Glucagon regulates its own synthesis by autocrine signaling

Leibiger, Barbara; Moede, Tilo; Muhandiramlage, Thusitha P.; Kaiser, Daniel R.; Sánchez, Pilar Fernández; Leibiger, Ingo B.; Berggren, Per Olof

doi:10.1073/pnas.1212870110

Cited by 42 publications

(33 citation statements)

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“…Glucagon secretion in the presence of reduced concentrations of glucose is coupled to stimulated transcription of the glucagon gene triggered by an auto-regulatory loop ensuring continuous hormone availability [5]. Our data support the existence of an ALX3-dependent counter regulatory glucose-sensing mechanism acting at the transcriptional level, by virtue of which overproduction of glucagon would be prevented under conditions in which glucose concentration is elevated and secretion inhibited.…”

Section: Discussionsupporting

confidence: 62%

“…In recent years, however, dysfunctional glucagon hypersecretion contributing to high blood glucose has been recognized as an additional and important aetiopathogenic factor [3,4]. Since hormonal stores depleted after secretion must be replenished by increasing glucagon gene expression and biosynthesis in a coordinated manner [5], the elucidation of the mechanisms that link glucagon gene transcription and glucagon secretion in response to fluctuations in glucose concentrations are of great importance for the understanding of the aetiopathogenic mechanisms of diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells

Mirasierra

Vallejo

2016

Diabetologia

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Aims/hypothesis The stimulation of glucagon secretion in response to decreased glucose levels has been studied extensively. In contrast, little is known about the regulation of glucagon gene expression in response to fluctuations in glucose concentration. PAX6 is a key transcription factor that regulates the glucagon promoter by binding to the G1 and G3 elements. Here, we investigated the role of the transcription factor ALX3 as a glucose-dependent modulator of PAX6 activity in alpha cells.Methods Experiments were performed in wild type or Alx3-deficient islets and alphaTC1 cells. We used chromatin immunoprecipitations and electrophoretic mobility shift assays for DNA binding, immunoprecipitations and pull-down assays for protein interactions, transfected cells for promoter activity, and small interfering RNA and quantitative RT-PCR for gene expression. Results Elevations in the concentration of glucose resulted in stimulated expression ofAlx3 and decreased glucagon gene expression in wild type islets. In ALX3-deficient islets, basal glucagon levels were non responsive to changes in glucose concentration.In basal conditions ALX3 bound to the glucagon promoter at G3, but not at G1. ALX3 could form heterodimers with PAX6 that are permissive for binding to G3 but not to G1. Thus, increasing the levels of ALX3 in response to glucose resulted in the sequestration of PAX6 by ALX3 for binding to G1, thus reducing glucagon promoter activation and glucagon gene expression. Conclusions/InterpretationGlucose-stimulated expression of ALX3 in alpha cells provides a regulatory mechanism for the downregulation of glucagon gene expression by interfering with PAX6-mediated transactivation on the glucagon G1 promoter element.3

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells

Mirasierra

Vallejo

2016

Diabetologia

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“…Somatostatin inhibits the transcription of glucagon potentially by suppressing the cAMP/PKA pathway in a pancreatic cell line (Kendall et al 1995). Through a positive autocrine feedback mechanism, glucagon increases its own transcription (Leibiger et al 2012) and secretion by stimulating the glucagon receptor/cAMP/PKA/CREB pathway in mouse and human pancreatic islets.…”

Section: α Cellmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

145

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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“…Furthermore, glucagon also plays a positive autocrine role by binding to glucagon receptors on alpha cells to enhance its own expression [98].…”

Section: Intra-islet Signalling Is Important For Human Islet Functionmentioning

confidence: 99%

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

et al. 2015

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The human genome project and its search for factors underlying human diseases has fostered a major human research effort. Therefore, unsurprisingly, in recent years we have observed an increasing number of studies on human islet cells, including disease approaches focusing on type 1 and type 2 diabetes. Yet, the field of islet and diabetes research relies on the legacy of rodent-based investigations, which have proven difficult to translate to humans, particularly in type 1 diabetes. Whole islet physiology and pathology may differ between rodents and humans, and thus a comprehensive cross-species as well as species-specific view on islet research is much needed. In this review we summarise the current knowledge of interspecies islet cytoarchitecture, and discuss its potential impact on islet function and future perspectives in islet pathophysiology research.

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Glucagon regulates its own synthesis by autocrine signaling

Cited by 42 publications

References 50 publications

Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells

Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

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