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)

Mitochondrial uncoupling protein-2 and -3 (UCP2 and UCP3) may be involved in the modulation of resting metabolic rate and energy balance. To investigate their variability, the influence of this on the variability of energy expenditure, and potential regulatory factors of the expression of the corresponding genes, we measured their messenger ribonucleic acids (mRNAs) in muscle and white adipose tissue of lean, healthy men and correlated the abundance of these mRNAs (attomoles per microg total RNA) with measures of resting metabolic rate, hormone levels (thyroid hormones, insulin, glucagon, leptin, and catecholamines), and fuels potentially involved in energy balance regulation. We also investigated whether the thiazolidinedione, troglitazone, stimulates UCP2 and UCP3 mRNA levels to follow up on the observation that this antidiabetic drug increases the levels of expression in cultured cells. We found UCP2 and UCP3 mRNA levels to be highly variable and poorly correlated with measures of energy expenditure and with most factors affecting energy balance. Only nocturnal urinary norepinephrine excretion could explain a significant fraction of the variability in both UCP2 and UCP3 expression in muscle, but not adipose tissue. Thyroid hormone and norepinephrine excretion were found to contribute to the variability of resting metabolic rate, but this could not be explained by an effect on UCP mRNAs. Troglitazone affected neither the expression of UCPs nor the hormones or the measures of metabolic rate investigated. In conclusion, our results show that the expression of UCP2 and UCP3 genes is quite variable in healthy males and that this variability does not explain that in resting energy expenditure, and suggest that sympathetic activity is an important potential regulator of the expression of these proteins in skeletal muscle. However, the data do not support the concept that regulation of the expression of these genes is the most important level of control of UCP3 and UCP2 functions, and other levels of control have to be invoked.
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PMID:Uncoupling protein-2 and -3 messenger ribonucleic acids in adipose tissue and skeletal muscle of healthy males: variability, factors affecting expression, and relation to measures of metabolic rate. 1084 84

The cDNA of an uncoupling protein (UCP) homologue was obtained by screening a chicken skeletal-muscle library. The predicted 307-amino-acid sequence of avian UCP (avUCP) is 55, 70, 70 and 46% identical with mammalian UCP1, UCP2 and UCP3 and plant UCP respectively. avUCP mRNA expression is restricted to skeletal muscle and its abundance was increased 1.3-fold in a chicken line showing diet-induced thermogenesis, and 3.6- and 2.6-fold in cold-acclimated and glucagon-treated ducklings developing muscle non-shivering thermogenesis respectively. The present data support the implication of avUCP in avian energy expenditure.
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PMID:An uncoupling protein homologue putatively involved in facultative muscle thermogenesis in birds. 1117 Oct 38

Stress hormones and pro-inflammatory cytokines are putative signals triggering increased energy expenditure or "hypermetabolism" commonly observed in inflammatory states. Cytokines also cause the release of reactive oxidants by immune cells resident in tissues in vivo. Therefore, we hypothesized that oxidative stress plays a role in the induction of hypermetabolism. We examined the effect of glucagon (1.0 nM), a catabolic stress hormone, and the oxidant H(2)O(2) (1.0 mM) on the metabolism of stable hepatocyte cultures for 4 days. Combined H(2)O(2) and glucagon treatment, but not H(2)O(2) or glucagon used alone, increased the hepatocyte oxygen uptake rate 25% above control untreated cells after a lag-time of 72 h. The same treatment also increased the expression of mitochondrial uncoupling protein-2 (UCP2). These effects were significantly inhibited by the antioxidant N-acetylcysteine (5mM) and the pentose phosphate pathway (PPP) inhibitor dehydroepianderosterone (200 microM). Glucagon alone induced urea synthesis and H(2)O(2) alone induced the PPP. These findings show, for the first time, that oxidative stress, in combination with glucagon, increases metabolic energy expenditure in cultured cells, and that this effect may be mediated by UCP-2. Furthermore, the results implicate the PPP in the induction of the hypermetabolic response.
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PMID:Induction of a hypermetabolic state in cultured hepatocytes by glucagon and H2O2. 1464 50

