The enteroinsular axis revisited. A novel role for an incretin.
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Blood Glucose↗
Biomedical subjects
J W Ensinck
Publications and source records attributed to J W Ensinck.
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.h-1 for 120 minutes or at least one interdigestive cycle. The two doses increased plasma somatostatin 28 levels within the physiological or into the supraphysiological range, respectively. Somatostatin 28 at 11 and 44 pmol.kg-1.h-1 decreased the length of the interdigestive motility cycle by 50% and 67% compared with controls, respectively (both P less than 0.002). Propagation velocity of the migrating motor complex (P less than 0.01) and plasma motilin were decreased (P less than 0.01). The smaller and larger dose decreased pancreatic enzyme outputs by 50% and 65%, respectively (P less than 0.005), but with the smaller dose, phase III-associated enzyme outputs were greater than phase I outputs. These findings suggest that small changes in somatostatin 28 plasma concentrations modulate human interdigestive motility and pancreatic enzyme output while coupling of motor and secretory events is preserved.
Adult↗
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. It is concluded that S-28 released from the gut during food intake modulates pancreatic exocrine function in humans.
Adult↗
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. Basal insulin concentrations were unaltered by fish oil without or with glyburide; however, postprandial insulin concentrations were decreased by fish oil. Although total cholesterol and triglyceride concentrations were unchanged, very-low-density-lipoprotein cholesterol concentrations decreased and low-density-lipoprotein cholesterol rose and apolipoprotein B concentrations trended higher. Thus, glyburide only partially rectified the impaired fuel homeostasis associated with fish-oil supplements in patients with NIDDM. Therefore, we do not recommend intake of fish oil concentrates containing n-3 fatty acids in patients with NIDDM.
Aged↗
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. The predicted amino acid sequence of the monkey precursor is 96% identical to that of the human protein; differences include one replacement in the signal peptide and three in the islet amyloid polypeptide domain. The sequence of the dog precursor is most closely related to that of the cat protein (85% identity); the sequences of dog and cat islet amyloid polypeptide differ only at two positions and are identical in the region of amino acids 20-29, the region thought to be primarily responsible for amyloidogenesis. Thus, amino acid residues in addition to those at positions 20-29 may facilitate the aggregation of islet amyloid polypeptide. The presence of amyloid deposits in some dog pancreatic endocrine tumours suggests that the dog protein can be amyloidogenic, perhaps due to elevated expression of islet amyloid polypeptide by the tumours relative to normal islets.
Amino Acid Sequence↗
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, 5.5, 8.8 and 16.7 mM) and to non-glucose secretagogues at different glucose concentrations in a neonatal rat islet monolayer culture preparation. Glucose alone stimulated IAPP and insulin secretion in a dose dependent fashion with maximal release for both peptides occurring at 8.8 mM. B-cell secretion of IAPP in response to arginine, isobutylmethylxanthine or both together was potentiated by increasing glucose concentrations from 1.67 to 16.7 mM. This same pattern of glucose potentiation was observed for insulin secretion. The data indicate that the pattern of peptide responses of cultured neonatal B-cells to glucose is similar for both IAPP and insulin release. Furthermore, the data suggest that glucose is capable of potentiating B-cell secretion of both IAPP and insulin.
1-Methyl-3-isobutylxanthine↗
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.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.
Adult↗
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 2.8 to 11.1 mM and 2) ramping of glucose at 0.28 mM/min throughout 45 min. S-28 concentrations of 16, 32, and 80 pM were separately coinfused for 40 min in the first condition and at 16 pM in the second condition. During square-wave glucose infusion, biphasic insulin secretion was elicited with marked attenuation of both phases during coinfusion with the two higher concentrations of S-28. At 16 pM S-28, which approximates postprandial At 16 pM S-28, which approximates postprandial concentrations, only first-phase secretion was suppressed. During ramping of glucose, insulin was released gradually and, in the presence of 16 pM S-28, was shifted to the right, indicating an increase in threshold glucose levels for insulin secretion. We concluded that S-28, at levels achieved postprandially, modulates the release of insulin by altering the threshold of sensitivity to glucose.
Adult↗
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. With carbohydrate, somatostatin-28 levels were unaltered. After 22 and 45 g of protein, somatostatin-28 increased equivalently within 60 min, representing 30% of the amount with the mixed meal. With 25 g fat, a somatostatin-28 increase similar to that with the meal was seen; this response was doubled with 50 g fat. No changes in prosomatostatin, somatostatin-14, or somatostatin-13 were observed with the mixed meal or with the separate macronutrients. The authors conclude that fat is the major stimulus for somatostatin-28 secretion in humans and hypothesize that somatostatin-28 is an inhibitor of the endocrine and exocrine pancreas during nutrient absorption.
