Diabetes Mellitus Definition:- Diabetes mellitu: s is a group of metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Classification:- 1. Type 1 Diabetes : deficiency, + Immune mediated * Idiopathic 2. Type 2 Diahetes :- relative insulin defi resistance, 3. Other specific types a. Genetic defects of B-cell function . Genetic defects in insulin action: ¢. Disease of exocrine pancreas: ° Pancreatitis ° Trauma / pancretopathy * Neoclassic B-cell destruction, usually leading to absolute insulin May range from predominantly insulin resistance with ciency to predominantly secretary defect with insulin * Cystic fibrosis d. Endocrinopathies * Acromegaly “* Cushing’s syndrome * Gulcagonoma Pheochromocytoma Hyperthyroidism Someastostaionoma . Drug-induced Glucocorticoids Pentamidine , Nicotinic acid Infections © Congenital rubella * CMV (cytomegalovirus ) * Others g- Uncommom froms of immune-mediated diabetes * Down’s syndrome * Klinefelter’s syndrome © Turner’s syndrome * Myotonic dystrophy eepee >Pathogenesis:- ‘Type 1 diabetes:- By the time | diabetes ap destroyed. 1. Genetic susceptibility — to the disease must be present. * The major histocomaptibility complex (MHC) is important because susceptibility appears to be linked to certain human ieucocyte antigen (HLA) ¢ MHC is located on short arm of chromosome 6-HLA. pears, most of the beta cells in pancreas have been 2. Enviro mental factors — ordinarily initiate the process in: a. Genetically susceptible individuals - The best evidence of environmental_is from monozygotic twins in whom the concordance rate diabetes is less than 50% . Viruses :- The viral hypothesés gained support from studies showing that certain strains of encephalomyocarditis virus cause diabetes in genetically susceptible. Congenital rubella is associated with subsequent development of IDDM in about 20% of affected individuals. Exposure to cow’s mill: Predispose to autoimmune diabetes Bévine albumin induces autoimmunity through mechanism of molecylar mimicry. It shares a structural homology with 69-kDa protei present on surface of pancreatic B-cells. L Insulitis - Monocytes / macrophages and activated T lymphocytes infiltrate pancreatic islets prior to or simultancously with development of diabetes. 4. Conversion of beta cell from self and activation of immune system- 5. Destruction of B-cell — Islets are now considered nonself 5 cytotoxic antibodies develop and act in concert with cell mediated immune mechanisam, destroying beta cells and thus appearance of diabetes. Type 2 Diabetes (NIDDM) It has two physiologic defects:a. Insulin resistance (reduced action of insulin in target tissues muscles and fat.) b. Abnormal insulin secretion. Three phases can be reco 1, 2. 3. gnized in usual clinical sequence. Plasma glucose is normal despite insulin resistance because insulil are elevated or compensating Insulin resistance worsens, so that that despite elevated insulin concentrations, post prandial hyperglycemia develops. Insulin resistance does not change, but insulin secretion declines, resulting in fasting hyperglycemia and overt diabetes. c insulin resistance. and degree of obesity influences the occurrence of type 2DM. The ‘thrifty phenotype’ hypothesis - Individuals with low birth weight appear to have higher risk of NIDDM, particularly if they become obese in later life. (This hypothesis suggests that intrauterine malnutrition leads to defective 0 levels. Environmental factors —Like physical inactivity, generous dietary intake pancreatic development. Such individuals may become susceptible to diabetes, hypertension and heart disease in later life.) Comparative clinical features of type 1 and type 2 diabetes _ Type Type 2 _| | Age at onset <40 years 150 years Duration of symptoms ‘Weeks Month to years Body weight Normal or low Obese to ketoacidosis Cause “| Severe insulin deficiency | Insulin resistance Rapid death without Yes No Treatment with insulin _| ‘Autoantibodies Yes No _| Diabetic complications No 25% at Diagnosis Family history of Uncommon Yes Diabetes _ _| Other autoimmune Yes Uncommon disease _ __ Ketonuria, tendency Yes Clinical features : Onset- Usually gradual in adults, but acute in children,Modes of presentation: * Presence of osmotic symptoms o’polyuria, oPolyphagia, : oPolydipsia j Weight loss, weakness and lassitude uritus vulvae in females or balanitis in males oss of libido or erectile dysfunction ¥Blurring of vision */Accidental discovery or asym examination.) * symptoms due to diabetes —related