Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive K+ channels (KATP channels) are present in various tissues, including pancreatic beta-cells, heart, skeletal muscles, vascular smooth muscles, and brain. KATP channels are hetero-octameric proteins composed of inwardly rectifying K+ channel (Kir6.x) and sulfonylurea receptor (SUR) subunits. Different combinations of Kir6.x and SUR subunits comprise KATP channels with distinct electrophysiological and pharmacological properties. Recent studies of genetically engineered mice have provided insight into the physiological and pathophysiological roles of Kir6.x-containing KATP channels. Analysis of Kir6.2 null mice has shown that Kir6.2/SUR1 channels in pancreatic beta-cells and the hypothalamus are essential in glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and that Kir6.2/SUR2 channels are involved in glucose uptake in skeletal muscles. Kir6.2-containing KATP channels in brain also are involved in protection from hypoxia-induced generalized seizure. In cardiovascular tissues, Kir6.1-containing KATP channels are involved in regulation of vascular tonus. In addition, the Kir6.1 null mouse is a model of Prinzmetal angina in humans. Our studies of Kir6.2 null and Kir6.1 null mice reveal that KATP channels are critical metabolic sensors in acute metabolic changes, including hyperglycemia, hypoglycemia, ischemia, and hypoxia.
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PMID:Roles of ATP-sensitive K+ channels as metabolic sensors: studies of Kir6.x null mice. 1556 8

Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (KATP channels) in the control of glucagon secretion from mouse pancreatic alpha-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50]=2.5 mmol/l) reduction of glucagon release. Maximum inhibition (approximately 50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 micromol/l) and glibenclamide (100 nmol/l) inhibited glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional KATP channels (SUR1-/-), glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0-20 mmol/l) and the sulfonylureas failed to inhibit glucagon secretion. Membrane potential recordings revealed that alpha-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the alpha-cell by approximately 7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the alpha-cell (approximately 17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K+ concentrations (threshold 25 mmol/l), glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6-15 mmol/l), and stimulation was first detectable at >25 mmol/l K+. In alpha-cells isolated from SUR1-/- mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1-/- alpha-cells. Recordings of the free cytoplasmic Ca2+ concentration ([Ca2+]i) revealed that, whereas glucose lowered [Ca2+]i to the same extent as application of tolbutamide, the Na+ channel blocker tetrodotoxin, or the Ca2+ channel blocker Co2+ in wild-type alpha-cells, the sugar was far less effective on [Ca2+]i in SUR1-/- alpha-cells. We conclude that the KATP channel is involved in the control of glucagon secretion by regulating the membrane potential in the alpha-cell in a way reminiscent of that previously documented in insulin-releasing beta-cells. However, because alpha-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the beta-cell, moderate membrane depolarization in alpha-cells is associated with reduced rather than increased electrical activity and secretion.
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PMID:ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse alpha-cells. 1556 9

The forkhead gene family, named after the founding gene member in Drosophila, is characterized by a unique DNA-binding domain. This so-called forkhead box encodes a winged-helix DNA-binding motif, the name of which describes the structure of the domain when bound to DNA. The three Fox (forkhead box) group A genes, Foxa1, Foxa2 and Foxa3, are expressed in embryonic endoderm, the germ layer that gives rise to the digestive system, and contribute to the specification of the pancreas and the regulation of glucose homoeostasis. Deletion of the Foxa2 gene in pancreatic beta-cells in mice results in a phenotype resembling PHHI (persistent hyperinsulinaemic hypoglycaemia of infancy). Molecular analyses have demonstrated that Foxa2 is an important regulator of the genes encoding Sur1, Kir6.2 and Schad (short chain L-3-hydroxyacyl-CoA dehydrogenase), mutation of which causes PHHI in humans. Foxa1 was shown to be an essential activator of glucagon gene expression in vivo. An additional winged-helix protein, Foxo1, contributes to pancreatic beta-cell function by regulating the Pdx1 gene, which is required for pancreatic development in cooperation with Foxa2.
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PMID:Winged-helix transcription factors and pancreatic development. 1563 23

The aim of the present study was to investigate the effect of a single dose of NN414 (a selective SUR1/Kir6.2 potassium channel opener). Sixty-four healthy male subjects were enrolled at 8 dose levels (0.625-12.5 mg/kg or placebo). The study consisted of a baseline day and a dosing day. NN414 or placebo was administered in the evening about 10 pm. On both study days, an oral glucose tolerance test (OGTT) was performed following an overnight fast (corresponding to 9 hours postdose), and glucose, insulin, glucagon, and growth hormone concentrations were determined. NN414 was well tolerated, with no clinically relevant changes in safety parameters, although there was an increase in gastrointestinal side effects. NN414 treatment lowered glucose during the OGTT and 24-hour insulin and glucose levels. In conclusion, a single dose of NN414 is associated with improvements in glucose-related parameters in healthy male subjects.
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PMID:The effects of NN414, a SUR1/Kir6.2 selective potassium channel opener, in healthy male subjects. 1595 66

