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PubMed2001

Suppression by exendin(9-39)amide of glucagon-like peptide-1 insulinotropic action in rats infused with dimethyl ester of succinic acid.

Glucagon-like peptide-1 (GLP-1) acts as a nutrient-dependent insulin-releasing agent, and its insulinotropic action is enhanced by nutrient secretagogues, such as the dimethyl ester of succinic acid (SAD). In the present study, a primed constant infusion of SAD (0.5 micromol followed by 0.25 micromol/min both per g of body wt) was found to increase plasma insulin concentration in fed anesthetized rats, to potentiate the B-cell secretory response to GLP-1 (0.5 pmol/g of body wt), and to unmask the hypoglycemic potential of the gastrointestinal hormone. In the SAD-infused rats, the infusion of exendin(9-39)amide (5.0 pmol/min per g of body wt), 1 min before and 3 min after GLP-1 injection, decreased plasma insulin concentration before GLP-1 injection, suppressed the B-cell secretory response to GLP-1, and both delayed and minimized its hypoglycemic action. It is proposed, therefore, that exendin (9-39)amide could represent a tool in the treatment of alimentary or reactive hypoglycemia.

Animals↗
PubMed1984

[Changes of gastrin levels in autoimmune thyroid disorders. Part I: Thyroid functions and gastrin levels].

The relationship between thyroid disorders and gastric pathophysiology has been studied mainly from standpoints of gastric histology and gastric acid output capacity. Though anti-gastric antibody has been thought to play a part in this relationship, there have been no clear conclusions obtained about that. Since blood gastrin levels are easily measurable by radioimmunoassay today, the relationship between thyroid disorders and gastric pathophysiology has drawn attention again from a standpoint of gastrin levels. Seino et al. have reported about hypergastrinemia in hyperthyroidism, speculating that beta-adrenergic hyperresponsiveness of gastrin-producing cells could be the mechanism of hypergastrinemia. However, there are other reports which mentioned feedback mechanism between gastrin and gastric acid or interaction of gastrointestinal hormones as the main mechanism of hypergastrinemia. In this study, the problem of gastrin in Graves' disease and chronic thyroiditis were studied by measurement of fasting serum gastrin levels and gastric juice excretion in view of feedback mechanism between gastrin-producing cells and parietal cells which are the target cells of gastrin. Following results were obtained. Fasting serum gastrin levels in Graves' disease were 236.2 +/- 39.1 (mean +/- SE) pg/ml for 39 hyperthyroid patients and 126.3 +/- 23.9 pg/ml for 35 euthyroid patients. These levels were significantly higher than those of sex and age-matched control subjects with P less than 0.001 and P less than 0.05, respectively. Fasting serum gastrin levels in serial studies of 13 patients with Graves' disease were 222.3 +/- 56.7 pg/ml before treatment and 167.3 +/- 56.6 pg/ml at the time of euthyroid state after a mean observation period of 6.6 +/- 1.1 months. Fasting serum gastrin levels at the time of euthyroid state decreased significantly when compared with fasting serum gastrin levels before treatment (P less than 0.05). Fasting serum gastrin levels in chronic thyroiditis were 160.7 +/- 51.1 pg/ml for 24 hypothyroid patients and 96.4 +/- 24.7 pg/ml for 31 euthyroid patients. Each of these levels had no significant differences when compared with sex and age-matched control subjects. Fasting serum gastrin levels in serial studies of 10 patients with chronic thyroiditis were 81.1 +/- 18.0 pg/ml at the time of hypothyroid state and 91.5 +/- 15.2 pg/ml at the time of euthyroid state after a mean observation period of 7.1 +/- 2.1 months. Fasting serum gastrin levels before treatment had no significant differences when compared with fasting serum gastrin levels in euthyroid state.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1978

Immunohistochemical changes of somatostatin cells in the pancreatic islets of rats after streptozotocin administration.

