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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies on the enteroinsular axis in Zucker rats, it was found that glucose-dependent insulinotropic polypeptide (GIP) levels were normal in obese animals, but the glucose threshold for the insulinotropic action of GIP in the perfused rat pancreas was reduced. Glucagon-like peptide I (GLP-I)(7-36) is also an important incretin, and in the current study, glucose, insulin, and immunoreactive (IR)-COOH-terminal GLP-I responses to oral glucose were compared in lean (Fa/?) and obese (fa/fa) rats. In addition, the concentration thresholds for stimulation and glucose dependence of perfused pancreases to GLP-I(7-36) were examined. Glucose responses to oral glucose were similar in fa/fa and Fa/? rats. Obese animals were hyperinsulinemic when fasting and after oral glucose. Significant increases in IR-GLP-I levels in response to glucose were only observed in fa/fa rats. Perfused pancreases from fa/fa rats hypersecreted insulin at all glucose concentrations. In the presence of 4.4 mmol/l glucose, GLP-I(7-36) increased insulin secretion in fa/fa pancreases approximately 25-fold, whereas there was only a 5-fold increase in Fa/? pancreases. Pancreases from fa/fa rats, perfused with a glucose gradient (2.8-11 mmol/l) in the presence of GLP-I(7-36), responded with an immediate increase in insulin secretion, i.e., at a glucose concentration of 2.8 mmol/l, whereas Fa/? pancreases required a minimum of 4.22 mmol/l glucose for stimulation. With high glucose (16.7 mmol/l), both fa/fa and Fa/? rat pancreases exhibited similar responsiveness to GLP-I(7-36), having thresholds of < 50 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 May
PMID:Altered glucose dependence of glucagon-like peptide I(7-36)-induced insulin secretion from the Zucker (fa/fa) rat pancreas. 772 5

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jun
PMID:Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. 778 25

In the insulin-secreting beta-cell line beta TC3, stimulation with 11.2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in only 18% of the tested cells. The number of glucose-responsive cells increased after pretreatment of the cells with glucagon-like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of the cells responded to glucose with a rise in [Ca2+]i. GLP-I(7-36)amide induces a rapid increase in [Ca2+]i only in cells exposed to elevated glucose concentrations (> or = 5.6 mmol/l). The action of GLP-I(7-36)amide and forskolin involved a 10-fold increase in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through voltage-dependent L-type Ca2+ channels, which then produced a further increase in [Ca2+]i by mobilization from intracellular stores. The latter effect reflected Ca(2+)-induced Ca2+ release and was blocked by ryanodine. Similar increases in [Ca2+]i were also observed in voltage-clamped cells, although there was neither activation of a background (Ca(2+)-permeable) inward current nor enhancement of the voltage-dependent L-type Ca2+ current. These observations are consistent with GLP-I(7-36) amide inducing glucose sensitivity by promoting mobilization of Ca2+ from intracellular stores. We propose that this novel action of GLP-I(7-36)amide represents an important factor contributing to its insulinotropic action.
Diabetes 1995 Jul
PMID:Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization. 778 44

The arylpiperazine L-686,398 was described as an oral hypoglycemic agent and is shown to be an insulin secretagogue in vitro. The characteristics of its activity were similar to those of the incretin glucagon-like peptide I (GLP-I). We demonstrate that both the peptide and L-686,398 increase the accumulation of cAMP in isolated ob/ob mouse pancreatic islet cells, but by different mechanisms. Although GLP-I activates adenylate cyclase, the arylpiperazine has no effect on this enzyme or on the binding of 125I-labeled GLP-I to its receptor on RINm5F rat insulinoma cell membranes. However, L-686,398 inhibits the total cAMP phosphodiesterase (PDE) activity in homogenates of ob/ob mouse pancreatic islets with an EC50 of approximately 50 mumol/l. To determine the mechanism of PDE inhibition by the arylpiperazine and to examine its specificity, we studied the kinetics of arylpiperazine inhibition of two recombinant PDEs. The arylpiperazine is a competitive inhibitor of both a human heart type III PDE and a rat type IV-D PDE. Inhibition of the type III and IV isozymes are characterized by Ki values of 27 and 5 mumol/l, respectively. Although not extremely potent, the arylpiperazine does exhibit modest selectivity between these PDEs. The observation that L-686,398 acts as a PDE inhibitor suggests that exploration for beta-cell-specific PDE isoforms may reveal novel PDEs as targets for the development of therapeutically useful glucose-dependent insulin secretagogues.
Diabetes 1995 Jan
PMID:A novel insulin secretagogue is a phosphodiesterase inhibitor. 781 16

