Islet Peptides Research Articles

Alzheimer's Disease and Non‐Insulin‐Dependent Diabetes Mellitus: Common Features Do Not Make Common Bedfellows

Alzheimer's Disease and Non‐Insulin‐Dependent Diabetes Mellitus: Common Features Do Not Make Common Bedfellows

A role for islet peptide YY in the regulation of insulin secretion.

The authors are grateful to Ms L. Bengtsson and Ms L. Kvist for technical assistance. The study was financially sup ported by The Swedish Medical Research Council (grants no. 14X‐6834 and 12X‐712); The Novo Nordic Founda tion; Swedish Diabetes Association; The Crafoord, Albert Pa~Olsson and Ernhold Lundstro~Dm Foundations and by the Faculty of Medicine, Lund University, Lund, Sweden.

Insulin Promotes Pancreatic Cancer: Evidence for Endocrine Influence on Exocrine Pancreatic Tumors

Type-II diabetes is a risk factor for pancreatic cancer. In addition, diabetic patients present with more advanced tumors and have shortened survival compared to stage-matched counterparts. We hypothesize that the diabetic endocrine milieu, particularly elevated plasma insulin, favors pancreatic cancer growth. This study examines six human pancreatic cancer cell lines for the presence of insulin receptors and the influence of insulin on tumor proliferation. Classical competitive binding assays are performed using [125I]insulin. Cell proliferation assays are conducted over 3 days on cultured cell lines (n= 6 replicates) with increasing concentrations of insulin. Insulin receptors are demonstrated on all six cell lines and dose dependent increases in cell proliferation (15–120% of control) are demonstrated in response to insulin. Patients with type-II diabetes hypersecrete insulin. The presence of high-affinity insulin receptors and dose dependent increases in pancreatic cancer cell proliferation with insulin supports the hypothesis that insulin may be an important tumor growth promoter in diabetes, particularly if paracrine mechanisms are involved. Additional study is required to determine whether other islet peptides altered in diabetes influence tumor growth and whether elevated plasma insulin favors pancreatic cancer induction.

Convulsant EEG patterns and cardiac arrhythmias following central administration of some neuropsychotropic drugs in animals

The influence of essential fatty acid (EFA) deficiency on pancreatic endocrine and exocrine function was studied in 120-day-old rats. The plasma insulin response was determined after in vivo administration of glucose and arginine. The plasma glucagon response was assessed after infusion of arginine. Islet peptides were examined by immunocytochemistry. The exocrine function of pancreas was studied by amylase secretion in isolated pancreatic acinar cells after stimulation with the cholinergic agonist carbacholine chloride. The EFA-deficient (EFAD) rats showed higher basal plasma insulin concentrations and lower basal glucose levels than control rats (P < .01 and P < .01, respectively). The plasma insulin response to glucose was potentiated in the EFAD rats (P < .001). Both insulin and glucagon responses to arginine were normal. The isolated pancreatic acinar cells showed a low basal amylase secretion, but a normal response to carbacholine chloride. There were no overt morphological changes seen in the pancreas and the immunocytochemical staining pattern of insulin, glucagon, somatostatin, and pancreatic polypeptide cells did not differ from controls. The results of the study show that the secretory function of the endocrine and exocrine pancreas is operational in EFA deficiency. The EFA deficiency was accompanied by a basal hyperinsulinemia and hypoglycemia and an exaggerated insulin response to glucose, the pathophysiology of which has to be further studied.