Adult↗
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. Distribution of these peptides was measured in extracts of pancreas and mucosa and submucosa/muscularis from the rat and human GI mucosal biopsies; the antisera were used to immunostain cells in these tissues. Extracts of human and rat intestinal mucosa contained both somatostatin-28 and somatostatin-14. By immunocytochemistry, D cells in stomach and pancreas and neural processes in the intestine, extending into the mucosal villi adjacent to endocrine cells, stained with both antisera indicating the presence of somatostatin-14, prosomatostatin, and possibly somatostatin-28. In contrast, endocrine cells in the gut reacting with antisera against somatostatin-28 did not immunostain with somatostatin-14-specific antisera. Thus, these data suggest that somatostatin-28 is the terminal peptide processed from prosomatostatin in intestinal mucosal cells, whereas somatostatin-14 is the major final product in gastric and pancreatic D cells and neurons. The localization of somatostatin-28 and somatostatin-14 in different cells in the pancreas and GI tract implies that they serve different functions.
Animals↗
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. Human CGRP I was infused into the descending aorta at 0.2, 0.4, 0.8, and 1.6 micrograms.kg-1.h-1 for consecutive 30-min intervals. Blood was collected from the venous catheters after each period. S-28 was separated from Pro-S, S-14, and S-13 by immunoaffinity chromatography and peptides were quantified by radioimmunoassay. CGRP primarily evoked release of peptides measured collectively as Pro-S, S-14, and S-13 into venous blood draining the fundus and corpus, and concentrations were significantly elevated above basal at 0.8 and 1.6 micrograms.kg-1.h-1 CGRP (P less than 0.05). Basal concentrations of S-28, Pro-S, S-14, and S-13 in blood from the antrum and small intestine were not significantly elevated by CGRP. In conclusion, CGRP stimulated release of Pro-S-derived peptides from the gastric fundus and corpus but not from the antrum or small intestine.
Animals↗
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. Nonetheless, whether CCK is responsible in part for the meal-induced rise in S-28 in man has not been established. Therefore, the present study was designed to determine if CCK, at both physiological and supraphysiological concentrations, increases the circulating levels of prosomatostatin (proS)-derived peptides in humans. On 3 separate days, five healthy men ate a mixed liquid meal or received iv infusions of CCK at rates of 18 or 38 pmol/kg.h. Plasma levels of pro-S-derived peptides, including pro-S, S-14, S-13, S-28, and CCK, were measured. Basal CCK levels averaged 0.9 +/- 0.1 pmol/L and increased after the meal to a peak level of 5.4 +/- 1.5 pmol/L and averaged 3.1 +/- 1.2 pmol/L over 90 min. The mean basal levels of pro-S, S-14, and S-13, measured collectively, was 6.1 +/- 0.4 pmol/L eq S14 and was unaltered by food intake. The S-28 level was 6.7 +/- 0.6 pmol/L and rose to a zenith of 13.1 +/- 3.3 pmol/L by 90 min. Infusion of CCK at 18 and 38 pmol/kg.h produced steady state plasma CCK levels of 4.1 +/- 1.1 and 9.9 +/- 1.5 pmol/L, respectively. Basal levels of pro-S-derived peptides were unaltered during the infusion of either the low or high dose of CCK. We conclude that CCK by itself is not a physiological signal to the release of pro-S-derived peptides in man.
Adult↗
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. Concentrations of SRIF-14 and SLI were also obtained. Subjects were admitted for study after an overnight fast, blood was collected before and at 30-min intervals for 4 h after a fat meal, and plasma samples were analyzed for SRIF-28 and SRIF-14 by specific methods. Basal glucose levels in the diabetic men were significantly higher than in control subjects (10.2 +/- 1 vs. 5.8 +/- 0.2 mM), but insulin levels were similar (79 +/- 14.2 vs. 93.3 +/- 14.2 pM). The diabetic men had significantly lower basal SRIF-28 levels than the control subjects (11.4 +/- 0.6 vs. 14.6 +/- 1.0 pM, P = 0.017). After fat intake, SRIF-28 levels throughout the 4 h of study were indistinguishable in the two groups (270 vs. 292% of basal). Basal SRIF-14 and SLI levels were not significantly different in the two groups, and SRIF-14 and SLI concentrations rose similarly after the meal. There were no correlations between basal SRIF-28 and glucose or insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
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, 16.7 mM glucose, and 16.7 mM glucose plus 10 mM arginine and 0.1 mM isobutylmethylxanthine (IBMX). The quantity of IAPP-LI, insulin, and glucagon in the cell extract was also determined. Mean +/- SE IAPP-LI in the incubation medium increased from 0.041 +/- 0.003 pmol in 1.67 mM glucose to 0.168 +/- 0.029 pmol in 16.7 mM glucose (P less than 0.05) and 1.02 +/- 0.06 pmol in 16.7 mM glucose plus arginine and IBMX (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Insulin secretion increased similarly from 4.34 +/- 0.27 to 20.2 +/- 0.6 pmol (P less than 0.05) and then to 135 +/- 5 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Glucagon release tended to decrease with the increase in glucose concentration (0.39 +/- 0.01 vs. 0.33 +/- 0.02 pmol, P less than 0.1), whereas with the addition of arginine and IBMX to high glucose, glucagon release increased to 1.32 +/- 0.03 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)
Amyloid↗
Circulating prosomatostatin-derived peptides. Differential responses to food ingestion.
