Effect of ingested nutrients on the release of thrittene into the human circulation.

Thrittene is a recently described peptide with a sequence homologous with somatostatin-28 ((1-13)) but is produced independent of the preprosomatostatin gene. It is localized in epithelial cells in stomach and gut mucosal crypts and in neuronal cell bodies in the myenteric plexus and enteric axons. It is also present in human plasma.

Thrittene, homologous with somatostatin-28((1-13)), is a novel peptide in mammalian gut and circulation.

Preprosomatostatin is a gene expressed ubiquitously among vertebrates, and at least two duplications of this gene have occurred during evolution. Somatostatin-28 (S-28) and somatostatin-14 (S-14), C-terminal products of prosomatostatin (ProS), are differentially expressed in mammalian neurons, D cells, and enterocytes. One pathway for the generation of S-14 entails the excision of Arg13-Lys14 in S-28, leading to equivalent amounts of S-28((1-12)).

Endogenous somatostatin-28 modulates postprandial insulin secretion. Immunoneutralization studies in baboons.

Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic D cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic B cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14.

Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone released after nutrient ingestion which is known to augment insulin secretion, inhibit glucagon release, and promote insulin-independent glucose disposition. To determine the overall effect of GLP-1 on glucose disposition after a meal we studied a group of healthy, conscious baboons before and after intragastric glucose administration during infusions of saline, and two treatments to eliminate the action of GLP-1: (a) exendin-[9-39] (Ex-9), a peptide receptor antagonist of GLP-1; or (b) an anti-GLP-1 mAb. Fasting concentrations of glucose were higher during infusion of Ex-9 than during saline (4.

Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I.

Glucagon-like peptide I (GLP-I)(7-36) amide is secreted by intestinal L-cells in response to food ingestion. GLP-I is a potent insulin secretagogue and also inhibits glucagon release. In addition, when given to humans in pharmacological amounts, GLP-I increases glucose disposal independent of its effects on islet hormone secretion.

Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse.

Islet amyloid polypeptide (IAPP) is a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. To study the role the inherent amyloidogenicity of human IAPP (hIAPP) plays in the formation of islet amyloid deposits and to investigate a possible hormonal role for IAPP, transgenic mice expressing hIAPP were developed. The transgene was composed of a fragment of an hIAPP cDNA linked to the rat insulin II promoter.

Cholecystokinin is a physiological regulator of gastric acid secretion in man.

CCK8 is a poor stimulant of gastric acid secretion in vivo, but is equipotent to gastrin-17 (G17) in in vitro systems. To further evaluate the role of cholecystokinin (CCK) in regulating acid output in humans, dose-response curves were constructed to CCK8 or G17 (6.4-800 pmol kg-1 per h) with and without a specific CCK-A receptor antagonist (loxiglumide).

Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal.

Glucagon-like peptide 1 [7-36 amide] (GLP-1) has been shown to enhance insulin secretion in healthy and type II diabetic humans, and to increase glucose disposal in type I diabetic patients. To further define its action on glucose kinetics, we studied six healthy subjects who received either GLP-1 (45 pmol/kg per h) or 150 mM saline on two mornings during which a modified intravenous glucose tolerance test was performed. Plasma insulin and glucose levels were analyzed using Bergman's minimal model of glucose kinetics to derive indices of insulin sensitivity (SI) and glucose effectiveness at basal insulin (SG), the latter a measure of glucose disposition independent of changes in insulin.

Circulating somatostatin-28 is not a physiologic regulator of gastric acid production in man.

Studies were designed to establish the acid inhibitory potency and plasma kinetics of somatostatin-28 (S-28) in humans and to determine whether the amount of S-28 released into the circulation after a meal is sufficient to regulate gastric acid secretion. A liquid meal induced a significant increase of S-28 (P < 0.01) whereas S-14 levels did not change.

Somatostatin 28 and coupling of human interdigestive intestinal motility and pancreatic secretion.