Phenytoin hypothalamic disorders

The influence of essential fatty acid (EFA) deficiency on pancreatic endocrine and exocrine function was studied in 120-day-old rats. The plasma insulin response was determined after in vivo administration of glucose and arginine. The plasma glucagon response was assessed after infusion of arginine. Islet peptides were examined by immunocytochemistry. The exocrine function of pancreas was studied by amylase secretion in isolated pancreatic acinar cells after stimulation with the cholinergic agonist carbacholine chloride. The EFA-deficient (EFAD) rats showed higher basal plasma insulin concentrations and lower basal glucose levels than control rats (P < .01 and P < .01, respectively). The plasma insulin response to glucose was potentiated in the EFAD rats (P < .001). Both insulin and glucagon responses to arginine were normal. The isolated pancreatic acinar cells showed a low basal amylase secretion, but a normal response to carbacholine chloride. There were no overt morphological changes seen in the pancreas and the immunocytochemical staining pattern of insulin, glucagon, somatostatin, and pancreatic polypeptide cells did not differ from controls. The results of the study show that the secretory function of the endocrine and exocrine pancreas is operational in EFA deficiency. The EFA deficiency was accompanied by a basal hyperinsulinemia and hypoglycemia and an exaggerated insulin response to glucose, the pathophysiology of which has to be further studied.

EEG asymmetry and the organization of the mono- and polysemantic context

The influence of essential fatty acid (EFA) deficiency on pancreatic endocrine and exocrine function was studied in 120-day-old rats. The plasma insulin response was determined after in vivo administration of glucose and arginine. The plasma glucagon response was assessed after infusion of arginine. Islet peptides were examined by immunocytochemistry. The exocrine function of pancreas was studied by amylase secretion in isolated pancreatic acinar cells after stimulation with the cholinergic agonist carbacholine chloride. The EFA-deficient (EFAD) rats showed higher basal plasma insulin concentrations and lower basal glucose levels than control rats (P < .01 and P < .01, respectively). The plasma insulin response to glucose was potentiated in the EFAD rats (P < .001). Both insulin and glucagon responses to arginine were normal. The isolated pancreatic acinar cells showed a low basal amylase secretion, but a normal response to carbacholine chloride. There were no overt morphological changes seen in the pancreas and the immunocytochemical staining pattern of insulin, glucagon, somatostatin, and pancreatic polypeptide cells did not differ from controls. The results of the study show that the secretory function of the endocrine and exocrine pancreas is operational in EFA deficiency. The EFA deficiency was accompanied by a basal hyperinsulinemia and hypoglycemia and an exaggerated insulin response to glucose, the pathophysiology of which has to be further studied.

Investigation into the presence of regulatory peptides in rat islets of Langerhans

Investigation into the presence of regulatory peptides in rat islets of Langerhans

Secretory, Biosynthetic, Respiratory, Cationic, and Metabolic Responses of Pancreatic Islets to Palmitate and Oleate

Palmitate and oleate (0.5 to 1.0 mM) caused a time- and concentration-related augmentation of insulin release evoked by D-glucose (6.0 to 16.7 mM) in rat isolated pancreatic islets. This contrasted with an inhibitory action of the fatty acids upon L-[4-3H]phenylalanine incorporation into TCA-precipitable material, but coincided with an increased biosynthesis of proinsulin relative to that of other islet peptides. The failure of palmitate to cause an immediate increase in insulin output at a low glucose concentration (6.0 mM) coincided with an unchanged rate of O2 uptake over a 10- to 15-min exposure to this fatty acid. Over prolonged incubation (90 min), however, both palmitate and oleate (1.0 mM) stimulated 45Ca net uptake by islets exposed to 6.0 mM D-glucose. Like their insulinotropic effect, the time course for the oxidation of [U-14C]palmitate and [U-14C]oleate was characterized by a progressive buildup in 14CO2 production rate. Moreover, palmitate and oleate decreased D-[5-3H]glucose conversion to 3HOH and D-[U-14C]glucose conversion to radioactive acidic metabolites over short (30 min) but not prolonged (120 min) incubation periods. The two fatty acids also interfered with the generation of 14CO2 from islets prelabeled with [U-14C]palmitate, but not L-[U-14C]glutamine. It is concluded that, at least during prolonged exposure to either palmitate or oleate, the secretory, cationic, and metabolic response to these fatty acids displays features comparable to those usually found in islets stimulated by nutrient secretagogues.

Expression of two proopiomelanocortin mRNAs in the islets of Langerhans of neonatal rats.

