Isoflurane aggravates peripheral and central insulin resistance in high-fat diet/streptozocin-induced type 2 diabetic mice.

Isoflurane anesthesia is reported to induce insulin resistance (IR) in the peripheral tissues. However, researches on the impact of isoflurane on insulin-related metabolism in the central nervous system, especially in type 2 diabetes mellitus (T2DM), are scarce. This study sought to explore whether isoflurane anesthesia had a negative effect on insulin sensitivity both in peripheral and central tissues. Moreover, the possible role of isoflurane anesthesia in T2DM mice with pre-existing IR was analyzed. T2DM model in C57BL/6J mice was established by high fat diet (HFD) and single intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). Both HFD/STZ-induced T2DM mice and normal mice received 6 h isoflurane exposure. Blood glucose level and serum insulin concentration were detected and the homeostasis model assessment of IR (HOMA-IR) index was calculated to estimate peripheral IR. Relative levels of genes and proteins in the insulin-dependent signaling pathway in mouse prefrontal cortex and hippocampus were determined to measure central IR. Results indicated that 6 h isoflurane exposure induced hyperglycemia, hyperinsulinemia and raised HOMA-IR index. Meanwhile, phosphorylated insulin receptor substrate-1 (pIRS1) (Ser639) and phosphorylated insulin receptor substrate-2 (pIRS2) (Ser731) were upregulated, while phosphorylated protein kinase B (pAKT) (Ser473) and phosphorylated glycogen synthase kinase-3 beta (pGSK3β) (Ser9) were downregulated in the prefrontal cortex and hippocampus of anesthetized mice. Notably, isoflurane anesthesia significantly aggravated the degree of central IR in the aspects of gene transcriptions and protein expressions in HFD/STZ-induced T2DM mice with pre-existing IR. This study suggested that isoflurane anesthesia induced peripheral and central IR and aggravated pre-existing insulin resistance in T2DM mice.