Abstract. 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.
E. Sandberg, B. Ahrén, D. Tendler and S. Efendic
P. De Moor, O. Steeno and A. Hendrikx
Clinical and biochemical studies have been made on sixty-one untreated patients with a low cortisol binding capacity (C. B. C.), as determined by a gel filtration technique, and no hypoproteinaemia or dysproteinaemia. Characteristic signs and symptoms were found. In the female group, obesity (65 per cent) sometimes suggesting Cushing's disease, diabetes or prediabctes (59 per cent), menstrual disturbances (55 per cent) and hypertension (46 per cent) were the most conspicuous findings. In adult men, diabetes or prediabetes (62 per cent), obesity (29 per cent) and hypertension (29 per cent) were noted. Twelve out of sixteen boys with an unexplained low C. B. C. had disorders of adolescent development, i. e. gynaecomastia (56 per cent), »pseudo-Froehlich« syndrome (44 per cent) and cryptorchidy (20 per cent).
In women, the urinary 17-ketosteroids and glucocorticoids were elevated, though the latter values were only slightly above normal; there was a negative and significant correlation between 17,21-dihydroxy-20-ketosteroids and 17-hydroxy-corticoids. In the group of male adults, an increase of urinary glucocorticoids was observed, whereas the excretion of 17-ketosteroids was normal. Both groups showed rather low 8 a. m. unconjugated plasma corticoid levels.
The low cortisol binding capacity in these patients was found to be independent of adrenocortical function, excess of weight, or technical artefacts. The response to oestrogens (endogenous or exogenous) was clearly defective.
Whether the low plasma cortisol binding capacity itself is the cause of the clinical and biochemical findings observed in these patients, remains to be elucidated.
B. Enk, B. Lund, A. Schmidt and T. Deckert
Intravenous injection of the gastro-intestinal hormone secretin elicits an increase in the insulin concentration in the cubital vein.
In 10 normal weight non-diabetics and 10 obese non-diabetics the latter group gave a hypernormal insulin response.
By the simultaneous determination of the insulin concentration in the cubital and portal veins and also by an investigation of 2 pancreatectomized patients, it was demonstrated that an increase in the cubital insulin concentration following intravenous injection of secretin was due to an altered secretion from the pancreas and not to an altered elimination of insulin.
Abstract. 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 < 0.001) and somatostatin (P < 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 10−11and 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.
RA Silvestre, EM Egido, R Hernandez, J Leprince, D Chatenet, H Tollemer, N Chartrel, H Vaudry and J Marco
OBJECTIVE: Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts. METHODS: The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA. RESULTS: Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC(50): 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr(6)]UII(4-11). In contrast, [Ala(8)]UII(4-11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII. CONCLUSIONS: Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only [3-iodo-Tyr(6)]UII(4-11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.
M Kawaguchi, K Koshimura, M Sohmiya, Y Murakami, T Gonda and Y Kato
OBJECTIVE: Recently we reported that insulin treatment improved hypertension by inducing nitric oxide synthase (NOS) in Zucker diabetic fatty (ZDF) rats. In the present study, we investigated subtypes of NOS induced by insulin in arteries in various organs of ZDF rats using immunohistochemistry. DESIGN: Following treatment with insulin, localization of two subtypes of NOS in the arterial tissues of various organs was identified. METHODS: Following 4 weeks of s.c. injection of insulin, the aorta, cerebral cortex, pancreas and kidney were stained with polyclonal anti-endothelial NOS (eNOS) or anti-inducible NOS (iNOS) antibodies. RESULTS: In the aortic tissue, eNOS-like immunostaining was observed equally in the insulin-treated group and the control group, whereas iNOS-like immunostaining was present more densely in the insulin-treated group. In the cerebral artery, eNOS-like immunostaining was observed in the endothelium and was enhanced in the insulin-treated group. In the control group, iNOS-like immunostaining was absent in the cerebral artery, whereas immunostaining was densely observed in the insulin-treated group. In the interlobular artery of the pancreas, both eNOS-like and iNOS-like immunostaining was present in the control group and was enhanced in the insulin-treated group. In kidney, both eNOS-like and iNOS-like immunostaining was more densely present in the arterial tissue of the insulin-treated group. CONCLUSIONS: These results taken together suggest that insulin treatment induced NOS in arteries in various organs and that iNOS was more strongly induced than eNOS by insulin treatment in the ZDF rat.
