| First Author | Zhang S | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 4 | Pages | 1383-94 |
| PubMed ID | 25368100 | Mgi Jnum | J:250465 |
| Mgi Id | MGI:5924204 | Doi | 10.2337/db14-1188 |
| Citation | Zhang S, et al. (2015) Global biochemical profiling identifies beta-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans. Diabetes 64(4):1383-94 |
| abstractText | 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. beta-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting beta-hydroxypyruvate production from d-serine. In vitro, beta-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. beta-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 beta-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and beta-cells by regulating beta-hydroxypyruvate levels. |
