Sumer Pek

A Newly Recognized Pancreatic Polypeptide; Plasma Levels in Health and Disease

Publisher Summary Immunohistochemical studies show that aPP is stored in an endocrine-type cell disseminated in the exocrine parenchyma of the chicken pancreas (aPP cells are seldom found in islets of chicken pancreas) and different from islet cell types A, B, and D. Moreover, hPP and several other mammalian pancreatic polypeptides have also been localized to an endocrine-type cell different from islet A, B, and D cells. The PP cells are found both in the peripheral part of the islets and scattered throughout the exocrine parenchyma. In man, hPP cells are found in the periphery of islets and also scattered in the exocrine pancreatic parenchyma and in the epithelium of small and medium-sized ducts. In 1976, Gersell and his associates confirmed that hPP cells are located both within and outside of the islets. This chapter explains distribution of pancreatic polypeptide in tissues, radioimmunoassay of hPP, regulation of secretion of hPP in healthy subjects, and hPP in disease states.

Synergistic Effect of Essential Amino Acids and Glucose upon Insulin Secretion in Man

Arginine, leucine, or histidine, and glucose were each administered intravenously, in 30-gm. amounts on separate occasions to the same healthy subjects. Each of the amino acids and glucose in these same amounts were administered also as mixtures. Synergism in the stimulation of the release of insulin was demonstrated when the sum of the increases in plasma insulin which resulted from the separate administrations of an amino acid and glucose was exceeded by that obtained when they were administered as a mixture. A synergistic effect was exerted by each of the three amino acid-glucose combinations; it was greatest with arginine and glucose and least with histidine and glucose. Synergism probably results from the effects of these stimuli upon the pancreatic beta cell; it is not dependent upon humoral gastrointestinal factors released after the ingestion of these nutrients.

Failure of Sulfonylureas to Suppress Plasma Glucagon in Man

Others2 have reported that sulfonylureas suppress the release of glucagon and concluded that this is an important mechanism by which these compounds lower blood glucose. The studies reported here demonstrate the following: 1) oral administration of chlorpropamide for three days or rapid intravenous injection of tolbutamide did not induce a significant change in basal levels of immunoreactive glucagon (IRG) ; 2) intravenous infusion of tolbutamide in saline over thirty minutes did not evoke significant decreases in IRC; 3) tolbutamide added to solutions of arginine or of a mixture of ten amino acids (10-AA) failed to reduce the increases in IRG evoked by the infusion of these amino acid solutions in the absence of tolbutamide; and 4) tolbutamide injected rapidly at the midpoint of infusions of arginine or of 10-AA did not alter the steady rise in IRG induced by these amino acid solutions. In addition, tolbutamide failed to prevent hypoglycemia-induced increases in IRG. These results indicated that in man sulfonylureas do not suppress plasma levels of glucagon and that sulfonylurea-induced decreases in blood glucose are not mediated through suppression of glucagon release.

Synergistic Effect of Certain Amino Acid Pairs upon Insulin Secretion in Man

Individual amino acids were administered intravenously in amounts of 15 gm. and again together with 15 gm. of a second amino acid as 30-gm. mixtures. Synergism in the stimulation of the release of insulin was demonstrated when the sum of the increases in plasma insulin which resulted from the separate infusions of two amino acids was exceeded by that obtained when they were administered as a mixture. A synergistic effect was exerted by arginine and leucine, arginine and phenylalanine, but not by arginine and lysine, arginine and histidine, or by leucine and histidine. Synergism was greater with arginine and leucine than with arginine and phenylalanine. It appears to result from the effects of these amino acid pairs upon the pancreatic beta cell.

Mechanisms and Management of Hyperosmolar Coma Without Ketoacidosis in the Diabetic

The mechanisms involved in the production, maintenance and progression of the state of nonketotic, hyperosmolar coma of mild diabetic patients are discussed; and a method is outlined for both initial therapy (before insulin activity is sufficiently increased) and subsequent therapy. Factors involved in the development of the syndrome include: (1) Persistence of enough insulin production to prevent ketoacidosis but very severe suppression of insulin release in relation to the level of blood glucose. (2) Insidious development of extreme hyperglycemia, increasingly great osmotic diuresis, severe depletion of body water and large volumes of urine. (3) Lack of appropriate response of the thirst center as the sensorium becomes inadequate. Because the mortality of this condition now approaches 50 per cent, careful attention to details of therapy is imperative. Delay in recognition and, therefore, of therapy leads to fatalities.

