Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration.

We determined islet amyloid polypeptide (IAPP) response in plasma to oral and intravenous glucose administration and intravenous insulin injection in nondiabetic subjects. Moreover, we studied the effect of somatostatin analogue SMS 201-995 on glucose-induced IAPP secretion in nondiabetic subjects. Plasma IAPP concentration was determined by radioimmunoassay. Oral administration of 75 g glucose (n = 8) significantly increased plasma IAPP levels from 4.5 +/- 0.7 to 14.0 +/- 1.7 pM (P less than 0.01) 60 min after administration. Intravenous administration of 10 g glucose (n = 7) also caused a significant increase in plasma IAPP from 5.0 +/- 0.4 to 11.6 +/- 0.9 pM (P less than 0.01) 5 min after injection. Plasma IAPP significantly decreased from 5.1 +/- 0.4 to 2.9 +/- 0.4 pM (P less than 0.01) 60 min after intravenous insulin injection (n = 8). Pretreatment with SMS 201-995 completely abolished IAPP and insulin secretion to intravenous glucose injection. A significant correlation was found between plasma IAPP and insulin levels in oral and intravenous glucose administration and between plasma IAPP and C-peptide levels during insulin-induced hypoglycemia. These results suggest that IAPP is cosecreted with insulin in response to a glucose load and secretion of IAPP is inhibited by hypoglycemia and somatostatin. IAPP may serve as a novel pancreatic hormone to control carbohydrate metabolism.

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in ventromedial hypothalamic-lesioned rats.

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in rats after ventromedial hypothalamic (VMH) lesions were evaluated by measuring fasting hormone levels and their secretion from the isolated perfused pancreas. Fasting peripheral insulin levels were not altered 1 week after the VMH lesions but became progressively elevated at 3-4, 8-9, and 11-12 weeks compared to the values in sham-operated and age-matched control rats. In the portal vein, insulin levels also progressively increased in VMH-lesioned rats, but the portal-peripheral gradient of insulin in the later phase of VMH obesity was significantly lower than in the early phase after VMH lesions. On the contrary, the arginine-induced insulin release from the perfused pancreas was highest at 1 week and gradually decreased thereafter, although it continued to remain higher than that of controls. The perfusate somatostatin response to arginine also was exaggerated in the VMH-lesioned rats. However, both the peripheral glucagon level and the glucagon secretion from the perfused pancreas of the VMH-lesioned rats were not significantly different from the controls. These results show that VMH lesions result in an increased insulin and somatostatin secretion. Using the cyclically perfused liver in situ, we have found that the hepatic extraction rate of insulin is indeed reduced in rats 8-9 weeks after VMH lesioning, and so have at least partly accounted for the decreased portal-peripheral gradient of insulin in the later VMH postoperative phase.

The role of endogenous gastric inhibitory polypeptide in the enteroinsular axis.

In order to elucidate the relationship between the release of gastric inhibitory polypeptide (GIP) and insulin, we compared plasma GIP and insulin concentration responses to meal ingestion in normal subjects and patients with various surgical modifications of the food pathway. Nine patients with Billroth I partial gastrectomy (BI), 7 patients with Billroth II partial gastrectomy (BII), and 6 patients with total gastrectomy (TG) were tested. In BI patients the increase in blood glucose was similar to that in normal subjects, but the response was significantly greater in BII and TG patients. In TG patients blood glucose rose significantly higher in response to a standard meal than in all other groups. In BI patients the mean peak GIP level after meal ingestion was significantly higher than in normal subjects. In BII and TG patients an extremely exaggerated GIP response after the meal was observed. The insulin response to feeding was increased only in the BII and TG patients. Since the insulin response was enhanced only when both the glucose and GIP responses were magnified, we conclude that endogenous GIP is a glucose-dependent insulinotropic factor. In addition, from the fact that meal-stimulated GIP release is most marked in patients with total gastrectomy, we conclude that the direct contact of food with the GIP-producing cells is a strong mechanical or chemical stimulus for GIP release.

