Subjects with
type 1 diabetes mellitus (T1DM) eventually develop
insulin resistance and other features of T2DM such as cardiovascular disorders. The exact mechanism has been not been completely understood. In this study, we tested the hypothesis that excessive or inappropriate exposure to
insulin is a primary mediator of
insulin resistance in T1DM. We found that continuous exposure of mice with non-obese diabetes to
insulin detemir, which is similar to some current conventional treatment of human T1DM, induced severe
insulin resistance, whereas untreated
hyperglycemia for the same amount of time (2 weeks) did not cause obvious
insulin resistance.
Insulin resistance was accompanied by decreased mitochondrial production as evaluated by
mitochondrial DNA and levels of transcripts and
proteins of mitochondrion-associated genes, increased ectopic fat accumulation in liver and skeletal muscle (gastrocnemius) evaluated by measurements of
triglyceride content, and elevated oxidative stress detected by the GSH/
GSSG ratio. Prolonged exposure of cultured hepatocytes to
insulin induced significant
insulin resistance, whereas the same length of exposure to a high level of
glucose (33 mm) did not cause obvious
insulin resistance. Furthermore, our results showed that prolonged exposure to
insulin caused oxidative stress, and blockade of mitochondrion-derived oxidative stress by overexpression of
manganese-superoxide dismutase prevented
insulin resistance induced by the prolonged exposure to
insulin. Together, our results show that excessive exposure to
insulin is a primary inducer of
insulin resistance in T1DM in mice.