Diabetes Mellitus definition, classification & aetiopathogenesis

1. CHAIR: Prof.Dr.B.Jayakumar. Diabetes Mellitusdefinition, classification & aetiopathogenesis

2. Introduction • The prevalence of Diabetes is increasing rapidly,particularly in children and young adults. • One third of cases of Diabetes remain undiagnosed. • The burden of death and disability from Diabetes remains great despite broad advances in understanding and therapeutic techniques.

3. Only few patients with Diabetes broadly achieve targets for blood pressure,lipid, or glucose management. • Only few patients with Diabetes receive all the recommended annual screening evaluations for complications or preventive services. • Organised system of health care delivery can achieve better control of diabetes and its comorbidities.

4. Definition: Second century understanding: • Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs in to urine. The patients never stop making water and the flow is incessant…….Life is short and unpleasant. Greek Physician Aretaeus of Cappadocia

5. Present WHO definition: • The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. • The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.

6. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. • In its most severe forms, ketoacidosis or a non-ketotichyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. • Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made.

7. The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. • People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease

8. Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. • The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.

9. Classification: • Now Diabetes Mellitus is classified on the basis of the pathogenic process that leads to hyperglycemia. • I. Type 1 diabetes A. Immune-mediated    B. Idiopathic II. Type 2 diabetes

10. III. Other specific types of diabetes •   A. Genetic defects of Beta cell function characterized by mutations in: •     1. Hepatocyte nuclear transcription factor (HNF) 4alfa (MODY 1) •     2. Glucokinase (MODY 2) •     3. HNF-1alfa (MODY 3) •     4. Insulin promoter factor-1 (IPF-1; MODY 4) •     5. HNF-1beta (MODY 5) •     6. NeuroD1 (MODY 6) •     7. Mitochondrial DNA •     8. Subunits of ATP-sensitive potassium channel •     9. Proinsulin or insulin conversion

11. B. Genetic defects in insulin action •     1. Type A insulin resistance •     2. Leprechaunism •     3. Rabson-Mendenhall syndrome •     4. Lipodystrophy syndromes • C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculouspancreatopathy, mutations in carboxyl ester lipase

12.   D. Endocrinopathies— acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma. • E. Drug- or chemical-induced— Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapine

13. F. Infections— congenital rubella, cytomegalovirus, coxsackie. • G. Uncommon forms of immune-mediated diabetes — "stiff-person syndrome , anti-insulin receptor antibodies.

14. H. Other genetic syndromes sometimes associated with diabetes— Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome. • IV. Gestational diabetes mellitus (GDM)

15. Aetiopathogenesis: • I.Type 1 Diabetes • A. Immune-mediated: • Type 1 DM is the result of interactions of Genetic Environmental & Immunological factors leading to destruction of beta cells and insulin deficiency.

16. Geneticfactors: • Susceptibility to type 1 DM involves multiple genes • The major susceptibility gene for type 1 DM is located in the HLA region on chromosome 6. • Commonly associated haplotypes are HLA DR3 and/or DR4, DQA1*0301, DQB1*0302, and DQB1*0201.

17. Genetic loci contributing susceptibility to Type 1 DM are polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin-2 receptor, and PTPN22. • Although the risk of developing type 1 DM is increased tenfold in relatives of individuals with the disease, most individuals with type 1 DM do not have a first-degree relative with this disorder.

18. Environmental factors: • Environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds. • Identification of an environmental trigger has been difficult because the event may precede the onset of DM by several years.

19. Immunologic Factors: • Following abnormalities in humoral and cellular arms of immune system have been identified. • 1)Islet cell autoantibodies 2)Activated lymphocytes in islets,peripancreatic lymph nodes and systemic circulation 3) T lymphocytes that proliferate when stimulated with islet proteins; and 4) release of cytokines within the insulitis

20. Pancreatic islet molecules targeted by the autoimmune process include • Insulin, glutamic acid decarboxylase (GAD), ICA-512/IA-2 , and phogrin (insulin secretory granule protein).

21. These Genetic Environmental & Immunological factors interact leading to destruction of beta cells and insulin deficiency. • Features of diabetes do not become evident until a majority of beta cells are destroyed. • These patients may alsohave other autoimmune disorders such as Graves’ disease,Hashimoto’sthyroiditis, and Addison’s disease.

23. B. Idiopathic • Some individuals who have the clinical phenotype of type 1 DM lack immunologic markers indicative of an autoimmune process involving the beta cells. • These individuals are thought to develop insulin deficiency by unknown, nonimmune mechanisms.

24. II. Type 2 diabetes • Environmental factors (such as obesity, nutrition, and physical activity) in Genetic susceptible patients leads to . a)Impaired insulin secretion b)Insulin resistance c)Excessive hepatic glucose & lipid production d)Abnormal fat metabolism.

25. a)Impaired insulin secretion • In type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance. • Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.

