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Insulin receptor endocytosis in the pathophysiology of insulin resistance.

ABSTRACT: Insulin signaling controls cell growth and metabolic homeostasis. Dysregulation of this pathway causes metabolic diseases such as diabetes. Insulin signaling pathways have been extensively studied. Upon insulin binding, the insulin receptor (IR) triggers downstream signaling cascades. The active IR is then internalized by clathrin-mediated endocytosis. Despite decades of studies, the mechanism and regulation of clathrin-mediated endocytosis of IR remain incompletely understood. Recent studies have revealed feedback regulation of IR endocytosis through Src homology phosphatase 2 (SHP2) and the mitogen-activated protein kinase (MAPK) pathway. Here we review the molecular mechanism of IR endocytosis and its impact on the pathophysiology of insulin resistance, and discuss the potential of SHP2 as a therapeutic target for type 2 diabetes.

SUBMITTER: Hall C

PROVIDER: S-EPMC7338473 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Insulin receptor endocytosis in the pathophysiology of insulin resistance.

Hall Catherine C Yu Hongtao H Choi Eunhee E

Experimental & molecular medicine 20200623 6

Insulin signaling controls cell growth and metabolic homeostasis. Dysregulation of this pathway causes metabolic diseases such as diabetes. Insulin signaling pathways have been extensively studied. Upon insulin binding, the insulin receptor (IR) triggers downstream signaling cascades. The active IR is then internalized by clathrin-mediated endocytosis. Despite decades of studies, the mechanism and regulation of clathrin-mediated endocytosis of IR remain incompletely understood. Recent studies ha ...[more]

PMID: 32576931

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Project description:ObjectivesNeuraminidase 1 (NEU1) cleaves terminal sialic acids of glycoconjugates during lysosomal catabolism. It also modulates the structure and activity of cellular surface receptors affecting diverse pathways. Previously we demonstrated that NEU1 activates the insulin receptor (IR) and that NEU1-deficient CathAS190A-Neo mice (hypomorph of the NEU1 activator protein, cathepsin A/CathA) on a high-fat diet (HFD) develop hyperglycaemia and insulin resistance faster than wild-type animals. The major objective of the current work was to reveal the molecular mechanism by which NEU1 desialylation activates the IR and to test if increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance.MethodsTo test if desialylation causes a conformational change in the IR dimer we measured interaction between the receptor subunits by Bioluminescence Resonance Energy Transfer in the HEK293T cells either overexpressing NEU1 or treated with the NEU1 inhibitor. The influence of NEU1 overexpression on insulin resistance was studied in vitro in palmitate-treated HepG2 cells transduced with NEU1-expressing lentivirus and in vivo in C57Bl6 mice treated with HFD and either pharmacological inducer of NEU1, Ambroxol or NEU1-expressing adenovirus. NEU1-deficient CathAS190A-Neo mice were used as a control.ResultsBy desialylation of IR, NEU1 induced formation of its active dimer leading to insulin signaling. Overexpression of NEU1 in palmitate-treated HepG2 cells restored insulin signaling, suggesting that increased NEU1 levels may reverse insulin resistance. Five-day treatment of glycemic C57Bl6 mice receiving HFD with the activator of the lysosomal gene network, Ambroxol, increased NEU1 expression and activity in muscle tissue, normalized fasting glucose levels, and improved physiological and molecular responses to glucose and insulin. Ambroxol did not improve insulin sensitivity in obese insulin-resistant CathAS190A-Neo mice indicating that the Ambroxol effect is mediated through NEU1 induction. Sustained increase of liver NEU1 activity through adenovirus-based gene transfer failed to attenuate insulin resistance most probably due to negative feedback regulation of IR expression.ConclusionTogether our results demonstrate that increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance suggesting that a pharmacological modulation of NEU1 activity may be potentially explored for restoring insulin sensitivity and resolving hyperglycemia associated with T2DM.

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Insulin receptor endocytosis in the pathophysiology of insulin resistance.

Publications

Insulin receptor endocytosis in the pathophysiology of insulin resistance.

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