Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intestinal incretin hormone glucagon-like peptide I (GLP-I) inhibits gastric motility and secretion in normal, but not in vagotomized subjects, pointing to a centrally mediated effect. Therefore, our aim was to study the availability of rat brain GLP-I receptors to peripherally injected 125I-labeled GLP-I. The specificity of the binding was tested by co-injection of excess amounts of unlabeled GLP-I. Using light microscopical autoradiography of rat brain sections, we found specific 125I-GLP-I binding exclusively in the subfornical organ and the area postrema. This binding was abolished when an excess amount of unlabeled GLP-I was co-injected with the labeled GLP-I. We conclude that cells in the subfornical organ and the area postrema could be responsive to blood-borne GLP-I. The observed binding of peripherally administered GLP-I to the subfornical organ and the area postrema, which both have close neuroanatomical connections with hypothalamic areas involved in water and appetite homeostasis, is consistent with the potential roles of circulating GLP-I in the central regulation of appetite and autonomic functions.
Diabetes 1996 Jun
PMID:Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. 863 62

The mechanisms by which glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion were investigated by measurements of whole-cell Ca2+ currents, the cytoplasmic Ca2+ concentration, and cell capacitance as an indicator of exocytosis in individual mouse pancreatic beta-cells maintained in short-term culture. GIP produced a 4.2-fold potentiation of depolarization-induced exocytosis. This stimulation of exocytosis was not associated with a change in the whole-cell Ca2+-current, and there was only a small increase (30%) in the cytoplasmic Ca2+ concentration [intercellular free Ca2+([Ca2+]i)]. The stimulatory effect of GIP on exocytosis was blocked by pretreatment with the specific protein kinase A (PKA) inhibitor Rp-8-Br-cAMPS. Glucagon-like peptide-I(7-36) amide (GLP-I) stimulated exocytosis (90%) in the presence of a maximal GIP concentration (100 nmol/l). Replacement of GLP-I with forskolin produced a similar stimulatory action on exocytosis. These effects of GLP-I and forskolin in the presence of GIP did not involve a change in the whole-cell Ca2+-current or [Ca2+]i. GIP was ineffective in the presence of both forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Under the same experimental conditions, the protein kinase C (PKC)-activating phorbol ester 4-phorbol 12-myristate 13-acetate (PMA) stimulated exocytosis (60%). Collectively, our data indicate that the insulinotropic hormone GIP stimulates insulin secretion from pancreatic beta-cells, through the cAMP/PKA signaling pathway, by interacting with the secretory machinery at a level distal to an elevation in [Ca2+]i.
Diabetes 1997 Apr
PMID:Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. 907 1

Glucagon-like peptide I (GLP-I), an intestine-derived incretin hormone, is a potent stimulator of insulin and somatostatin secretion. In some studies, GLP-I is an inhibitor of glucagon secretion. It remains uncertain, however, whether the effect of GLP-I on the inhibition of glucagon secretion is direct, owing to interactions with GLP-I receptors on alpha-cells, or indirect, via paracrine suppression by insulin or somatostatin. The localization of the GLP-I receptor on insulin and somatostatin-producing cells in the islets is well established. Whether the GLP-I receptor also resides on the glucagon-producing alpha-cells remains controversial and is reported to be absent on rat alpha-cells. To investigate the distribution of the GLP-I receptor on islet cells, we examined the expression of GLP-I receptor mRNA in phenotypically distinct islet cell lines and islets, and the presence of immunoreactive GLP-I receptor in dispersed rat islet cells using a specific antiserum. GLP-I receptor mRNA was readily detected by reverse transcription-polymerase chain reaction (RT-PCR) in both rat islets and in established islet cell lines representing distinct alpha-, beta-, and delta-cell phenotypes. In addition, GLP-I receptor expression was detected in single rat alpha-cells by single-cell RT-PCR. In dispersed rat islet cells analyzed by double immunofluorescent staining, 90% of the insulin, 76% of the somatostatin, and 20% of the glucagon positive cells colocalized with the GLP-I receptor immunoreactivity. Thus, a substantial population of glucagon immunoreactive a-cells express the GLP-I receptor. These findings imply that GLP-I may have a direct receptor-mediated action in the regulation of the physiological functions on a substantial subpopulation of alpha-cells. We suggest that a possible role for GLP-I receptors on alpha-cells may be to provide positive autocrine feedback control on glucagon secretion during fasting and/or to dampen the potent paracrine suppression of glucagon secretion by insulin during feeding.
Diabetes 1997 May
PMID:Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. 913 45

