Pancreastatin inhibits insulin secretion as induced by glucagon, vasoactive intestinal peptide, gastric inhibitory peptide, and 8-cholecystokinin in the perfused rat pancreas

Pancreastatin is a 49-amino acid straight chain molecule isolated from porcine pancreatic extracts. In the perfused rat pancreas, this peptide has been shown to inhibit unstimulated insulin release and the insulin responses to glucose, arginine, and tolbutamide. To further explore the influence of pancreastatin on islet cell secretion, the effect of synthetic porcine pancreastatin (a 2-micrograms priming dose, followed by constant infusion at a concentration of 15.7 nmol/L) was studied on the insulin, glucagon, and somatostatin responses to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), and 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK). The effect of pancreastatin on the insulin and somatostatin secretion elicited by glucagon (20 nmol/L) was also examined. Pancreastatin infusion consistently reduced the insulin responses to VIP, GIP, and 8-CCK without modifying glucagon or somatostatin release. It also inhibited the insulin release but not the somatostatin output induced by glucagon. These observations broaden the spectrum of pancreastatin as an inhibitor of insulin release. The finding that pancreastatin does not alter glucagon or somatostatin secretion supports the concept that it influences the B cell directly, and not through an A cell or D cell paracrine effect.     

Effects of galanin on hormone secretion from the in situ perfused rat pancreas and on glucose production in rat hepatocytes in vitro

Galanin is a novel peptide, widely distributed throughout the central and peripheral nervous system, including nerve endings surrounding the pancreatic islets. In dogs, galanin infusion has been reported to induce hyperglycemia along with a reduction of circulating insulin. In this work, we have studied the effect of galanin (a 200 ng bolus followed by constant infusion at a concentration of 16.8 ng/ml for 22-24 min) on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. In addition, we have investigated the effect of galanin (10 and 100 nM) on glycogenolysis and gluconeogenesis in isolated rat hepatocytes. In the rat pancreas, galanin infusion marked inhibited unstimulated insulin release as well as the insulin responses to glucose (11 mM), tolbutamide (100 mg/liter) and arginine (5 mM). Galanin failed to alter the glucagon and somatostatin responses to glucose, tolbutamide, and arginine. In isolated rat hepatocytes, galanin did not influence glycogenolysis or glucagon phosphorylase a activity. Gluconeogenesis and the hepatocyte concentration of fructose 2,6-bisphosphate were also unaffected by galanin. In conclusion: in the perfused rat pancreas, galanin inhibited insulin secretion without modifying glucagon and somatostatin output, thus pointing to a direct effect of galanin on the B cell; and in rat hepatocytes, galanin did not affect glycogenolysis or gluconeogenesis; hence, the reported hyperglycemia induced by exogenous galanin does not seem to be accounted for by a direct effect of this peptide on hepatic glucose production.     

Effects of galanin on the release of insulin, glucagon and somatostatin from the isolated, perfused dog pancreas

Galanin is a 29 amino acid peptide which has been found in intrapancreatic nerves. The effects of galanin, adrenergic and cholinergic blockade as well as somatostatin on the hormone release from the isolated perfused dog pancreas were studied. It was found that galanin dose-dependently inhibited insulin (P less than 0.001) and somatostatin (P less than 0.001) but not glucagon secretion at normal glucose levels. The lowest galanin concentration that caused a significant suppression of insulin and somatostatin secretion was 10(-11) and 10(-10) mol/l, respectively. Similar effects were evident during stimulation with 2.5 mmol/l arginine. Galanin (10(-9) mol/l) caused a more pronounced inhibition of insulin and somatostatin secretion at high (10 mmol/l) and normal (5 mmol/l) than at low glucose (1.3 mmol/l). In contrast, suppression of the glucagon secretion was only seen at low glucose (1.3 mmol/l). Perfusion of 10(-6) mol/l of atropine, phentolamine and propranolol had no effect on the galanin-mediated (10(-10) mol/l) inhibition of insulin and somatostatin secretion. Galanin (10(-12)-10(-10) mol/l) and somatostatin (10(-12)-10(-10) mol/l) were equipotent in inhibiting insulin secretion whereas only somatostatin exerted a suppression of the glucagon secretion at normal glucose. Thus, galanin exerts a differential effect on islet hormone secretion and may participate in the hormonal control of insulin, glucagon and somatostatin secretion.     

Effects of rat pancreatic polypeptide on islet-cell secretion in the perfused rat pancreas.