27. The reason(s) for the decline in insulin secretory capacity in type 2 DM is • 1)A second genetic defect—superimposed upon insulin resistance—leads to beta cell failure. 2)Glucose toxicity - Chronic hyperglycemia paradoxically impairs islet function. 3) Lipotoxicity - Elevation of free fatty acid levels and dietary fat also worsen islet function

28. b)Insulin resistance • Insulin resistance, the decreased ability of insulin to act effectively on target tissues is a prominent feature of Type2 DM.

30. Insulin binds to receptors on target site • Receptor autophosphorylation • Recruitment of intracellular signalling molecules • Insulin Receptor Substrate(IRS) and other protein complex initiate a cascade of phosphorylation and autophosphorylation reactions resulting in metabolic and mitogenic effects of insulin.

31. Postreceptor defects in insulin-regulated phosphorylation/dephosphorylation plays the predominant role in insulin resistance. • The accumulation of lipid within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production leading to insulin resistance.

32. Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect. • Insulin resistance in Liver Failure to supressgluconeogenesis Fasting hyperglycemia. .

33. Insulin Resistance in liver • Decreased glycogen storage in postprandial state • Postprandial hyperglycemia

34. Peripheral insulin resistance. • Decreased peripheral gluose usage. • Postprandial hyperglycemia.

35. c)Excessive hepatic glucose & lipid production: • Insulin resistance in liver Excess production of glucose. • Insulin resistance in Adipose tissue Free Fatty Acid flux from adipocytes Increased lipid synthesis in hepatocytes.

36. d)Abnormal fat metabolism: • The obesity accompanying type 2 DM, is thought to be part of the pathogenic process • The adipocytes secrete a number of biologic products. • The increased production of Resistin,TNFalfa, IL-6 by adipocytes are associated with insulin resistance. • Adiponectin and Leptin secreted by adipocytes increase insulin sensitivity and are decreased in obesity.

37. III. Other specific types of diabetes • A. Genetic defects of Beta cell function characterized by mutations : • I. (MODY 1) : Mutation in Hepatocyte nuclear transcription (HNF) 4 alfa. • This transcription network plays a role in the early development of the pancreas. • In the pancreas these genes influence expression of, among others, the genes for insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.

38. MODY2: • MODY 2 is due to any of several mutations in the GCK gene on chromosome 7 for glucokinase. • Glukokinase serves as the glucose sensor for the beta cell. • These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose.

39. 3. HNF-1alfa (MODY 3) • MODY 3 is caused by mutations of the HNF1α gene, a homeobox gene on chromosome 12. • HNF1α is a transcription factor important for differentiation of beta cells. • Mutations of this gene lead to reduced beta cell mass or impaired function

40. 4. Insulin promoter factor-1 (IPF-1; MODY 4) MODY 4 arises from mutations of the IPF1homeobox gene on chromosome 13. • IPF1 is a transcription factor vital to the development of the embryonic pancreas. • Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin

41. 5. HNF-1 . (MODY5): • HNF1β is involved in early stages of embryonic development of several organs, including the pancreas. • Most of those who develop diabetes show atrophy of the entire pancreas, with mild or subclincal deficiency of exocrine as well as endocrine function (MODY 5).

42. 6. NeuroD1 (MODY 6) • MODY 6 arises from mutations of the gene for the transcription factor referred to as neurogenic differentiation . • NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of beta cells and parts of the nervous system  

43. 7.MitochondrialDNA: Point mutations in mitochondrial DNA have been found to beassociated with diabetes mellitus and deafness. • 8. Subunits of ATP-sensitive potassium channel : Mutations in subunits of the ATP-sensitive potassium channel subunits are the major causes of permanent neonatal diabetes.

44. 9. Proinsulin or insulin conversion: Genetic abnormalities that result in the inability to convertproinsulin to insulin and the resultant carbohydrate intolerance have been identified

45.   B. Genetic defects in insulin action •     1. Type A insulin resistance: • Individuals with the type A insulin resistance syndrome have an undefined defect in the insulin-signaling pathway

46.  2. Leprechaunism and 3. Rabson-Mendenhall syndrome are two paediatric syndromes that have mutations in the insulin receptor gene with subsequentalterations in insulin receptor function and extreme insulinresistance.

47. C. Diseases of the pancreas : • Any process that diffusely injures the pancreas can cause diabetes pancreas: • pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculouspancreatopathy.

48. D. Endocrinopathies— • Several hormones (e.g. growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. • Diseases associatedwith excess secretion of these hormones can cause diabetes. (e.g. Acromegaly, Cushing’s Syndrome, Glucagonoma and Phaeochromocytoma). • These forms of hyperglycaemia typically resolve when the hormone excess is removed.

49. E. Drug- or chemical-induced DM: • Many drugs can impair insulin secretion. • These drugs maynot, by themselves, cause diabetes but they may precipitate diabetes in persons with insulin resistance. • Vacor, pentamidine, canpermanently destroy pancreatic beta cells. • Nicotinic acid, glucocorticoids, can impair insulin action.

50. F. Infections— • Certain viruses have been associated with beta–celldestruction. • Congenital rubella, cytomegalovirus, coxsackie, adenovirus and mumps have beenimplicated in inducing the disease.