Magnus Pettersson

Neuropeptide Y: intrapancreatic neuronal localization and effects on insulin secretion in the mouse

SummaryThe intrapancreatic localization and the effects on basal and stimulated insulin secretion of neuropeptide Y (NPY) were investigated in the mouse. Immunocyto-chemistry showed NPY to be confined to intrapancreatic nerve fibers mainly associated with blood vessels. Fine varicose NPY fibers were also detected in the exocrine parenchyma and occasionally also within the islets. Double-staining experiments with the use of antisera for both NPY and tyrosine hydroxylase (TH) indicated that most of the NPY fibers were nonadrenergic in nature. Only a population of the NPY fibers occurring around blood vessels showed TH immunoreactivity. Under in vivo conditions, NPY was found to elevate plasma insulin levels slightly when injected intravenously at the high dose level of 8.5 nmol/kg. At lower dose levels, NPY did not affect basal plasma insulin levels, but instead inhibited glucose-induced insulin secretion. Thus, the glucose-induced increment in plasma insulin levels, which was 120±7μU/ml in controls, was reduced to 87 ±5 μU/ml by NPY at 4.25 nmol/kg (p<0.01) and to 98±6μU/ml by NPY at 1.06 nmol/kg (p<0.05). In contrast, the insulin secretory response to the cholinergic agonist carbachol was not affected by NPY. We conclude that NPY nerve fibers occur in the mouse pancreas and that most of these NPY nerve fibers are nonadrenergic. Furthermore, in the mouse, NPY enhances basal plasma insulin levels at high dose levels and inhibits glucose-induced, but not cholinergically induced insulin secretion at lower dose levels under in vivo conditions.

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.

Insulin and glucagon secretion in rats: effects of calcitonin gene-related peptide

Immunoreactive calcitonin gene-related peptide (CGRP) has been shown to occur in intrapancreatic nerves and islet somatostatin cells in the rat. Therefore, we investigated the effects of CGRP on insulin and glucagon secretion in the rat. CGRP was infused i.v. at one of 3 dose levels (4.3, 17 or 68 pmol/min). Infusion of CGRP alone was found to elevate basal plasma levels of both insulin and glucagon. In contrast, CGRP impaired the plasma insulin responses to both glucose (7 mg/min; P less than 0.001) and arginine (8.5 mg/min; P less than 0.001), and inhibited the arginine-induced increase in plasma glucagon concentrations (P less than 0.001). Since CGRP and somatostatin are colocalized within the D-cells, we also infused CGRP and somatostatin together at equimolar dose levels (17 pmol/min), with glucose (7 mg/min). By that, the increase in plasma insulin concentrations decreased more rapidly than during infusion of either peptide alone. Since alpha 2-adrenoceptor activation is known to inhibit glucose-stimulated insulin secretion, we also infused CGRP together with the specific alpha 2-adrenoceptor antagonist yohimbine (37 nmol/min). In that way, the plasma insulin-lowering effect of CGRP was prevented. We have shown in the rat: (1) that CGRP stimulates basal insulin and glucagon secretion; (2) that CGRP inhibits stimulated insulin and glucagon secretion; (3) that CGRP and somatostatin more rapidly induce a potent inhibitory action on glucose-stimulated insulin secretion when given together; and (4) that the alpha 2-adrenoceptor antagonist, yohimbine, counteracts the inhibitory action of CGRP on glucose-stimulated insulin secretion. We suggest that CGRP is of importance for the regulation of insulin and glucagon secretion in the rat. The mechanisms behind the islet effects of CGRP can not be established by the present results, though they apparently require intact alpha 2-adrenoceptors.

Neuropeptide Y and Calcitonin Gene-Related Peptide: Effects on Glucagon and Insulin Secretion in the Mouse

Neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) are both intrapancreatic neuropeptides that are known to inhibit stimulated insulin secretion. In the present study, we examined their influences on basal and stimulated glucagon and insulin secretion in the mouse. Either NPY or CGRP was injected intravenously at two dose levels (0.85 or 4.25 nmol/kg). When injected alone, neither of them did affect basal plasma glucagon levels but CGRP reduced basal plasma insulin levels. Glucagon secretion stimulated by the cholinergic agonist carbachol was modestly inhibited by NPY at 4.25 nmol/kg (P less than 0.01) but not affected by CGRP. In contrast, glucagon secretion stimulated by the beta 2-adrenoceptor agonist terbutaline was markedly inhibited by NPY already at the lower dose level (P less than 0.01) and potentiated by CGRP (P less than 0.01). Insulin secretion stimulated by carbachol was inhibited by CGRP (P less than 0.01) but not affected by NPY, whereas terbutaline-induced insulin secretion was inhibited by both NPY (P less than 0.05) and CGRP (P less than 0.01). We conclude that the two intrapancreatic neuropeptides NPY and CGRP have opposite actions on stimulated glucagon secretion in the mouse: NPY in an inhibitory and CGRP in a potentiatory direction. Both peptides, however, inhibit insulin secretion stimulated by terbutaline.

Calcitonin gene-related peptide (CGRP) and amylin and the endocrine pancreas

ConclusionsTwo newly discovered peptides, CGRP and amylin, have both been demonstrated to occur in the pancreas: CGRP in nerves and endocrine cells and amylin in insulin cells and the islet content of amylin insulin biosynthesis or degradation increase in diabetes. CGRP inhibits stimulated insulin secretion in normal experimental animals and in vitro, whereas amylin seems to lack such an effect, except in one study at a very high dose level. Both peptides seem to counteract the peripheral effects of insulin when investigated in vitro and in vivo. The studies summarized in this review have thus placed CGRP and amylin in the focus of intrapancreatic peptide research. The four main issues to address in further research within this field are now: (1) are CGRP and amylin secreted from the pancreas under normal conditions and in diabetes?, (2) do specific CGRP and/or amylin receptors occur in the islets?, (3) is CGRP involved in the physiological neural regulation of islet hormone secretion?, and (4) are CGRP and amylin involved in the pathogenesis of type 2 diabetes? All these issues offer great challenges to the groups involved not only in studies on effects and mechanisms of intrapancreatic peptides, but also in studies on the basic understanding of diabetes.

Modelling of an electric IR heater at transient and steady state conditions Part I: model and validation

A model for an electric infrared (IR) heater has been developed. The model includes non-grey radiative heat transfer between the different parts of the IR heater, as well as conduction in reflector material and convective cooling of surfaces. The geometry is simplified into one dimension. Using IR module voltage as the only input, the model predicts the temperature of heater components and cooling air, as well as the net radiation heat transfer to the surroundings at steady state and transient conditions. The model has been validated against both steady state and transient experimental results from a small electric IR heater. The model predictions are in good agreement with experimental data both regarding steady state results and the transient response over a wide range of voltages.

Modelling of an electric IR heater at transient and steady state conditions Part II: modelling a paper dryer

A model for an electric infrared (IR) paper dryer has been developed. The model includes non-grey radiative heat transfer between the different parts of the IR heater, as well as conduction in reflector material and convective cooling of surfaces. Such heat transfer calculations are combined with energy balances to provide a system of equations that simulates the behaviour of an electric IR dryer. Using IR module voltage as the only input, the model predicts the temperature of dryer components and cooling air, as well as the net radiation heat transfer to the paper sheet at steady state and transient conditions. The model has been used to investigate trends in efficiency and component temperature with changing voltage and paper grade. Emphasis has been on back reflector temperature and dryer efficiency. Also, the transients during start-up of an IR paper dryer have been investigated. The study indicates that the transients of the back reflector is important for the time needed to reach steady state heat flux at the paper sheet.