High-resolution capacitance measurements were used to explore the effects of the gut hormones GLP-I(7-36) amide [glucagon-like peptide I(7-36) amide] and GIP (glucose-dependent insulinotropic polypeptide) on Ca2+-dependent exocytosis in glucagon-secreting rat pancreatic alpha-cells. Both peptides produced a greater than threefold potentiation of secretion evoked by voltage-clamp depolarizations, an effect that was associated with an approximately 35% increase of the Ca2+ current. The stimulatory actions of GLP-I(7-36) amide and GIP were mimicked by forskolin and antagonized by the protein kinase A (PKA)-inhibitor Rp-8-Br-cAMPS. The islet hormone somatostatin inhibited the stimulatory action of GLP-I(7-36) amide and GIP via a cyclic AMP-independent mechanism, whereas insulin had no effect on exocytosis. These data suggest that the alpha-cells are equipped with receptors for GLP-I and GIP and that these peptides, in addition to their well-established insulinotropic capacity, also stimulate glucagon secretion. We propose that the reported inhibitory action of GLP-I on glucagon secretion is accounted for by a paracrine mechanism (e.g., mediated by stimulated release of somatostatin that in turn suppresses exocytosis in the alpha-cell).
Diabetes 1997 May
PMID:Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. 913 46

To establish potential effects of glucagon-like peptide I (GLP-I) on blood glucose control in insulin-deficient states, GLP-I [GLP-I(7-36) amide; 10 pmol x kg(-1) x min(-1)] was infused intravenously in six fasting, canine C-peptide-negative, chronically diabetic dogs for 8 h. Blood samples were saved for the analysis of hormones, metabolites, and turnover rates of glucose (6-(3)H-glucose), alanine (U-(14)C-alanine), and urea ((15)N(2)-urea) starting 22 h after the last subcutaneous dose of exogenous insulin. Circulating plasma GLP-I levels rose under infusion from 2.9 +/- 0.8 to 41.4 +/- 10.1 pmol/l. This was efficient to significantly reduce the preexisting diabetic hyperglucagonemia. Since in the utilized model functioning pancreatic beta-cells are lacking, GLP-I had no insulinogenic effect. Compared with control experiments in the same animals receiving saline infusion, glycemia dropped from 20.8 +/- 1.9 to 16.2 +/- 1.0 mmol/l (P < 0.05). This was in parallel to the infusion of GLP-I and was most likely caused by a decrease of elevated glucose production since overall glucose turnover decreased with no alteration in glucose metabolic clearance. Alanine turnover was significantly reduced, obviously reflecting a decline in alanine production in relation to changed muscle glucose uptake under conditions of lower glycemia and overall glucose turnover. There was, however, neither an effect of GLP-I on alanine conversion into circulating glucose nor an effect on urea production rate, indicating unchanged gluconeogenesis from amino acid precursors. We conclude that the blood glucose-lowering effect of GLP-I in an animal model of insulinopenia was shown to be due to a reduction in hepatic glucose output, possibly secondary to reduction in glucagon concentrations leading to decreased glycogenolysis. Whether GLP-I might be therapeutically useful in clinical insulin-deficient diabetes needs to be verified.
Diabetes 1997 May
PMID:Blood glucose lowering and glucagonostatic effects of glucagon-like peptide I in insulin-deprived diabetic dogs. 913 50

To search if biological effects of GLP-I on glucose metabolism in extrapancreatic tissue are present in diabetic states, we have studied the action of GLP-I and insulin on glycogen-enzyme activity, glycogen synthesis, and glucose metabolism in isolated hepatocytes and soleus muscle from adult streptozotocin (STZ)- and neonatal STZ-treated diabetic rats. This work confirms the previously reported insulin-like effects of GLP-I on glucose metabolism in both muscle and liver tissue from normal rats (control). The present study extends those observations to the muscle and liver tissue of diabetic animals. In both muscle and liver tissue, the metabolism of D-glucose, in the absence of added peptides, was more severely affected in adult STZ (IDDM model) than in neonatal STZ (nSTZ; NIDDM model) rats, and the magnitude of hormonal effect on metabolic variables was lower in diabetic rats than in control rats, as a rule. Nevertheless, in liver and muscle tissue of diabetic rats, GLP-I was able to increase glycogen synthase activity, augment the net rate of D-[U-14C]glucose incorporation into glycogen, and increase D-[5-3H]glucose utilization, D-[U-14C]glucose oxidation, and lactate production. In conclusion, GLP-I exerts insulin-like effects on D-glucose metabolism in both muscle and liver tissue in IDDM or NIDDM animal models, and present observations reinforce the view that GLP-I may represent a most promising tool in the treatment of diabetic patients.
Diabetes 1997 Aug
PMID:Preserved GLP-I effects on glycogen synthase a activity and glucose metabolism in isolated hepatocytes and skeletal muscle from diabetic rats. 923 49

