- Week 20: Diabetes - Type 1 - Diabetes was rare until the 20th century - Paul Langerhans discovered islets of Langerhans in 1869 - 1922 insulin treatment for human type 1 diabetes -Immunofluorescence - Insulin def i ciency - Animal models of Type 1 diabetes: NOD mouse, BB rat: Spontaneously develop insulin-dependent diabetes with characteristics similar to those of the human disease. -Includes:Lymphocyticinfiltrationofislets.Circulatingautoantibodies.Genetic association with MHC. - Transgenic and gene knockouts: Used to def i ne role of specif i c cell types and gene products in disease process - T-cell targeted immunosuppression prolongs beta cell function in Type 1 diabetes - Interferon-alpha detected in endocrine cells in the Type 1 diabetic pancreas - Type 2 diabetes - Diabetes is hyperglycaemia caused by defects in insulin secretion, insulin action or both. - Fasting bood glucose >7 mM, OGGT conf i rms diagnosis - Type 1 - 10%, Type 2 - 90%, can also get gestational diabetes, MODY and LADA - Insulin insenstitivity: defective insulin action (type 2 diabetes), determind by hyperinsulinemic eugycemic glucose clamp - Fat within muscle increases with ageing - Fat is an endocrine organ: leptin (secreted in proportion to fat mass, appetite regulation high in obesity but associated with leptin resistance), adiponectin (increases insulin sensitivity, secreted in inverse proportion to fat mass, low in obesity), TNF-alpha, interleukin-6 (increased in obesity, stimulate lipolysis, promote inflammation)
- Mechanism of insulin resistance - Defects in pancreatic islet function in type 2 diabetes - Type 2 diabetes susceptibility genes: - FTO is a gene on chromosome 16 encoding enzyme that demethylates methyl- thymine on DNA, high expression in hypothalamus and pancreatic islets, in hypothalamus, regulates expression of peptide involved in stimulating appetite. - TCF7L2 - transcription factor 7 like 2, on chromosome 10q regulating number of genes inc. pro-glucagon, risk variants associated with decreased insulin secretion, may be result of uncertain ef fect on insulin secretion or beta cell proliferation - PPARG - peroxisome proliferator activated receptor gamma, nuclear receptor expressed in adipose tissue, fatty acids act as ligands, regulated genes involved in adipogenesis and fatty acid oxidation, polymorphism associated with increase in insulin sensitivity, protection against T2D - KCNJ11, aka Kir6.2, component of K-ATP channel, closure leads to depolarisation of beta cell membrane, required for glucose-induced insulin secretion. Polymorphism resulting in Glu23Lys substitution associated with T2D, 2x increase in K-ATP channel activity, modest impairment in insulin secretion - T2D susceptibility genes mainly linked to beta cell development or function - Islet amyloid polypeptide (IAPP): secretory product of pancreatic beta cells, act locally to inhibit insulin/glucagon secretion, may regulate satiety in brain/gastric emptying, aggregated under certain conditions to form amyloid - Amyloids can deposit in T2D islet - Amyloid f i brils extend from granules in beta cells to amyloid plaques -T2DPathogenesis:obesitydrives^visceralfat,leadstoinflammatoryresponseand insulin sensitivity