Prosomatostatin (pro-S) and its bioactive posttranslational products, somatostatin-14 (S-14), somatostatin-13 (S-13), and somatostatin-28 (S-28), were measured in human plasma by the use of immunoglobulins to the NH2-terminus of S-28 conjugated with agarose to separate them and, thereafter, by RIA with an antiserum recognizing the COOH-terminus of pro-S, and by specific RIA for the NH2-terminus of S-14 and pro-S. In healthy men, mean basal levels of pro-S were 4 pg equivalent S-14/ml; S-14/S-13 combined were 9 pg equivalent S-14/ml; and S-28 levels were 16 pg/ml. After a 700-kcal meal, pro-S, S-14, and S-14/S-13 did not change, whereas S-28 levels doubled by 120 min and remained elevated for 240 min. To evaluate the origins of these peptides, their levels were compared in peripheral, portal, gastric, and mesenteric veins of anesthetized patients and in patients with total resection of stomach and pancreas before and after nutrient intake. The stomach and small intestine were sources of both peptides; however, most S-28 originated in the small intestine. These findings suggest that, in contrast to S-14, S-28 is a hormone and may modulate postprandial nutrient absorption and use.
Adult↗
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. Subjects were given a bolus of glucose (0.1 g/kg) after 120 min. Insulin responses during S-28 infusions were compared to a control study using a saline infusion in the same individuals. Glucose-stimulated insulin secretion was inhibited during the infusion of 50 ng/kg per h S-28 when compared to control (P less than 0.05). (b) Insulin secretion during elevations of endogenous S-28 was studied in healthy men who received a bolus of 2.5 g arginine (n = 14) or 25 U of secretin (n = 8) 120 min after swallowing 50 g fat, or, on a separate day, an equivalent volume of water. S-28 levels rose significantly after fat ingestion but did not change after water. Arginine and secretin-stimulated insulin secretion was inhibited following ingestion of fat compared with intake of water (P less than 0.05). Arginine-enhanced glucagon secretion was not changed by fat ingestion. We conclude that elevations in plasma S-28 levels, occurring during the postprandial state, attenuate B-cell secretion and this peptide may be a physiologic modulator of nutrient-stimulated insulin release.
Administration, Oral↗
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. The interaction of GLP-I-(7-36) with nutrient substrates was assessed by adding amino acids and differing glucose concentrations to the cultures. Islet cell cultures (n = 5) were incubated for 1 h in medium containing 1.67 or 16.7 mM glucose or 1.67 mM glucose supplemented with amino acids and GLP-I-(7-36) at 10(-13)-10(-7) M. Hormone release was compared with control cultures containing no GLP-I-(7-36); 1.67-16.7 mM glucose with and without GLP-I-(7-36) at 10(-11) M; and 1.67, 3.3, 8.3, or 11.1 mM glucose alone or supplemented with amino acids, GLP-I-(7-36) 10(-11) M, or both amino acids and GLP-I-(7-36). In medium with 1.67 or 16.7 mM glucose or 1.67 mM glucose and amino acids, GLP-I-(7-36) increased insulin secretion two- to threefold over control at concentrations of 10(-9), 10(-11), and 10(-12) M, respectively. In medium with increasing concentrations of glucose, GLP-I-(7-36) at 10(-11) M significantly increased insulin secretion at glucose concentrations greater than or equal to 3.34 mM.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes.
We studied the effect of omega-3 fatty acids (omega 3FA) on glucose homeostasis and lipoprotein levels in eight type II (non-insulin-dependent)-diabetic subjects ingesting 8 g/day omega 3FA for 8 wk as marine-lipid concentrate capsules. After omega 3FA supplementation, fasting plasma glucose levels increased 22% (P = .005) and meal-stimulated glucose increased 35% (P = .036). The percentage of glucose elevation correlated with percentage ideal body weight (r = .73, P = .04). No significant changes were seen in fasting or meal-stimulated plasma insulin, glucose disposal, or insulin-to-glucagon ratios. Very-low-density lipoprotein cholesterol and triglyceride (TG) levels showed consistent reductions of 56% (P less than .001) and 42% (P less than .001), respectively, after omega 3FA supplementation. Total cholesterol levels decreased 7% (P less than .05) without alteration in low- or high-density lipoprotein cholesterol. Thus, omega 3FA supplementation at a dose of 8 g/day significantly improves plasma TG levels but increases fasting and meal-stimulated glucose concentrations in the type II diabetic patient not treated with insulin or sulfonylurea agents. Marine-lipid concentrate capsules supplying large amounts of omega 3FAs should be used cautiously in the type II diabetic patient.
Aged↗