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) regulates several cellular functions, but its physiological role in pancreatic islet cells remains to be investigated. In this study, we confirmed the presence of PPAR-gamma in rat isolated islets and examined its role on insulin and glucagon secretion by using PPAR-gamma-overexpressed islets. PPAR-gamma overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose (p<0.05). In addition, insulin secretion evoked by high potassium depolarization also was significantly decreased from PPAR-gamma-overexpressed islets (p<0.05). On the other hand, no significant change in glucagon release was observed after high potassium depolarization between PPAR-gamma-overexpressed and control islets. Insulin and glucagon content in islets was not statistically different between the two groups. In addition, the expression of uncoupling protein-2 (UCP-2) was found to be induced in PPAR-gamma-overexpressed islets. This result clearly indicates that the deteriorative effect of PPAR-gamma overexpression on the secretory machinery is selective for pancreatic beta-cells. And it is possible that its site of action can be located in the energy-consuming exocytotic process of insulin secretory granules, and that the reduction of ATP production through increased UCP-2 reduces insulin exocytosis.
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PMID:PPAR-gamma overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein. 1547 99

Glucagon-like peptide 2 (GLP-2) is an intestinal epithelium-specific growth factor. However, its protective effects and related mechanism on the small intestine injured by ischemia-reperfusion (I/R) in mice remain unclear. This study aimed to reveal the effects of GLP-2 and its functional relationship with uncoupling protein 2 (UCP2) on the small intestine after I/R injury in mice. Male Balb/c mice were given GLP-2 (250 microg/kg/day, ip) for 3 days and underwent 30 min of superior mesenteric artery occlusion followed by 1 hr of reperfusion on day 4. Histological damage, bacterial translocation, diamine oxidase, and malondialdehyde level were assessed, and UCP2 expression was measured by immunohistochemistry and Western blot. GLP-2 attenuated the intestinal histological damage caused by I/R and increased the villous height by 28% and the crypt depth by 10%, respectively. Compared to the I/R group, diamine oxidase activity was increased, the incidence of bacterial translocation and malondialdehyde level were decreased, and UCP2 expression was increased in GLP-2-treated mice. GLP-2 protected the small intestine from I/R injury and increased UCP2 expression. These results suggested that effects of GLP-2 should be related to the upregulation of mitochondrial UCP2, which antagonized reactive oxygen species production.
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PMID:Uncoupling protein 2 involved in protection of glucagon-like peptide 2 in small intestine with ischemia-reperfusion injury in mice. 1581 Jun 42

Foxa1 (formerly hepatic nuclear factor 3alpha) belongs to the family of Foxa genes that are expressed in early development and takes part in the differentiation of endoderm-derived organs and the regulation of glucose homeostasis. Foxa1-/- pups are growth retarded and hypoglycemic but glucose intolerant in response to an intraperitoneal glucose challenge. However, the mechanism of glucose intolerance in this model has not been investigated. Here, we show that Foxa1-/- islets exhibit decreased glucose-stimulated insulin release in islet perifusion experiments and have significantly reduced pancreatic insulin and glucagon content. Moreover, Foxa1-/- beta-cells exhibit attenuated calcium influx in response to glucose and glyburide, suggesting an insulin secretion defect either at the level or upstream of the ATP-sensitive K+ channel. Intracellular ATP levels after incubation with 10 mmol/l glucose were about 2.5 times lower in Foxa1-/- islets compared with controls. This diminished ATP synthesis could be explained by increased expression of the mitochondrial uncoupling protein uncoupling protein 2 (UCP2) in Foxa1-deficient islets, resulting in partially uncoupled mitochondria. Chromatin immunoprecipitation assays indicate that UCP2 is a direct transcriptional target of Foxa1 in vivo. Thus, we have identified a novel function for Foxa1 in the regulation of oxidative phosphorylation in pancreatic beta-cells.
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PMID:Foxa1-deficient mice exhibit impaired insulin secretion due to uncoupled oxidative phosphorylation. 1700 37

