PubMed · 4176348
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1968-11-09. Glucagon.. https://pubmed.ncbi.nlm.nih.gov/4176348/
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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.
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Werner syndrome (WS) is a rare autosomal recessive disease with poor growth, premature aging, scleroderma-like skin changes, endocrine abnormalities, and deficiencies of adipose tissue. Could there be a genetic obesity syndrome which offers an instructive contrast to at least one form of WS? At least one form of WS might result from an enzyme defect that causes hypertriglyceridemia, hyperinsulinism, and hyperglucagonism; the defective enzyme might play a key role in the utilization of tryptophan, riboflavin (vitamin B2), or other vitamins or in the synthesis of prostaglandins that inhibit insulin secretion. At least one form of genetic obesity might result from an enzyme defect that causes hypotriglyceridemia and hyperinsulinism without hyperglucagonism; the defective enzyme might be unable to bind properly to a product that inhibits some step in the process of conversion of free fatty acid (FFA) CoA into ketoacids.