Pancreatic Islet Hormones | Term Paper | Endocrine Glands | Biology

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Term Paper # 1. Introduction to Pancreatic Islet Hormones:

Hormones of the islets of Langerhans play a vital role in the regulation of fuel metabolism. One of the commonest serious disorders of man, diabetes mellitus, affecting 5 per cent of the United States population, represents a disturbance of the ability of the islet cells to properly regulate the glucose concentration.

Glucagon is synthesized by the A cells, insulin by the B cells, and somatostatin by the D cells. About 60 per cent of the cells, occupying the central zone of the gland, are B cells. Cell to cell contact is largely B to B cell. At the margin of the organ, a thick rim of A cells, one to two cells thick, makes up about 30 per cent of the total. Interspersed between A and B cells, or occasionally between A cells, are the somatostatin-secreting D cells.

There are numerous gap and tight junctions between cells. The areas where the three cell types meet is invested with a rich blood and nerve supply. The islets act as a sensor of the glucose concentration and its rate of change, constantly adjusting the rate of secretion of glucagon and insulin to match conditions.

Glucagon:

Release of glucagon is stimulated by decreasing glucose concentrations. The level of glucagon in plasma after fasting ranges from 30 to 200 ng/1 and is lowered after a carbohydrate meal. Increases in amino acid concentration or stimulation of the sympathetic nervous system also stimulate glucagon secretion.

Glucagon is usually measured by a radioimmunoassay technique. Four immune reactive forms have been reported in human plasma. A form with a molecular weight of 3,500 appears to have the greatest hormonal activity. The others include a smaller product (M.W. = 2,000), a possible proglucagon (M.W. = 9,000), and a very large form (M.W. = 180,000).

Glucagon stimulates adenyl cyclase in the liver and adipose tissue, thereby causing mobilization of glucose from the liver glycogen stores and of fatty acids from the adipose tissue triglyceride stores. The cAMP-dependent protein kinase in the liver also phosphorylates pyruvate kinase, making it inactive, and thereby hangs a tale.

The conversion of phospho-enol-pyruvate to pyruvate by the pyruvate kinase reaction and the conversion of pyruvate back to phospho-enol-pyruvate via oxaloacetate both occur in hepatocytes and constitute a futile cycle. The cycle is evidently controlled by alterations in the pyruvate kinase activity, as well as by the effect of acetyl coenzyme A in activating pyruvate carboxylase.

At times of carbohydrate surplus, fructose bisphosphate activates the enzyme by relieving an inhibition by ATP, and this promotes the utilization of triose phosphates to make pyruvate, and then acetyl coenzyme A. Glucagon, on the other hand, is a signal of glucose deprivation, and it shuts off the flow of triose phosphates toward acetyl coenzyme A by tripping an inhibitory phosphorylation of pyruvate kinase.

Glucagon therefore stimulates gluconeogenesis from lactate or amino acids. In sum, glucagon stimulates the delivery of glucose to the extracellular fluid by both glycogenolysis and gluconeogenesis in the liver. By raising the glucose concentration, glucagon can indirectly stimulate insulin release to enable use of the glucose.

The diversion of oxaloacetate to gluconeogenesis by the action of glucagon probably augments the ketosis seen with starvation, low-carbohydrate diets, or diabetes, although the presence of glucagon is not obligatory for development of ketosis.

Insulin:

Active insulin is made by progressive modification of preproinsulin. A rise in the concentration of blood glucose is a primary signal for secretion of insulin, and the release is prompt, beginning within one minute. Insulin is also secreted in response to a rise in blood amino acid concentration; arginine is the most effective signal, and arginine-loading tests are used to test beta cell function. The sympathetic nervous system inhibits insulin secretion through alpha adrenergic receptors.

Receptors for insulin are present in a variety of tissues, although the dependence of the tissues on insulin varies. Even the brain has some receptors, but it can use glucose very well in the absence of insulin. The number of receptors in cells of a given tissue varies between individuals, and an inverse relationship has been demonstrated between receptor concentration and the ambient insulin level.

Where non-obese normal individuals had a basal insulin level of 35 to 145 pM, obese non-diabetic individuals had the high basal insulin levels of 180 to 440 pM in their blood, but they had a decrease in the concentration of insulin receptors. This may explain a seeming resistance to insulin in some of these patients.

The classic result of insulin action is a dramatic increase in the rate of transport of glucose into skeletal muscle and adipose tissue. Insulin also promotes the uptake of amino acids by skeletal muscles and increases protein synthesis. It accelerates lipid synthesis and inhibits lipolysis and gluconeogenesis.

Although the effects of insulin occur rapidly, the concentration required to elicit different effects varies. Release of free fatty acids from adipose tissue is inhibited by 200 to 350 pM. Suppressing gluconeogenesis requires 700 to 1,400 pM, levels approaching the maximum physiological insulin concentrations.

Inhibition of hepatic glycogenolysis requires less insulin than does inhibition of gluconeogenesis. Glucose uptake by peripheral tissues increases with insulin concentration until a maximum is reached at about 1,400 pM. Disposal of D-3-hydroxybutyrate requires concentrations of 350 to 700 pM.

The mechanism(s) by which insulin produces these purposeful but diverse effects, like the mechanisms of many polypeptide hormones, is not clear. It may act through a distinct protein kinase; it may inhibit the cAMF-dependent protein kinase; it may block some of the effects of Cat⁺.