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic alpha-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/K(IR)6.2-type ATP-sensitive K(+) (K(ATP)) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type K(ATP) channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca(2+) and is inhibited by nifedipine. Consistent with a regulatory interaction between K(ATP) channels and intra-islet zinc-insulin, WT islets exhibit an inverse correlation between beta-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of alpha-cell K(ATP) channels uncouples glucagon release from inhibition by beta-cells and reveals a role for K(ATP) channels in the regulation of glucagon release by low glucose.
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PMID:Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement. 1612 62

Neural and endocrine factors (i.e., Ach and GLP-1) restore defective glucose-stimulated insulin release in pancreatic islets lacking sulfonylurea type 1 receptors (SUR1(-/-)) (Doliba NM, Qin W, Vatamaniuk MZ, Li C, Zelent D, Najafi H, Buettger CW, Collins HW, Carr RD, Magnuson MA, and Matschinsky FM. Am J Physiol Endocrinol Metab 286: E834-E843, 2004). The goal of the present study was to assess fuel-induced respiration in SUR1(-/-) islets and to correlate it with changes in intracellular Ca(2+), insulin, and glucagon secretion. By use of a method based on O(2) quenching of phosphorescence, the O(2) consumption rate (OCR) of isolated islets was measured online in a perifusion system. Basal insulin release (IR) was 7-10 times higher in SUR1(-/-) compared with control (CON) islets, but the OCR was comparable. The effect of high glucose (16.7 mM) on IR and OCR was markedly reduced in SUR1(-/-) islets compared with CON. Ach (0.5 microM) in the presence of 16.7 mM glucose caused a large burst of IR in CON and SUR1(-/-) islets with minor changes in OCR in both groups of islets. In SUR1(-/-) islets, high glucose failed to inhibit glucagon secretion during stimulation with amino acids or Ach. We conclude that 1) reduced glucose responsiveness of SUR1(-/-) islets may be in part due to impaired energetics, as evidenced by significant decrease in glucose-stimulated OCR; 2) elevated intracellular Ca(2+) levels may contribute to altered insulin and glucagon secretion in SUR1(-/-) islets; and 3) The amplitudes of the changes in OCR during glucose and Ach stimulation do not correlate with IR in normal and SUR1(-/-) islets suggesting that the energy requirements for exocytosis are minor compared with other ATP-consuming reactions.
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PMID:Cholinergic regulation of fuel-induced hormone secretion and respiration of SUR1-/- mouse islets. 1663 20

A growth factor-mediated selection method was used to obtained insulin-secreting cells from human embryonic stem cells (hESC; Royan H1). Our resultant cells were positive for dithizone, a zinc-chelating agent known to selectively stain pancreatic beta cells and immunoreactive for antibodies against insulin, glucagon, and C-peptide. Semi-quantitative reverse transcription-polymerase chain reaction detected expression of proinsulin, insulin and other pancreatic beta-cell-related genes, such as Nkx6.1, Is11, Glut2, Pax4, and prohormone convertase2 (PC2). Moreover, glucagon, somatostatin, K(ATP)-channel genes KIR6.2 and SUR1, islet amyloid polypeptide (IAPP), PC1/3, and glucokinase (GCK) were expressed in the differentiating hESC in a developmental stage-dependent manner. Also, the addition of glucose to the culture medium triggered insulin release from differentiated cells, but transmission electron microscopy of the differentiated cells did not show typical beta-cell granules, even though secretary granules were detected. The results showed that hESC have the ability to transcribe and process insulin, but further improvements of the current method are required to generate a sufficient source of true beta cells for the treatment of diabetes mellitus.
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PMID:Generation of insulin-secreting cells from human embryonic stem cells. 1675 82