Comparison of the effect of somatostatin and an analogue, SMS 201-995, on gastrin and insulin secretion from isolated perfused rat stomach and pancreas.

The effects of a somatostatin analogue, SMS 201-995, and somatostatin-14 on gastrin and insulin release from the isolated perfused rat stomach and pancreas were studied. Equipotent effects were observed on the inhibition of basal gastrin release from the stomach. SMS 201-995 was approximately 14 times less effective than somatostatin-14 (molar basis) in the pancreas. At a high glucose concentration (17.6 mM), neither the analogue nor the peptide inhibited insulin release, but at a glucose concentration of 8.8 mM, there was significant inhibition. In the presence of 10 mM arginine plus glucose at a concentration of either 8.8 or 17.6 mM, insulin secretion was reduced by both SMS 201-995 and somatostatin-14 to levels obtained with glucose alone. However, when gastric inhibitory polypeptide (10 ng/ml) in the presence of 8.8 mM glucose was used to stimulate insulin release, somatostatin-14 completely inhibited the insulinotropic action of gastric inhibitory polypeptide while SMS 201-995 was without effect. Studies with this analogue suggest that arginine and gastric inhibitory polypeptide stimulate insulin release via different mechanisms.

Changes in plasma cholecystokinin concentrations after oral glucose tolerance test in anorexia nervosa before and after therapy.

There is considerable evidence that the gastrointestinal hormone cholecystokinin (CCK) induces satiety and reduces food intake in both animals and humans. Impaired CCK secretion was recently reported in patients with bulimia nervosa (BN) in whom plasma CCK responses to a standardized mixed-liquid meal were significantly lower than in controls. The present study was undertaken to determine whether CCK levels were abnormal in another relatively common eating disorder, anorexia nervosa (AN), before and after therapy and to investigate the relationship to the abnormal eating behavior. Plasma CCK, serum glucose, and immunoreactive insulin (IRI) responses to a 50-g oral glucose load were measured in 13 women with AN and in nine normal sex- and age-matched controls. The AN patients were all hospitalized during treatment; following partial restoration of body weight, the tests were repeated. Initial body weights were 70.8% +/- 1.8% (mean +/- SEM) of ideal body weight (IBW), and following partial restoration were 84.3% +/- 1.4%. Body weights in normal controls were 96.3% +/- 2.1% of IBW. Initial basal CCK concentrations in the AN patients before nutritional and cognitive behavioral therapy were significantly greater than those in controls (P < .01). After partial restoration of body weight, basal CCK concentration in AN patients approached that of control subjects. When AN patients were given a glucose load before therapy, the change in CCK response was diminished when compared with that of controls. However, CCK responses to the glucose load in AN patients following therapy were similar to those of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin, glucagon, and insulin secretion from isolated perfused pancreas of new genetically obese hyperglycemic rats.

Insulin, somatostatin, and glucagon release from the perfused pancreas was studied in the newly developed genetically obese hyperglycemic hyperinsulinemic (Wistar fatty) rat. Insulin and somatostatin levels rose significantly compared to those in lean littermate controls during arginine infusion. The glucagon increase, however, was significantly less when total amounts during arginine infusion were calculated. These results show that hypersecretion of insulin and somatostatin in vitro may suppress glucagon release in Wistar fatty rats.

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.

Effect of truncal vagotomy on pancreatic polypeptide response after intravenous glucose administration.

Intravenous glucose infusion was performed in six dogs with and without truncal vagotomy, and plasma pancreatic polypeptide (PP) responses were compared before and after truncal vagotomy. Following truncal vagotomy, basal PP levels decreased significantly from 286 +/- 64 pg/ml (mean +/- S.E.) to 94 +/- 14 pg/ml (P less than 0.05). Basal plasma insulin and blood glucose levels also tended to be lower, but not significantly. During the infusion of glucose, blood glucose concentrations rose rapidly in both groups and after 15 min reached peak values which were not significantly different from each other. In the vagotomized group the plasma insulin response to intravenous glucose infusion was significantly lower than in the control group. Following intravenous glucose loading, plasma PP concentrations decreased rapidly in both groups, but the PP level in the vagotomized group was suppressed only to 77 +/- 4% of the basal level whereas in the control group it decreased by 45 +/- 8%, significantly lower than in the vagotomized group (P less than 0.01). These results suggest that basal PP is regulated by vagal tonus and that vagus controls, at least in part, suppression by intravenous glucose administration.

