Type 2 diabetes

Describe how genetics play a role in development of type 2 diabetes

Genetic mutations can cause excessive insulin secretion leading to insulin resistance, or impaired beta cell function leading to reduced insulin production in response to glucose Different ethnicities have different levels of risk of developing type 2 DM, even within the same environment Family histor Lifetime risk if a first degree relative has type 2 diabetes is 5-10 times higher

State the first step in treatment of type 2 diabetes

Lifestyle changes to reduce fat in diet, increase exercise and lower weight

Give the defining characteristics of type 2 diabetes

Relative insulin deficiency and increased resistance of body tissues to the effects of insulin

State the UK population prevalence of type 2 diabetes

4-6%

Explain how obesity leads to increased risk of diabetes

Central adipose tissue releases free fatty acids which compete with glucose as a fuel supply Excess visceral fat accumulation results in altered release of adipokines (eg. leptin, adiponectin, resistin) Major effect is hepatic insulin resistance as visceral adipose drains to the portal vein Hepatic insulin resistance impairs suppression of liver glucose production

State the macrovascular complications associated with type 2 diabetes mellitus

Cerebral infarction Myocardial infarction Peripheral arterial disease

Describe how diabetes mellitus can lead to macrovascular complications

Chronic inflammation and injury to vessel walls from superoxidatives, C-reactive protein, and advanced glycosylated end products, leads to vasoconstriction and thrombosis Inflammation, vasoconstriction, and thrombosis lead to accelerated atherosclerotic disease

Describe the stages of atheroma development in atherosclerosis

Chronic inflammation/endothelial injury in vessels LDL particles deposit lipids on vessel walls Infiltration of monocytes which mature into macrophages Macrophages take up lipids, oxidising them and forming foam cells Smooth muscle cells migrate from the media to the intima and proliferate Deposition of collagen and other ECM molecules forming a fibrous cap Some cells die, attracting T lymphocytes and forming the lipid/necrotic core

State the causes of secondary diabetes

Drug related: antipsychotics, antietrovirals, steroid therapy, immunosuppressant therapy, cardiovascular drugs Endocrinopathy related: Cushing's, Acromegaly, Thyrotoxicosis Pancreatopathy related: Cystic Fibrosis, Chronic pancreatitis, Hereditary haemochromatosis

Explain how exercise is a preventative factor in the development of type 2 diabetes

Exercise promotes non-insulin dependant uptake of glucose into muscle and other tissues This decreases the reliance on insulin to reduce glucose levels in the blood

State the main adverse effects associated with metformin

GI effects (nausea, vomiting, etc)

Describe the pathogenesis of type 2 diabetes mellitus

Insulin resistance predates hyperglycaemia Development of insulin resistance is associated with increasing age, obesity and genetic susceptibility Insulin resistance initially stimulates excessive insulin production by beta cells Excessive demand for insulin leads to deposition of amyloid Amyloid fibrils, glucotoxicity and lipotoxicity damage beta cells and reduce their capacity for insulin production Beta cell function may also be impaired by genetic factors

Describe the management plan for macrovascular complications of type 2 diabetes

Intensive treatment of diabetes is ineffective so treatment focuses on reducing cardiovascular risk ACE inhibitors and Angiotensin 2 receptor antagonists used to lower blood pressure Statins are used to lower LDL cholesterol in the blood

State the first line pharmacological treatment for normal weight patients and its mechanism of action

Metformin Inhibits hepatic gluconeogenesis

State the first line pharmacological treatment for overweight patients and its mechanism of action

Sulphonylurea Stimulates insulin release from beta cells Sulphonylurea receptor activation blocks K+ channel which depolarises the beta cell and triggers insulin release

Name the other classes of drugs that may be combined with metformin or sulphonylurea or both

Thiazolidinediones (improve insulin sensitivity) Meglitinides (short acting insulin secretagogues) DPP4 inhibitors and GLP-1 agonists (increase incretin effect) SGLT2 inhibitors (inhibits renal resoprtion of glucose)

State the main adverse effects associated with sulphonylureas

Weight gain

Name the conditions associated with type 2 diabetes that are collectively referred to as 'metabolic syndrome'

central obesity hypertension hypertriglyceridaemia reduced HDL cholesterol