Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation

Dean, E. Danielle; Li, Mingyu; Prasad, Nripesh; Wisniewski, Scott; Deylen, Alison Von; Spaeth, Jason M.; Maddison, Lisette A.; Botros, Anthony; Sedgeman, Leslie R.; Bozadjieva, Nadejda; Ilkayeva, Olga; Coldren, Anastasia; Poffenberger, Greg; Shostak, Alena; Semich, Michael C; Aamodt, Kristie; Phillips, Neil; Yan, Hai; Bernal-Mizrachi, Ernesto; Corbin, Jackie D.; Vickers, Kasey C.; Levy, Shawn; Dai, Chunhua; Newgard, Christopher B.; Gu, Wei; Stein, Roland; Powers, Alvin C.

doi:10.1016/j.cmet.2017.05.011

Cited by 167 publications

(274 citation statements)

References 52 publications

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“…The circulating factors released by the liver to promote mTor-directed α cell proliferation when Gcgr is deleted or pharmacologically antagonized in mouse liver are amino acids that were not used for gluconeogenesis (Bozadjieva et al, 2017; Dean et al, 2017; Galsgaard et al, 2018; Kim et al, 2017; Solloway et al, 2015). It is possible that Foxn3 modulates amino acid metabolism in the liver, alters production of other α cell trophic factors, or both.…”

Section: Discussionmentioning

confidence: 99%

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

et al. 2018

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SUMMARY The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose. In Brief Karanth et al. find that glucagon lowers liver expression of Foxn3. Deletion of the Foxn3 gene decreases fasting blood glucose and the number of glucagon-producing α cells in the primary islet of zebrafish. Human carriers of the hyperglycemia risk allele of FOXN3 gene fail to suppress glucagon during oral glucose challenge.

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Section: Discussionmentioning

confidence: 99%

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

et al. 2018

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“…Therefore, our results cannot be extrapolated to general hyperaminoacidaemia, but they do show that a link seems to exist between certain glucagonotropic amino acids and plasma levels of glucagon. Indeed, the non-BCAAs included in our analysis have recently been linked to alpha cell proliferation in animal models [39,40]. Assuming that ureagenesis would be the outcome of glucagon action on amino acid metabolism, we also measured plasma urea levels in all samples.…”

Section: Discussionmentioning

confidence: 99%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

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Aims/hypothesis The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon. Methods To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance. Results Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. Conclusions/interpretation This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

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“…The amino acids arginine, alanine, and glutamine potentiate glucagon secretion and this effect is suppressed by high glucose in an insulin-independent manner (13). Recent studies demonstrate that interruption of glucagon receptor signaling by genetic inactivation or treatment with small molecules or glucagon receptor antibodies increases amino acid availability and leads to increased α cell proliferation in an mTORdependent manner (12,(14)(15)(16)(17). These findings support the concept that α cell mass and glucagon secretion are sensitive to extracellular signals including nutrients (amino acids, glucose) and growth factors (insulin) and that the mTORC1 pathway may be involved as a downstream regulator of one or both of these processes.…”

Section: Introductionmentioning

confidence: 99%

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Bozadjieva¹,

Blandino-Rosano²,

Chase³

et al. 2017

Journal of Clinical Investigation

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Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissuespecific deletion of the mTORC1 regulator Raptor in α cells (αRaptor KO ), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 3 8 0 jci.org Volume 127 Number 12 December 2017 transcription of critical α cell genes. This work provides insights into how nutrient-dependent glucagon secretion and α cell mass are regulated and suggest that pharmacologic inhibition of this pathway using immunosuppressant medications, such as everolimus or rapamycin, could alter glucagon levels and glucose homeostasis. ResultsLack of mTORC1 signaling after deletion of Raptor in α cells. α Cell-specific deletion of Raptor was achieved by crossing glucagon-Cre and Raptor fl/fl mice (αRaptor KO ) (18,19). Deletion of flanked exon 6 exclusively in α cells from αRaptor KO mice was demonstrated by nested reverse transcription PCR (RT-PCR) for exon 6 using different tissues and single α cells ( Figure 1A) (19). Loss of mTORC1 signaling was confirmed by lack of phospho-S6 (Ser240) immunofluorescence staining only in glucagon-positive cells in dispersed islets from 1-month-old αRaptor KO mice ( Figure 1B). To validate the reduction in mTORC1 signaling in α cells from αRaptor KO mice, we assessed phospho-S6 (Ser240), glucagon, and insulin staining in dispersed islets by flow cytometry using quantitative mean fluorescence intensity (MFI). Figure 1C shows pS6 MFI levels in α cells (glucagon + cell count) and Figure 1D includes pS6 MFI levels in β cells (insulin + cell count). Phospho-S6 (Ser240) levels were nearly lost in glucagon-positive cells from αRaptor KO mice (red curve) compared with controls (black curve) (Figures 1C). In contrast, the MFI for phospho-S6 (Se240) was similar in insulin-positive cells from αRaptor ...

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Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation

Cited by 167 publications

References 52 publications

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

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