Diabetes mellitus pathophysiology

Types, Pathophysiology and signs symptoms of Diabetes mellitus

1. Diabetes Mellitus Pathophysiology Dr. Santosh Kumar Ranajit Associate Professor Pharmacology

2. Diabetes mellitus is a abnormal metabolic conditions characterized by hyperglycaemia. The associated pathophysiology indicates about ineffective insulin function. Major r isk factor of microvascular damage (retinopathy, nephropathy and neuropathy) Major risk factor of macrovascular complications (ischaemic heart disease, stroke and peripheral vascular disease). These comorbidities reduced the life expectancy and diminished quality of life. .

3. Epidemiology& Types As per the WHO estimation, there were 171 million people in the world with diabetes in the year 2000 and will be increase to 366 million by 2030. India is with 41 million of diabetes people, it will be increased up to 68 million by the year of 2025. TYPES OF DIABETES MELLITUS Mainly classified into 4 types Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus Other specific types ( mono genic diabetes)

4. TYPES

5. NORMAL STRUCTURE OF PANCREAS The endocrine pancreas --islets of Langerhans weight of endocrine pancreas is: 1-1.5 gm Total weight of pancreas 60-100 gm. The islet cell tissue are more in the tail than in the head or body Ultrastructurally and immunohistochemically: 4 major and 2 minor types of islet cells A. Major cell types: 1. Beta (β) : 70% of islet cell, secrete insulin 2. Alpha (α) : 20% of islet cells, secrete glucagon 3. Delta (δ) : 5-10% of islet cells, secrete somatostatin 4. Pancreatic polypeptide (PP) cells or F cells comprise 1-2%, secrete pancreatic polypeptide- gastrointestinal effects. B. Minor cell types: 1. D1 cells elaborate vasoactive intestinal peptide (VIP): glycogenolysis -hyperglycaemia -secretory diarrhoea by gastrointestinal fluid secretion. 2 . Enterochromaffin c ells: synthesise serotonin

6. Pathogenesis of T1DM IDDM / juvenile onset diabetes Mainly immune mediated & hereditary It is an autoimmune disease (islet destruction) The basic phenomenon in Type 1B DM: idiopathic, Type 1A DM: immune-mediated Pathogenesis of type 1ADM have 3 mutually-interlinked mechanisms 1. genetic susceptibility, 2. autoimmune factors, 3. certain environmental factors

7. Pathogenesis of T1DM 1. Genetic susceptibility. i) identical twins : about 50% chance of the second twin ii) 1A DM have the susceptibility gene located in the HLA region of chromosome 6 (MHC class II region), ex. HLA DR3, HLA DR4 and HLA DQ locus. 2. Autoimmune factors. Type 1A DM have shown several immunologic abnormalities: i)Presence of islet cell antibodies against GAD (glutamic acid decarboxylase), insulin etc, ii) Occurrence of lymphocytic infiltrate in and around the pancreatic islets termed insulitis. Consists of CD8+T , CD4+ T& macrophages. iii) Selective destruction of β-cells by T-cell mediated cytotoxicity or by apoptosis. iv) Transfer of type 1A DM from diseased animal by infusing T lymphocytes v) Association of type 1A DM with other autoimmune diseases: Graves’ disease, Addison’s disease, Hashimoto’s thyroiditis, pernicious anaemia. vi) Remission of type 1A DM in response to immunosuppressive therapy (cyclosporin A)

8. Pathogenesis of T1DM 3. Environmental factors. Trigger may precede the occurrence of the disease by several years. Certain viral and dietary proteins mediated immune attack on β-cells i) Certain viral infections e.g. mumps, measles, coxsackie B virus, cytomegalovirus and infectious mononucleosis. ii) Experimental induction of type 1A DM: e.g. alloxan, streptozotocin & pentamidine. iii) Geographic and seasonal variations iv) Early exposure to bovine milk proteins --autoimmune Type 1A DM

9. Pathogenesis of T2DM I. impaired insulin secretion: Delayed insulin secretion relative to glucose load II. insulin resistance : at peripheral tissues 1. Genetic factors. i) 80% chance of developing diabetes in the other identical twin ii) 40% chance : If both parents have type 2 DM 2. Constitutional factors. obesity, hypertension, and sedentary life style 3. Insulin resistance. L ack of responsiveness of peripheral tissues to insulin, especially of the skeletal muscle and liver

10. Mechanism of hyperglycaemia i) insulin resistance: impairs glucose utilisation leads to hyperglycaemia. ii) Increased hepatic synthesis of glucose. iii) Hyperglycaemia in obesity due to high FFA & cytokines (e.g. TNF-α and adiponectin) Impaired glucose utilisation increased hepatic synthesis of glucose, Insulin resistance syndrome: persist hyperglycaemia and hyperinsulinaemia. clinical features: cardiovascular diseases like, mild hypertension (related to endothelial dysfunction) and dyslipidaemia (reduced HDL level, increased triglycerides and LDL level). Increased hepatic glucose synthesis in diabetes as insulin promote hepatic storage of glucose as glycogen and suppress gluconeogenesis.

11. Insulin resistance

12. Signs and Symptoms

13. Systemic complication

14. Treatment..Insulin Therapy Preproinsulin :110 amino acids; Proinsulin : 86 amino acids The A-chain: 21 ;B-chain: 30 &‘C’ chain: 35 amino acids . MW: about 6000. 1 mg = 28 units. (1 U reduces FBS of rabbit to 45 mg/dl)

15. Oral hypoglycemic drugs A. Enhance Insulin secretion 1. Sulfonylureas : Tolbutamide, Glibenclamide,Glipizide 2. Meglitinide: Repaglinide, Nateglinide 3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs): Exenatide, Liraglutide 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, B. Overcome Insulin resistance 1. Biguanide: Metformin 2. Thiazolidinediones : Pioglitazone