Effects of aging on plasma islet amyloid polypeptide basal level and response to oral glucose load.

To delineate the effects of aging on basal and glucose-stimulated secretion of islet amyloid polypeptide (IAPP), we compared the basal level of plasma IAPP and its response to an oral glucose load in elderly subjects with those of young subjects. Plasma IAPP level was determined by radioimmunoassay. Basal level of plasma IAPP in 20 elderly subjects (mean age 63 yr) was 5.3 +/- 0.4 pmol/l, which was not significantly different from 5.0 +/- 0.3 pmol/l in 22 young subjects (mean age 26 yr). Plasma glucose levels after an oral glucose load in elderly subjects (n = 8, mean age 67 yr) and young subjects (n = 8, mean age 29 yr) were within normal limits. However, the plasma glucose response in the aged group was significantly higher than that in the young group. The plasma insulin response to a glucose load in elderly subjects was not different from that in young subjects. The plasma IAPP level in the aged group significantly increased from 5.3 +/- 0.5 to 16.4 +/- 2.3 pmol/l 120 min after the oral glucose load. This result was quite similar to that in the young group whose plasma IAPP level increased from 4.9 +/- 0.5 to 14.1 +/- 1.5 pmol/l 120 min after the glucose load. We concluded that the basal level of plasma IAPP and its response to glucose were not affected by aging.

Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus.

We examined the response of plasma islet amyloid polypeptide (IAPP) to an oral glucose load in non-obese and obese subjects with normal glucose tolerance or impaired glucose tolerance (IGT), and in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma IAPP response to intravenous glucagon injection in NIDDM patients was also studied. Plasma IAPP concentration was determined by a sensitive and specific radioimmunoassay. Basal levels of plasma IAPP in non-obese subjects with normal glucose tolerance, IGT and NIDDM were not significantly different from each other. Non-obese subjects with IGT showed delayed and higher plasma IAPP response to oral glucose load compared to normal non-obese subjects. In NIDDM patients, IAPP response to glucose was delayed and lower when compared to normal non-obese subjects. Basal levels of plasma IAPP in normal obese subjects and obese subjects with IGT were significantly higher than those in normal non-obese subjects. Plasma IAPP response to glucose load in these obese subjects was higher than that in normal non-obese subjects. Plasma IAPP response was decreased in diabetic patients treated with diet, oral hypoglycemic agents and insulin in that order. We conclude that the secretion of IAPP is reduced with progression of NIDDM, although it appears to be rather augmented in IGT compared to normal non-obese subjects.

Effect of 1,25-dihydroxyvitamin D3 on pancreatic B and D cell function.

To investigate the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on pancreatic B and D cell function in normal rats, 1 microgram of 1,25(OH)2D3 was administered intravenously 20 hours before the experiment. The plasma 1,25(OH)2D3 and calcium concentrations were significantly elevated, and plasma insulin levels also increased in 1,25(OH)2D3-administered rats compared with controls. Glucose-induced insulin and somatostatin release from the isolated pancreas perfused with lower calcium, however, was the same between the 1,25(OH)2D3-administered group and the controls. On the other hand, when the isolated pancreas was perfused with higher calcium, the glucose-induced insulin release was significantly increased in the 1,25(OH)2D3-administered group, while no significant difference in somatostatin release was observed in any group. These results suggest that the sensitivity of pancreatic B cells to glucose perfused with more calcium may increase when 1,25(OH)2D3 has been previously administered. In addition, 1,25(OH)2D3 does not seem to affect the somatostatin release from the pancreatic D cells.

Thyroid anaplastic carcinoma producing granulocyte-colony-stimulating factor and parathyroid hormone-related protein.

