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