Crosstalk between autophagy and insulin resistance: evidence from different tissues

Abstract

Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.

Keywords: Adipose tissue; Autophagy; Diabetes complications; Insulin resistance; Type 2 diabetes.

Fig. 1

The mechanism of the autophagy pathway in mammalian cells. The autophagy process includes four main steps: induction, phagophore formation, phagophore elongation, and fusion with the lysosome. In the first step, different signals, such as starvation, rapamycin, and similar factors, inhibit mTOR and activate the ULK complex, thereby inducing autophagy. Active ULK stimulates the Vps34 complex to produce PI3P, which is needed for phagophore formation. In the following step, the phagophore expands, engulfs cytoplasmic constituents, and finally fuses with the lysosome to degrade their contents

Fig. 2

Molecular mechanism of lipophagy. Under nutrient deprivation, lipophagy forms phagophores. Patatin-like phospholipase domain-containing enzyme (PNPLA) interacts with LDs and performs critical functions in the breakdown of LDs. Autophagosomes engulf LDs and fuse with a lysosome to form an autolysosome. Then, lysosomal lipases hydrolyze the neutral lipids of LDs

Fig. 3

The insulin signaling under physiological and pathological conditions in various organs. 3.1: autophagy regulation in lean and obese adipose tissue and its effects on adipocytes. In the lean state (3.1.a), the stimulation of mTORC1 by insulin results in to autophagy inhibition. The inhibition of autophagy induces the ‘browning’ phenotype of the adipocytes. In obesity (3.1.b), ER stress, hypoxia and inflammation stimulate insulin resistance, resulting in mTORC1 inhibition and subsequently to induction of autophagy. Autophagy improve adipocyte function through eliminating damaged organelles and misfolded proteins and prohibiting the proinflammatory responses. Furthermore, excessive stimulation of autophagy may increase energy storage of adipocyte and promote cell death. 3.2: in physiological state (3.2.a), following the binding of insulin to its receptor, Akt is activated and leads to the inhibition of glycogen synthase kinase 3 and forkhead box O (FOXO) 1 in liver. Inhibition of glycogen synthase kinase leads to increased glycogen synthase activity, therefore, increased glycogen synthesis. Following the inhibition of FOXO1, the expression of glucose 6 phosphatase and phosphoenol pyruvate carboxykinase genes decreases, as a result, decreases the hepatic glucose production. Also, insulin decreases autophagy by activating Akt and inhibiting FOXO1. Akt increases lipid synthesis in hepatocytes by activating SREBP1c. The increase in lipid content by SREBP1c causes disruption in lipophagy and hepatic steatosis. In insulin resistance state (3.2.b), glycogen synthase kinase is activated and inhibits glycogen synthase. FOXO1 activity is increased, subsequently, gluconeogenesis pathway, lipid synthesis and very-low-density lipoprotein (VLDL) as well as autophagy are activated. SREBP1c increases its activity through ER stress or through IRS-1. 3.3: in the physiological state during starvation (3.3.a), the insulin hormone binding to its receptors causes the signaling adapter IRS-1 to be recruited and activate AMPK. Active AMPK causes mTORC1 reduction and an increase in autophagy. In a pathological state and during hyperglycemia (3.3.b), the binding of insulin to its receptor causes IRS-1 phosphorylation and recruits PI3K in muscles. Then, the PI3K converts PIP2 to PIP3, as a result, PIP3 induces Akt phosphorylation and increases glucose uptake. Also, Akt phosphorylation increases mTORC1 and decreases autophagy. mTORC1; mammalian target of rapamycin complex 1, ER; endoplasmic reticulum, FOXO1; forkhead box O1, SREBP1c; sterol regulatory element-binding transcription factor 1, VLDL; very-low-density lipoprotein, IRS-1; insulin receptor substrate 1, AMPK; AMP-activated protein kinase, IR; insulin receptor, PI3K; phosphatidylinositol-3-kinase, PIP2; phosphatidylinositol 4,5-bisphosphate, PIP3; phosphatidylinositol-3, 4, 5-triphosphate