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and is considered as a new therapeutic tool in the treatment of diabetes mellitus. This study was designed to precisely characterize the binding behavior and activation of the recombinant GLP-I receptor against naturally occurring ligands of the glucagon/VIP/secretin peptide hormone family. CHO-cells were stably transfected with a plasmid containing a cDNA encoding for the rat GLP-I receptor. Northern blot analysis with this cDNA showed a single band of 2.7 kb in CHO cells, while in RINm5F cells, three bands of 2.7, 3.4, and 3.6 kb were specifically labelled. In receptor-binding studies 125I-GLP-I was displaced by GLP-I and weakly by PHI and oxyntomodulin but not by helodermin, helospectin I, helospectin II, secretin, VIP, and PACAP-38. Intracellular cAMP generation was stimulated by GLP-I, PHI, and oxyntomodulin. Helodermin, helospectin I, helospectin II, secretin, VIP, and PACAP-38 were not able to displace 125I-GLP-I from its receptor or to stimulate intracellular cAMP production. This data shows that the GLP-I receptor is characterized by a high ligand specificity.
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PMID:Ligand-specificity of the rat GLP-I receptor recombinantly expressed in Chinese hamster ovary (CHO-) cells. 801 94

Using specific radioimmunoassays, we studied the occurrence of amidated and glycine-extended glucagon-like peptide I (GLP-I) molecules in the human small intestine and pancreas and in the circulation system in response to a breakfast meal. Through gel permeation chromatography of extracts of the human pancreas (n = 5), we found that 71% of the GLP-I immunoreactivity eluted as a large molecule corresponding to the major proglucagon fragment, 24% corresponded to GLP-I 1-36 amide, and 5% to GLP-I 1-37. By gel permeation chromatography of extracts of human small intestine (n = 6), we found that all immunoreactivity eluted in one peak at the common elution position of the two insulin-releasing peptides, GLP-I 7-36 amide and GLP-I 7-37. Of the GLP-I immunoreactivity, 80% corresponded to GLP-I 7-36 amide and 20% to GLP-I 7-37. The mean concentrations of amidated GLP-I and glycine-extended GLP-I in fasting plasma were 7 +/- 1 and 6 +/- 1 pM, respectively (n = 6). In response to a breakfast meal, the concentration of amidated GLP-I rose significantly amounting to 41 +/- 5 pM 90 min after the meal ingestion, whereas the concentration of glycine-extended GLP-I only rose slightly to a maximum of 10 +/- 1 pM. Thus, both amidated and glycine-extended GLP-I molecules are produced in the small intestine and in the pancreas in humans. Both amidated and glycine-extended GLP-I are measurable in fasting plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Apr
PMID:Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. 813 58

Potentiation of glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major peptides with potent insulinotropic action have been recognized: gastric inhibitory peptide and truncated forms of glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a glucose-competent state. Interactions between glucoincretin signaling and glucose-induced insulin secretion may result from the phosphorylation of key elements of the glucose signaling pathway by cAMP-dependent protein kinase. These include the ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory peptide and glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these hormones on the beta-cells are probably altered. At pharmacological doses, infusion of glucagon-like peptide I but not gastric inhibitory peptide, can ameliorate postprandial insulin secretory response in NIDDM patients. Agonists of the glucagon-like peptide I receptor have been proposed as new therapeutic agents in NIDDM.
Diabetes 1993 Sep
PMID:Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM. 834 31