Yoshimasa Tasaka, Sachiko Inoue, Koji Marumo and Yukimasa Hirata
Abstract. The plasma responses of pancreatic polypeptide (PP), glucagon (IRG) and insulin (IRI) after administration of beef soup were studied in normal and alloxan diabetic dogs kept in a poor metabolic state for 4 weeks, and their regional levels in the pancreas were determined and compared at the uncinate process, head, body and tail. The plasma PP levels of the diabetic dogs were significantly higher than those of the normal dogs and they increased after beef soup administration in both groups. The plasma IRG levels did not change significantly after beef soup administration in either group, but significantly high levels were found in the diabetic dogs. The IRI content in the normal dog pancreas was highest at the tail, followed in order by the body, head and uncinate process, and was decreased to about one-tenth to one-fortieth in the alloxan diabetic dogs. On the other hand, the amounts of PP in the pancreas of both normal and diabetic dogs were greatest at the uncinate process, followed in order by the head, body and tail. In an inverse relationship with the PP findings, the IRG content in the pancreas was highest at the tail and lowest at the uncinate process in both kinds of dogs. The differences in both PP and IRG between diabetic and normal dogs were generally not significant. These results show that irrespective of the high plasma levels of PP and IRG in the diabetic dogs, their levels in the pancreas did not change significantly.
Seiki Ito, Satoko Isemura, Eiichi Saitoh, Kazuo Sanada, Toshimitsu Suzuki and Akira Shibata
Abstract. Antisera against proline rich peptide P-C, recently isolated from human whole saliva were raised in rabbits by injections of peptide P-C-BSA conjugates. Immunohistochemical study using the antisera was carried out on human salivary glands, gut and pancreas. The results showed that peptide P-C like immunoreactivity was present not only in the salivary glands but also in the pancreatic islets, though not in the gut. Furthermore, immunostaining of adjacent thin sections revealed that cells reacting with antisera against peptide P-C were identical to those reacting with insulin antisera. As the antisera against peptide P-C did not have any cross-reactivities to insulin, glucagon, somatostatin, pancreatic polypeptide, VIP and human C-peptide, the antisera were considered to recognize specifically either peptide P-C related antigen or peptide P-C itself in human pancreatic B-cells. A novel substance, peptide P-C like immunoreactivity, may be present in pancreatic B-cells independent of pro-insulin and insulin.
Morphological similarity between the salivary glands and the pancreas has been reported, and amylase, kallikrein and glucagon are present in both. These findings seem to suggest some functional relation between the pancreas and salivary glands. Detection of peptide P-C like immunoreactivity in the pancreas and salivary glands would be a additional support for this idea. Although it is suggested that peptide P-C like immunoreactivity in pancreatic B-cells may play some role in the function of B-cells, its exact pathophysiological role remains obscure.
EM Egido, J Rodriguez-Gallardo, RA Silvestre and J Marco
OBJECTIVE: Ghrelin is a 28 amino acid residue peptide identified in both human and rat stomach and which acts as an endogenous ligand for the GH secretagogue receptor (GHS-R) and stimulates GH release. GHS-Rs are expressed in a number of tissues, including the pancreas, and ghrelin-like immunoreactivity is present in peripheral plasma, where its levels increase during fasting and decrease after food intake. The relationship between nutritional status and circulating ghrelin concentrations prompted us to investigate the effect of this peptide on pancreatic hormone secretion. METHODS: The study was performed in the isolated rat pancreas perfused in situ. Insulin, glucagon and somatostatin were measured by radioimmunoassay. RESULTS: Addition of 10 nM ghrelin to the perfusate significantly reduced the insulin response to the secretagogues glucose, arginine and carbachol, which act on the B-cell via different mechanisms, as well as the somatostatin response to arginine. Ghrelin was without effect on the glucagon output induced by this amino acid. At a lower concentration (2 nM) ghrelin was also found to inhibit glucose-induced insulin release. CONCLUSION: These findings support the proposal that the inhibitory effect of ghrelin on insulin release constitutes a tonic regulation of the B-cell, contributing to restrain its secretory activity in the state of food deprivation. On the other hand, the inhibition of pancreatic somatostatin release by ghrelin suggests a blocking effect of this hormone on the widely distributed D-cell population.
S. Lenzen and H. Kücking
Both l-thyroxine and d-thyroxine induced an inhibition of glucose-induced insulin secretion with comparable time- and dose-dependent characteristics. l-thyroxine was ten times more potent than d-thyroxine. While l-thyroxine and a ten times higher dose of d-thyroxine had a similar potency in inducing hyperthermia and hypocholesterolaemia, hyperglycaemia in response to d-thyroxine was less pronounced than in response to l-thyroxine. This difference may be explained by a greater depletion of liver glycogen stores and consequently more limited capacity for provision of glucose for the circulation. The results support the view that the differences between l-thyroxine and d-thyroxine are quantitative. Adrenergic contribution to l-thyroxineand d-thyroxine-induced inhibition of insulin secretion by rat pancreas is apparently of minor importance. Treatment of the rats with propranolol as well as with reserpine or 6-hydroxydopamine did not alleviate l-thyroxine- or d-thyroxine-induced inhibition of insulin secretion by rat pancreas.