Abstract
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.
Highlights
Came to light, it was noticed that the application of insulin in type 1 diabetes mellitus (T1DM) was associated with the development of cardiovascular disorders [1,2,3,4,5]
To determine which of these two inducers is a stronger inducer of insulin resistance, a group of NOD diabetic mice with hyperglycemia was treated with saline for 2 weeks, and another group of diabetic NOD mice was treated with two doses of the long acting insulin reagent detemir, with one dose in the early morning and another in the evening
The application of insulin in T1DM has inadvertently led to cardiovascular disorders and insulin resistance [1,2,3,4,5, 9]
Summary
Came to light, it was noticed that the application of insulin in T1DM was associated with the development of cardiovascular disorders [1,2,3,4,5]. It has been shown previously that a high level of glucose and its byproducts such as glucosamine might play a critical role in the development of insulin resistance [11,12,13,14,15,16,17,18,19,20,21]. It is clear that ectopic fat accumulation in liver and skeletal muscles, increased oxidative stress, and decreased mitochondrial capacity/biogenesis are clustered together with insulin resistance. Ectopic fat accumulation has been shown to be correlated with insulin resistance in T1DM [25]. Suppression of mitochondrial biogenesis by antiretroviral nucleoside analogues is associated with the development of insulin resistance/hyperinsulinemia in patients with AIDS [35]. In this study, we have tested the hypothesis that inappropriate exposure to insulin plays a primary role in the development of insulin resistance in T1DM
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