Effect of naloxone on pancreatic and gastric endocrine function in response to carbohydrate and fat-rich test meals

The present study was designed to determine the effect of naloxone, a specific opiate receptor antagonist, on postprandial levels of insulin, glucagon, pancreatic polypeptide (PP), somatostatin-like immunoreactivity (SLI) and gastrin in response to carbohydrate and fat-rich test meals in a group of 6 healthy volunteers. The addition of naloxone to a meal consisting of 50 g sucrose dissolved in 200 ml water augmented the rise of plasma insulin levels significantly during the first 30 min after its ingestion and reduced the decrease of plasma glucagon. During the ingestion of a fat-rich meal in form of 200 ml cream naloxone reduced the rise in plasma insulin and pancreatic polypeptide and elevated glucagon levels during the last 30 min of the experimental period. When sucrose was dissolved in 200 ml cream the addition of naloxone augmented the postprandial rise of insulin levels between 15 and 60 min after ingestion of the meal and elicited an increase of plasma SLI and PP levels throughout the entire experimental period which indicates that post-prandial levels of insulin, glucagon, PP and SLI are modulated via endogenous opiate receptors during the ingestion of carbohydrate and fat test meals and that this effect depends on the composition of the ingested nutrients. These data raise the possibility that endogenous opiates participate in the regulation of postprandial insulin, glucagon, somatostatin and pancreatic polypeptide release not only in certain disease states as demonstrated recently for insulin secretion in type II diabetes mellitus but endogenous opiates may also be of importance under physiological conditions.     

Oral administration of somatostatin reduces postprandial plasma triglycerides, gastrin and gut glucagon-like immunoreactivity.

The present study was designed to determine if orally administered somatostatin can reduce the postprandial rise in plasma triglycerides, gastrin, gut glucagon-like immunoreactivity (GLI) and the pancreatic hormones insulin and glucagon. Ten overnight fasted dogs were fed a fat-protein meal with or without 2 mg synthetic somatostatin, followed by another 2 mg somatostatin 90 min later. After the meal with somatostatin, postprandial plasma triglyceride levels were significantly lower for 5 hours, GLI levels for 3.5 hours and gastrin levels for 1 hour compared to the controls. Plasma insulin, glucagon and somatostatin-like immunoreactivity was not different from the control experiments. It is concluded that orally administered somatostatin lowers the postprandial levels of triglycerides, GLI and gastrin in dogs. This may have therapeutic implications for the management of gastrointestinal and metabolic disorders.     

Metabolic and hormonal effects of test meals with various protein contents in pigs

The postprandial release of immunoreactive insulin, glucagon, gastrin, somatostatin, pancreatic polypeptide (PP), and gastric inhibitory polypeptide (GIP) was studied in parallel with the absorption of sugars and amino acids in conscious pigs. Six pigs fitted with permanent catheters in the portal vein and arterial blood system as well as within an electromagnetic flow probe around the portal vein received successively at 3-day intervals, three meals of 800 g each containing 0, 14, or 28% protein (semisynthetic diets based on fish protein). Blood samples were collected and portal blood flow was recorded during a postprandial period of 8 h. For the same level of feed intake, an increase in the dietary protein concentration led to a higher alpha-amino nitrogen absorption and to a lower appearance of reducing sugars in the portal vein; in addition, the carbohydrate absorption efficiency (amounts absorbed as a percentage of amounts ingested) was reduced, showing the competition between the absorption of amino acids and glucose. The largest absorption occurred during the first 4 h after the meal, but neither the digestion of proteins nor that of carbohydrates were finished 8 h after the meal since portoarterial differences could still be observed. All test meals induced a rise of portal and peripheral concentrations of insulin, gastrin, somatostatin, and PP, and of the systemic level of GIP. Glucagon increased after the 28% protein meal only. The rise of plasma insulin paralleled that of blood glucose, and bore a significant positive relationship to the systemic GIP level in the early postprandial period. In terms of absolute amounts, portoarterial concentration gradients increased postprandially. Insulin release was significantly the highest after intake of the 14% protein diet. The gastrin response was significantly correlated to the amount of protein. Similarly the release of glucagon and somatostatin tended to increase with increasing dietary amount, but differences failed to reach significance (P less than 0.05), except for glucagon 2 h after the meal. There were very close relationships between the hourly amounts of alpha-amino nitrogen absorbed and gastrin and glucagon production, as between insulin and PP secretions. From the present results, the induction of physiological increments of plasma peptide concentration in 60-kg pigs would require infusion rates of about 50-250 micrograms/h for insulin, 1-4 micrograms/h for gastrin 17, 5-10 micrograms/h for glucagon and somatostatin, and 5-50 micrograms/h for PP.     

