Published online Sep 15, 2022. doi: 10.4239/wjd.v13.i9.765
Peer-review started: April 29, 2022
First decision: May 29, 2022
Revised: June 9, 2022
Accepted: August 25, 2022
Article in press: August 25, 2022
Published online: September 15, 2022
Processing time: 133 Days and 13.4 Hours
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.
To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics.
The pancreatic microcirculatory partial oxygen pressure (PO2), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO2) 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).
Significantly lower PO2, rHb, and SO2 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 SO2 and bioenergetic parameters.
Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.
Core Tip: The pancreatic islet microvasculature adapts its metabolism to cope with limited oxygen availability and nutrient delivery. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis under glucotoxicity. Our findings demonstrate that insulin ameliorates the suppression of the integrated microcirculatory oxygen profile in type 1 diabetes mellitus mice and improves mitochondrial ultrastructural abnormalities in islet microvascular endothelial cells (IMECs). Additionally, insulin administration restores glucotoxicity-induced microcirculatory failure by increasing the mitochondrial basal respiration and glycolytic capacity of IMECs.