Pancreatic hormones, insulin/glucagon molar ratios, and somatostatin as determinants of avian carbohydrate metabolism

The endocrine pancreas of birds contains cell populations similar, if not identical, to those found in mammalian pancreata, although the topographical distributions of these cell types differ to some extent. Insulin-secreting (B) cells, glucagon-secreting (A) cells, somatostatin-secreting (D) cells, and pancreatic polypeptide-secreting (PP or F) cells are distributed unequally among the four pancreatic lobes, with most of the A cells located in the third and splenic lobes and PP cells residing in both islet tissue and in acinar tissue. Glucagon appears to be a (the?) major pancreatic hormone involved in metabolic glucoregulation in birds. Yet the essentiality of insulin for this regulatory purpose also has been established. As a result, current thought is directed toward the molar ratio of insulin to glucagon (I/G) as a dominant force in homeostasis rather than toward either of the two hormones separately. Molar I/G ratios have been useful in mammals in studying the needs of the organism to produce glucose to meet a metabolic crisis/need and, when compared with that found in normal Aves, a value of 1.8-2.2 has been established. Such a molar ratio is indicative of a catabolic recovery of nutrients in mammals, suggesting that birds normally are in a catabolic mode (like diabetic, starving, or exercising mammals). Somatostatin (SRIF) is known to inhibit the release of all pancreatic hormones but has a greater inhibitory action on glucagon secretion than it does on any of the other peptides. (It has least effect on APP).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationships between glucose, insulin and glucagon during fasting in late gestation in the rat

Plasma glucose, insulin and glucagon were measured in pregnant and age-matched virgin rats in the fed state and after fasting 6, 48 or 120 hours during day 16–21 of gestation. The fed state in pregnancy was characterized by a metabolic setting favoring anabolism. The lower plasma glucose in the fed pregnant rats was associated with higher insulin, slightly lower glucagon and higher insulin/glucose and insulin/glucagon ratios than in virgin rats. During fasting, glucose fell to sustained hypoglycemic levels in the pregnant animals whereas glucose declined but did not achieve hypoglycemia at any point in the virgins. Despite the hypoglycemia, greater levels of plasma insulin persisted in the pregnant throughout the 120 hours of fasting and insulin/glucagon ratios did not differ significantly from the euglycemic virgins. Thus, “accelerated starvation” in pregnancy cannot be ascribed to relative glucagon excess. Rather, the preservation of normal insulin/glucagon ratios despite prevailing hypoglycemia, may provide a mechanism during fasting in pregnancy for restraining maternal protein catabolism in the face of the added fuel demands of the conceptus.     

Pancreatic signals controlling food intake; insulin, glucagon and amylin

The control of food intake and body weight by the brain relies upon the detection and integration of signals reflecting energy stores and fluxes, and their interaction with many different inputs related to food palatability and gastrointestinal handling as well as social, emotional, circadian, habitual and other situational factors. This review focuses upon the role of hormones secreted by the endocrine pancreas: hormones, which individually and collectively influence food intake, with an emphasis upon insulin, glucagon and amylin. Insulin and amylin are co-secreted by B-cells and provide a signal that reflects both circulating energy in the form of glucose and stored energy in the form of visceral adipose tissue. Insulin acts directly at the liver to suppress the synthesis and secretion of glucose, and some plasma insulin is transported into the brain and especially the mediobasal hypothalamus where it elicits a net catabolic response, particularly reduced food intake and loss of body weight. Amylin reduces meal size by stimulating neurons in the hindbrain, and there is evidence that amylin additionally functions as an adiposity signal controlling body weight as well as meal size. Glucagon is secreted from A-cells and increases glucose secretion from the liver. Glucagon acts in the liver to reduce meal size, the signal being relayed to the brain via the vagus nerves. To summarize, hormones of the endocrine pancreas are collectively at the crossroads of many aspects of energy homeostasis. Glucagon and amylin act in the short term to reduce meal size, and insulin sensitizes the brain to short-term meal-generated satiety signals; and insulin and perhaps amylin as well act over longer intervals to modulate the amount of fat maintained and defended by the brain. Hormones of the endocrine pancreas interact with receptors at many points along the gut-brain axis, from the liver to the sensory vagus nerve to the hindbrain to the hypothalamus; and their signals are conveyed both neurally and humorally. Finally, their actions include gastrointestinal and metabolic as well as behavioural effects.     

A possible role for somatostatin in depression of insulin and glucagon levels during hemorrhage

The hypothesis that depression of insulin and glucagon levels during rapid, acute hemorrhage is controlled by somatostatin was supported by hormonal changes measured in the cat. By 5 min of hemorrhage to 50 mmHg (1 mmHg = 133.322 Pa) arterial blood pressure, insulin and glucagon were severely depressed and somatostatin levels rose to 232% of basal levels. Insulin and glucagon suppression was maintained for the 30-min period of hemorrhage. Following return of the blood, somatostatin levels remained high and insulin and glucagon suppression was maintained. The data support, but do not prove, the hypothesis.     

Effect of glucagon antiserum on somatostatin,glucagon and insulin release from the isolated perfused rat pancreas

In order to elucidate the effect of glucagon antiserum on the endocrine pancreas, the release of somatostatin, glucagon, and insulin from the isolated perfused rat pancreas was studied following the infusion of arginine both with and without pretreatment by glucagon antiserum. Various concentrations of arginine in the presence of 5.5 mM glucose stimulated both somatostatin and glucagon secretion. However, the responses of somatostatin and glucagon were different at different doses of arginine. The infusion of glucagon antiserum strongly stimulated basal secretion in the perfusate total glucagon (free + antibody bound glucagon) and also enhanced its response to arginine, but free glucagon was undetectable in the perfusate during the infusion. On the other hand, the glucagon antiserum had no significant effect on either insulin or somatostatin secretion. Moreover, electron microscopic study revealed degrannulation and vacuolization in the cytoplasm of the A cells after exposure to glucagon antiserum, suggesting a hypersecretion of glucagon, but no significant change was found in the B cells or the D cells. We conclude that in a single pass perfusion system glucagon antiserum does not affect somatostatin or insulin secretion, although it enhances glucagon secretion.     