Increased sensitivity to somatostatin in obese Zucker rats

The release of somatostatin from the pancreas and stomach following the ingestion of a meal and its increase in the peripheral circulation elicits an attenuation of postprandial hormone secretion such as insulin, pancreatic polypeptide and gastrin and retards the rate at which nutrients enter the circulation. Reduced tissue somatostatin content and/or an attenuated somatostatin release is associated with hyperinsulinism and obesity in certain animal models. In the obese Zucker rat, however, tissue somatostatin levels are increased and therefore the present study was designed to determine the effect of synthetic somatostatin on basal and postprandial arterial insulin levels in obese and lean Zucker rats. Synthetic somatostatin was infused at doses of 0.25, 0.5, 1 and 5 ng/kg X min before and after the intragastric instillation of a liver extract/sucrose test meal. In the obese rats somatostatin at a dose of 5 ng/kg X min reduced basal plasma insulin levels significantly, whereas no effect of somatostatin was observed on basal insulin levels in the lean animals at all doses employed. The integrated postprandial insulin response was reduced during 0.25, 0.5, 1 and 5 ng/kg X min somatostatin in the obese animals, whereas only 0.5 ng/kg X min and higher doses had an inhibitory effect in the lean rats. The degree of inhibition in relation to the postprandial insulin response during saline infusions was 35-230% in the obese and 30-100% in the lean Zucker rats within the range of somatostatin infusions employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbohydrates modulate opiate receptor mediated mechanisms during postprandial endocrine function

The present study was designed to determine the role of carbohydrates during naloxone-induced opiate receptor blockade upon the postprandial rise of plasma somatostatin (SLI), insulin and pancreatic polypeptide (PP) levels in response to protein and fat test meals in conscious dogs. Test meals consisting of 50 g liver extract + 50 g sucrose or 50 g corn oil + 50 g sucrose dissolved in 300 ml water were instilled intragastrically, respectively. Additionally, liver extract and fat meals were given with a concomitant intravenous infusion of glucose. To all test meals either naloxone (4 mg) or saline was added. The addition of sucrose to liver extract or the infusion of i.v. glucose during the liver meal abolished the inhibitory effect of naloxone on the rise of postprandial somatostatin levels which has been described recently. The addition of carbohydrate either orally or intravenously to the fat meal resulted in an even stimulatory effect of naloxone upon the rise of postprandial somatostatin levels. Insulin levels were not changed during liver extract + sucrose or i.v. glucose, respectively. When sucrose or i.v. glucose was administered together with the fat meal the addition of naloxone augmented postprandial insulin secretion. Pancreatic polypeptide (PP) release was augmented during the combination of sucrose or i.v. glucose with the fat and liver meal when naloxone was present in the meals. The present data demonstrate that the addition of carbohydrates either orally or intravenously to fat and protein meals modulates the effect of endogenous opiates in the regulation of postprandial somatostatin, insulin and pancreatic polypeptide release in dogs in a way that carbohydrates induce inhibitory mechanisms that are mediated via endogenous opiate receptors.     

Physiological significance of gastrointestinal somatostatin

Somatostatin participates in the regulation of nutrient entry from the intestinal tract into the circulation. Thus, dietary fats and proteins may elicit significant increases of gastropancreatic somatostatin. Regulation of postprandial somatostatin secretion may occur via neural, hormonal and humoral factors. This peptide, in pharmacological doses, inhibits virtually all gastrointestinal exo- and endocrine functions as well as local motor activity. Neutralization of endogenous circulating somatostatin with specific antiserum is followed by increases in GH and enteroglucagon, augmenting also the postprandial rise of gastrin, insulin and pancreatic polypeptide. Somatostatin deficiency can be observed in obese subjects with hyperinsulinism. Concomitant elevation of insulin and gastrin levels can be antagonized by exogenous somatostatin. These findings confirm the importance of somatostatin as a peripheral regulator in experimental and human biology.     