Pancreatic polypeptide (PP) secretory cells are abundant in the islets of Langerhans. Results concerning the effects of exogenous PP on islet-cell secretion are controversial. This might be due in part to species specificity, given that most reports refer to studies performed using PP of bovine, porcine, or human origin in a heterologous animal model. Thus, we have investigated the influence of synthetic rat PP (80 nmol/L) on unstimulated insulin, glucagon, and somatostatin release, and on the responses of these hormones to glucose (11 mmol/L) and to arginine (3.5 mmol/L) in a homologous animal model, the perfused rat pancreas. Infusion of rat PP (rPP) reduced unstimulated insulin release by 35% (P = .03), and the insulin responses to glucose by 65% (P = .029) and to arginine by 50% (P = .026), without modifying glucagon output. rPP did not affect somatostatin secretion, either in unstimulated conditions or in the presence of 11 mmol/L glucose. However, it induced a clear-cut increase in somatostatin release during 3.5 mmol/L arginine infusion. Our observation that rPP inhibited insulin secretion without affecting glucagon and somatostatin output points to a direct effect of PP on B-cell function. However, during aminogenic priming of the D cell, the inhibition of insulin output induced by rPP was accompanied by an increase in somatostatin release. Thus, in this circumstance, it might be considered that the blocking effect of PP on B-cell secretion could be, at least in part, mediated by a D-cell paracrine effect.     

Interaction of glucagon-like peptide-1(7-36) amide and gastric inhibitory polypeptide or cholecystokinin on insulin and glucagon secretion from the isolated perfused rat pancreas.

The interaction of three incretin candidates, glucagon-like peptide-1(7-36)amide (t-GLP-1), gastric inhibitory polypeptide (GIP), and sulfated COOH-terminal octapeptide of cholecystokinin (CCK-8-S), on insulin and glucagon release from the isolated perfused rat pancreas was studied. Under the perfusate condition of 8.3 mmol/L glucose, coinfusion of 0.1 nmol/L t-GLP-1 and 0.1 nmol/L GIP resulted in an augmented insulin release greater than that obtained by the same dose of each peptide alone. The degree of stimulation elicited by t-GLP-1 and GIP reached a plateau at 0.3 nmol/L for both infusates, and no cooperative effect was observed by coinfusion at 0.3 nmol/L. Coinfusion of 0.1 nmol/L t-GLP-1 and and 0.1 nmol/L CCK-8-S also resulted in an augmented insulin release greater than that obtained by the same dose of each peptide alone. A similar cooperative effect was observed by coinfusion at 0.3 nmol/L, 1 nmol/L, and 3 nmol/L. With the same perfusion experiments, glucagon release was not significantly affected by any peptide at concentrations of 0.1, 0.3, 1, or 3 nmol/L. The coinfusion of 1 nmol/L t-GLP-1 and GIP elicited a transient, but significant, increase in glucagon release. A similar result was obtained by the coinfusion of 0.3 nmol/L and 3 nmol/L t-GLP-1 and GIP, respectively. The coinfusion of t-GLP-1 and CCK-8-S did not affect the glucagon release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cholecystokinin-33 potentiates and vasoactive intestinal polypeptide inhibits gastric inhibitory polypeptide--induced insulin secretion in the perfused rat pancreas

Gastric inhibitory polypeptide (GIP), cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) stimulate insulin secretion. In this study we investigated whether CCK-33 and VIP could influence the insulinogenic effect of simultaneously administered GIP and 6.7 mmol/l glucose in the perfused rat pancreas. We found that at 0.1 nmol/l, GIP markedly potentiated glucose-induced insulin release whereas CCK-33 and VIP had a weak stimulatory effect and only during the late phase. At this low dose level, CCK-33 potentiated but VIP inhibited the late phase of insulin release stimulated by glucose and GIP. At 1.0 nmol/l, GIP, CCK-33, and VIP markedly potentiated both phases of glucose-induced insulin secretion. At this dose level CCK-33 and GIP exerted additive stimulatory effects on the late phase of insulin release triggered by glucose. In contrast, 1.0 nmol/l VIP inhibited insulin secretion augmented by glucose and GIP. In summary 1) GIP, CCK-33 and VIP all potentiate glucose-induced insulin secretion from the perfused rat pancreas, and 2) CCK-33 potentiates and VIP inhibits GIP-induced insulin secretion. We suggest that interactions of this kind are of importance for the precise regulation of insulin secretion.     

Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat

The effects of gastric inhibitory polypeptide (GIP) on insulin secretion as well as on the intra-islet accumulation of [3H]cyclic AMP were investigated in isolated pancreatic islets of the rat. In the presence of 6.7 mmol/l of glucose, 3.0 and 30 nmol/l of GIP induced both insulin and [3H]cyclic AMP responses, while lower and higher concentrations of the peptide were ineffective. A coupling of the two parameters was also found with regard to interaction between glucose and GIP. Thus while 30 nmol/l of GIP was stimulatory together with 6.7, 16.7 or 33.3 mmol/l of glucose, the peptide stimulated neither insulin release, nor the accumulation of [3H]cyclic AMP in the presence of a low concentration of glucose (3.3 mmol/l). The concomittant release of insulin and somatostatin was studied in the perfused pancreas in order to assess a possible influence by somatostatin on the dose-response pattern for GIP-induced insulin release. In this preparation 1.0 to 10 nmol/l of GIP stimulated insulin and somatostatin secretion; however while these concentrations were equipotent on insulin release, 10 nmol/l of GIP stimulated somatostatin release more than 1 nmol/l, indicating differences in dose-response curves for the GIP-induced stimulation of the two hormones. It is concluded that 1) modulation of GIP-induced insulin release is coupled to changes in cyclc AMP response in the islet, 2) GIP-induced somatostatin secretion may influence the concomittant insulin response.     

Neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), but not galanin, are autonomic cotransmitters in the porcine pancreas.

The neuropeptide galanin has been identified as a potential sympathetic cotransmitter in the canine pancreas. Immunoreactive galanin, also present in nerve fibers of the pig pancreas, was therefore measured in the effluent from isolated perfused pig pancreas with preserved sympathetic (splanchnic) or parasympathetic (vagal) innervation with radioimmunoassays directed against both the N-terminus and the C-terminus of galanin. Electrical vagus stimulation increased the pancreatic exocrine secretion, the secretion of insulin and glucagon, and the release of VIP, but did not influence galanin release. Splanchnic nerve stimulation increased perfusion pressure and glucagon secretion, inhibited insulin secretion, and increased the release of NPY, but galanin release was not affected. We conclude that the pancreatic galanin nerve fibers belong neither to the sympathetic nor to the parasympathetic divisions of the efferent nerve supply to the pig pancreas.     

The interaction of Vasoactive Intestinal Polypeptide (VIP), glucose and arginine on the secretion of insulin,glucagon and somatostatin in the perfused rat pancreas

Summary Vasoactive Intestinal Polypeptide (VIP) increased the release of insulin, glucagon and somatostatin from the perfused rat pancreas. The amount of these hormones released was dependent upon the prevailing glucose concentration. VIP stimulated glucagon release in the absence of glucose, while insulin and somatostatin release were increased by VIP only in the presence of glucose concentrations of 4.4 mmol/l and above. Glucagon secretion stimulated by arginine in the presence of 4.4 mmol/l glucose was potentiated by VIP. In contrast, VIP did not induce any further increase in the secretion of insulin and somatostatin over that stimulated by arginine. At higher concentrations of glucose (6.7, 16.7, and 33.3 mmol/l) VIP continued to stimulate insulin and somatostatin release, this effect being synergistic on early-phase insulin release. The effects of VIP on islet cells thus depend on the levels of modulating nutrients.     

On the nature of the galanin action on the endocrine pancreas: studies with six galanin fragments in the perfused dog pancreas

Galanin, a 29 amino acid peptide, inhibits insulin and somatostatin secretion from the isolated, perfused dog pancreas. To assess the nature of the influences of galanin on the endocrine pancreas, we examined the effects of porcine galanin and six different galanin analogues at the equimolar concentration of 1 nmol/l on the hormone release from the isolated, perfused dog pancreas. It was found that galanin2-29 (by 75 +/- 4%), like the native galanin1-29 (by 90 +/- 3%) potently inhibited insulin secretion (p less than 0.001). In contrast, galanin3-29 did not significantly affect insulin secretion. This indicates that removal of the two N-terminal amino acids markedly reduces the potency of galanin. Also, the replacement of the amino acid number 2 (Trp) by Tyr or Phe was followed by a loss of the insulin lowering effect of galanin at this dose level. Likewise, galanin10-29 had no significant effect on insulin secretion. In contrast, the C-terminally deleted galanin1-15 significantly inhibited insulin secretion (by 24 +/- 5%; p less than 0.01), though with a lower potency than did native galanin (p less than 0.05). Consequently, the C-terminal end of galanin is also of importance for the effect. Somatostatin secretion was inhibited by galanin (p less than 0.001), but not by any of the other investigated peptides. Glucagon secretion was not affected by galanin. It is concluded that the two N-terminal amino acids of galanin are essential for the inhibitory action on the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of exogenous insulin, glucagon, and somatostatin on islet hormone secretion in the perfused chicken pancreas

