Global biochemical profiling identifies ß-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans.
Diabetes
; 64(4): 1383-94, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25368100
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. ß-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting ß-hydroxypyruvate production from d-serine. In vitro, ß-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. ß-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 ß-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and ß-cells by regulating ß-hydroxypyruvate levels.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piruvatos
/
Polipeptídeo Inibidor Gástrico
/
Células Enteroendócrinas
/
Diabetes Mellitus Tipo 2
/
Peptídeo 1 Semelhante ao Glucagon
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Macau