ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

Abstract

The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin β1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle—an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans

“…ADAMTS9 is a risk gene for type 2 diabetes development and its over-expression is associated with impaired insulin signaling in peripheral tissues and also with insulin resistance [69]. Its risk allele (rs4607103 C) has been demonstrated to decrease mitochondrial function and to alter glucose and lipid metabolism [70]. Another gene identified as differentially expressed after PS juice consumption is adenylate cyclase 8 (ADCY8), which is involved in insulin secretion and glucose homeostasis.…”

Insulin Sensitivity Is Associated with Lipoprotein Lipase (LPL) and Catenin Delta 2 (CTNND2) DNA Methylation in Peripheral White Blood Cells in Non-Diabetic Young Women

“…The gustation pathway may also be related since inhibition of sweet chemosensory receptors alters insulin responses during glucose ingestion [32]. Specifically, statistically significant CpGs (FDR < 0.05) from our study that were previously related to insulin were located in the genes LPL [33], GRB10 [34], WISP1 [35], PRDM16 [36], TMEM132C [37], ADAMTS9 [38], and NOX4 [39].…”

Global transcriptomic analysis reveals Lnc-ADAMTS9 exerting an essential role in myogenesis through modulating the ERK signaling pathway

“…ADAMTS9 , locating in cell surface/pericellular matrix proteolysis in diverse contexts, is a highly conserved secreted protease that remodels provisional ECM in morphogenetic processes [ 49 ] and takes part in the regulation of skeletal muscle insulin sensitivity [ 50 ]. In humans, ADAMTS9-AS2 was identified as an antisense transcript of the ADAMTS9 [ 51 ].…”