Selective stimulation of G-6-Pase catalytic subunit but not G-6-<i>P</i>transporter gene expression by glucagon in vivo and cAMP in situ

Hornbuckle, Lauri A.; Everett, Carrie A.; Martin, Carley; Gustavson, Stephanie S.; Svitek, Christina A.; Oeser, James K.; Neal, Doss W.; Cherrington, Alan D.; O’Brien, Richard M.

doi:10.1152/ajpendo.00455.2003

Cited by 24 publications

(12 citation statements)

References 82 publications

(98 reference statements)

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“…Glucagon effects on hepatic glucose metabolism are primarily mediated by their acute effects on enhancing glycogen phosphorylase enzyme activity and the gene expression and mRNA content of the catalytic component of the enzyme glucose-6-phosphatase (6,24). Furthermore, glucagon inhibits glycogen synthase activity and glycolysis while also stimulating the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, but in vivo such an effect is delayed (21).…”

Section: Discussionmentioning

confidence: 99%

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

Mallad

Man

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments. Am J Physiol Endocrinol Metab 309: E474 -E486, 2015. First published July 7, 2015; doi:10.1152/ajpendo.00236.2015.-Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia. glucagon; type 1 diabetes; endogenous glucose production A CUTTING-EDGE ARTIFICIAL PANCREAS (AP) system applied in type 1 diabetes (T1D) needs to prevent and treat hypoglycemia. This is a critical goal determined by the Food and Drug Administration in their recent guidance document for an AP system (50). To meet this goal, the main counterregulatory hormone glucagon may be utilized not only to "rescue" from but also to prevent hypoglycemia. Glucagon acutely stimulates hepatic glycogenolysis and thereby endogenous glucose production (EGP) (11-13, 32). However, although the dose response of glucagon on EGP (viz., hepatic glucagon sensitivity) in T1D is currently unknown during hypoglycemia, a recent study (20) did demonstrate a dose response at euglycemia that was modulated by prevailing insulin concentrations. Furthermore, whether this is contingent on prevailing glucose concentrations and whether glucagon clearance is influenced by changing glucagon concentrations are also undetermined. Filling such knowledge gaps in glucagon physiology are vital to inform and design a control algorithm where the intensity of the "controller" can be modulated based on the information obtained. For example, if hepatic glucagon sensitivity increases with hypoglycemia, a lesser dose of glucagon could evoke an equivalent glucose response than at euglycemia. On the other hand, if hepatic glucagon sensitivity does not alter with glucose levels, then th...

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Section: Discussionmentioning

confidence: 99%

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

Mallad

Man

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…CREB is a ubiquitously expressed transcription factor that induces the expression of key genes involved in the gluconeogenesis pathway, such as those encoding PEPCK, G6Pase, and pyruvate carboxylase. Accordingly, CREB binding sites have been identified in the PEPCK and G6Pase promoters (81,112,223), but not in that of pyruvate carboxylase. Additional mechanisms for cAMP-mediated transcriptional response are required to explain the full range of responsive genes and the specificity of the response in gluconeogenic tissues, i.e., liver, kidney, and small intestine.…”

Section: Transcriptional Regulation Of Metabolism By Low Glucose Lmentioning

confidence: 93%

Transcriptional Regulation of Metabolism

Desvergne¹,

Michalik²,

Wahli³

2006

Physiological Reviews

755

677

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Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the molecular level, the crucial role of transcription factors is particularly well-illustrated by the link between alterations of their functions and the occurrence of major metabolic diseases. In addition, the possibility of manipulating the ligand-dependent activity of some of these transcription factors makes them attractive as therapeutic targets. The aim of this review is to summarize recent knowledge on the transcriptional control of metabolic homeostasis. We first review data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism. Then, we analyze how transcription factors integrate signals from various pathways to ensure homeostasis. One example of this coordination is the daily adaptation to the circadian fasting and feeding rhythm. This section also discusses the dysregulations causing the metabolic syndrome, which reveals the intricate nature of glucose and lipid metabolism and the role of the transcription factor PPARγ in orchestrating this association. Finally, we discuss the molecular mechanisms underlying metabolic regulations, which provide new opportunities for treating complex metabolic disorders.