A 65-year-old woman noticed a rapidly enlarging neck mass with tenderness and complained of dyspnea. She was diagnosed as having anaplastic thyroid carcinoma. She died of respiratory failure 14 days after admission. Marked leukocytosis and hypercalcemia were observed in the clinical course. Both serum granulocyte-colony-stimulating factor and parathyroid hormone-related protein levels were elevated. The cancerous tissue was also immunohistochemically stained for both peptides. We conclude that the leukocytosis and hypercalcemia of this patient were induced by these two factors produced by the tumor.

Effect of a high-protein diet on insulin and glucagon secretion in ventromedial hypothalamic (VMH) lesioned rats.

The effects of a high-protein diet on insulin and glucagon secretion in ventromedial hypothalamic (VMH) lesioned and sham-operated (sham) rats were studied in vivo as well as in perfusate from isolated pancreas. Two weeks after VMH destruction or sham operation, the rats were given either a balanced diet (protein 27%, carbohydrate 61%, fat 12%) or a high-protein diet (protein 55%, carbohydrate 30%, fat 15%) for the following 2 weeks. The calorie intake and body weight changes after the commencement of the diets were almost the same in the groups of VMH lesioned rats, but these were much greater than those in the two sham-operated groups. Fasting blood glucose, plasma insulin, and plasma glucagon concentrations were also similar between the two VMH groups, but in the sham-operated rats fasting blood glucose and plasma insulin concentrations of those rats on high-protein diet were significantly increased when compared to those on balanced diet. In the isolated, perfused pancreas, an arginine-induced excess insulin and glucagon secretion was not significantly different between the VMH lesioned rats. An arginine-induced rise in insulin concentration in the sham-operated rats on high-protein diet was significantly higher than for rats on balanced diet. We therefore suggest that hyperinsulinemia already produced in the VMH lesioned rats may not be influenced by the change in the composition of the dietary protein and carbohydrate.

The effects of concentric versus eccentric isokinetic strength training of the rotator cuff in the plane of the scapula at various speeds.

This study compares the effects of three modes of isokinetic resistance training at the shoulder--concentric, eccentric, and a combination of both concentric and eccentric, with a group that received no training at all. Twenty-eight healthy volunteers (male and females), 18 to 36 years of age, with no history of shoulder pathology, were randomly assigned to one of four groups; concentric training, eccentric training, a combination of both concentric and eccentric training, or control (no training). Testing and training of the dominant shoulder was performed on an isokinetic dynamometer. All subjects were pretested and post-tested both concentrically and eccentrically for humeral internal/external rotation and abduction at speeds of 60 degrees/sec and 120 degrees/sec. Each training session consisted of a total of twelve sets of ten maximal repetitions, and was repeated three times a week for four weeks. The absolute and percent difference in peak force and peak torque for each group between the pretest and post-test was calculated for each combination of position, mode, and speed. A significant difference between the concentric/eccentric group and the eccentric group was found for abduction (p < 0.05). The eccentric group showed a significantly greater increase from the pretest to post-test for absolute differences in peak force and peak torque compared to the concentric/eccentric group (p < 0.05).

Acetic acid is not involved in enhanced intestinal protein synthesis by the presence of the gut microflora in chickens.

1. The present study was conducted to clarify whether or not acetic acid was responsible for enhanced intestinal protein synthesis by the gut microflora in chickens. 2. Conventional and germ-free chicks were fed a practical experimental diet supplemented with or without powdered distilled acetic acid for 10 days from 8 to 18 days of age. At the end of the experimental period, intestinal protein synthesis was measured by injecting a large dose of L-[4-3H]phenylalanine through a wing vein. 3. The results showed that the responses of fractional synthesis rate and protein: DNA ratio to acetic acid supplementation in the jejuno-ileum and caecum were opposite to those observed by the presence of the gut microflora. 4. It was conducted, therefore, that acetic acid was not involved in enhanced intestinal protein synthesis by the presence of the gut microflora in chickens.