期刊
DIABETES
卷 64, 期 4, 页码 1383-1394出版社
AMER DIABETES ASSOC
DOI: 10.2337/db14-1188
关键词
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资金
- National Institutes of Health [1R01-DK-088126, 5RC1-DK-086163, T32-DA-015036, R01-MH-51290]
- American Diabetes Association [1-10-CT-58, 1-13-CE-46]
- Blum-Kovler Foundation
- Live Cell Imaging Facility of the Center for Investigation of Membrane Excitability Diseases (CIMED) at Washington University
- Washington University Diabetes Research Center Immunoassay and Metabolomics Cores [P30-DK-020579]
- Washington University Nutrition Obesity Research Center from the National Institute of Diabetes and Digestive and Kidney Diseases [P30-DK-056341]
- Washington University Clinical and Translational Science Award [UL1-RR-024992]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000448] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024992] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020579, R01DK088126, RC1DK086163, P30DK056341] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH051290] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA015036] Funding Source: NIH RePORTER
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. -Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting -hydroxypyruvate production from d-serine. In vitro, -hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. -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 -hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and -cells by regulating -hydroxypyruvate levels.
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