Diabetes mellitus type 2

Diabetes mellitus 

Physiology

The human body is constantly producing, consuming or storing glucose. It uses many molecular signals to coordinate these activities and maintain "homeostasis" (balance) of glucose.
The main signals are insulin (stores glucose) and glucagon (releases glucose into the bloodstream).

Healthy glucose metabolism

Pathophysiology

In people with a chronically high calorific intake (particularly obese people), the body becomes less capable of responding to insulin signalling. This is called insulin insensitivity. Once your 'oral glucose tolerance' reaches a certain point, in the absence of other explanations, you are diagnosed with type 2 diabetes mellitus.

When the glucose levels in your bloodstream are persistently high, you are more prone to infections. The most common severe complications concern the blood vessels themselves. High levels of glucose cause damage to the inner lining of large blood vessels (macrovascular disease), medium vessels, and small vessels (microvascular disease).

Macrovascular disease causes a range of problems from increased risk of strokes (cerebrovascular infarction), heart attacks (myocardial infarction) and other vascular necrotising (tissue killing) events (e.g. bowel infarction, retinal artery occlusion). Peripheral vascular disease may reduce blood flow to limbs and digits, leading to claudication (pain which arises when using the limb for a long time, but recedes when resting), ulceration, infarctions, necrosis, and eventually amputation.

Microvascular disease usually presents as a slow, gradual decline in function, due to the rich supply of tiny blood vessels slowly degrading. This causes gradual decline in eyesight, renal function, and nerve function. Peripheral neuropathy (nerve disease), can be divided into motor neuropathy (weakness of muscle control), sensory neuropathy (numbness, chronic neuropathic pain), and autonomic neuropathy (errors in the automatic nervous regulatory signals of the body, such as mechanisms for temperature regulation).

Chronic high glucose intake and insulin desensitisation

Pharmacology

Medications for type 2 diabetes mellitus target various stages in the body's management of glucose.

• They directly inhibit the absorption of glucose into the body. E.g. alpha-glucosidase inhibitors.
• They directly inhibit production of new glucose (gluconeogenesis). E.g. biguanides.
• They promote the uptake of glucose from the blood and into cells.  E.g. biguanides.
• They increase serum insulin levels. E.g. meglitinides, sulfonylureas, exogenous insulins.
• They increase cellular insulin sensitivity. E.g. thiazolidinediones, biguanides. 
• They directly promote removal of glucose from the body into the urine. E.g. SGLT2 inhibitors.

The only biguanide currently used on human patients is metformin. The other biguanides, phenformin and buformin, were withdrawn from the market due to toxicity. Metformin is so successful that it is widely recommended as a first-line therapy for type 2 diabetes mellitus. There is evidence that it could be used to extend the human life-span and reduce age-related disease processes.