A Transient Metabolic Recovery from Early Life Glucose Intolerance in Cystic Fibrosis Ferrets Occurs During Pancreatic Remodeling

作者：Yi Yaling; Sun Xingshen; Gibson Corley Katherine; Xie Weiliang; Liang Bo; He Nan; Tyler Scott R; Uc Aliye; Philipson Louis H; Wang Kai; Hara Manami; Ode Katie Larson; Norris Andrew W^*; Engelhardt John F^*

来源：Endocrinology, 2016, 157(5): 1852-1865.

DOI：10.1210/en.2015-1935

Cystic fibrosis (CF)-related diabetes in humans is intimately related to exocrine pancreatic insufficiency, yet little is known about how these 2 disease processes simultaneously evolve in CF. In this context, we examined CF ferrets during the evolution of exocrine pancreatic disease. At 1 month of age, CF ferrets experienced a glycemic crisis with spontaneous diabetic-level hyperglycemia. This occurred during a spike in pancreatic inflammation that was preceded by pancreatic fibrosis and loss of beta-cell mass. Surprisingly, there was spontaneous normalization of glucose levels at 2-3 months, with intermediate hyperglycemia thereafter. Mixed meal tolerance was impaired at all ages, but glucose intolerance was not detected until 4 months. Insulin secretion in response to hyperglycemic clamp and to arginine was impaired. Insulin sensitivity, measured by euglycemic hyperinsulinemic clamp, was normal. Pancreatic inflammation rapidly diminished after 2 months of age during a period where beta-cellmassroseandgene expression of is lethormones, peroxisome proliferator-activated receptor-gamma, and adiponectin increased. We conclude that active CF exocrine pancreatic inflammation adversely affects beta-cells but is followed by islet resurgence. We predict that very young humans with CF may experience a transient glycemic crisis and postulate that pancreatic inflammatory to adipogenic remodeling may facilitate islet adaptation in CF.

• 出版日期2016-5