Proopiomelanocortin-(POMC) derived peptides have been found in pituitary and in nonpituitary tissues including the endocrine pancreas. However, only a truncated 800-base POMC-like mRNA is demonstrable in most nonpituitary tissues. The functional relevance of this RNA is doubtful, because it lacks the sequences of translation initiation and signal peptide (exon 1 and 2). Recently we have demonstrated the truncated POMC-like mRNA in pancreatic islets. Using PCR techniques in this paper we prove the existence of a full-length POMC mRNA in this tissue. This RNA contains the sequences of exon 1 and 2, as shown by Southern blot technique and by sequencing parts of the PCR products. We suppose that this RNA is the source of the POMC peptides in islets despite of its small amount.

Pancreatic function in the essential fatty acid deficient rat

The influence of essential fatty acid (EFA) deficiency on pancreatic endocrine and exocrine function was studied in 120-day-old rats. The plasma insulin response was determined after in vivo administration of glucose and arginine. The plasma glucagon response was assessed after infusion of arginine. Islet peptides were examined by immunocytochemistry. The exocrine function of pancreas was studied by amylase secretion in isolated pancreatic acinar cells after stimulation with the cholinergic agonist carbacholine chloride. The EFA-deficient (EFAD) rats showed higher basal plasma insulin concentrations and lower basal glucose levels than control rats ( P < .01 and P < .01, respectively). The plasma insulin response to glucose was potentiated in the EFAD rats ( P < .001). Both insulin and glucagon responses to arginine were normal. The isolated pancreatic acinar cells showed a low basal amylase secretion, but a normal response to carbacholine chloride. There were no overt morphological changes seen in the pancreas and the immunocytochemical staining pattern of insulin, glucagon, somatostatin, and pancreatic polypeptide cells did not differ from controls. The results of the study show that the secretory function of the endocrine and exocrine pancreas is operational in EFA deficiency. The EFA deficiency was accompanied by a basal hyperinsulinemia and hypoglycemia and an exaggerated insulin response to glucose, the pathophysiology of which has to be further studied.

Effects of islet hormones on amylase secretion and localization of somatostatin binding sites

The interaction of insulin and somatostatin on amylase secretion was examined in the isolated perfused rat pancreas. Exogenous insulin (10 mU/ml) significantly potentiated cholecystokinin- (CCK; 0.5 mU/ml) stimulated amylase secretion (12.47 +/- 2.9 micrograms/ml, n = 7). Glucose (16.7 mM) stimulated endogenous insulin secretion (523 +/- 66 microU/ml) and also significantly enhanced CCK-stimulated amylase secretion (13.41 +/- 2.8 micrograms/ml, n = 11). When somatostatin was included in the perfusion media, containing insulin and CCK, amylase secretion was reduced to 3.17 +/- 0.83 micrograms/ml (n = 7), a level comparable to that of CCK-stimulated amylase secretion alone. Similarly, addition of exogenous somatostatin to perfusion media, containing 16.7 mM glucose and CCK, reduced amylase secretion to 4.29 +/- 1.09 micrograms/ml (n = 9). The effect of somatostatin and insulin on carbamylcholine-stimulated amylase secretion was also examined. Exogenous insulin (50 mU/ml) potentiated carbamylcholine- (10(-8) M) stimulated amylase secretion, and addition of exogenous somatostatin to the media containing both insulin and carbamylcholine suppressed the insulin potentiation. Uptake of 125I-[Tyr11]somatostatin in the perfused pancreas was saturable as it decreased significantly with the addition of excess unlabeled somatostatin. Autoradiograms revealed uptake of the ligand by both the endocrine islets and the exocrine pancreas with the highest density of grains observed over the acini. These results support the hypothesis that islet peptides modulate the exocrine pancreas, that somatostatin inhibits amylase secretion by inhibiting the action of insulin, and that somatostatin may act directly on the exocrine pancreas via specific receptors on acinar cells.