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“…Specifically, hepatic glycogen content and G6Pase gene expression were assessed in six female wild type and UGRP Ϫ/Ϫ mice following a 6-h fast. Glucagon stimulates both hepatic glycogenolysis (2,36) and G6Pase gene expression (37). For this study we purposefully chose to use six UGRP Ϫ/Ϫ mice that exhibited elevated glucagon levels at 4 months of age (Fig.…”

Section: Phenotypic Analysis Of Ugrp Knock-out Mice-ugrpmentioning

confidence: 99%

Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-β Results in Lowered Plasma Cholesterol and Elevated Glucagon

Wang

Oeser

Yang

et al. 2006

Journal of Biological Chemistry

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In liver, glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate, the final step in the gluconeogenic and glycogenolytic pathways. Mutations in the glucose-6-phosphatase catalytic subunit (G6Pase) give rise to glycogen storage disease (GSD) type 1a, which is characterized in part by hypoglycemia, growth retardation, hypertriglyceridemia, hypercholesterolemia, and hepatic glycogen accumulation. Recently, a novel G6Pase isoform was identified, designated UGRP/G6Pase-␤. The activity of UGRP relative to G6Pase in vitro is disputed, raising the question as to whether G6P is a physiologically important substrate for this protein. To address this issue we have characterized the phenotype of UGRP knock-out mice. G6P hydrolytic activity was decreased by ϳ50% in homogenates of UGRP ؊/؊ mouse brain relative to wild type tissue, consistent with the ability of UGRP to hydrolyze G6P. In addition, female, but not male, UGRP ؊/؊ mice exhibit growth retardation as do G6Pase ؊/؊ mice and patients with GSD type 1a. However, in contrast to G6Pase ؊/؊ mice and patients with GSD type 1a, UGRP ؊/؊ mice exhibit no change in hepatic glycogen content, blood glucose, or triglyceride levels. Although UGRP ؊/؊ mice are not hypoglycemic, female UGRP ؊/؊ mice have elevated (ϳ60%) plasma glucagon and reduced (ϳ20%) plasma cholesterol. We hypothesize that the hyperglucagonemia prevents hypoglycemia and that the hypocholesterolemia is secondary to the hyperglucagonemia. As such, the phenotype of UGRP ؊/؊ mice is mild, indicating that G6Pase is the major glucose-6-phosphatase of physiological importance for glucose homeostasis in vivo.In liver, glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate (G6P) 2 to glucose and inorganic phosphate, the final step in the gluconeogenic and glycogenolytic pathways (1, 2). Glucose-6-phosphatase is located in the endoplasmic reticulum membrane and is postulated to exist as a multi-component enzyme system in which a glucose-6-phosphatase catalytic subunit has its catalytic site directed toward the lumen of the endoplasmic reticulum, and a G6P transporter serves to deliver G6P from the cytosol to the active site of the catalytic subunit (3-6). It also postulates the existence of transporters for inorganic phosphate and glucose that return the reaction products back to the cytosol, but neither transporter has yet been identified. In contrast, the glucose-6-phosphatase catalytic subunit (G6Pase or G6PC) (7, 8) and a G6P transporter (9, 10) have been well characterized, although their stoichiometry and topological relationships remain unclear (3-6).Mutations within G6Pase cause glycogen storage disease (GSD) type 1a, which is characterized by severe hypoglycemia in the post-absorptive state, hepatomegaly associated with excessive glycogen deposition, growth retardation, hepatic adenomas, hyperuricemia, anemia, proteinuria or microalbuminuria, kidney calcifications, osteopenia, increased alkaline phosphatase and ␥-glutamyltransferase activities...

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Selective stimulation of G-6-Pase catalytic subunit but not G-6-Ptransporter gene expression by glucagon in vivo and cAMP in situ

Cited by 24 publications

References 82 publications

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

Transcriptional Regulation of Metabolism

Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-β Results in Lowered Plasma Cholesterol and Elevated Glucagon

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