Effect of vagotomy and atropine on plasma somatostatin response to a meal in conscious dogs

In 4 conscious dogs with gastric fistulas the somatostatin responses to a meal were measured and compared to the responses seen after i.v. infusion of atropine sulfate (20 and 50 micrograms.kg-1.h-1) or cimetidine (8 mg.kg-1.h-1). The experiments were repeated after truncal vagotomy. The somatostatin responses to bombesin (0.5 micrograms.kg-1.h-1) were also measured before and after vagotomy. Vagotomy decreased basal and postprandial somatostatin levels and reduced the somatostatin responses to feeding during the first 30-min period following the ingestion of the meal but not during subsequent periods. Bombesin-induced somatostatin release was increased after vagotomy. Atropine decreased the somatostatin responses to the meal before and after vagotomy. Cimetidine had no significant effect. These studies suggest that, in conscious dogs, somatostatin released into the circulation is partly under vagal control and that, as for gastrin release, vagal pathways for stimulation and inhibition are present. Our studies also suggest that cholinergic mechanisms are involved in the control of postprandial somatostatin release.     

Effect of cimetidine, ranitidine and omeprazole on postprandial gastrin and somatostatin release in conscious dogs

During a first series of experiments, the gastrin responses to a meal were measured and compared to the responses seen after administration of cimetidine (2.5 mg/kg/h) or omeprazole (2 mg/kg). During a second series of experiments the effects of cimetidine (2.5 mg/kg/h), ranitidine (0.5 mg/kg/h) and omeprazole (2 mg/kg) on post-prandial gastrin and somatostatin release were determined in experiments during which the intragastric pH was maintained close to 6.4. During a third series of experiments, the effects of cimetidine (2.5 mg/kg/h) and omeprazole (2 mg/kg) on basal gastrin and somatostatin release were estimated. Postprandial gastrin release was increased by cimetidine and by omeprazole. When acidification of the gastric content was prevented by intragastric titration, postprandial gastrin release was increased by about 100%. No further increase was observed when the animals were concomitantly treated with cimetidine, ranitidine or omeprazole. Intragastric titration did not alter postprandial somatostatin release. Concomitant administration of H2 blockers decreased the somatostatin response to the meal, while concomitant administration of omeprazole did not alter this release. No significant changes were observed in basal gastrin or somatostatin levels after administration of cimetidine or omeprazole.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach

Ghrelin release in man depends on the macronutrient composition of the test meal. The mechanisms contributing to the differential regulation are largely unknown. To elucidate their potential role, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), insulin, gastrin and somatostatin were examined on isolated rat stomach ghrelin secretion, which offers the advantage of avoiding systemic interactions. Basal ghrelin secretion was in a range that did not permit to consistently evaluate inhibiting effects. Therefore, the effect of gastrointestinal hormones and insulin was analyzed during vagal prestimulation. GLP-1(7-36)amide 10(-8) and 10(-7) M decreased ghrelin secretion significantly. In contrast, GIP 10(-8) and 10(-7) M augmented not only prestimulated, but also basal ghrelin secretion (p<0.05). Insulin reduced ghrelin at 10(-10), 10(-8) and 10(-6) M (p<0.05). Both gastrin 10(-8) M and somatostatin 10(-6) M also significantly inhibited ghrelin secretion. These data demonstrate that GLP-1(7-36)amide, insulin, gastrin and somatostatin are potential candidates to contribute to the postprandially observed inhibition of ghrelin secretion with insulin being the most effective inhibitor in this isolated stomach model. GIP, on the other hand, could attenuate the postprandial decrease. Because protein-rich meals do not effectively stimulate GIP release, other as yet unknown intestinal factors must be responsible for protein-induced stimulation of ghrelin release.     