Glucagon Release Precedes Insulin Release in Response to Common Secretagogues

The dynamics and interrelationships of glucagon and insulin secretion were studied in the isolated perfused rat pancreas by utilizing a series of compounds that stimulate the release of both hormone. Leucine, arginine, prostaglandins F2α and E2, bovine growth hormone, and isoproterenol were administered individually over 60-second intervals. The release of glucagon preceded that of insulin in response to all compounds tested. The rapidity of glucagon release varied in response to different secretagogues; the time course of insulin release was fairly constant. The timing and the magnitude of glucagon and insulin release did not correlate statistically. Conclusions: (1) pancreatic alpha cells respond more rapidly than beta cells to the same stimulus; (2) antecedent release of glucagon is not the principal mediator of insulin release in response to stimuli common to both hormones; and (3) endogenous glucagon may at best modify the release of insulin evoked by certain secretagogues.

Effect of Protein Meals on Plasma Insulin in Mildly Diabetic Patients

We have reported that in mildly diabetic patients increases in plasma insulin are subnormal in response to infused amino acids while others have reported excessive increases in response to ingested protein. Increases in plasma insulin exhibited by nonobese, mildly diabetic patients in response to the ingest ion of protein meals and to the intravenous administration of a mixture of ten essential amino acids were compared to those of healthy nonobese control subjects. The plasma insulin responses to protein meals were also determined in a group of mildly obese, mildly diabetic patients. The results of these studies indicate that: (1) the mean insulin response of nonobese mildly diabetic patients to protein meals is subnormal and not excessive, (2) mildly obese, mildly diabetic patients respond excessively to protein meals as compared to control subjects of normal weight, and (3) the excessiye insulin response to protein meals reported by others to occur in diabetics is probably the result of a greater degree of adiposity in their diabetics than in their control subjects, rather than of the presence of diabetes mellitus. Unless the degree of adiposity is similar in diabetic and healthy subjects, meaningful comparison of their insulin responses to protein meals or other stimuli cannot be made.

Inhibition of Glucagon Secretion by Diazoxide In Vitro

The effect of diazoxide on the secretion of glucagon and insulin was studied using the isolated perfused rat pancreas. The perfusate concentration of D-glucose was kept constant at 5.6 mM. Five secretagogues of both glucagon and insulin—10 mM L-arginine, 5 mM L-leucine, 1.4 μM prostaglandin F2α, 100 nM bovine growth hormone, and 10 mM theophylline—were administered individually in the presence or absence of 325 μM diazoxide. Basal secretion of glucagon or insulin was not discernibly affected by diazoxide. With diazoxide the secretion of glucagon was (a) abolished completely in response to L-arginine or L-leucine; (b) inhibited partially in response to prostaglandin F2α; (c) unaltered in response to growth hormone; and (d) unchanged or, at times, enhanced in response to theophylline. On the other hand, the secretion of insulin induced by each of these agents was inhibited effectively by diazoxide. Conclusions: (a) Diazoxide inhibits the secretion of glucagon as well as insulin in response to certain secretagogues independent of any changes in prevailing levels of glucose, (b) At the concentration tested, diazoxide is a more potent and consistent inhibitor of the release of insulin than of glucagon.

Effect of Chlorpropamide on Basal and Arginine-Stimulated Plasma Levels of Glucagon and Insulin in Diabetic Patients

To ascertain whether chronic administration of a sulfonylurea compound affects plasma levels of glucagon, the effect of chlorpropamide (CP) on plasma glucagon was determined in 17 patients with diabetes mellitus in the basal state and in response to infused arginine. Plasma levels of insulin were measured also. In these patients the increases in plasma levels of glucagon in response to arginine were significantly reduced by prior chlorpropamide administration. Arginine-stimulated levels of insulin were reduced significantly in 10 lean patients.

A search for macroangiopathy in patients with latent diabetes.

Publisher Summary This chapter discusses macroangiopathy in patients with latent diabetes. In an experiment described in the chapter, the results of the initial diagnostic glucose tolerance tests performed on patients aged 9–17 at diagnosis were shown. The results of the highest glucose tolerance tests obtained in these subjects were presented. Plasma levels of insulin for 15 of these patients who were nonobese were also presented. After administration of glucose, the diabetic group exhibited a significantly subnormal increase in plasma insulin. The mean sum of increments in plasma insulin above fasting levels for all six intervals of the test was significantly less than for control subjects. Results of the glucose tolerance tests performed on patients aged 18–25 years at diagnosis were shown. The mean increase in plasma insulin in 21 of these patients who were nonobese was delayed. 17 of these 21 patients had subnormal levels similar to those of younger patients, while 4 showed responses which, although delayed in reaching peak levels, were greater than the mean response of control subjects.