title: 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.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Songyan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Puhl
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO.
authors.forename: Krzysztof L
authors.initials: KL
authors.lastname: Hyrc
authors.affiliation: 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.
authors.forename: Erin
authors.initials: E
authors.lastname: Laciny
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wallendorf
authors.affiliation: Metabolon, Inc., Durham, NC.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Pappan
authors.affiliation: Laboratory for Psychiatric and Molecular Neuroscience, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
authors.affiliation: 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.
authors.forename: Burton M
authors.initials: BM
authors.lastname: Wice
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008822:Mice, Transgenic; D011773:Pyruvates / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D011773:Pyruvates; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C012375:hydroxypyruvic acid