Diabetic ketoacidosis

It is much less common in type 2 diabetes because that is closely related to cell insensitivity to insulin, not shortage or absence of insulin. Some type 2 diabetics have lost their own insulin production and must take external insulin; they have some susceptibility to DKA. Although glucagon plays a role as an antagonistic hormone to insulin when there are low blood glucose levels, mainly by stimulating the process of glycogenolysis in hepatocytes (liver cells), insulin is the much more important hormone with more widespread effects throughout the body. Its presence or absence can by itself regulate most of DKA's pathological effects; notably, it has a short half-life in the blood of only a few minutes (typically about 6), so little time is needed between cessation of insulin release internally and the reduction of insulin levels in the blood.

Most cells in the body are sensitive to one or more of insulin's effects; the main exception being erythrocytes, neurons, liver cells, some intestinal tissue, and pancreatic beta-cells who do not require insulin to absorb glucose from the blood. The difference is due to different glucose transporter (GLUT) proteins. Most cells contain only GLUT-4 proteins which move to the cell surface membrane when stimulated by a second messenger cascade initiated by insulin, thus enabling uptake of glucose. Conversely, when insulin concentrations are low, these transporters dissociate from the cell membrane, and so prevent uptake of glucose.

Other effects of insulin include stimulation of the formation of glycogen from glucose and inhibition of glycogenolysis; stimulation of fatty acid (FA) production from stored lipids and inhibition of FA release into the blood; stimulation of FA uptake and storage; inhibition of protein catabolism and of gluconeogenesis, in which glucose is synthesised (mostly from some amino acid types, released by protein catabolism). A lack of insulin therefore has significant effects, all of which contribute to increasing blood glucose levels, to increased fat metabolism and protein degradation. Fat metabolism is one of the underlying causes of DKA. Muscle wasting occurs primarily due to the lack of inhibition of protein catabolism; insulin inhibits the breakdown of proteins, and since muscle tissue is protein, a lack of insulin encourages muscle wasting, releasing amino acids both for to produce glucose (via gluconeogenesis) and for the synthesis of ATP via partial respiration of the remaining amino acids.

In those suffering from starvation, blood glucose concentrations are low due to both low consumption of carbohydrates and because most of the glucose available is being used as a source of energy by tissues unable to use most other sources of energy, such as neurons in the brain. Since insulin lowers blood glucose levels, the normal bodily mechanism here is to prevent insulin secretion, thus leading to similar fat and protein catabolic effects as in type 1 diabetes. Thus the muscle wastage visible in those suffering from starvation also occurs in type 1 diabetics, normally resulting in weight loss. Despite possibly high circulating levels of plasma glucose, the liver will act as though the body is starving if insulin levels are low. In starvation situations, the liver produces another form of fuel: ketone bodies. Ketogenesis, that is fat metabolic processing (beginning with lipolysis), makes ketone bodies as intermediate products in the metabolic sequence as fatty acids (formerly attached to a glycerol backbone in triglycerides) are processed. The ketone bodies beta-hydroxybutyrate and acetoacetate enter the bloodstream and are usable as fuel for some organs such as the brain, though the brain still requires a substantial proportion of glucose to function. If large quantities of ketone bodies are produced, the metabolic imbalance known as ketosis may develop, though this condition is not necessary harmful. The negative charge of ketone bodies causes decreased blood pH. An extreme excess of ketones can cause ketoacidosis.

In starvation conditions, the liver also uses the glycerol produced from triglyceride metabolism to make glucose for the brain, but there is not nearly enough glycerol to meet the body's glucose needs. Normally, ketone bodies are produced in minuscule quantities, feeding only part of the energy needs of the heart and brain. However, in DKA, the body enters a starving state. Eventually, neurons (and so the brain) switches from using glucose as a primary fuel source to using ketone bodies.

As a result, the bloodstream is filled with an increasing amount of glucose that it cannot use (as the liver continues gluconeogenesis and exporting the glucose so made). This significantly increases its osmolality. At the same time, massive amounts of ketone bodies are produced, which, in addition to increasing the osmolal load of the blood, are acidic. As a result, the pH of the blood begins to change. Glucose begins to spill into the urine as the proteins responsible for reclaiming it from urine reach maximum capacity. As it does so, it takes a great deal of body water with it, resulting in dehydration.

Dehydration worsens the increased osmolality of the blood, and forces water out of cells and into the bloodstream in order to keep vital organs perfused. A vicious cycle is now set up, positively feeding back upon itself, and if untreated will lead to coma and death.