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Beta‐aminoisobutyrate, a circulating metabolite which regulates beta‐cell insulin secretory function
Author(s) -
Solomon Thomas P,
Gillum Matthew
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1008.8
Subject(s) - medicine , endocrinology , insulin , metabolite , insulin oscillation , insulin resistance , diabetes mellitus , beta cell , islet , hyperinsulinemia , type 2 diabetes , biology , pancreas , secretion
Glucose‐stimulated insulin secretion and insulin‐stimulated glucose disposal (insulin sensitivity) are related by an inverse function. A reduction in insulin sensitivity promotes increased insulin secretion in order to compensate. The mechanism for this is unknown. The objective of this work was to identify a circulating metabolite that may explain this regulation between the insulin sensitive tissue and the endocrine pancreas. By elevating plasma glucose to ~11 mM for 24 hours we experimentally‐induced a diabetic‐like state of hyperglycemia in healthy human subjects. This caused insulin resistance and compensatory hyperinsulinemia. Using metabolomics (LC and GC‐MS) we measured 358 metabolites in plasma samples collected at baseline and after 24 hours of hyperglycemia. We then identified a short‐list of circulating metabolites which were associated with hyperglycemia‐induced changes in insulin secretory compensation. We then measured the same 358 metabolites in the plasma of patients with type 2 diabetes. Some of these compounds were also differentially‐regulated in plasma between healthy subjects and patients with type 2 diabetes, a disease where insulin secretory function is impaired. The shortlist of compounds which correlated with group differences (i.e. healthy vs. diabetic) and hyperglycemic‐induced changes in insulin secretion were then used to incubate rat islets in culture experiments. We identified beta‐aminoisobutyrate as a metabolite that suppressed glucose‐stimulated insulin secretion from rat islets in a dose‐response fashion. Interestingly, beta‐aminoisobutyrate is a metabolite that has been demonstrated in mice to be secreted from skeletal muscle, thus identifying it as a potential muscle‐derived regulator of beta‐cell insulin secretion. Ongoing work is determining the in vivo effect of beta‐aminoisobutyrate on insulin secretory function and determining whether it is secreted from skeletal muscle in humans. Support or Funding Information This work was primarily funded by the Novo Nordisk Foundation (TS).