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Endocrinology. 2016 May;157(5):1852-65. doi: 10.1210/en.2015-1935. Epub 2016 Feb 10.

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

Author information

1
Anatomy and Cell Biology (Y.Y., X.S., W.X., B.L., N.H., S.R.T., J.F.E.), Departments of Pathology (K.G.-C.) and Pediatrics (A.U., K.L.O., A.W.N.), Fraternal Order of Eagles Diabetes Research Center (A.W.N., J.F.E.), and Department of Biostatistics (K.W.), College of Public Health, University of Iowa, Iowa City, Iowa 52242; and Department of Medicine (L.H.P., M.H.), University of Chicago, Chicago, Illinois 60637.

Abstract

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 β-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 β-cell mass rose and gene expression of islet hormones, peroxisome proliferator-activated receptor-γ, and adiponectin increased. We conclude that active CF exocrine pancreatic inflammation adversely affects β-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.

PMID:
26862997
PMCID:
PMC4870869
DOI:
10.1210/en.2015-1935
[Indexed for MEDLINE]
Free PMC Article

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