Dose-dependent inhibitory and non-inhibitory action of somatostatin on insulin release in rats

The dose-dependent effect of intravenously infused synthetic somatostatin-14 on basal and postprandial insulin and gastrin release was assessed in anesthetized rats.Infusion of 1 ng · kg^?1 · min^?1 elicited a significant reduction of basal and postprandial insulin levels compared to the saline control group. At 15 ng · kg^?1 · min^?1 basal insulin was not affected but postprandial insulin levels were still significantly reduced. At 30 ng · kg^?1 · min^?1 neither basal nor stimulated insulin levels were affected. At the highest concentration of 120 ng · kg^?1 · min^?1 basal and postprandial insulin levels were suppressed similar to the lowest infusion rate of 1 ng · kg^?1 · min^?1. Basal gastrin levels were significantly reduced only at the highest rate of 120 ng · kg^?1 · min^?1. A significant reduction of postprandial gastrin levels was observed at 15 ng · kg^?1 · min^?1 and all higher infusion rates employed. Measurements of plasma somatostatin-like immunoreactivity (SLI) demonstrated that plasma SLI levels during the lowest infusion rate of 1 ng · kg^?1 · min^?1 were not different from the controls. No significant rise of plasma SLI levels was observed in response to the test meal. The higher infusion rates elicited a dose-dependent increase in plasma SLI levels. These data demonstrate that in rats somatostatin exerts a biological effect on insulin release at very low doses while certain greater infusion rates have no suppressive effect. Gastrin secretion is inhibited in a more linear pattern.     

Effect of bombesin upon plasma somatostatin-like immunoreactivity, insulin and glucagon in normal and chemically sympathectomized dogs

The present study was designed to determine the effects of intravenously infused bombesin (10 ng/kg/min) upon basal and postprandial plasma somatostatin-like immunoreactivity (SLI), glucagon, insulin and triglyceride levels in normal (n = 12) and chemically sympathectomized (n = 11) dogs. Basal plasma SLI, glucagon and insulin levels rose significantly during the infusion of bombesin in the normal dogs, and this was not altered by chemical sympathectomy. Bombesin infusion enhanced the postprandial SLI response, while attenuating the postprandial glucagon response by 50% and the insulin response in the early postprandial phase of the meal. Sympathectomy did not significantly alter the basal levels of these polypeptides, but augmented the postprandial plasma SLI response during the first 90 min, and reduced the postprandial glucagon response during the infusion of bombesin. The postprandial insulin response was not affected by sympathectomy. In both normal and chemically sympathectomized dogs the rise in postprandial triglyceride levels was attenuated by bombesin infusion.     

Evidence for a role of endogenous opiates in postprandial somatostatin release

Previously, we have demonstrated the effects of exogenously administered opiates on somatostatin release in dogs and therefore the present study was designed to determine the effect of endogenous opiates via naloxone-induced opiate receptor blockade on somatostatin release. Additionally, plasma insulin and pancreatic polypeptide (PP) levels were determined in response to intragastrically instilled protein, carbohydrate and fat test meals in a group of eight conscious dogs. To all test meals either naloxone (4 mg) or saline was added. The rise of plasma somatostatin levels in response to liver extract, sucrose and fat was attenuated significantly by naloxone. Naloxone had no effect on the rise of postprandial plasma insulin and PP levels. The present data demonstrate that endogenous opiates have a stimulatory effect on postprandial somatostatin release in dogs which indicates a tight interaction that might be of relevance for nutrient homeostasis.     

Evidence for a regulatory role of the stomach in islet cell function.

Recent studies have suggested that gastric factors other than gastrin may be released in response to gastric test meals and stimulate islet cell function. The present study was designed to examine this further. In anesthetised, laparotomized dogs with a bisected pylorus and a gastric fistula, a liver meal at pH 2 or pH 7 was instilled intragastrically. Although gastrin levels were lower with the acidified meal, inferior vena cava, insulin, glucagon and plasma glucose levels were significantly higher than after a meal at pH 7. These differences were not changed by truncal vagotomy. The differences in insulin or plasma glucose levels were not altered by infusion of atropine, although the difference in glucagon levels was reduced considerably. The present data suggest that factors other than gastrin and unrelated to the vagus or to atropine sensitive pathways are able to influence islet cell function and possibly glucose homeostasis.     

D-Trp8-D-Cys14-somatostatin--demonstration of its differential suppressive activity in juvenile diabetics.