The whole-cell patch-clamp method was used to examine the effect of glucagon-like peptide I (GLP-I)(7-36) amide on the activation process of L-type Ca2+ channels of rat pancreatic beta-cells. After depolarization, GLP-I (1-100 nmol/l) caused action potentials in cells exposed to a glucose-free solution for 10 min. The percentage of cells producing action potential depended on the concentration of GLP-I. In some cells, GLP-I caused action potentials without the prior depolarization of the membrane. In cells exposed to the glucose-free solution for longer than 30 min, or in cells that were deprived of ATP by a means of the conventional whole-cell configuration, GLP-I (20 nmol/l) did not cause the electrical excitation. Application of GLP-I augmented the maximum Ba2+ current (IBa) through L-type Ca2+ channels and shifted the current voltage curve to the left. Values of changes in the maximum IBa depended on GLP-I concentration. Application of dibutyryl cAMP (dbcAMP, 1 mmol/l) also augmented IBa. In cells pretreated with Rp-cAMP, dbcAMP did not change the magnitude of IBa. Also in cells pretreated with Rp-cAMP, GLP-I failed to augment IBa. These results suggest that in pancreatic beta-cells, GLP-I, by a cAMP-dependent mechanism, increases opening of L-type Ca2+ channels. cAMP-dependent augmentation of Ca2+ entry as well as cAMP production itself by GLP-I plays a crucial role in controlling insulin secretion.
Diabetes 1997 Nov
PMID:GLP-I(7-36) amide augments Ba2+ current through L-type Ca2+ channel of rat pancreatic beta-cell in a cAMP-dependent manner. 935 22

Glucagon-like peptide I (GLP-I) stimulates glucose-dependent insulin secretion and inhibits food intake in the central nervous system. Because leptin reduces food intake but inhibits insulin secretion, we examined leptin action in mice with a null mutation in the GLP-I receptor. Intracerebroventricular leptin administration inhibited food intake in both wild-type and GLP-I receptor (GLP-IR) -/- mice, and daily intraperitoneal administration of leptin for 2 weeks produced comparable reductions in food intake and body weight in control and GLP-IR -/- mice. Glucose tolerance was improved in both wild-type and GLP-IR -/- mice, whether pair fed or leptin treated; however, blood sugars were significantly lower in the leptin-treated GLP-IR -/- mice following oral glucose challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and leptin-treated mice (P < 0.01-0.001); however, insulin levels were significantly lower in leptin-treated versus pair-fed GLP-IR -/- mice (P < 0.01). A single leptin injection had no effect on glucose tolerance in GLP-IR -/- mice, but decreased hepatic PEPCK mRNA in both wild-type and GLP-IR -/- mice. The improvement in blood glucose excursion, despite lower levels of glucose-stimulated insulin in lean leptin-treated GLP-IR -/- mice, suggests that leptin may have beneficial effects on control of blood glucose in the absence of obesity. Furthermore, the greater effects of leptin on glucose and insulin in leptin-treated versus pair-fed GLP-IR -/- mice raises the possibility that disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.
Diabetes 1997 Dec
PMID:Leptin sensitivity in nonobese glucagon-like peptide I receptor -/- mice. 939 91

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon. This precursor is processed by tissue-specific proteolysis to produce glucagon in pancreatic alpha-cells and a glucagon-like peptide-1 (GLP-1) in the intestine. GLP-1 is a hormone that is released by intestinal cells into the circulation in response to food intake. GLP-1 and gastric inhibitory peptide (GIP) which has also been termed glucose-dependent insulinotropic peptide appear to account for most of the incretin effect in the augmentation of glucose-stimulated insulin secretion. These two hormones have specific beta-cell receptors that are coupled to GTP binding proteins to induce production of cyclic AMP and activation of cyclic AMP-dependent protein kinase. It is proposed that at least one factor contributing to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is desensitization of the GLP-1 receptor on beta-cells. At pharmacological doses, infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin response in NIDDM patients. Agonists of GLP-1 receptor have been proposed as new potential therapeutic agents in NIDDM patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of NIDDM.
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PMID:Glucagon-like peptide-1 structure, function and potential use for NIDDM. 939 46

Glucagon-like peptide-I (GLP-I) is a potent insulinotropic incretin hormone. Since the insulinotropic action of GLP-I is preserved in patients with diabetes mellitus, the peptide is now tested as new therapeutic agent for the treatment of diabetes. The number of GLP-I receptors present on B cells is regulated by several signal transduction pathways. In this study, we generated several Chinese hamster ovary (CHL) cell lines stably expressing different numbers of GLP-I receptors. The effects on binding properties and signal transduction were characterized. The lowest number of receptors was 1,791 per cell; the highest was 378,720 per cell. A comparable affinity against GLP-I was obtained with all clones. The three clones with the lowest numbers of receptors (1,791, 4,371, and 5,633 per cell) did not show any cyclic AMP (cAMP) generation in response to GLP-I (1 pM-1 microM). Cells expressing 13,175, 41,872, 271,003, and 378,720 receptors, respectively, increased cAMP concentration-dependently after GLP-I. The cell line with the highest number of receptors had the maximal response (352% of controls) but a dramatically reduced EC50 (100 nM, compared to 8 and 7 nM). All cell lines showed an identical cAMP response to 1 and 10 microM forskolin. These data demonstrate that a minimum number of GLP-I receptors is required for signal transduction. The GLP-I receptor is desensitized when expressed in high numbers on the cells. In this case, the signal transduction properties remain unchanged.
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PMID:High-level expression of the GLP-I receptor results in receptor desensitization. 978 47


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