The effects of exogenous insulin were examined in the isolated perfused chicken pancreas with the duodenum excluded. At low background glucose (50 mg/dl), exogenous insulin infused at a concentration of 20,000 microU/ml elicited clear stimulation of somatostatin secretion while simultaneously inhibiting glucagon release. When the background glucose concentration was elevated to 750 mg/dl, exogenous insulin, had no effect on either somatostatin or glucagon release. When graded doses of exogenous insulin were infused into the chicken pancreas at low background glucose, low concentrations (200 microU/ml) had little effect on somatostatin or glucagon release, but higher concentrations (2000 and 20,000 microU/ml) had clear effects on both somatostatin and glucagon secretion. Glucagon infused at 100 ng/ml stimulated both insulin and somatostatin release. When somatostatin was infused at 25 ng/ml, clear inhibition of glucagon was seen with insulin inhibited to a lesser extent. This study supports the notion of a negative feedback relation between B and D-cells of the pancreatic islets and suggests a paracrine mediation.     

Effects of gastric inhibitory polypeptide, vasoactive intestinal polypeptide and peptide histidine isoleucine on the secretion of hormones by isolated mouse pancreatic islets

The release of insulin, glucagon, somatostatin and pancreatic polypeptide (PP) by isolated mouse pancreatic islets was determined during 30-min incubations at 5.6 and 16.7 mmol glucose/l in the absence and presence of gastric inhibitory polypeptide (GIP), vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) at concentrations of 1-1000 nmol/l. Insulin release was enhanced (greater than 50%) by GIP (100-1000 nmol/l) and VIP (1 mumol/l) at 5.6 mmol glucose/l, but not at 16.7 mmol glucose/l. Glucagon release was increased by GIP (100-1000 nmol/l), and by VIP and PHI (1-1000 nmol/l) at both glucose concentrations in a dose-related manner (maximum increases greater than tenfold). Somatostatin release was similarly increased by GIP (10-1000 nmol/l) at both glucose concentrations. Only the highest concentration (1 mumol/l) of PHI tested increased somatostatin release (twofold) at 5.6 mmol glucose/l, whereas PHI and VIP (1-1000 nmol/l) reduced (greater than 37%) somatostatin release at 16.7 mmol glucose/l. PP release was increased (49-58%) by 100-1000 nmol GIP/l, but was not significantly altered by VIP, and was reduced (39-56%) by PHI. The results indicate that GIP, VIP and PHI each stimulate glucagon release in a dose-related manner, but they exert discretely different effects on other islet hormones depending upon the dose and the prevailing glucose concentration.     

Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetanide) on the endocrine pancreas: studies in vitro

Treatment with thiazide diuretics causes an impairment of the glucose metabolism. To study whether this is due to a direct effect on the endocrine pancreas, the effects of the thiazide hydroflumethiazide on the release of glucagon, insulin, and somatostatin from the isolated perfused pancreas of normal and alloxan diabetic dogs were examined. Hydroflumethiazide at concentrations ranging from 1 to 50 micrograms/mL stimulated the normal secretion of glucagon (P less than 0.001), insulin (P less than 0.001), and somatostatin (P less than 0.001) in a dose-dependent manner. The normal hormone responses evoked by 50 micrograms/mL of the thiazide were, however, modified by the prevailing glucose level: higher insulin (P less than 0.05) and somatostatin (P less than 0.05) and lower glucagon (P less than 0.05) were obtained at the high glucose concentration of 11 mmol/L rather than at the low glucose concentration of 1.3 mmol/L. In alloxan diabetes, insulin secretion was almost extinct and did not respond to hydroflumethiazide, whereas glucagon was dose-dependently stimulated (P less than 0.001). In addition, we looked at the effect of the loop diuretic, bumetanide. The infusion of bumetanide at doses ranging from 0.5 to 3 micrograms/mL did not alter the release of glucagon, insulin, and somatostatin in the presence of 5.5 mmol/L glucose. The results suggest that hydroflumethiazide possesses the ability to directly stimulate A cell secretion in the normal and alloxan diabetic pancreas. Whether this effect is of clinical importance for the diminution in glucose tolerance observed during thiazide therapy remains, however, uncertain.     

