Glucagon as a Critical Factor in the Pathology of Diabetes

Edgerton, Dale S.; Cherrington, Alan D.

doi:10.2337/db10-1594

Cited by 47 publications

(37 citation statements)

References 37 publications

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“…The abnormal glucagon secretion in T2DM and its key role in the development of fasting and postprandial hyperglycemia has recently been a focus of attention (1,7,29). Therefore, the suppression of glucagon secretion or the inhibition of its action in the liver constitutes potential therapeutic targets for diabetes (30)(31)(32).…”

Section: Glucagon As a Target For Diabetesmentioning

confidence: 99%

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Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

et al. 2014

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Pancreatic a-cells express voltage-gated Na + channels (NaChs), which support the generation of electrical activity leading to an increase in intracellular calcium, and cause exocytosis of glucagon. Ranolazine, a NaCh blocker, is approved for treatment of angina. In addition to its antianginal effects, ranolazine has been shown to reduce HbA 1c levels in patients with type 2 diabetes mellitus and coronary artery disease; however, the mechanism behind its antidiabetic effect has been unclear. We tested the hypothesis that ranolazine exerts its antidiabetic effects by inhibiting glucagon release via blockade of NaChs in the pancreatic a-cells. Our data show that ranolazine, via blockade of NaChs in pancreatic a-cells, inhibits their electrical activity and reduces glucagon release. We found that glucagon release in human pancreatic islets is mediated by the Na v 1.3 isoform. In animal models of diabetes, ranolazine and a more selective NaCh blocker (GS-458967) lowered postprandial and basal glucagon levels, which were associated with a reduction in hyperglycemia, confirming that glucose-lowering effects of ranolazine are due to the blockade of NaChs. This mechanism of action is unique in that no other approved antidiabetic drugs act via this mechanism, and raises the prospect that selective Na v 1.3 blockers may constitute a novel approach for the treatment of diabetes.

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Section: Glucagon As a Target For Diabetesmentioning

confidence: 99%

“…This hyperglucagonemia increases hepatic glucose production, thereby contributing importantly to diabetic hyperglycemia (4,5). Therefore, not surprisingly, the lowering of glucagon levels or antagonizing its actions via blockade of glucagon receptors can significantly reduce hyperglycemia (6,7).…”

mentioning

confidence: 99%

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

et al. 2014

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“…tion or impaired insulin signaling on the ␣-cells, respectively [10,14,20,27,38]. Orally active glucagon antagonists might have therapeutic potential in diabetes [2].…”

Section: Abbreviationsmentioning

confidence: 99%

“…Physiologically, glucagon secretion by the pancreas Langerhans islets ␣-cells decreases with increasing glycemia, thanks to a paracrine regulation by insulin secreted by the neighboring ␤-cells [10,14,20,27,38]. In the absence of insulin, glucose actually activates glucagon secretion [19]: in patients suffering from type I or type II diabetes the glucagon concentration is therefore paradoxically elevated due to reduced insulin secre-…”

Section: Introductionmentioning

confidence: 99%

Analysis of the glucagon receptor first extracellular loop by the substituted cysteine accessibility method

2011

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a b s t r a c tGlucagon is an important hormone for the prevention of hypoglycemia, and contributes to the hyperglycemia observed in diabetic patients, yet very little is known about its receptor structure and the receptor-glucagon interaction. In related receptors, the first extracellular loop, ECL1, is highly variable in length and sequence, suggesting that it might participate in ligand recognition. We applied a variant of the SCAM (Substituted Cysteine Accessibility Method) to the glucagon receptor ECL1 and sequentially mutated positions 197 to 223 to cysteine. Most of the mutations (15/27) affected the glucagon potency, due either to a modification of the glucagon binding site, or to the destabilization of the active receptor conformation. We reasoned that side chains accessible to glucagon must also be accessible to large, hydrophilic cysteine reagents. We therefore evaluated the accessibility of the introduced cysteines to maleimide-PEO 2 -biotin ((+)-biotinyl-3-maleimido-propionamidyl-3,6-dioxa-octanediamine), and tested the effect of pretreatment of intact cells with a large cationic cysteine reagent, MTSET ([2-(trimethylammonium)ethyl]methanethiosulfonate bromide), on glucagon potency. Our results suggest that the second and third transmembrane helices (TM2 and TM3) are extended to position 202 and from position 215, respectively, and separated by a short ␤ stretch (positions 203-209). Glucagon binding induced a conformational change close to TM2: L198C was accessible to the biotin reagent only in the presence of glucagon. Most other mutations affected the receptor activation rather than glucagon recognition, but S217 and D218 (at the top of TM3) were good candidates for glucagon recognition and V221 was very close to the binding site.

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“…In addition, a negative feedback loop between ChREBP and GCGR may further contribute to the regulation of glucose-induced gene expression. The plasma glucagon concentration is normally elevated in the fasted state and suppressed in the fed state; however, in diabetic conditions the plasma glucagon concentration is elevated in both the fasted and fed states [64]. In the pathogenesis of type 2 diabetes mellitus, the constant abnormal elevation in both GCGR and plasma glucagon concentration may contribute to both fasting and postprandial hyperglycemia.…”

Section: Krüppel-like Factor-10 (Klf10)mentioning

confidence: 99%

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

Iizuka

2013

Endocr J

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Abstract. Carbohydrate response element binding protein (ChREBP) is a transcription factor activated by glucose that is highly expressed in liver, pancreatic β-cells, brown and white adipose tissues, and muscle. We reported that hepatic suppression of the Chrebp gene improves hepatic steatosis, glucose intolerance, and obesity in genetically obese mice. Moreover, we have studied the role of ChREBP with special reference to feedforward and feedback looping in liver and pancreatic β-cells. Recently, several groups reported that (1) glucose activates ChREBP-α transactivity and in turn ChREBP-α induces ChREBP-β on both transcriptional and translational levels in adipose tissues, and (2) ChREBP regulates glucose transporter type 4 mRNA levels, which may affect glucose uptake in adipose tissues. Moreover, in adipose tissues of obese patients, Chrebpb mRNA levels were much lower than those in lean subjects, while the levels were much higher in liver of obese patients than those in lean subjects. These findings suggest that Chrebpb mRNA levels are different in various tissues and probably in the stages of diabetes mellitus. Herein, we review recent progress in the study of ChREBP with special references to (1) the mechanisms regulating ChREBP transactivity (posttranslational modifications, intramolecular glucose sensing module, feedforward mechanism, and the feedback loop between ChREBP and its target genes), and (2) the role of ChREBP in liver, pancreatic islets and adipose tissues. Understanding the role of ChREBP in each tissue will provide important insight into the pathogenesis of metabolic syndrome.

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Glucagon as a Critical Factor in the Pathology of Diabetes

Cited by 47 publications

References 37 publications

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

Analysis of the glucagon receptor first extracellular loop by the substituted cysteine accessibility method

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

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