Diabetes Mellitus—IDDM (Type I) and NIDDM (Type II). Insulin has a central role in regulating blood glucose. It is secreted by the b cells in the islets of Langerhans in the human pancreas; the daily output is some 40 to 50 units, which is about 15 to 20% of the amount stored in the gland. The glucose level in the blood controls insulin release; high blood glucose levels (hyperglycemia) cause secretion of insulin, low levels (hypoglycemia) inhibit. When the pancreas is unable to secrete insulin or secretes too little, the medical condition is known as diabetes mellitus. This disease, the third most prevalent in the Western world, is normally classified as type I, or insulin-dependent (IDDM), or type II, non-insulin-dependent (NIDDM). NIDDM accounts for approximately 90% of all diabetic patients. IDDM patients have an autoimmune disease of the b cells—they cannot make insulin and need daily injections of the hormone. IdDm affects children and younger adults predominantly and becomes manifest when about 80% of the b cells are destroyed. Those with NIDDM are mature adults. They have reduced secretion of the hormone and reduced metabolic response to it (peripheral insulin resistance). The cause(s) of this insulin resistance is still to be identified. There are conflicting findings about the role of GLUT 4 in the insensitivity. One group of workers has reported that there are no changes in GLUT 4 mRNA or protein ( 29), but others have found a small (18%) decrease (30). The insulin resistance may be due to a defect in translocation of GLUT 4 to the muscle membrane (19).
Mechanism of Insulin Secretion. The mechanism of the regulation of insulin secretion by the external glucose level has been studied using patch clamp techniques to control the ionic channels (see Ch.a.pie.L3.8) in the b-cell membrane. The resting membrane potential of the b cells is maintained by the Na +-K+ ATPase and ATP-sensitive K+ channels (KATP channels). Normally these are open, but they close following glucose metabolism, when there is a concomitant increase in the
ATP:ADP ratio (31). This depolarizes the cell membrane and opens voltage-gated Ca2+ channels. The resulting increase in the intracellular free Ca 2+ concentration activates secretion of insulin through exocytosis—the fusion of insulin-containing granules with the plasma membrane and the release of their contents ( 32). A number of drugs (sulfonylureas), such as tolbutamide and glibenclamide, cause insulin secretion by inhibiting the K ATP channels of the b cells and are used medically to treat NIDDM. KATP channels are a heteromultimeric complex of the inward rectifier K+ channel (KIR 6.2) and a receptor for sulfonylureas, SUR1, a member of the ABC or traffic family of plasma membrane proteins (33).
Apart from a high level of glucose in the blood, a variety of compounds increase insulin secretion, including amino acids, free fatty acids, ketone bodies, and the hormones glucagon and secretin. In human pregnancy, the hormones placental lactogen, estrogens, and progestin all increase insulin secretion. Hence, insulin levels are higher in the pregnant than in the nonpregnant. Other hormones, such as epinephrine and norepinephrine (noradrenaline), inhibit its release. Inhibitory mechanisms are important as they protect individual b cells from overresponding and exhausting themselves (e.g., effects of chronic administration of growth hormone). Local controls by a host of autocrine, paracrine, and neurocrine substances ( 34) are thought to be involved in the inhibition of insulin secretion; these include the peptide pancreastatin, neuropeptide Y (NPY), somatostatin, calcitonin gene-related peptide (CGRP), galanin, and amylin (islet amyloid polypeptide or IAPP).
Insulin acts to lower blood glucose levels by facilitating its entrance into insulin-sensitive tissues and the liver. It does this by increasing the level of transporters in tissues such as muscle. In the liver, however, insulin stimulates storage of glucose as glycogen or enhances its metabolism via the glycolytic pathway. Surprisingly, glucose entry into liver cells is not mediated by changes in glucose transporter function, despite the fact that hepatocytes have these transporters present in their sinusoidal membranes (35). There is a functional specialization in the liver in regard to the disposition of GLUTs 1 and 2. GLUT 2 has higher expression in the periportal hepatocytes than in the perivenous hepatocytes. In the perivenous region, however, GLUT 1 is also present in the sinusoidal membranes of the hepatocytes, which form rows around the terminal hepatic venules. Periportal hepatocytes are more gluconeogenic than the more glycolytic perivenous cells ( 36). Why hepatocytes have GLUT 2 in their membranes is an enigma, as it is certainly not necessary for the ingress or egress of glucose. It has been suggested that GLUT 2 may be transporting fructose, since GLUT 5, the fructose transporter, is not expressed in the liver. However, GLUT 1 expression correlates well with the glycolytic activity of cells; in general, the higher the activity, the greater the concentration of GLUT 1. Thus, the presence of GLUT 1 in the perivenous liver cells may aid the efficient functioning of their glycolytic pathway.
While insulin has a primary influence on glucose homeostasis, it also influences many other cellular functions ( TableA^). Glucose has a profound effect on the secretion of insulin, and insulin strongly affects the normal storage of ingested fuels and cellular growth and differentiation (as exemplified in Iable.3,5). Thus, indirectly, glucose also influences these cellular events, which underscores the crucial role of glucose in influencing metabolism and catabolism, both directly and indirectly.
Rtiw Elftes NegftrfE^t
Gfaoffif-t^nyn toten ïfttc» GNtytiefa HrK*ptff() Genee^Bwi
Table 3.5 Influence of Glucose via Insulin
Was this article helpful?
All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.