Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER), 3 are degraded by lysosomes for an alternative energy source during starvation (1, 2). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (1) but inhibited by amino acids and/or insulin through the mTOR-or/and Akt-dependent pathways after food intake (3, 4). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (1, 5). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (1) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (6 -10).Insulin resistance is either a precursor or...

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 mitochondrionderived 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.Since the beginning of the insulin era, most patients with T1DM 2 have been able to live almost normally. However, as early as the 1940s, long before the concept of insulin resistance came to light, it was noticed that the application of insulin in T1DM was associated with the development of cardiovascular disorders (1-5). Since the 1960s, it has been established that the application of insulin in T1DM always leads to insulin resistance (6 -10). Mechanisms associated with cardiovascular disorders and insulin resistance in patients with T1DM have been studied extensively but have not been completely understood.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 (11-21). However, it is unclear whether the effects of glucose and glucosamine on the development of insulin resistance can occur in the absolute absence of insulin. It is known that insulin can desensitize insulin signaling through activation of ERK1/2 MAPKs and/or Akt/ S6K (9, 22). It is unclear whether this scenario actually represents physiology and pathophysiology. However, 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. It has been shown that no matter how severe the obesity is, insulin resistan...