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide,inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Aims/hypothesis  The glucose-lowering effect of glucagon-like peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour. Methods  At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. Results  In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0 ± 6.3% (p < 0.004; n = 5; SSTR2 series; each vs pre-infusion level) and to 48.0 ± 2.6% (p < 0.001; n = 6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p < 0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration. Conclusions/interpretation  We conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.     

Comparison of GLP-1 (7-36amide) and GIP on release of somatostatin-like immunoreactivity and insulin from the isolated rat pancreas

The effect of equimolar doses of GIP and GLP-1 (7-36amide) on insulin and somatostatin secretion in the isolated perfused rat pancreas was compared. At a perfusate glucose concentration of 70 mg/dl GLP-1 (7-36amide) 10(-9) and 10(-8) M and GIP 10(-9) M elicited a significant stimulation of insulin while GIP 10(-8) M and lower doses of both peptides (10(-11) and 10(-10) M) were ineffective. At elevated perfusate glucose levels of 150 mg/dl both peptides stimulated insulin release at 10(-11), 10(-10), 10(-9) and 10(-8) M but not at 10(-12) M. The insulin response at the higher glucose level was significantly greater compared to the effect of the same doses at normoglycemic conditions. Somatostatin release was stimulated significantly by GLP-1 (7-36amide) at 10(-10) and 10(-9) M at perfusate glucose level 70 mg/dl. At a glucose concentration of 150 mg/dl this effect was abolished. GIP did not alter somatostatin release at a perfusate glucose concentration of 70 mg/dl while at 150 mg/dl only the highest dose of GIP (10(-8) M) stimulated somatostatin release significantly. In conclusion, the present data demonstrate that in vitro in the rat pancreas both peptides are equally effective secretagogues of insulin release at normal and moderately elevated perfusate glucose levels. In contrast, somatostatin secretion is stimulated by GLP-1 (7-36amide) at normoglycemic conditions while only a rather high and presumably pharmacological dose of GIP is a stimulus of somatostatin secretion at moderate hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of galanin and vagal integrity on insulin release in dogs

In four conscious dogs infusions of glucose (1 g/kg/h) alone or glucose and galanin (2 micrograms/kg/h) were undertaken during cryogenic vagal blockade at -2 degrees C or following atropine (100 micrograms/kg i.v.). When compared to parenteral glucose alone, the addition of galanin substantially elevated plasma glucose and blunted plasma insulin responses. Vagal blockade or atropine failed to alter these effects of galanin on plasma insulin or glucose responses. Moreover, plasma levels of somatostatin, pancreatic glucagon, pancreatic polypeptide, growth hormone, and cortisol were unaffected by galanin infusions. Thus, the inhibition of plasma insulin responses to glucose by galanin is mediated by a nonvagal, noncholinergic mechanism and is independent of changes in either plasma pancreatic glucagon or somatostatin levels. Galanin at the dose employed in the study may have direct and selective actions on the B cell and thus play an important role in the neuromodulation of insulin release.     

Modulation by IBMX, fasting and experimental diabetes of glibenclamide-induced islet hormone release from the perfused rat pancreas

The impact of increased c-AMP levels, short-term fasting as well as experimental diabetes on glibenclamide-induced secretion of somatostatin, insulin and glucagon was studied in the isolated perfused rat pancreas. Dose-response curves revealed that 1 microgram/ml of glibenclamide (in the presence of 3.3 mmol/l of glucose) induced maximal stimulation of insulin and near maximal stimulation of somatostatin release, but did not significantly affect glucagon release. A combination of glibenclamide and the phosphodiesterase inhibitor IBMX synergistically and equally increased both B- and D-cell secretion. Fasting the rats for 24 h significantly suppressed the insulin and glucagon responses to glibenclamide while the concomitant somatostatin response was slightly enhanced. Rats injected with alloxan 3 days prior to perfusion were rendered either moderately diabetic or severely ill with ketoacidosis. Their insulin responses were poor or absent, respectively. In the moderately diabetic rats glibenclamide-induced somatostatin release was blunted while it was abolished in the ketotic rats. The results indicate that glibenclamide-induced B- and D-cell secretion are both modulated by c-AMP, that short-term fasting differentially affects B- and D-cell secretion and that D-cell secretion is inhibited in alloxan diabetes of short duration. It is concluded that the balance of effects by glibenclamide on hormones of the endocrine pancreas may depend on the nutritional and metabolic environment.     