Radioimmunoassay for Rat Pancreatic a-Amylase and the Effect of Phe-Met-Arg-Phe-Amide on Amylase Secretion in the Isolated Perfused Rat Pancreas

In this study a radioimmunoassay was developed to measure secreted amylase from the isolated perfused rat pancreas. Using Sephadex G-75 gel chromatography, rat pancreatic amylase was purified to a single migrating protein band as determined by SDS polyacrylamide gel electrophoresis. Specificity of a rat pancreatic amylase antiserum, raised in rabbits, was determined using immunodiffusion, immunoelectrophoresis, and immunoblotting techniques. Secreted amylase concentrations, obtained using the radioimmunoassay, were not significantly different than those measured with the amylase enzyme assay. The rat pancreatic amylase radioimmunoassay was used to measure the amylase secretion in the isolated perfused rat pancreas. Phe-Met-Arg-Phe-amide (FMRF-NH2) immunoreactivity has been shown to be co-localized with pancreatic polypeptide in the rat pancreatic islet, and evidence suggests that islet peptides modulate amylase secretion from the exocrine pancreas. In the present study, FMRF-NH2 significantly (p less than 0.05) suppressed cholecystokinin (CCK)-stimulated amylase secretion by 55%. The average pancreatic amylase secretion in response to CCK was 10.89 +/- 2.0 micrograms/ml/min (n = 6); with the addition of FMRF-NH2, CCK-stimulated amylase secretion was reduced to 4.79 +/- 1.6 micrograms/ml/min (n = 6). These results are consistent with the insuloacinar hypothesis in that an FMRF-NH2-like substance in the islet may act to modulate the exocrine pancreas.

Heterogeneities of the islets in the rabbit pancreas and the problem of "paracrine" regulation of islet cells.

In addition to "external" signals conveyed by the circulation or the nervous system, the pancreatic islets obviously are regulated also by "internal" (intra-islet) signals, e.g. by the islet hormones: insulin (B-), glucagon (A-), and somatostatin (D-) cells are able to affect the secretion of the heterologous cell types. It is, however, unclear whether this functional cooperation between islet cells occurs by an intercellular route (paracrinia sensu strictore), by intra-islet "portal" vessels, or by the systemic circulation. These likely interactions are limited by islet anatomy. To identify the anatomical basis for the mutual functional relationships between the islet cells, islets of Langerhans in the rabbit pancreas were completely analyzed in immunostained serial semithin (0.5 micron) sections. The islets were found to be largely heterogenous. They were classified in three basic types: a) polycellular islets, composed of all established endocrine cells, and including two subtypes of islets, b) bicellular islets, containing only B- and A-cells or B- and D-cells, and c) monocellular islets, exclusively made up of B-cells. Concerning the modes of paracrine regulation of islet cells, the findings suggest primarily an endocrinous route of transport of the islet peptides to heterologous endocrine cells. The corresponding functional cooperation between islet cells probably is mediated rather by the systemic circulation than by intra-islet portal vessels.

The amino-acid sequences of sculpin islet somatostatin-28 and peptide YY

Two pancreatic peptides, somatostatin-28 and peptide YY, have been isolated from the Brockmann bodies of the teleost fish Cottus scorpius (daddy sculpin). Following purification by reverse-phase HPLC, each peptide was sequenced completely through to the carboxyl-terminus by gas-phase Edman degradation. Somatostatin-28 was the major form of somatostatin detected and is similar to the gene II product from angler-fish. Peptide YY (36 amino acids) more closely resembles porcine neuropeptide YY and intestinal peptide YY than it does the pancreatic polypeptides.

Opioid peptides in rat islets of Langerhans. Immunoreactive met- and leu-enkephalins and BAM-22P

Opioid peptides in rat islets of Langerhans. Immunoreactive met- and leu-enkephalins and BAM-22P

Opioid peptides in rat islets of Langerhans. Immunoreactive met- and leu-enkephalins and BAM-22P.