In 8 insulin-dependent diabetics, the effect of D-Trp8-D-Cys14-somatostatin on blood glucose, growth hormone, and glucagon levels as well as on insulin requirements from an artificial endocrine pancreas was studied during a balanced meal. The somatostatin analogue was infused at a rate of 25 microgram/h preceeded by a bolus injection of 25 microgram 30 minutes before ingestion of the meal. At this dose the analogue had no effect on glucagon levels and insulin requirements from the artificial pancreas. On the other hand, there was a significant lowering effect on fasting blood glucose levels, possibly indicating a direct inhibition of hepatic glucose production. Furthermore, there might be a slight effect on growth hormone levels, as was demonstrated by a rebound increase after termination of analogue infusion.     

2 型糖尿病患者胰高血糖素及胰岛素水平检测及临床意义

目的:探讨2型糖尿病患者经标准馒头餐试验后胰高血糖素、胰岛素水平变化及其临床意义。方法:选取我院2014年3月至2015年3月收治的80例2型糖尿病患者为试验组,均接受标准馒头餐试验,对其餐前及餐后0.5 h、1 h、2 h胰高血糖素及胰岛素水平进行检测,并与同期80例血糖无异常的健康对照组作比较。结果:健康对照组餐前及餐后胰高血糖素水平无明显变化(P0.05),而试验组餐前胰高血糖素水平明显高于健康对照组(P0.05),且餐后明显升高,在餐后1 h达到峰值,餐后0.5 h、1h、2 h均明显高于健康对照组(P0.01)。健康对照组餐后胰岛素水平明显升高,在餐后1 h达到峰值后开始降低,较餐前略高,但差异平无统计学意义(P0.05);试验组餐前胰岛素水平明显低于健康对照组(P0.05),且餐后水平升高幅度缓慢,餐后0.5 h、1 h、2h均明显低于健康对照组(P0.05);实验组胰岛素抵抗指数(HOMA-IR)明显高于健康对照组,经Pearson相关分析,试验组餐后0.5 h、1 h、2 h胰高血糖素水平与HOMA-IR均呈明显的正相关(r=0.273、0.335、0.368,P0.05)。结论:2型糖尿病患者血糖高表达与胰高血糖素、胰岛素水平密切相关,胰高血糖素可拮抗胰岛素,及时检测二者的水平对临床准确评估病情具有重要的意义。     

Relationship of glucagon-somatostatin and gastrin-somatostatin cells in the stomach of the monkey

The stomach of the monkey Tupaia belangeri was investigated by serial sections utilizing the indirect immunoperoxidase reaction to demonstrate the distribution of glucagon, gastrin and somatostatin immunoreactive cells. A striking topographical distribution was found. Glucagon and somatostatin immunoreactive cells were located in the upper parts, whereas gastrin and somatostatin immunoreactive cells were situated in the lower parts of the stomach. The remaining regions of the stomach did not contain cells immunoreactive to the antisera applied. Similarly, the ultrastructural study revealed the same distribution of endocrine cell types identified as A-cells, D-cells, and G-cells. Thus, there may be a glucagon-somatostatin area in the upper part and a gastrin-somatostatin endocrine surface in the lower part of the stomach. This spatial relationship of the endocrine cells suggests a functional cell interaction between glucagon and somatostatin cells in the cranial stomach and between gastrin and somatostatin in the caudal parts of the stomach.     

Effect of glucagon antiserum on somatostatin,glucagon and insulin release from the isolated perfused rat pancreas

In order to elucidate the effect of glucagon antiserum on the endocrine pancreas, the release of somatostatin, glucagon, and insulin from the isolated perfused rat pancreas was studied following the infusion of arginine both with and without pretreatment by glucagon antiserum. Various concentrations of arginine in the presence of 5.5 mM glucose stimulated both somatostatin and glucagon secretion. However, the responses of somatostatin and glucagon were different at different doses of arginine. The infusion of glucagon antiserum strongly stimulated basal secretion in the perfusate total glucagon (free + antibody bound glucagon) and also enhanced its response to arginine, but free glucagon was undetectable in the perfusate during the infusion. On the other hand, the glucagon antiserum had no significant effect on either insulin or somatostatin secretion. Moreover, electron microscopic study revealed degrannulation and vacuolization in the cytoplasm of the A cells after exposure to glucagon antiserum, suggesting a hypersecretion of glucagon, but no significant change was found in the B cells or the D cells. We conclude that in a single pass perfusion system glucagon antiserum does not affect somatostatin or insulin secretion, although it enhances glucagon secretion.     