By the enzyme-labeled antibody method, cells containing somatostatin (SRIF) as well as insulin or glucagon were identified in pancreatic islets of the rat. SRIF antiserum was raised in rabbits followin immunization with synthetic SRIF coupled with human serum alpha-globulin and did not cross-react with hypothalamic, pituitary or gastrointestinal hormones using our immunoassay method. In the control rats, SRIF-containing cells were scattered in the periphery of the islets in close proximity to the outer glucagon containing cells. These latter cells were distributed in the outermost periphery of the islets. Insulin-containing cells were located in the central portion of the islets and dominantly occupied most of the islet. In the streptozotocin-diabetic rat, SRIF-containing cells were significantly increased in number whereas insulin-containing cells were markedly reduced. It is suggested from these findings that the number as well as the distribution of SRIF-, insulin- and glucagon-containing cells was important to the physiological and pathophysiological functioning of the islet.

Animals↗
PubMed2003

Characterisation of human dipeptidyl peptidase IV expressed in Pichia pastoris. A structural and mechanistic comparison between the recombinant human and the purified porcine enzyme.

Dipeptidyl peptidase IV/CD26 (DP IV) is a multifunctional serine protease cleaving off dipeptides from the N-terminus of peptides. The enzyme is expressed on the surface of epithelial and endothelial cells as a type II transmembrane protein. However, a soluble form of DP IV is also present in body fluids. Large scale expression of soluble human recombinant His(6)-37-766 DP IV, using the methylotrophic yeast Pichia pastoris, yielded 1.7 mg DP IV protein per litre of fermentation supernatant. The characterisation of recombinant DP IV confirmed proper folding and glycosylation similar to DP IV purified from porcine kidney. Kinetic comparison of both proteins using short synthetic substrates and inhibitors revealed similar characteristics. However, interaction analysis of both proteins with the gastrointestinal hormone GLP-1(7-36) resulted in significantly different binding constants for the human and the porcine enzyme (Kd = 153.0 +/- 17.0 microM and Kd = 33.4 +/- 2.2 microM, respectively). In contrast, the enzyme adenosine deaminase binds stronger to human than to porcine DP IV (Kd = 2.15 +/- 0.18 nM and Kd = 7.38 +/- 0.54 nM, respectively). Even though the sequence of porcine DP IV, amplified by RT-PCR, revealed 88% identity between both enzymes, the species-specific variations between amino acids 328 to 341 are likely to be responsible for the differences in ADA-binding.

Adenosine Deaminase↗
PubMed1997

Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance.

OBJECTIVE: The gastrointestinal hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are both released from the gut after oral glucose ingestion and stimulate insulin secretion. This study examined the release of these hormones in subjects with impaired glucose tolerance (IGT), which precedes the development of non-insulin-dependent diabetes. DESIGN AND METHODS: Six postmenopausal women with IGT, aged 59 years, underwent a 75 g oral glucose tolerance test and plasma levels of GIP and GLP-1 were determined regularly during the following 2 h. The results were compared with those in seven age- and weight-matched women with normal glucose tolerance (NGT). RESULTS: Basal plasma levels of GIP and GLP-1 were not different between the groups. In response to the oral glucose ingestion, plasma levels of both GIP and GLP-1 increased in both groups. The plasma GIP increase after glucose ingestion was, however, reduced in women with IGT. Thus, the GIP response as determined as the area under the curve for the 60 min after oral glucose was 34.8 +/- 3.2 pmol/l per min in women with IGT versus 56.4 +/- 7.8 pmol/l per min in those with NGT (P = 0.021). In contrast, the GLP-1 response to oral glucose was not different between the groups. By definition, the glucose response to oral glucose was markedly increased in women with IGT, and the insulin response during the second hour after glucose ingestion was exaggerated. CONCLUSIONS: The GIP response to oral glucose is impaired in postmenopausal women with IGT, whereas the plasma GLP-1 response is not affected.

Administration, Oral↗
PubMed1979

[In-vitro motility studies on the strips of the canine gallbladder (author's transl)].