Catecholamine-induced changes in plasma glucose, glucagon and insulin in rabbits: effects of somatostatin.

The present study was conducted to determine if glucagon release is involved in the hyperglycemic response to epinephrine and isoproterenol in the fasted and fed, unanesthetized rabbit. Epinephrine produced dose-related increases in plasma glucose and glucagon levels in fed and fasted rabbits whereas isoprotereol produced modest hyperglycemia without hyperglucagonemia. Infusion of somatostatin suppressed epinephrine-induced glucagon release and this was correlated with a 50% reduction in the hyperglycemic response. These data suggest that epinephrine-induced glucagon release is the primary reason for the difference in hyperglycemic activity between epinephrine and isoproterenol in the unanesthetized rabbit.     

Isolation and structural characterization of insulin, glucagon and somatostatin from the turtle, Pseudemys scripta

The chelonians occupy an important position in phylogeny representing a very early branching from the ancestral reptile stock. Hormonal polypeptides in an extract of the pancreas of the red-eared turtle were purified to homogeneity by reversed phase HPLC and their primary structures were determined. Turtle insulin is identical to chicken insulin. Turtle glucagon differs from chicken glucagon by the substitution of a serine by a threonine residue at position 16 and from mammalian glucagon by an additional substitution of an asparagine by a serine residue at position 28. Turtle pancreatic somatostatin is identical to mammalian somatostatin-14. The crocodilians are phylogenetically much closer to the birds than are the chelonians. Alligator insulin, however, contains three amino acid substitutions relative to chicken insulin. Thus, caution is required when inferring phylogenetic relationships based upon a comparison of amino acid sequences of homologous peptides.     

Effects of somatostatin and adrenergic blockade on glucagon, insulin and glucose in exercising sheep

This study was conducted to characterize the mechanisms of hyperglycaemia in exercising sheep. Sheep were run on a treadmill for 45 min (5.5 km h-1, 8% incline) during adrenergic blockade (propranolol or phentolamine mesylate infusions) and during suppression of the rise in glucagon by infusion of somatostatin (SRIF). Propranolol did not alter the glucagon, insulin or glucose responses, except it tended to increase the metabolic clearance of glucose, presumably as a result of blocking the beta-adrenergic inhibition of glucose uptake. Phentolamine mesylate administration was associated with a suppression of the rise in glucagon concentrations, a reversal of alpha-adrenergic inhibition of insulin release and a reduction in glucose appearance during exercise. SRIF prevented the rise in glucagon and reduced insulin concentrations to below resting values. Propranolol and phentolamine mesylate did not alter the glucagon, insulin or glucose response to SRIF. However, SRIF prevented the insulin rise that occurred during phentolamine administration. The increment in glucose appearance produced in response to exercise was the same for SRIF, plus phentolamine mesylate and phentolamine mesylate in the first 25 min of exercise, but was significantly less than in the controls. During the last 20 min of exercise, glucose appearance was not significantly different from the control for any of the groups. The depression by SRIF and alpha-adrenergic blockade of the increment in glucose appearance due to exercise was associated with an impairment of the glucagon response. It appears, therefore, that glucagon may stimulate glucose production early in exercise in sheep directly, as well as by having a permissive effect.     

Effect of obestatin on insulin, glucagon and somatostatin secretion in the perfused rat pancreas

Obestatin is a 23-amino acid peptide derived from preproghrelin, purified from stomach extracts and detected in peripheral plasma. In contrast to ghrelin, obestatin has been reported to inhibit appetite and gastric motility. However, these effects have not been confirmed by some groups. Obestatin was originally proposed to be the ligand for GPR39, a receptor related to the ghrelin receptor subfamily, but this remains controversial. Obestatin and GPR39 are expressed in several tissues, including pancreas. We have investigated the effect of obestatin on islet cell secretion in the perfused rat pancreas. Obestatin, at 10 nM, inhibited glucose-induced insulin secretion, while at 1 nM, it potentiated the insulin response to glucose, arginine and tolbutamide. The potentiated effect of obestatin on glucose-induced insulin output was not observed in the presence of diazoxide, an agent that activates ATP-dependent K(+) channels, thus suggesting that these channels might be sensitive to this peptide. Obestatin failed to significantly modify the glucagon and somatostatin responses to arginine, indicating that its stimulation of insulin output is not mediated by an alpha- or delta-cell paracrine effect. Our results allow us to speculate about a role of obestatin in the control of beta-cell secretion. Furthermore, as an insulinotropic agent, its potential antidiabetic effect may be worthy of investigation.     

Effects of pancreastatin on insulin, glucagon and somatostatin secretion by the perfused rat pancreas

Pancreastatin is a novel peptide, isolated from porcine pancreatic extracts, which has been shown to inhibit glucose-induced insulin release "in vitro". To achieve further insight into the influence of pancreastatin on pancreatic hormone secretion, we have studied the effects of this peptide on unstimulated insulin, glucagon and somatostatin output, as well as on the responses of these hormones to glucose and to tolbutamide in the perfused rat pancreas. Pancreastatin strongly inhibited unstimulated insulin release as well as the insulin responses to glucose and to tolbutamide. It did not significantly affect glucagon or somatostatin output under any of the above-mentioned conditions. These findings suggest that pancreastatin inhibits B-cell secretory activity directly, and not through an A-cell or D-cell paracrine effect.