When the homozygous active form of porcine TGF-beta1 transgene (Tgf/Tgf) (under control of the rat glucagon promoter) is introduced into the nonobese diabetic mouse (NOD) genetic background, the mice develop endocrine and exocrine pancreatic hypoplasia, low serum insulin concentrations, and impaired glucose tolerance. To identify genetic modifiers of the diabetic phenotypes, we crossed hemizygous NOD-Tgf with DBA/2J mice (D2) or C3H/HeJ mice (C3H) and used the "transgenic mice" for quantitative trait loci (QTL) analysis. Genome-wide scans of F(2)-D Tgf/Tgf (D2 x NOD) and F(2)-C Tgf/Tgf (C3H x NOD), homozygous for the TGF-beta1 transgene, identified six statistically significant modifier QTLs: one QTL (Tdn1) in F(2)-D Tgf/Tgf, and five QTLs (Tcn1 to Tcn5) in F(2)-C Tgf/Tgf. Tdn1 (Chr 13, LOD = 4.39), and Tcn3 (Chr 2, LOD = 4.94) showed linkage to body weight at 8 weeks of age. Tcn2 (Chr 7, LOD = 4.38) and Tcn4 (Chr 14, LOD = 3.99 and 3.78) showed linkage to blood glucose (BG) concentrations in ipGTT at 30, 0, and 120 min, respectively. Tcn1 (Chr 1, LOD = 4.41) and Tcn5 (Chr 18, LOD = 4.99) showed linkage to serum insulin concentrations in ipGTT at 30 min. Tcn2 includes the candidate gene, uncoupling protein 2 (Ucp2), and shows linkage to Ucp2 mRNA levels in the soleus muscle (LOD = 4.90). Identification of six QTLs for diabetes-related traits in F(2)-D Tgf/Tgf and F(2)-C Tgf/Tgf raises the possibility of identifying candidate susceptibility genes and new targets for drug development for human type 2 diabetes.
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PMID:Diabetic modifier QTLs in F(2) intercrosses carrying homozygous transgene of TGF-beta. 1816 Sep 96

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.
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PMID:Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure. 1880 47

In pancreatic beta-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that alpha-cells express significantly higher levels of UCP2 than do beta-cells. Greater mitochondrial UCP2-related uncoupling was observed in alpha-cells compared with beta-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in alpha-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2(-/-) mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2(-/-) alpha-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining alpha-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.
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PMID:UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival. 1870 16

Currently, the physiological function of uncoupling protein-2 (UCP2) in pancreatic islets and its role in the development of diabetes is a matter of great debate. To further investigate the impact of UCP2 on diabetes development, we used streptozotocin (STZ) to experimentally generate diabetes in both wild-type (WT) and UCP2-knockout (UCP2KO) mice. While multiple low-dose STZ injections led to hyperglycemia development over a 14-day period in both WT and UCP2KO mice, we found the development of hyperglycemia to be significantly less severe in the UCP2KO mice. Measurement of insulin and glucagon secretion (in vitro), as well as their plasma concentrations (in vivo), indicated that UCP2-deficiency showed enhanced insulin secretion but impaired alpha-cell function. Glucagon secretion was attenuated, despite reduced insulin secretion after exposure to STZ, which together contributed to less severe hyperglycemia development in UCP2KO mice. Further experimentation revealed that UCP2-deficient alpha- and beta-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal beta- and alpha-cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced beta-cell function and impairment of alpha-cell function, leading to an attenuation of STZ-induced hyperglycemia development.
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PMID:Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin. 1963 59


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