In-vitro motility of the gallbladder was studied in the longitudinally cut full-thickness strips obtained from 61 mongrel dogs. The strips, 5 mm in width and 15 mm in length, were prepared from the fundus, body and infundibulum of the gallbladder wall and the motility was examined by the changes of contractile dynamics which were transduced on a pen chart recorder. The results were summarized as follows: 1. The specimen from three parts of the gallbladder exhibited spontaneous motility which was comprised of tonic and rhythmic contractions and they seemed to be stable approximately during the period from three and half an hour to six hours in the Tyrode solution. 2. There was a characteristic pattern which was specific for each three parts in the waves of spontaneous rhythmic contraction. The specimen from infundibulum showed almost regular waves which were predominantly comprised of greater amplitude than those of other two parts. 3. The effects of gastrointestinal hormones and similar substance, caerulein, tetragastrin and secretin were investigated on the activity. Caerulein and tetragastrin were found to be potent stimulant of the dog gallbladder. The stimulated contraction waves were uniform and the pattern could be described with using a certain mathematical expression.

Animals↗
PubMed2002

Secretin treatment for autistic disorder: a critical analysis.

We assessed evidence of the effects of secretin on behavior in individuals with autistic disorder. Articles were obtained through a MEDLINE search of the English-language literature from January 1966-November 2001; all investigations and case reports on the topic were included. Press releases obtained from the World Wide Web also were included. Secretin, a gastrointestinal hormone, is suggested to improve autistic symptoms, particularly social function and communication. Two formulations, porcine and synthetic human secretin, were evaluated in humans. A small body of literature and popular belief in autistic disorder communities supported the agent's efficacy. A number of controlled clinical trials did not show improvement in autistic symptoms with secretin compared with placebo, possibly indicating no role for the drug in autistic disorder.

Amino Acid Sequence↗
PubMed2006

Neurotensin phosphorylates GSK-3alpha/beta through the activation of PKC in human colon cancer cells.

Neurotensin (NT), a gastrointestinal hormone, binds its receptor [neurotensin receptor (NTR)] to regulate the growth of normal and neoplastic intestinal cells; molecular mechanisms remain largely undefined. Glycogen synthase kinase-3 (GSK-3) regulates diverse cellular processes, including cell growth and apoptosis. Here, we show that NT induces the phosphorylation of GSK-3alpha/beta in the human colon cancer cell line HT29, HCT116, or SW480, which possesses high-affinity NTR. The effect of NT was blocked by inhibitors of protein kinase C (PKC), but not by inhibitors of MEK1 or phosphatidylinositol-3 kinase, suggesting a predominant role for PKC in GSK-3beta phosphorylation by NT. Pretreatment with Gö6976 (which inhibits PKCalpha and PKCbeta1) or downregulation of endogenous PKCalpha or PKCbeta1 blocked NT-mediated GSK-3beta (but not GSK-3alpha) phosphorylation. Moreover, a selective PKCbeta inhibitor, LY379196, reduced NT-mediated GSK-3beta (but not GSK-3alpha) phosphorylation, suggesting a role for PKCbeta1 in the NT-mediated phosphorylation of GSK-3beta and an undefined kinase in the NT-mediated phosphorylation of GSK-3alpha. Treatment with NT or the GSK-3 inhibitor SB216763 increased the expression of cyclin D1, a downstream effector protein of GSK-3 and a critical protein for the proliferation of various cells. Our results indicate that NT uses PKC-dependent pathways to modulate GSK-3, which may play a role in the NT regulation of intestinal cell growth.

Cell Line, Tumor↗
PubMed1983

Disturbances of the alimentary tract motility and hypermotilinemia in the patients with diabetes mellitus.

Lower esophageal sphincter pressure (LESP), gastric emptying, small bowel transit time and plasma motilin levels were measured in diabetics and normal subjects in order to investigate the disturbances of the alimentary tract motility and the participation of motilin in these motility disorders. Hypermotilinemia was observed in all diabetics with or without autonomic neuropathy. Low response of LESP to tetragastrin found in diabetics with autonomic neuropathy could not be explained by motilin. Gastric emptying was highly correlated with fasting plasma motilin levels and a significantly accelerated gastric emptying observed in diabetics without complications or diabetics with diarrhea was considered to be due to hypermotilinemia. On the contrary, no significant correlation was observed between small bowel transit time and plasma motilin levels, suggesting no participation of endogenous motilin in the regulation of small bowel transit.

Adolescent↗
PubMed1994

Spermine-induced precocious intestinal maturation in suckling rats: possible involvement of glucocorticoids.

