Role of insulin in pancreatic microcirculatory oxygen profile and bioenergetics

Abstract

BACKGROUND The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery. In diabetes, the balance between oxygen delivery and consumption is impaired. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity. AIM To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics. METHODS The pancreatic microcirculatory partial oxygen pressure (PO 2 ), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO 2 ) were evaluated in nondiabetic, type 1 diabetes mellitus (T1DM), and insulin-treated mice. A three-dimensional framework was generated to visualize the microcirculatory oxygen profile. Ultrastructural changes in the microvasculature were examined using transmission electron microscopy. An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells (IMECs). RESULTS Significantly lower PO 2 , rHb, and SO 2 values were observed in T1DM mice than in nondiabetic controls. Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs. Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity. Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs ( P < 0.05). An energy map revealed increased energetic metabolism in insulin-treated IMECs, with significantly increased ATP production, non-mitochondrial respiration, and oxidative metabolism (all P < 0.05). Significant negative correlations were revealed between microcirculatory SO 2 and bioenergetic parameters. CONCLUSION Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.