second • Gluco watch biographer: - Low level electric current moves glucose across the skin by electroosmosis where measured by GOD

Noninvasive glucose monitoring • Glucose has specific absorption at 1035nm - Near infrared spectroscopy - Raman scattering spectroscopy - Photoacoustic spectroscopy • All under active investigation and considerable success has been achieved but none is FDA approved for clinical use.

Monitoring long term glucose control • • - Glycated hemoglobin Gives an idea of glucose control over past 3 months Goal is to keep it below 7%. Should be repeated every 6 months in patients meeting the treatment goal Estimated average glucose mg% = 28.7*HbA1c – 46.7 Altered life span of RBCs affect the result significantly. Fructosamine Proteins (other than Hb) with nonenzymatic attachment of glucose are known as fructosamine. Reflect glucose control over past 2-3 weeks. Should not be done in patients with hypoalbuminemia.

others • Microalbuminuria • Evaluating complications- creat, lipid profile, ketone bodies, electrolytes, lactate etc. • HOMA-IR = insulin (mU/L) * glucose (mg%) / 405 • C-peptide assessment.

Thank you…

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