The mechanism(s) involved in the spermine-induced precocious postnatal maturation of the intestine in the unweaned rat was examined. Spermine given orally to 11-day-old rats stimulated ACTH and corticosterone secretion. Maximum serum levels of ACTH and corticosterone were observed between 4 and 6 h after spermine ingestion and were five- and sevenfold greater respectively than those of control rats receiving saline alone. Intraperitoneal injection of the polyamine had no effect on corticosterone production. Repeated intraperitoneal administration of gastrin, cholecystokinin, glucagon(1-37) and secretin to 11-day-old rats had no effect on the specific activity of intestinal disaccharidases. These data indicate that (1) the hypophysial-adrenal axis is implicated in the postnatal development of the gastrointestinal tract induced by spermine and (2) spermine affects ACTH and corticosterone secretion indirectly, probably by stimulating the release of gastrointestinal hormone(s).

Administration, Oral↗
PubMed1981

Effect of motilin on the sphincter of Oddi in the dog.

To investigate the action of motilin on the sphincter of Oddi, the flow rate of the perfusate (FRP) discharged into the duodenal lumen through the orifice of the common bile duct was measured by means of an electric drop counter in decerebrated dogs. Motilin in doses above 0.5 micrograms/kg i.v. reduced or stopped the FRP. The fifty percent recovery time of FRP was 20 min and full recovery time was 30 min. The reduction of FRP induced by motilin was unaffected by denervation and atropinization. These results suggest that motilin caused an increase in tone of the sphincter of Oddi by acting on the sphincter muscle.

Ampulla of Vater↗
PubMed1996

Anorexia in older persons: epidemiology and optimal treatment.

Anorexia and weight loss are common findings in older persons. Over a life-time, normal persons decrease their food intake to counterbalance the decrease in physical activity and resting metabolic rate that occurs with aging. This physiological anorexia of aging increases the propensity to develop pathological anorexia and weight loss when an older person develops either a medical or psychological illness. The physiological anorexia of aging is due to a decreased opioid (dynorphin) feeding drive and an increase in the satiating effect of the gastrointestinal hormone, cholecystokinin. Nitric oxide deficiency may play a role in the early satiation commonly seen in older persons. A variety of social, psychological and medical conditions can lead to pathological anorexia. Depression is the most common cause of weight loss and anorexia in older persons. A number of conditions such as cancer and rheumatoid arthritis produce their anorectic and wasting effects by releasing cytokines. An idiopathic pathological senile anorexia has been characterised which also appears to be a cytokine-dependent syndrome. Early screening for malnutrition is a cornerstone of the management of anorexia; the Mini Nutritional Assessment is a well validated screening tool available for this purpose. Aggressive use of caloric supplements, enteral tube feeding and peripheral parenteral nutrition all have a role in the early management of anorexia. Numerous drugs (growth hormone, megestrol, cyproheptadine, tetrahydrocannabinol, anabolic steroids, prokinetic agents and antidepressants) have been utilised to treat the anorexia of aging with varying success.

Aged↗
PubMed2005

Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus.

The 'incretin effect' describes the phenomenon of an enhanced insulin response following oral ingestion of glucose compared with that after intravenous administration of glucose, leading to identical postprandial plasma glucose excursions. It accounts for up to 60% of the postprandial insulin secretion, but is diminished in patients with type 2 diabetes mellitus. Gastrointestinal hormones that promote the incretin effect are called incretins. Glucagon-like peptide-1 (GLP-1) is an important incretin. Under hyperglycemic conditions in humans, it stimulates insulin secretion and normalizes blood glucose levels. GLP-1 does not stimulate insulin secretion at normal glucose levels; therefore, it does not cause hypoglycemia. Furthermore, it inhibits glucagon secretion and delays gastric emptying. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting the apoptosis of islet cells. The improvement of beta-cell function due to GLP-1 can be indirectly observed from the increased insulin secretory capacity of humans receiving such treatment. GLP-1 may represent an attractive therapeutic method for patients with type 2 diabetes because of its multiple effects, including the simulation of satiety in the CNS by acting as a transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. liraglutide) and exendin-4 (exenatide) that are resistant to degradation, called 'incretin mimetics', are being investigated in clinical trials. Dipeptidyl peptidase-IV inhibitors (e.g. vildagliptin, sitagliptin, and saxagliptin) that inhibit the enzyme responsible for incretin degradation are also being studied.

