“NO” To Autophagy: Fat Does The Trick For Diabetes

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  1. paymanz

    paymanz Member

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    “NO” to Autophagy: Fat Does the Trick for Diabetes

    During the progression from obesity to diabetes, a critical attribute is inability to maintain metabolic homeostasis under excessive energy and nutrient exposure, which triggers insulin resistance. Intensive research efforts have linked chronic inflammation, redox changes, and intracellular stress responses to dysregulated energy metabolism, particularly insulin resistance (1). Autophagy, a lysosomal degradation pathway for damaged organelles or long-lived proteins, was recently identified as a key regulatory pathway to preserve lipid homeostasis and insulin sensitivity under metabolic stress conditions (24). Dysfunction of autophagy is associated with obesity and type 2 diabetes. However, the mechanisms underlying the cause of autophagic defect in metabolic disorders remain elusive. In this issue of Diabetes, a study conducted by Qian et al. (5) revealed a mechanism by which obesity cripples autophagy in the liver through S-nitrosylation, an inhibitory protein modification process induced by nitric oxide (NO). Their data argue that in obese animals, NO-induced repression of hepatic autophagy causes hepatic steatosis, impairs hepatic insulin signaling, and eventually contributes to the progression of type 2 diabetes

    Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia:... - Abstract - Europe PMC

    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.
     
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