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Diabetes Revision

Diabetes Revision. PBL28 12 th August. Diagnosis. Random glucose >11mmol/L (200mg/L) with classical signs and symptoms Fasting glucose >7mmol/L (126mg/ dL ) on more than one occasion Oral glucose tolerance test >11mol/L (200mg/ dL ) two hours post-carbohydrate load. Causes of Diabetes.

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Diabetes Revision

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  1. Diabetes Revision PBL28 12th August

  2. Diagnosis • Random glucose >11mmol/L (200mg/L) with classical signs and symptoms • Fasting glucose >7mmol/L (126mg/dL) on more than one occasion • Oral glucose tolerance test >11mol/L (200mg/dL) two hours post-carbohydrate load

  3. Causes of Diabetes • Type 1 – destruction of pancreatic B-cells (5-10%) • Type II diabetes – insulin resistance and B-cell dysfunction • Genetic defects of B-cell function • Neonatal diabetes • Maturity-onset diabetes of the young (MODY) • Maternally inherited diabetes and deafness (MIDD) • Defects in proinsulin conversation • Insulin gene mutations

  4. 4. Defects in insulin action 5. Exocrine pancreatic defects (chronic pancreatitis, pancreatectomy / trauma, neoplasia, cystic fibrosis, haemachromatosis, fibrocalculouspancreatopathy) 6. Endocrinopathies (acromegaly, Cushings, hyperthyroidism, phaemchromocytoma) 7. Infections (CMV, coxsackie B, congenital rubella) 8. Drugs (glucocorticoids, thyroid, IFN-a, B-agonists, thiazides) 9. Genetic syndromes (Down, Kleinfelter, Turner, Prader-Willi) 10. Gestational DM

  5. Complications of Diabetes • Pathogenesis is caused by glucotoxicity • Measured by Hb1AC (covalent glucose moieties to Hb, lifespan of RBC is 120 days). Should be <7% • Obesity, smoking worsen complications • How does glucose cause complications?

  6. Three metabolic pathways • Formation of advanced glycation end products (AGEs) – bind to RAGE receptor on macrophages and T cells, endothelium and vascular smooth muscle • Releases pro-inflammatory cytokines, growth factors from tissue macrophages • ROS from endothelium • Increased procoagulant, proliferation of VSM and ECM • AGEs cross-link collagen I in large vessels, decreasing elasticity and trapping LDL • AGEs cross-link collagen IV in the BM, causing endothelial cell adhesion and extravasation of fluids Greatly accelerates atherogenesis in arteries, causes diabetic microangiopathy (e.g. BM thickening in glomeruli)

  7. 2. Intracellular hyperglycaemia increased synthesis of diacylglucerol  activates protein kinase C. Causing: • Production of VEGF • Elevated levels of endothelin-1 • Production of TGF-B, increasing ECM and BM deposition • Production of PAI-1, reducing fibronolysis • Increased pro-inflammatory cytokines

  8. 3. Intracellular hyperglycaemia disturbs polyol pathways in tissues that do not require insulin for uptake. • Excess glucose is metabolised to sorbitol then fructose, using up NADPH  depleted glutathione  oxidative stress • Affects nerves, lenses, kidneys, blood vessels

  9. Morphology of Diabetes • Macrovascular disease • Pancreas does not have severe morphological changes (T1DM = reduction in islets) • Accelerated atherosclerosis (normal atheromas though) • MI • Renal artery stenosis • Peripheral vascular disease / gangrene of lower extremities • CVA • Hyaline atherosclerosis (hypertension)

  10. Diabetic microangiopathy • Diffuse thickening of BM in: • Skin • Skeletal muscle • Retina • Renal glomeruli, medulla, tubules, Bowman’s capsule • Peripheral nerves • Placenta • Leaky capillaries • Diabetic nephropathy • Glomerular lesions: • Thickened glomerular BM • Diffuse mesangial sclerosis • Nodular glomerulosclerosis • Renal vascular lesions • Pyelonephritis  necrotizing papilliitis • Diabetic ocular complications: retinopathy, cataract formation, glaucoma • Neuropathy occurs from vasa nervorummicroangiopathy as well as glucose toxicity in the neuron

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