Diabetes mellitus

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Diabetes mellitus is a very common metabolic disease that is caused by absolute or relative insulin deficiency. The lack of this peptide hormone (see p. 76) mainly affects carbohydrate and lipid metabolism. Diabetes mellitus occurs in two forms. In type 1 diabetes (insulin-dependent diabetes mellitus, IDDM), the insulin-forming cells are destroyed in young individuals by an autoimmune reaction. The less severe type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) usually has its first onset in elderly individuals. The causes have not yet been explained in detail in this type.

A. Insulin biosynthesis O

Insulin is produced by the B cells of the islets ofLangerhans in the pancreas. As is usual with secretory proteins, the hormone's precursor (preproinsulin) carries a signal peptide that directs the peptide chain to the interior of the endoplasmic reticulum (see p. 210). Proinsulin is produced in the ER by cleavage of the signal peptide and formation of disulfide bonds. Proinsulin passes to the Golgi apparatus, where it is packed into vesicles—the p-granules. After cleavage of the C peptide, mature insulin is formed in the p-granules and is stored in the form of zinc-containing hexam-ers until secretion.

B. Effects of insulin deficiency 3

The effects of insulin on carbohydrate metabolism are discussed on p. 158. In simplified terms, they can be described as stimulation of glucose utilization and inhibition of gluconeogenesis. In addition, the transport of glucose from the blood into most tissues is also insulin-dependent (exceptions to this include the liver, CNS, and erythrocytes).

The lipid metabolism of adipose tissue is also influenced by the hormone. In these cells, insulin stimulates the reorganization of glucose into fatty acids. This is mainly based on activation of acetyl CoA carboxylase (see p. 162) and increased availability of NADPH+H+ due to increased PPP activity (see p. 152). On the other hand, insulin also inhibits the degradation of fat by hormone-

sensitive lipases (see p. 162) and prevents the breakdown of muscle protein.

The effects of insulin deficiency on metabolism are shown by arrows in the illustration. Particularly noticeable is the increase in the glucose concentration in the blood, from 5 mM to 9 mM (90 mg dL-1) or more (hyperglycemia, elevated blood glucose level). In muscle and adipose tissue - the two most important glucose consumers—glucose uptake and glucose utilization are impaired by insulin deficiency. Glucose utilization in the liver is also reduced. At the same time, gluconeogenesis is stimulated, partly due to increased proteolysis in the muscles. This increases the blood sugar level still further. When the capacity of the kidneys to resorb glucose is exceeded (at plasma concentrations of 9 mM or more), glucose is excreted in the urine (glucosuria).

The increased degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipi-demia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and /3-hydroxy-butyrate see p. 312). As H+ ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients' breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria).

Diabetes mellitus can have serious secondary effects. A constantly raised blood sugar level can lead in the long term to changes in the blood vessels (diabetic angiopathy), kidney damage (nephropathy) and damage to the nervous system (neuropathy), as well as to cataracts in the eyes.

- A. Insulin biosynthesis -

B cells

Preproinsulin (T)

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