PubMed · 1567014
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R B Vadhera. 1992. Propranolol overdose.. https://doi.org/10.1111/j.1365-2044.1992.tb02157.x
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Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell-intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (G6PC2) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell-specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid-stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.
The structure of monomeric glucagon in dilute aqueous solution was studied by 500 MHz NMR. Hydrogen-deuterium exchange experiments monitored by NMR showed that the backbone amide NHs form intrastrand hydrogen bonds suggesting the existence of some degree of compact structure. The temperature dependent shift of several amide NH resonances supported the above conclusion. The small J coupling constants arising from the interactions between 6 amide NHs and C alpha Hs (less than 6 Hz) imply a helical structure.