To determine the effects of small increases in somatostatin 28 plasma concentrations on human interdigestive gastrointestinal motility and pancreatic secretion, six fasting volunteers were intubated with gastroduodenal multilumen tubes and motility and pancreatic enzyme secretion were measured. Subjects received intravenous NaCl and somatostatin 28 at 11 and 44 pmol.kg-1.

Effect of glyburide and omega 3 fatty acid dietary supplements on glucose and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.

Using a random crossover design, we examined the effects of glyburide for 4 wk on glucose, insulin, lipid, and lipoprotein metabolism in 10 men with non-insulin-dependent diabetes (NIDDM) receiving dietary fish-oil concentrates containing omega 3 (n-3) fatty acids (8 g/d). Compared with glyburide alone, fasting plasma glucose concentrations increased with fish oil. Although glyburide with fish oil decreased fasting glucose concentrations, they did not return to baseline.

Evidence for hormonal inhibition of exocrine pancreatic function by somatostatin 28 in humans.

Somatostatin 28 (S-28), originating in gastrointestinal cells, is secreted into the circulation and increases in humans after ingestion of a mixed meal. To evaluate the possibility that the increased levels of S-28 post cibum might modulate the release of enzymes and bicarbonate from the exocrine pancreas, S-28 was infused intravenously into healthy volunteers to levels seen after food intake. During S-28 infusion, the output of lipase, trypsin, amylase, and bicarbonate stimulated by either exogenous cholecystokinin octapeptide or endogenous signals from intraduodenal administration of tryptophan or a mixture of amino acids was significantly reduced.

Glucose stimulates and potentiates islet amyloid polypeptide secretion by the B-cell.

Islet amyloid polypeptide (IAPP) has been shown to be actively secreted by the pancreatic B-cell along with insulin. To determine whether the modulation of B-cell IAPP secretion is similar to that of insulin, we assessed IAPP release in response to glucose at 4 different concentrations (1.67, 5.

Effect of somatostatin-28 on dynamics of insulin secretion in perfused rat pancreas.

Somatostatin-28 (S-28), originating in gastrointestinal cells, is secreted into the circulatory system and rises in human plasma after ingestion of a mixed meal. Pancreatic beta-cells contain specific, high-affinity receptors for S-28, and it is plausible that this peptide is a physiological modulator of insulin secretion. To evaluate the effects of physiological concentrations of S-28 on glucose-mediated insulin secretion, we used the perfused in situ rat pancreas under two conditions: 1) "square-wave" glucose infusion from 2.

Sequences of islet amyloid polypeptide precursors of an Old World monkey, the pig-tailed macaque (Macaca nemestrina), and the dog (Canis familiaris).

The 37-amino acid islet amyloid polypeptide represents the major protein component present in islet amyloid deposits. Although the presence of islet amyloid is a characteristic pathological feature of the islets of humans, monkeys and cats with Type 2 (non-insulin-dependent) diabetes mellitus, it is not found in the islets of diabetic rats, mice or dogs. To further explore the molecular basis for these species differences in amyloid deposition we have used a polymerase chain reaction based method to clone cDNAs encoding the monkey (Macaca nemestrina) and dog (Canis familiaris) islet amyloid polypeptide precursors.

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans.

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.

Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans.

Somatostatin-14 and somatostatin-28 are biologically active peptides derived from the posttranslational cleavage of prosomatostatin. Because both peptides are found in variable concentrations in the gastrointestinal (GI) tract and pancreas, it has been contended that somatostatin-28 is either an intermediate in the processing to somatostatin-14 or a terminal product derived from prosomatostatin. To address this question, two antisera were used to recognize epitopes in two regions of somatostatin-14; one with high specificity for somatostatin-14 and the other interacting with prosomatostatin, somatostatin-28, and somatostatin-14.

Fasting and postprandial concentrations of somatostatin-28 and somatostatin-14 in type II diabetes in men.

