Global biochemical profiling identifies β-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans

Sheng Zhang, Songyan Wang, Matthew D. Puhl, Xuntian Jiang, Krzysztof L. Hyrc, Erin Laciny, Michael J. Wallendorf, Kirk L. Pappan, Joseph T. Coyle, Burton M. Wice

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the "incretin response." To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin-expressing (DT) mice that specifically lack GIPproducing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. β-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting β-hydroxypyruvate production from D-serine. In vitro, β-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. β-Hydroxypyruvate-to-D-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to β-hydroxypyruvate-to-D-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and β-cells by regulating β-hydroxypyruvate levels.

Original languageEnglish
Pages (from-to)1383-1394
Number of pages12
JournalDiabetes
Volume64
Issue number4
DOIs
StatePublished - Apr 2015

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    Zhang, S., Wang, S., Puhl, M. D., Jiang, X., Hyrc, K. L., Laciny, E., Wallendorf, M. J., Pappan, K. L., Coyle, J. T., & Wice, B. M. (2015). Global biochemical profiling identifies β-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans. Diabetes, 64(4), 1383-1394. https://doi.org/10.2337/db14-1188