The Islet Neogenesis Associated Protein (INGAP) increases pancreatic beta-cell mass and potentiates glucose-induced insulin secretion. We currently studied the effects of a pentadecapeptide having the 104-118 amino acid sequence of INGAP (INGAP-PP) on insulin secretion and on transcript profile expression in 4-day-cultured normal pancreatic neonatal rat islets. Islets cultured with INGAP-PP released significantly more insulin in response to 2.8 and 16.7 mM glucose than those cultured without the peptide. The macroarray analysis showed that 210 out of 2352 genes spotted in the nylon membranes were up-regulated while only 4 were down-regulated by INGAP-PP-treatment. The main categories of genes modified by INGAP-PP included several related with islet metabolism, insulin secretion mechanism, beta-cell mass and islet neogenesis. RT-PCR confirmed the macroarray results for ten selected genes involved in growing, maturation, maintenance of pancreatic islet-cells, and exocytosis, i.e., Hepatocyte nuclear factor 3beta (HNF3beta), Upstream stimulatory factor 1 (USF1), K(+)-channel proteins (SUR1 and Kir6.2), PHAS-I protein, Insulin 1 gene, Glucagon gene, Mitogen-activated protein kinase 1 (MAP3K1), Amylin (IAPP), and SNAP-25. INGAP-PP also stimulated PDX-1 expression. The expression of three transcripts (HNF3beta, SUR1, and SNAP-25) was confirmed by Western blotting for the corresponding proteins. In conclusion, our results show that INGAP-PP enhances specifically the secretion of insulin and the transcription of several islet genes, many of them directly or indirectly involved in the control of islet metabolism, beta-cell mass and islet neogenesis. These results, together with other previously reported, strongly indicate an important role of INGAP-PP, and possibly of INGAP, in the regulation of islet function and development.
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PMID:Islet Neogenesis Associated Protein (INGAP) modulates gene expression in cultured neonatal rat islets. 1676 50

In congenital hyperinsulinism of infancy (CHI), the loss of K-ATP channels (composed of Kir6.2 and SUR1 subunits) in beta cells induces permanent insulin secretion and severe hypoglycaemia. By contrast, Sur1 ( -/- ) mice do not present such defects. We have investigated the impact of Sur1 gene inactivation on mouse islet cell morphology, structure and basic physiology. Pancreata were collected from young, adult and old wild-type (WT) and Sur1 ( -/- ) mice. After immunostaining for hormone, the total endocrine tissue, cell proportion, cell size and intra-insular distribution, hormone content and Glut-2 expression were quantified by morphometry. Basic physiological parameters were also measured. In young Sur1 ( -/- ) mice, the total endocrine tissue and proportion of beta cells were higher (P<0.05) than in WT mice, whereas the proportion of delta cells was lower (P<0.01). In old Sur1 ( -/- ) mice, alpha cells were frequently located in the central regions of islets (unlike WT islets) and their proportion was increased (P<0.05). Glut-2 protein and mRNA levels were lower in old Sur1 ( -/- ) islets (P<0.02). Insulinaemia, fasting insulin and glucagon contents were equivalent in both groups of pancreata. Thus, the islets of Sur1 ( -/- ) mice present morphological modifications that have not been described in CHI and that might reflect an adaptive mechanism controlling insulin secretion in these mice.
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PMID:Impact of Sur1 gene inactivation on the morphology of mouse pancreatic endocrine tissue. 1914 66

We evaluated the effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) upon islet beta- and non-beta cell differentiation from mouse embryonic stem (mES) cells. ES-D3 cell lines were cultured following Lumelsky's protocol with or without INGAP-PP (5 microg/ml) at different stages. Gene expression was quantified using qPCR. mES cells were fixed and immunostained using anti insulin-, somatostatin-, glucagon-, Pdx-1-, Ngn-3-, Nkx-6.1 and PGP9.5 specific antibodies. PCNA was used to measure replication rate. Bcl(2) (immunostaining) and caspase-3 (enzyme activity and gene expression) were determined as apoptosis markers. INGAP-PP increased IAPP, Glut-2, Kir-6.2, SUR-1 and insulin gene expression, and the percentage of insulin-immunostained cells. Conversely, INGAP-PP reduced significantly glucagon and somatostatin gene expression and immunopositivity. While nestin gene expression was not affected, there was a significant reduction in the percentage of PGP9.5-immunostained cells. Pdx-1 gene expression increased by 115% in INGAP-PP treated cells, as well as the percentage of Pdx-1, Ngn-3 and Nkx-6.1 immunopositive cells. Neither caspase-3 (expression and activity) nor Bcl(2) positively immunostained cells were affected by INGAP-PP. Accordingly, INGAP-PP would promote stem cell differentiation into a beta-like cell phenotype, simultaneously decreasing its differentiation toward non-beta-cell precursors. Therefore, INGAP-PP would be potentially useful to obtain beta-cells from stem cells for replacement therapy.
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PMID:Selective effect of INGAP-PP upon mouse embryonic stem cell differentiation toward islet cells. 1915 49


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