Hormonal Regulation of Fuel Metabolism:- Diabetes Mellitus Arises from Defects in Insulin Production or Action
Diabetes mellitus, caused by a deficiency in the secretion or action of insulin, is a relatively common disease: nearly 6% of the United States population shows some degree of abnormality in glucose metabolism that is indicative of diabetes or a tendency toward the condition. There are two major clinical classes of diabetes mellitus: type I diabetes, or insulin dependent diabetes mellitus (IDDM), and type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), also called insulin-resistant diabetes. In type I diabetes, the disease begins early in life and quickly becomes severe. This disease responds to insulin injection, because the metabolic defect stems from a paucity of pancreatic β cells and a consequent inability to produce sufficient insulin. IDDM requires insulin therapy and careful, lifelong control of the balance between dietary intake and insulin dose. Characteristic symptoms of type I (and type II) diabetes are excessive thirst and frequent urination (polyuria), leading to the intake of large volumes of water (polydipsia) (“diabetes mellitus” means “excessive excretion of sweet urine”). These symptoms are due to the excretion of large amounts of glucose in the urine, a condition known as glucosuria. Type II diabetes is slow to develop (typically in older, obese individuals), and the symptoms are milder and often go unrecognized at first. This is really a group of diseases in which the regulatory activity of insulin is defective: insulin is produced, but some feature of the insulin-response system is defective. These individuals are insulin-resistant. The connection between type II diabetes and obesity (discussed below) is an active area of research.
Individuals with either type of diabetes are unable to take up glucose efficiently from the blood; recall that insulin triggers the movement of GLUT4 glucose trans porters to the plasma membrane of muscle and adipose tissue (see Fig. 12–8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by β oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and -hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to β-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate:
Acetone is volatile and is exhaled, and in uncontrolled diabetes, the breath has a characteristic odor sometimes mistaken for ethanol. A diabetic individual who is experiencing mental confusion due to high blood glucose is occasionally misdiagnosed as intoxicated, an error that can be fatal. The overproduction of ketone bodies, called ketosis, results in greatly increased concentrations of ketone bodies in the blood (ketonemia) and urine (ketonuria). The ketone bodies are carboxylic acids, which ionize, releasing protons. In uncontrolled diabetes this acid production can overwhelm the capacity of the blood’s bicarbonate buffering system and produce a lowering of blood pH called acidosis or, in combination with ketosis, ketoacidosis, a potentially life-threatening condition. Biochemical measurements on blood and urine samples are essential in the diagnosis and treatment of diabetes. A sensitive diagnostic criterion is provided by the glucose-tolerance test. The patient fasts overnight, then drinks a test dose of 100 g of glucose dis solved in a glass of water. The blood glucose concentration is measured before the test dose and at 30 min intervals for several hours thereafter. A healthy individual assimilates the glucose readily, the blood glucose rising to no more than about 9 or 10 mM; little or no glucose appears in the urine. Diabetic individuals assimilate the test dose of glucose poorly; their blood glucose level far exceeds the kidney threshold (about 10 mM), causing glucose to appear in the urine.
