Coadministration of GLP-1 and Y2R Receptor Agonists Synergize to Promote Muscle Glucose Uptake and Induce Diabetic Remission
DIABETES(2018)
摘要
One proposed mechanism for the effects of bariatric surgery is the enhanced postprandial release of enteroendocrine L-cell hormones, such as PYY and GLP-1. Four week co-administration of Fc-conjugated GLP-1R and Y2R-selective agonists induced weight loss, reduced %HbA1c, and improved glucose tolerance in DIO and KS db/db mice compared to vehicle or monotherapy control groups. To assess the impact of this combination on glucose control, a hyperinsulinemic/euglycemic clamp was performed in KS db/db mice following two week treatment with vehicle or co-administration of GLP-1/Y2R agonists. A vehicle-treated group weight-matched to combination-treated mice was also assessed. Compared to KS db/db vehicle animals, combination-treated mice exhibited a 16-fold greater glucose infusion rate compared to only 4-fold in weight-matched controls. Glucose uptake was increased 4-fold in the skeletal muscle of combination-treated animals, but was unaltered in adipose or brain. Weight-matched controls did not exhibit increased glucose uptake in any tissue. To better characerize the mechanism of Fc-GLP-1/Fc-Y2R action on peripheral glucose metabolism, lean mice were acutely administered Fc-GLP-1 and/or Fc-Y2R, and then sacrificed to assess brain c-Fos activation. Compared to monotherapies, combination administration led to additive c-Fos activation in hindbrain regions. Strikingly, whereas monotherapy had no effect on the PVH, combination administration led to a synergistic 2-fold increase in c-Fos immunoreactivity. These findings implicate a neuronal population in the PVH as a putative driver of the antidiabetic efficacy observed following co-administration of GLP-1R and Y2R selective peptides, and may represent a novel mechanism to improve insulin sensitivity and skeletal muscle glucose uptake. Disclosure B. Boland: Employee; Self; MedImmune. V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Regeneron Pharmaceuticals, Inc., AstraZeneca. M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. J. Grimsby: Employee; Self; AstraZeneca.
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