complication. ptomatic glycosuria (e.g. during life insurance Symptoms of hyperglycemia associated with diabetes | “Thirst * Polyuria * Nocturia * Tiredness, fatigue, irritability, apathy + Recent change in weight * Blurring of vision * Pruritus vulvae, balanitis (genital candidiasis) +Nausea; headache + Hyperphagia; predilection for sweet foods. Complications of diabetes:- Micro Retinopathy, cataract _ © Imparied vision Nephropathy Renal failure Peripheral neuropathy © Sensory loss ¢ Motor weakness| Autonomic neuropathy oO * Postural hypotension ° G.1 problems Foot disease > Ulceration ’ * Arthropathy ~ Macrovascular Coronary circulation — * Myocardial ischaemia /infarctin— Cerebral circulation “© ‘Transient ischaemia/ attack “© Stroke Peripheral Circulation e Claudication —e Ischaemic Diagnosis of Diabetes : 1. Symptoms of diabetes 200 mg/dl 7 “Casual Random is defined as any time to day without regard to time since last meal. The classic symptoms of diabetes included polyuria, polydipsia and unexplained weight loss. 3. Fasting plasma phicose mg/dl, Fasting is defined as no calorie intake for at least 8 hrs. 4. OGIT : 2 hours > mg/dl during an OGIT. The test should be performed using a ghucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, a, Intermediate groups + Fasting plasma glucose (FPG) < 1 10mg/dI= Normal fasting + FPG > 110 and <126mp/dl== Impaired fasting glucose, Corresponding categories in OGIT- * 2hour post load glucose < 140 mg/dl = normal glucose tolerance. * 2 hour post glucose > 140 and < 200 mg/dl = impaired glucose tolerance. + 2Zhour post glucose > 200 mg/dl = provisional diagnosis of diabetes. 5. Glycosylated haemoglobin ( GHBy ~~ It is used to measure long term glycemic control. Glucose has a unique capacity to react covalently with proteins. Slow non enzymatic plus causal plasma glucose concentration > aeattachment of glucose to haemoglobin result in formation of glycosylated haemoglobin or glycohaemoglobin. ele Management :- 1. Diet: a) Forbidden foods ~ Suger, jellies, honey, jaggary, tinned fruits and Juices, sweets, choclate, ice creams, pasiries, glucose drinks, food made with suger, pudding, sauces. b) Foods allowed in moderation — Bread of all kinds and chapattis made from wheat or millets, Plain biscuits, all fresh fruit, baked beans, breakfast cereals. ©) Free foods — All meat, fish eggs (no fired) , clear soup or meat extracts; tea or coffee, vegetables such as cabbage, cauliflower, spinach, pumpakin, brinjal, lady’s finger, turnip, French beans, cucumber, lettuce, tomato, spring onions, radish, asparagus. Spices, salt pepper and mustard; butter and margarine. Saccharine for sweetening. 2. Exercise — .t Maintenance of desirable body weight * Enhanced insulin sensitivity * Improved glucose control Programme ~ * Stretching ( 5-10 mins) * Warm up (5-10 mins) * Exercise (20-45 mins) _-* Warm down (10 mins at 30.%6f fall exercise intensity ) Exercise should be avoided plasma glucose concentration is > 250 to 300 mp/dl and / or presence or ketones in urine 3. Insulin sensitizer : A. Biguanides _Metformin—a guanidine derivative, effective and safe for control of hyperglycemia NIDDM patients, obese or normal weight as Monotherapy or in combination with sulphonylurea or insulin Dosages — 1.5g to 2.5g/day in 3 divided doses after meals. B. Thiazlidenediones — Troghtazone,Rosiglitazone, pioglitazone. The effects of these drugs are independent of pancreas and are a novel class of agents which primarily act against insulin resitance. C. Sulphonylurea Characteristics of commonly used sulphonylurea :Drug "| Duration of | Daily Dose / day Effect Dose (No.) 7 (Ar) (Mg) _| Generation | Acetohexamide | 12-18 250-1500 20 Chlorpropamide | 36-48 100-500 1 Tolbutamide | 6-10 500-300 —_B Tolazanide 16-24 100-1000 jar 2" generation 7 3 3 | Glibenclamide | 13-24 25-20 12 Glipizide 12-24 2.5-40 12 Gliclazide 12-24 40-320 v2 Glimepiride 16-24 1-16 12 4. Insulin secretogogues (Glinides ) Mechanism of action — Closely resembles that of sulphonylurea. Doses —pepaglininide — 0.5 mg three times a day maximum of 4mg per does and 16mg /per day. ‘Nateglinide — 60- 120mg t. d. s. to be taken 30 minutes prior to meals. 5. Insulin Type of insulin — Species of origin Bovine, procine, Human. Time course of insulin action Insulin preparation Onset an Hrs _ Hrs. Rapid onset ; - Regular 12-1 68 Lispro (analogue) —_[’-R aa Intermediate acting _ ~ NPII (isophane ) 1-4 20 Lente 14 12-20 (insulin zine suspension ) | Long acting 1-4 18-24 | Ultralente _ |