Previous studies have shown that met- and leu-enkephalins are present in extracts of whole pancreas obtained from guinea pigs and human cadavers. The present studies demonstrate that immunoreactive methionine (met)- and leucine (leu)-enkephalins present in rat pancreas are localized in islets of Langerhans. Immunohistochemical staining of fixed, whole pancreas indicated that only islet endocrine cells were heavily stained when any of four different met- and leu-enkephalin-directed antisera or an anti-BAM-22P (bovine adrenal medulla docosapeptide) antiserum was used. The peptides were characterized by a combination of gel-filtration chromatography, high-performance liquid chromatography (HPLC), and specific radioimmunoassay. Free met-enkephalin content in extracts of rat islets was 90-fold enriched over content in extracts of whole pancreas (1.72 +/- 0.35 versus 0.019 +/- 0.007 pmol/mg protein). Treatment with trypsin and carboxy-peptidase-B of high-molecular-weight peptides extracted from pancreas or islets resulted in release of additional met-enkephalin immunoreactivity, which was 39-fold enriched in islets compared with pancreas (5.90 +/- 0.58 and 0.153 +/- 0.032 pmol/mg protein, respectively). Total islet content (per milligram protein) of met-enkephalin-containing peptides was similar to that reported elsewhere for bovine hypothalamus. The immunohistochemical data as well as the enrichment of extractable enkephalins in islets compared with whole pancreas indicate that essentially all the met-enkephalin present in pancreas is localized in islets, while the presence of BAM-22P immunoreactivity in islets is consistent with biosynthesis of enkephalins in islet cells via a preprohormone, such as that described in the bovine adrenal medulla and rat brain.

Transglutaminase and cellular motile events: Retardation of proinsulin conversion by glycine methylester

Glycine methyl ester, an inhibitor of transglutaminase, decreased glucose-stimulated insulin release and delayed proinsulin conversion in rat pancreatic islets pulse-labelled with L-[4-3H]phenylalanine. Sarcosine methyl ester, which does not inhibit transglutaminase activity, failed to affect insulin release and proinsulin conversion. The incorporation of L-[4-3H]phenylalanine into islet peptides, the ratio of hormonal to total tritiated peptides and the insulin content of the islets failed to be affected by either of these methyl esters. It is proposed that transglutaminase participates in the control of motile events involved in both the transfer of proinsulin from its site of synthesis to its site of conversion, and the translocation of insulin from its site of storage to its site of release.

Pancreatic islet hormone response to oral glucose in morbidly obese patients.

Pancreatic islet peptides, as well as other gastrointestinal hormones, have been implicated in both the pathogenesis of obesity and the etiology of associated metabolic derangements. This study evaluated the pancreatic islet and gastrointestinal (GI) hormone response to oral glucose in 20 morbidly obese (151% above ideal body weight) patients. Glucose intolerance, hyperinsulinism, and exaggerated gastric inhibitory polypeptide (GIP) release occurred following glucose ingestion. Significant release of PP occurred in 14 patients, while only six patients had release of somatostatin. No significant changes in plasma concentrations of glucagon occurred. Since GIP is insulinotropic in the presence of hyperglycemia, the hyperinsulinism of morbid obesity may be secondary to the abnormally high glucose-stimulated GIP levels in these patients. Failure of glucagon suppression in response to oral glucose many contribute to the hyperglycemia noted. Somatostatin and pancreatic polypeptide may be responsible for some of the metabolic derangements of morbid obesity.

Pancreatic peptides regulate C1− secretion in the marine teleost gill

Hormonal regulation of the ionoregulatory function of the branchial epithelium in marine teleosts has been investigated using an isolated gill preparation of the seawater-adapted flounder Platichthys flesus. Agents which are assumed to elevate the effective intracellular concentration of cyclic AMP caused a stimulation of C1− secretion as determined by measurement of the transepithelial electrical potential difference in the isolated gill. The pancreatic endocrine glucagon may act as an endogenous regulator of ion excretion in the gill as this peptide stimulated the transepithelial potential. Another islet peptide, somatostatin, inhibited branchial electrogenic ion transport. Attempts to investigate the mode of action of these peptides by measuring cyclic AMP levels in isolated gills were unsuccessful, since it appears that the pool of cyclic nucleotide which specifies the epithelial C1− transport rate is small compared to total cyclic AMP content. A second approach investigating the ability of somatostatin to inhibit the transepithelial potential in gills stimulated by different secretagogues suggested dual modes of action for this peptide.

On the contamination of commercially available aprotinins with pancreatic islet peptides

On the contamination of commercially available aprotinins with pancreatic islet peptides