1. Dr Zaranyika MBChB(Hons) UZ, MPH, FCP SA Department of Medicine UZ-CHS

2. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

3.  The prevalence of DM was 10.2% in 2005 (STEPS Zimbabwe)

4. 7 studies included in the meta analysis 29 514 study participants Pooled prevalence before 1980 - 0.44% ( 95% CI 0.0- 1.9%) Pooled prevalence after 1980 - 5.7% ( 95% CI 3.3- 8.6%)

5.  Based on pathogenic process  *Age not criterion  Type 1  Type 2  Other types  Gestational Diabetes * Diabetes 2014;63:4100–4114

6.  Primary - Type 1 ◦ β cell destruction  absolute insulin deficiency  Immune-mediated (type 1A)  Associated vitiligo, thyroid disease, Addison’s, pernicious anaemia, coeliac disease  Idiopathic (type 1B) - Type 2 ◦ Range: predominant insulin resistance  insulin secretory defect  Idiopathic - Monogenic ◦ Defects in β cell function  MODY (maturity onset diabetes of the young) 1 – 6 ◦ Defects in insulin action  Type A insulin resistance  Lipodystrophy syndromes

7.  Secondary  Drugs ◦ Steroids ◦ Protease inhibitors ◦ CNIs (especially tacrolimus) ◦ Thiazides ◦ β-blockers  Endocrinopathies ◦ Cushing’s ◦ Acromegaly ◦ Hyperthyroidism ◦ Phaeochromocytoma  Pancreatic disease ◦ Chronic pancreatitis ◦ Cystic fibrosis ◦ Haemochromatosis ◦ Cancer  Genetic syndromes ◦ Down’s, Klinefelter, Turner, myotonic dystrophy, Friedreich’s ataxia  Gestational diabetes ◦ Insulin resistance in late pregnancy  impaired glucose tolerance (IGT) ◦ Screen with random glucose  GGT if > 7 ◦ Management:  Diet initially  Use insulin: does not cross placenta ◦ High risk of developing T2DM later

10.  Type 1 - Genetic considerations - Pathophysiology

11.  MHC locus short arm of chromosome 6  HLA class II- DQ and DR  Professional APCs use class 2 molecules on their surfaces to present peptide antigens to T lymphocytes through T cell receptor  variation in amino acid sequences of individual HLA class 2 molecules impact their ability to present certain specific self peptides to T cells in the process of central and peripheral tolerization and later during the development of the autoimmune response.

12.  Immune mediated >95%  Idiopathic < 5%

13.  Islet cell antibodies ICA  Insulin autoantibodies IAA  Glutamic acid decarboxylase GAD 65  Tyrosine phosphatase IA2 (ICA 512)  Zinc transporter 8 (ZnT8)  Antibodies useful for diagnosis but do not directly cause destruction of B cells in type 1 diabetes  Cellular immune system- T lymphocytes infiltrate islets ( a process called insulitis) and destroy the B cell  Breakdown in self tolerance

14.  Viruses- mumps, rubella, coxackie B4  Toxins  Breastfeeding first 6 months protects  Modernization and improved public health increases incidence

16.  Type 2 -Genetic considerations- monogenic, polygenic  Pathophysiology

17.  Resistance to the action of insulin in peripheral tissues, particularly muscle,fat and also liver  Defective insulin secretion, particularly in response to a glucose stimulus  Increase glucose production by the liver

19.  Accelerated lipolysis in the fat cell  Incretin hormone deficiency and resistance  Hyperglucagonemia  Increased renal tubular reabsorption  CNS metabolic regulation

20.  Acute - Diabetic ketoacidosis - Hyperglycemic hyperosmolar state

22.  Vascular - Microvascular - Macrovascular  Non- vascular

23. McCance et al.