Somatostatin:

The pancreatic islets are a major source of somatostatin, a tetradecapeptide:

Here we have an example of a hormone synthesized and secreted in different regions of the body, including the hypothalamus. Somatostatin inhibits release of the following hormones, thyrotropin, corticotropin, and somatotropin (growth hormone) by the adenohypophysis; insulin and glucagon by the pancreas; gastrin by the gastric mucosa; secretin by the intestinal mucosa; and renin by the kidney. Somatostatin also inhibits the emptying of the stomach and secretion of both gastric acid and pancreatic enzymes.

Term Paper # 2. Diabetes Mellitus:

Diabetes is a group of diseases having in common an insulin effect that is inadequate for the uptake of glucose from the blood. The resultant hyperglycemia frequently causes glucose to appear in the glomerular filtrate at rates exceeding the capacity of the kidney to reabsorb it. This results in glucosuria and the voiding of large volumes of urine (polyuria), frequently at night (nocturia).

Large volumes of water are drunk to replace the losses (polydipsia). Polyuria and polydipsia are also symptoms of diabetes insipidus, but they demand further attention in any event. Even in the absence of such overt symptoms, diagnosis is easily made when blood glucose concentrations are measured after an overnight fast. Single fasting values in excess of 7 mm (120 mg/dl), or in excess of 9 mM (160 mg/dl) one hour after a breakfast containing 100 grams of carbohydrate, are suggestive, and repeated excessive values are diagnostic.

Diabetes is also accompanied by abnormalities in fat and protein metabolism. Not only is there an increased mobilization of fatty acids, but the liver converts a larger fraction to the oxybutyrates rather than to the triglycerides and phospholipids.

palmitoyl residue + 7 O₂ → 4 acetoacetate^Å + 4 H^Å

Up to one mole of oxybutyrates may be excreted per day, and the concomitant production of H⁺ results in acidosis, or ketoacidosis as it is commonly called in view of the simultaneous production of both ketone bodies and hydrogen ions.

Diabetes usually occurs in two forms, commonly designated as juvenile and adult-onset. Perhaps a better terminology would be to speak of a rapid-onset severe form and a slow-onset mild form, since there is age overlap in the appearance of the forms. Even so, many of the cases appearing in adolescence are severe and difficult to control with insulin, whereas most of the much more common cases appearing in middle and late life develop stealthily and can be controlled by dietary management for years without insulin or other drugs.

Although the genetic factors involved in diabetes are complex and not resolved, it appears that the severe and mild forms do have different genetics. The severe form in many cases is provoked by other events, such as a viral infection.

A patient with diabetes may present with diabetic ketoacidosis —comatose, dehydrated, and with acidosis, glucosuria, and ketonuria. This frequent medical emergency may be the first indication of the juvenile form of the disease, or it may have occurred in an insulin-dependent patient who failed to take his insulin, or who developed an infection. In any event, it is a lethal condition, with a mortality remaining between 5 and 10 per cent in major medical centers.

A diabetic patient may become unconscious with hypoglycemia caused by taking too much insulin. This insulin shock represents starvation of the brain, and patients on insulin may carry supplies of readily absorbed sugar to counteract its first indications.

Complications:

While the mortality from diabetic ketoacidosis has been dropping with better management and patient education, there has been a disappointing persistence of morbidity and mortality from other complications of the disease. Even with the best control, vascular disease involving any and all organs and regions of the body is likely to appear, causing blindness, renal failure, coronary artery disease, gangrene, and so on. The considerable thickening of the basement membrane in blood vessels likely to be seen upon microscopic examination in patients with diabetes.

It is not even known if tight regulation of the glucose level aids in avoiding these complications, since it would require an almost heroic effort to monitor closely the hourly fluctuations of glucose concentration, even if a large number of unbelievably cooperative subjects could be corralled for this purpose.

Sensors permitting continuous measurement are being developed, but since we presently lack this technology, the use of concentrations of hemoglobin Alc or Alb has been proposed as a device for assessing average glucose concentrations over long intervals. The, level of Hb Alc was observed to decrease within a few weeks in patients under strict control in a hospital.

Therapeutic Measures:

We must remember that the basic disturbance in diabetes is a failure to achieve adequate results of insulin action within the receptor tissues that are appropriate to the metabolic state. It is not a low insulin concentration per se; the circulating insulin concentration may be high in a definitely diabetic person who requires supplemental insulin for control. Many obese diabetic patients regain effective tissue responses to the level of insulin that they can produce simply by losing weight. Exercise also helps through adaptive increases in the capacity to use fuels effectively.

Patients with severe diabetes lose weight; they are losing fuel in the urine and have a diminished effectiveness for utilizing amino acids to make proteins. Not only is amino acid transport into the tissues impaired, but increased amounts of the amino acids are being degraded to make glucose, which is spilled into the urine. In contrast to the usual maturity-onset diabetic, these patients require insulin to avoid loss of weight.

Giving exogenous insulin one or more times during the day does not provide the adjustment in insulin level that normal pancreatic islet cells do as they constantly adjust the delivery of insulin (and glucagon) in response to the changing glucose level and other signals. Although insulin has been modified to provide different times of action (immediate, 6-8 hours, etc.) and although intake of food can be altered to try to match insulin effect and glucose level, proper control of diabetes with avoidance of both hyperglycemia and hypoglycemia can be extremely difficult in some people.

An artificial pancreas is now in the stage of human experimental application. In this system venous blood is continuously analyzed for glucose level. A computer is programmed to respond to the glucose concentration and rate of change of concentration by releasing insulin or glucagon into the blood stream.