Effects of cholecystokinin (CCK)-8, CCK-33, and gastric inhibitory polypeptide (GIP) on basal and meal-stimulated pancreatic hormone secretion in man.

Gastrointestinal hormones with insulinotropic effects, like cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP) might tentatively be used in the treatment of non-insulin-dependent diabetes mellitus. We therefore examined the effects of intravenous injection of pharmacological dose levels of CCK-8 (100 and 300 pmol/kg), CCK-33 (100 pmol/kg), GIP (100 pmol/kg), and CCK-8 plus GIP (100 pmol/kg of each) on plasma levels of glucose, insulin, somatostatin, glucagon, and pancreatic polypeptide (PP) in healthy human volunteers. The peptides were given under basal conditions or in combination with a mixed meal. CCK-8, CCK-33, and GIP were all found to increase the basal plasma levels of insulin, somatostatin, and PP; the increases were observed already in samples taken at 2 min after the injection. In contrast, the plasma glucagon levels were unaffected by the peptides. CCK-8, CCK-33, and GIP (100 pmol/kg) all potentiated the meal-induced plasma responses of insulin and PP, whereas plasma levels of glucagon after the meal were not affected. Plasma somatostatin levels after the meal were increased by GIP but not affected by CCK-8 or CCK-33. CCK-8 and GIP together (100 pmol/kg for both) increased plasma levels of insulin, PP and somatostatin as much as each of the peptides given alone, both under basal conditions and after the meal intake. Plasma levels of glucagon were not affected by CCK-8 and GIP together. We conclude that in man, both CCK-8, CCK-33, and GIP moderately stimulate basal and meal related insulin release without any synergistic effects and that the peptides do not inhibit the secretion of glucagon.     

Influence of glucagon, gastric inhibitory polypeptide, pancreatic polypeptide and somatostatin on beta-adrenergically induced insulin secretion in the mouse

The effect of four polypeptides, glucagon, Gastric Inhibitory Polypeptide (GIP), Pancreatic Polypeptide (PP) and somatostatin on beta-adrenoceptor stimulated insulin secretion in vivo in the mouse was investigated. The beta-adrenoceptor stimulation was induced by isoprenaline (IPNA). It was found that at dose levels without influence on basal insulin secretion the polypeptides produced the following pattern of interaction with IPNA. Insulin secretion induced by IPNA was increased by glucagon and inhibited by somatostatin. GIP and PP did not change IPNA-induced insulin release. It is concluded from this and earlier published studies that glucagon, but not always GIP, serves as a positive modulator of basal and stimulated insulin secretion, and that somatostatin is a general inhibitor of insulin release. beta-Adrenoceptor-induced insulin secretion however, seems to be less sensitive to somatostatin than insulin release induced by glucose.     

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in ventromedial hypothalamic-lesioned rats

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in rats after ventromedial hypothalamic (VMH) lesions were evaluated by measuring fasting hormone levels and their secretion from the isolated perfused pancreas. Fasting peripheral insulin levels were not altered 1 week after the VMH lesions but became progressively elevated at 3-4, 8-9, and 11-12 weeks compared to the values in sham-operated and age-matched control rats. In the portal vein, insulin levels also progressively increased in VMH-lesioned rats, but the portal-peripheral gradient of insulin in the later phase of VMH obesity was significantly lower than in the early phase after VMH lesions. On the contrary, the arginine-induced insulin release from the perfused pancreas was highest at 1 week and gradually decreased thereafter, although it continued to remain higher than that of controls. The perfusate somatostatin response to arginine also was exaggerated in the VMH-lesioned rats. However, both the peripheral glucagon level and the glucagon secretion from the perfused pancreas of the VMH-lesioned rats were not significantly different from the controls. These results show that VMH lesions result in an increased insulin and somatostatin secretion. Using the cyclically perfused liver in situ, we have found that the hepatic extraction rate of insulin is indeed reduced in rats 8-9 weeks after VMH lesioning, and so have at least partly accounted for the decreased portal-peripheral gradient of insulin in the later VMH postoperative phase.