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1.
J Biol Chem ; 298(1): 101431, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34801552

RESUMEN

Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in ß-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.


Asunto(s)
Diabetes Mellitus Tipo 2 , Dieta Alta en Grasa , Intolerancia a la Glucosa , Transportador de Glucosa de Tipo 4 , Hiperglucemia , Resistencia a la Insulina , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Transportador de Glucosa de Tipo 4/biosíntesis , Transportador de Glucosa de Tipo 4/metabolismo , Hiperglucemia/sangre , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
2.
Cell Rep ; 38(1): 110179, 2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34986353

RESUMEN

G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.


Asunto(s)
Células Enteroendocrinas/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Mucosa Intestinal/metabolismo , Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Animales , Glucemia/análisis , Calcio/metabolismo , Línea Celular , AMP Cíclico/metabolismo , Diabetes Mellitus/patología , Femenino , Polipéptido Inhibidor Gástrico/metabolismo , Prueba de Tolerancia a la Glucosa , Células HEK293 , Células HeLa , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Secreción de Insulina/fisiología , Mucosa Intestinal/citología , Masculino , Ratones , Ratones Noqueados , Obesidad/patología , Receptores de la Hormona Gastrointestinal/metabolismo
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