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

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 GIP-producing 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.

• Authors: 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
• Journal: Diabetes (Diabetes) Vol. 64 Issue 4 Pg. 1383-94 (Apr 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25368100 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Blood Glucose
• Pyruvates
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• hydroxypyruvic acid

Topics

• Animals
• Blood Glucose
• Diabetes Mellitus, Type 2 (metabolism)
• Enteroendocrine Cells (metabolism)
• Female
• Gastric Inhibitory Polypeptide (metabolism)
• Glucagon-Like Peptide 1 (metabolism)
• Humans
• Insulin-Secreting Cells (metabolism)
• Male
• Metabolomics
• Mice
• Mice, Transgenic
• Pyruvates (metabolism)