The exocrine pancreas displays structural and functional abnormalities in type 1 diabetes, such as acinar atrophy and fibrosis. Metabolic dysfunction may occur alongside these changes. Real-time exocrine pancreatic metabolism was investigated using nuclear magnetic resonance (NMR) and hyperpolarized (HP) pyruvate. This work used the hyperglycemic NOD.Rag1-/-.AI4α/β mouse model of T1D (n=4), normoglycemic NOD.Rag1-/-.AI4α/β mice (n=3) to model the pre-T1D state, and the NOD.Rag1-/- control (n=3). NMR spectra were collected at 14 T after injection of 4 mM HP [1-13C] pyruvate into the common bile duct, and 13C signals from several central carbon metabolites were detected. Pancreata from diabetic mice produced significantly more (p<0.05) fumarate and aspartate compared to control mice, indicating increased pyruvate carboxylase flux. Alanine to lactate and bicarbonate to lactate ratios were significantly altered in pre-diabetic and diabetic mice compared to the control, indicating a detectable shift in tissue redox balance prior to altered glycemia. Separately, immunofluorescence imaging of pancreas slices revealed pyruvate carboxylase levels were increased in T1D mice. Ultimately, these results indicate that the diabetic pancreas displays increased pyruvate carboxylase (PC) flux and altered redox balance, thus providing unique insights into uncharacterized metabolic shifts in the exocrine pancreas in T1D.
A. Rushin: None. D.S. Graham: None. C. Hardin: None. M. Merritt: None.
National Institutes of Health (T32 DK10876); National Science Foundation (DMR-1644779)