Somatostatin-induced inhibition of insulin secretion from isolated islets of rat pancreas in presence of glucagon.

In order to study the oeffect of somatostatin on the endocrine pancreas directly, islets isolated from rat pancreas by collagenase were incubated for 2 hrs 1) at 50 and 200 mg/100 ml glucose in the absence and presence of somatostatin (1, 10 and 100 mg/ml) and2) at 200 mg/100 ml glucose together with glucagon (5 mug/ml), with or without somatostatin (100 ng/ml). Immunologically measurable insulin was determined in the incubation media at 0, 1 and 2 hrs. Insulin release was not statistically affected by any concentration stomatostatin. On the other hand, somatostatin exerted a significant inhibitory action on glucagon-potentiated insulin secretion (mean +/- SEM, mu1/2 hrs/10 islets: glucose and glucagon: 1253 +/- 92; glucose, glucagon and somatostatin: 786 +/- 76). The insulin output in th epresence of glucose, glucagon and somatostatin was also significantly smaller than in thepresence of glucose alone (1104 +/- 126) or of glucose and somatostatin (1061 +/- 122). The failure of somatostatin to affect glucose-stimulated release of insulin from isolated islets contrasts its inhibitory action on insulin secretion as observed in the isolated perfused pancreas and in vivo. This discrepancy might be ascribed to the isolation procedure using collagenase. However, somatostatin inhibited glucagon-potentiated insulin secretion in isolated islets which resulted in even lower insulin levels than obtained in the parallel experiments without glucagon. It is concluded that the hormone of the alpha cells, or the cyclic AMP system, might play a part in the machanism of somatostatin-induced inhibition of insulin release from the beta-cell.     

Disturbed gastric motility and pancreatic hormone release in diabetes mellitus.

BACKGROUND AND AIMS: The influence of glucose metabolism and postprandial release of glucagon on gastric emptying in diabetes mellitus is still unclear. The aim of this study was to assess the relationship between glucose, insulin and glucagon and alterations of gastric motility in symptomatic diabetic subjects with delayed gastric emptying. METHODS: Scintigraphy for solids and liquids, 13C-acetate breath test, electrogastrography and antral manometry were assessed in 20 symptomatic subjects with diabetes mellitus type II and in 20 healthy controls. Simultaneously, serum glucose, glucagon and insulin levels were determined during the functional studies. RESULTS: Postprandial increase in antral motility and myoelectrical activity were seen in controls, but were missing in the group with diabetes mellitus. Moreover, in the fasting state the dominant frequency instability coefficient observed in healthy individuals and in subjects with diabetes of short (<5 years) duration was significantly reduced in subjects with longer duration of diabetes while the postprandial increase in dominant frequency instability coefficient was missing in all diabetics. Following the standard test meal, serum glucose and plasma glucagon in the diabetics increased to a significantly higher degree when compared to controls. CONCLUSIONS: Symptomatic subjects with delayed gastric emptying present abnormal patterns of gastric motor and electrical activity. Higher than normal postprandial plasma levels of glucagon may, at least in part, be responsible for disturbed gastric motility in non-insulin-dependent diabetic subjects.     

Effects of prostaglandin E2 and D2 on gastric somatostatin and gastrin secretion

The effects of PGE2 and PGD2 on gastric somatostatin and gastrin releases were investigated using the isolated perfused rat stomach. In the presence of 5.5 mM glucose, the infusion of PGE2 elicited a significant augmentation in somatostatin release, but suppressed gastrin secretion from the perfusate. On the other hand, PGD2 did not affect somatostatin release, although the gastrin secretion decreased significantly, the same as after PGE2 infusion. These results suggest that PGE2 and PGD2 may be important in the regulation of gastric endocrine function, but that PGD2 does not affect gastric somatostatin secretion.