PMID- 25368100 OWN - NLM STAT- MEDLINE DCOM- 20150522 LR - 20211021 IS - 1939-327X (Electronic) IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 64 IP - 4 DP - 2015 Apr TI - Global biochemical profiling identifies beta-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans. PG - 1383-94 LID - 10.2337/db14-1188 [doi] AB - 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. CI - (c) 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. FAU - Zhang, Sheng AU - Zhang S AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO. FAU - Wang, Songyan AU - Wang S AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO. FAU - Puhl, Matthew D AU - Puhl MD AD - Laboratory for Psychiatric and Molecular Neuroscience, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA. FAU - Jiang, Xuntian AU - Jiang X AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO. FAU - Hyrc, Krzysztof L AU - Hyrc KL AD - Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO. FAU - Laciny, Erin AU - Laciny E AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO. FAU - Wallendorf, Michael J AU - Wallendorf MJ AD - Division of Biostatistics, Washington University School of Medicine, St. Louis, MO. FAU - Pappan, Kirk L AU - Pappan KL AD - Metabolon, Inc., Durham, NC. FAU - Coyle, Joseph T AU - Coyle JT AD - Laboratory for Psychiatric and Molecular Neuroscience, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA. FAU - Wice, Burton M AU - Wice BM AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO bwice@dom.wustl.edu. LA - eng GR - 1R01-DK-088126/DK/NIDDK NIH HHS/United States GR - P30 DK056341/DK/NIDDK NIH HHS/United States GR - R01-MH-51290/MH/NIMH NIH HHS/United States GR - UL1-RR-024992/RR/NCRR NIH HHS/United States GR - P30-DK-020579/DK/NIDDK NIH HHS/United States GR - P30 DK020579/DK/NIDDK NIH HHS/United States GR - RC1 DK086163/DK/NIDDK NIH HHS/United States GR - R01 MH051290/MH/NIMH NIH HHS/United States GR - UL1 RR024992/RR/NCRR NIH HHS/United States GR - P30-DK-056341/DK/NIDDK NIH HHS/United States GR - T32-DA-015036/DA/NIDA NIH HHS/United States GR - T32 DA015036/DA/NIDA NIH HHS/United States GR - UL1 TR000448/TR/NCATS NIH HHS/United States GR - R01 DK088126/DK/NIDDK NIH HHS/United States GR - 5RC1-DK-086163/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141103 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Blood Glucose) RN - 0 (Pyruvates) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 934B2KHY0S (hydroxypyruvic acid) SB - IM CIN - Diabetes. 2015 Apr;64(4):1099-101. PMID: 25805762 MH - Animals MH - Blood Glucose MH - Diabetes Mellitus, Type 2/*metabolism MH - Enteroendocrine Cells/*metabolism MH - Female MH - Gastric Inhibitory Polypeptide/*metabolism MH - Glucagon-Like Peptide 1/*metabolism MH - Humans MH - Insulin-Secreting Cells/metabolism MH - Male MH - Metabolomics MH - Mice MH - Mice, Transgenic MH - Pyruvates/*metabolism PMC - PMC4375086 EDAT- 2014/11/05 06:00 MHDA- 2015/05/23 06:00 PMCR- 2016/04/01 CRDT- 2014/11/05 06:00 PHST- 2014/11/05 06:00 [entrez] PHST- 2014/11/05 06:00 [pubmed] PHST- 2015/05/23 06:00 [medline] PHST- 2016/04/01 00:00 [pmc-release] AID - db14-1188 [pii] AID - 1188 [pii] AID - 10.2337/db14-1188 [doi] PST - ppublish SO - Diabetes. 2015 Apr;64(4):1383-94. doi: 10.2337/db14-1188. Epub 2014 Nov 3.