Animals↗
PubMed1988

Quin 2 and manganese define multiple alterations in cellular calcium homeostasis in diabetic rat pancreas.

The effects of streptozocin-induced diabetes on Ca2+ fluxes and intracellular free-Ca2+ [( Ca2+]i) levels were studied in isolated rat pancreatic acini. The basal rates of 45Ca influx in acini and of 45Ca efflux from acini that were preloaded with 45Ca were similar in normal and diabetic rats. The gastrointestinal hormone cholecystokinin octapeptide (CCK-8, 0.1 nM) and the Ca2+ ionophore A23187 (2 microM) increased 45Ca influx to the same extent in both groups of acini. CCK-8 and the divalent cation manganese exerted marked stimulatory effects on 45Ca efflux. In contrast to the rapid effect of CCK-8 on 45Ca efflux, the effect of manganese was slow in onset and was greater in diabetic rat acini. The diabetic state was also associated with a significant decrease in resting [Ca2+]i levels, as determined with the Ca2+ indicator quin 2. Furthermore, the ability of CCK-8 to raise [Ca2+]i levels was significantly attenuated in these cells. Insulin did not alter either basal or CCK-8-mediated increases in [Ca2+]i levels. Our findings suggest that insulin deficiency is associated with multiple alterations in Ca2+ homeostasis in the pancreatic acinar cell. These include a decrease in basal [Ca2+]i levels, perturbations in the signal transduction system that mediates the rapid mobilization of [Ca2+]i after CCK-8-receptor binding, and enhanced sensitivity to the actions of manganese on intracellular Ca2+ pools.

Aminoquinolines↗
PubMed1989

Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide.

We examined the effect of glucagonlike peptides (GLPs), which are cleaved from preproglucagon in the enteroglucagon cells, on rat endocrine pancreas with the isolated perfused system. GLP-I-(7-36)-amide, a truncated form of full-sequence GLP-I-(1-37), showed a potent inhibitory effect on glucagon secretion. This inhibitory effect of GLP-I-(7-36)-amide was demonstrated at concentrations of 0.25, 2.5, and 25 nM in 11.2 and 2.8 mM glucose. In contrast, insulin release was significantly stimulated by GLP-I-(7-36)-amide at its concentration from 0.025 to 25 nM in a high glucose concentration, whereas in a low glucose concentration, the stimulation was seen only at the highest concentration (25 nM). Neither GLP-I-(1-37) nor GLP-II showed any effect on glucagon and insulin release. Although several gastrointestinal hormones have been nominated as incretins, none of them may suppress the glucagon secretion. A truncated form of GLP-I, GLP-I-(7-36)-amide thus seems to be a unique incretin that exerts glucagonostatic action.

Animals↗
PubMed1998

Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.

Animals↗
PubMed1990

Characterization and significance of sulfonylurea receptors.

This study describes and characterizes a putative sulfonylurea receptor. The radioligand used was [3H]glipizide (9 Ci/mmol). The beta-cell plasma membranes were derived from a transplantable rat insulinoma generated by subcutaneous injection of RINm5F cells and purified by ultracentrifugation on a 15-55% sucrose gradient. Specific binding of [3H]glipizide to purified beta-cell plasma membranes was determined to be maximal at temperatures of 4-23 degrees C, pH 7.3, and an incubation of 2 h. Scatchard analysis indicated a single binding site with Kd = 7 nM and sulfonylurea binding of 0.93 pmol/mg membrane protein. Displacement of [3H]glipizide from the purified beta-cell plasma membranes by various sulfonylureas and their analogues correlated well with their known hypoglycemic and insulin-releasing activities. Various agents, including nutrients, agents affecting Ca2+ flux, gastrointestinal hormones, and pancreatic hormones, had no effect on [3H]glipizide binding to the beta-cell plasma membranes. Putative sulfonylurea receptors on beta-cell and brain cell plasma membranes have been reported by several groups of investigators. Sulfonylurea binding to the beta-cell is hypothesized to close an ATP-sensitive K+ channel, which leads to depolarization of the membrane and activation of a voltage-dependent Ca2+ channel.

ATP-Binding Cassette Transporters↗