Rat pancreatic alpha- and beta-cells are critically dependent on hormonal signals generating cyclic AMP (cAMP) as a synergistic messenger for nutrient-induced hormone release. Several peptides of the glucagon-secretin family have been proposed as physiological ligands for cAMP production in beta-cells, but their relative importance for islet function is still unknown. The present study shows expression at the RNA level in beta-cells of receptors for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide I(7-36) amide (GLP-I), while RNA from islet alpha-cells hybridized only with GIP receptor cDNA. Western blots confirmed that GLP-I receptors were expressed in beta-cells and not in alpha-cells. Receptor activity, measured as cellular cAMP production after exposing islet beta-cells for 15 min to a range of peptide concentrations, was already detected using 10 pmol/l GLP-I and 50 pmol/l GIP but required 1 nmol/l glucagon. EC50 values of GLP-I- and GIP-induced cAMP formation were comparable (0.2 nmol/l) and 45-fold lower than the EC50 of glucagon (9 nmol/l). Maximal stimulation of cAMP production was comparable for the three peptides. In purified alpha-cells, 1 nmol/l GLP-I failed to increase cAMP levels, while 10 pmol/l to 10 nmol/l GIP exerted similar stimulatory effects as in beta-cells. In conclusion, these data show that stimulation of glucagon, GLP-I, and GIP receptors in rat beta-cells causes cAMP production required for insulin release, while adenylate cyclase in alpha-cells is positively regulated by GIP.
Diabetes 1996 Feb
PMID:Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. 854 71

Intestinal proglucagon is thought to be synthesized primarily by the distal gut, although the role of proglucagon-derived glucagon-like peptide I (GLP-I) as a major physiological incretin would seem to be associated with production in proximal small bowel. To better characterize the sites of production of proglucagon and GLP-I in the small intestine and evaluate nutrient regulation of small bowel proglucagon and derived peptides, we evaluated the effects of fasting for 72 h and subsequent refeeding or jejunal infusion of long-chain triglyceride (LCT) for 24 h on local expression of proglucagon in proximal and distal small bowel. Proglucagon mRNA abundance and cellular localization were determined and correlated with wet weight of bowel. In jejunum, proglucagon mRNA abundance decreased by 40% with fasting (P < 0.005) and increased with refeeding to levels similar to those of ad libitum-fed animals. In ileum, fasting resulted in a 20% decrease in proglucagon mRNA (P < 0.005); in contrast to jejunum, refeeding did not result in a significant rise in ileal proglucagon mRNA abundance from fasting values. In jejunum, signal intensity of proglucagon mRNA per cell, determined by in situ hybridization, decreased with fasting (P < 0.05) and increased with refeeding (P < 0.005) in proportion to changes in mRNA abundance. Plasma enteroglucagon and GLP-I levels correlated with jejunal proglucagon mRNA. Intrajejunal infusion of LCT increased expression of proglucagon to a greater extent in jejunum than in ileum. In conclusion, enteral nutrient intake stimulates small bowel proglucagon expression; this effect is greater in jejunum than ileum, consistent with greater intraluminal nutrient exposure and the role of jejunum as a source of the major incretin GLP-I.
Diabetes 1996 Apr
PMID:Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum. 860 64

Glucagon-like peptide I (GLP-I) decreases plasma glucose in type II diabetic patients and in healthy subjects indirectly by stimulation of insulin and inhibition of glucagon secretion, whereby the hepatic glucose production decreases. However, recent studies indicate that GLP-I may also directly influence peripheral and hepatic glucose uptake. We infused somatostatin (SS) intravenously (500 or 1,000 microgram/h) in 13 healthy subjects to suppress insulin and glucagon secretion from the endocrine pancreas, together with infusion of either GLP-I (50 pmol / kg / h) or saline intravenously. After 30 min, a 25-g intravenous glucose tolerance test (IVGTT) was carried out, and plasma concentrations of glucose, insulin, glucagon, and GLP-I were measured during the following 2 h. IVGTT together with GLP-I infusion significantly elevated insulin during 500 microgram/h SS but not during 1,000 microgram/h SS. Plasma glucagon was strongly depressed in all experiments. During 500 microgram/h SS, the glucose disappearance constant, Kg, was 0.49 +/- 0.03% per minute with GLP-I and 0.39 +/- 0.04% per minute with saline (n = 8, P = 0.004). With 1,000 microgram/h SS, Kg was 0.42 +/- 0.03% per minute with GLP-I and 0.40 +/- 0.03% per minute without (NS). In conclusion, when endogenous insulin secretion is held at a constant low level, which may be accomplished only with very large doses of SS, GLP-I has no effect on glucose elimination. Thus, an insulin-independent effect of GLP-I on glucose disposal could not be demonstrated.
Diabetes 1996 May
PMID:The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. 862 Oct 2


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