Recent evidence suggests that somatostatin-28 (SRIF-28), cleaved from prosomatostatin by cells of the upper intestine, acts as a nutrient-stimulated inhibitor of insulin secretion in healthy men. A role for SRIF-28 in the pathophysiology of diabetes has not been previously explored, although several groups have measured circulating somatostatinlike immunoreactivity (SLI) in diabetic subjects. To investigate the possible mediation of abnormal insulin secretion in diabetes by SRIF-28, plasma levels were measured in 10 non-insulin-dependent diabetic men and 9 age- and weight-matched control subjects.

Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells.

Islet amyloid polypeptide (IAPP) has been identified as the major constituent of the pancreatic amyloid of non-insulin-dependent diabetes mellitus (NIDDM) and is also present in normal beta-cell secretory granules. To determine whether IAPP is a pancreatic secretory product, we measured the quantity of IAPP-like immunoreactivity (IAPP-LI), insulin, and glucagon released into 5 ml of incubation medium during a 2-h incubation of monolayer cultures (n = 5) of neonatal (3- to 5-day-old) Sprague-Dawley rat pancreases under three conditions: 1.67 mM glucose, 16.

Cholecystokinin does not stimulate prosomatostatin-derived peptides in man.

In man, plasma cholecystokinin (CCK) and somatostatin-28 (S-28) levels increase after ingestion of a mixed meal. Both peptides originate from the gastrointestinal tract. In supra- and periphysiological doses, CCK stimulates the release of somatostatin-14 from in vitro pancreatic islets and gastric cells and increases circulating somatostatin-like immunoreactivity in dogs, leading to the conjecture that CCK regulates somatostatin-like immunoreactivity secretion.

Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans.

The level of somatostatin-28, a bioactive peptide derived from pro-somatostatin in gastrointestinal epithelial cells, increases in human plasma after food intake. To determine if an equivalent response occurs with individual components of a mixed meal, somatostatin-28 and prosomatostatin, somatostatin-14, and somatostatin-13, in combination, were measured in healthy men before and after intake of (a) a mixed meal (715 kcal), (b) carbohydrate (100 g equivalent glucose), (c) protein (22 and 45 g), and (d) fat (25 and 50 g). After the mixed meal, somatostatin-28 levels doubled within 120 min and gradually declined by 4 h.

CGRP stimulates the release of pro-somatostatin-derived peptides from the gastric fundus.

Calcitonin gene-related peptide (CGRP) stimulates release of peptides derived from pro-somatostatin (Pro-S) into the general circulation. The purpose of this investigation was to elucidate the origin and molecular heterogeneity of Pro-S-derived peptides secreted in response to CGRP. Catheters were placed into the vena cava and veins draining the gastric fundus and corpus, antrum, and small intestine of anesthetized pigs.

Effects of glucagonlike peptide I-(7-36) on release of insulin, glucagon, and somatostatin by rat pancreatic islet cell monolayer cultures.

Glucagonlike peptide I (GLP-I-(7-36] is cleaved from proglucagon in ileal epithelial cells and increases in human plasma after nutrient ingestion. This peptide has been shown to stimulate insulin secretion in vitro and in vivo and thus potentially acts as an incretin. To characterize its action on islet cells, the release of insulin, glucagon, and somatostatin by rat pancreatic islet monolayer cultures at varying concentrations of GLP-I-(7-36) was measured.

A physiologic role for somatostatin 28 as a regulator of insulin secretion.

Somatostatin 28 (S-28) is a peptide produced in the intestinal tract which rises in the circulation during nutrient absorption. We tested the hypothesis that S-28 regulates B-cell function by (a) studying the effects on insulin secretion of "physiologic" infusions of S-28 and (b) measuring insulin responses during elevated nutrient-stimulated endogenous S-28 levels. (a) Synthetic S-28 was infused on separate days into six healthy men at rates of 25 and 50 ng/kg per h which mimicked postprandial levels.