Evidence of Extrapancreatic Glucagon Secretion in Man

Lund, Asger; Bagger, Jonatan I.; Albrechtsen, Nicolai J. Wewer; Christensen, Mikkel B.; Grøndahl, Magnus F.; Hartmann, Bolette; Mathiesen, Elisabeth R.; Hansen, Carsten P.; Storkholm, Jan Henrik; Hall, Gerrit van; Rehfeld, Jens F.; Hornburg, Daniel; Meissner, Felix; Mann, Matthias; Larsen, Steen; Holst, Jens J.; Vilsbøll, Tina; Knop, Filip K.

doi:10.2337/db15-1541

Cited by 143 publications

(120 citation statements)

References 50 publications

(62 reference statements)

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“…This could indicate that glucagon is produced in the gut, as recently suggested by Lund et al [32]. In line with this, it could be speculated that the greater PCSK2 expression in the small intestine of individuals with type 2 diabetes leads to formation of excess glucagon, contributing to type 2 diabetic hyperglucagonaemia.…”

Section: Discussionsupporting

confidence: 61%

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals

et al. 2017

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Aims/hypothesis Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. Methods In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age-and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. Results Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucosedependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. Conclusions/interpretation Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4450-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionsupporting

confidence: 61%

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals

et al. 2017

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“…Notably, other variants that associated with increased GIP concentrations did not associate with glucagon concentrations, suggesting that this effect is unique to SGLT1. One possibility is that the variants affect extrapancreatic glucagon secretion, since recent data demonstrate that, at least in pancreatectomized individuals, glucagon is secreted from extrapancreatic sources in response to oral glucose stimulation, the L cells being the likely source (35).…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of circulating GIP and GLP-1 concentrations

Almgren¹,

Lindqvist²,

Krus³

et al. 2017

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“…Radio-immunological determinations of glucagon were performed as previously described [18] using a C-terminusspecific antibody (codename 4305), which reliably measures pancreatic glucagon as validated by sandwich ELISA and mass spectrometry [19]. The analytical detection limit was 1 pmol/l, and the intra-assay and inter-assay CVs were <6% and <15%, respectively.…”

Section: Study Populationmentioning

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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Evidence of Extrapancreatic Glucagon Secretion in Man

Cited by 143 publications

References 50 publications

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals

Genetic determinants of circulating GIP and GLP-1 concentrations

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

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