New molecular mechanisms linked to insulin resistance

Insulin resistance precedes and predicts the onset of type 2 diabetes mellitus (DM2), a chronic disease that causes high morbidity and mortality worldwide. In affected people, insulin is unable to facilitate the uptake of glucose through tissues and organs, leading to an increase in blood glucose (chronic hyperglycaemia). Since skeletal muscle is the tissue that uses the most glucose in response to insulin action, it is the most affected tissue by insulin resistance.

Now, a study published in Cell Communication and Signaling describes new molecular mechanisms to understand insulin resistance in skeletal muscle and to outline future drug targets for DM2.

The study is led by Manuel Vázquez-Carrera, from the UB’s Faculty of Pharmacy and Food Sciences, the Institute of Biomedicine of the UB (IBUB) and the Sant Joan de Déu Research Institute (IRSJD) and the Networking Biomedical Research Centre’s Diabetes and Associated Metabolic Diseases area (CIBERDEM). Ricardo Rodríguez-Calvo (CIBERDEM and Universitat Rovira i Virgili), Antoni Camins (UBNeuro and CIBERNED) and Walter Wahli, from the University of Lausanne (Switzerland), among other experts, also signed the paper.

Exploring the role of the insulin receptor
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Poorly controlled diabetes is a serious global health problem that can damage patients’ blood vessels, heart, eyes, kidneys and other organs. Studies have shown that during the development of insulin resistance, many steps in the metabolic pathway activated by insulin are altered. However, much less attention has so far been paid to what happens to the insulin receptor.

Professor Manuel Vázquez-Carrera notes that “the insulin signalling pathway is initiated when insulin binds to a receptor on the cells of insulin-responsive tissues. This receptor is composed of the α-subunit of the insulin receptor (InsRα) and the β-subunit (InsRβ)”.
“Insulin binding to InsRα derepresses the tyrosine kinase activity of the β-subunit (InsRβ). This initiates a whole metabolic pathway with different steps that eventually allow glucose transporters to translocate from the interior to the cell membrane to allow glucose to enter”, he continues.

The study assesses whether peroxisome proliferator-activated receptor (PPAR) β/δ can regulate InsRβ levels in mouse muscle and myotubes in culture. “The results show that deletion of the PPARβ/δ gene in mice reduces InsRβ protein levels in skeletal muscle compared to non-genetically modified mice. GW501516 — a PPARβ/δ agonist — has also been shown to increase InsRβ protein levels in mice muscle”, says Vázquez-Carrera.

The expert adds that “the reduction of InsRβ levels in cultured myotubes caused by an activator of endoplasmic reticulum stress — a process involved in the development of insulin resistance and DM2 — is partially reversed when cells are incubated in the presence of this PPARβ/δ agonist”. “Specifically, this agonist also decreased reticulum stress and lysosomal activity, the latter of which is responsible for degrading the InsRβ protein, which could explain the beneficial effect of this compound on the levels of this protein”, he says.

The results also reveal how protein levels of ephrin receptor tyrosine kinase B4 (EphB4) — a factor that binds to InsRβ and facilitates its endocytosis and degradation in lysosomes — were increased in skeletal muscle from PPARβ/δ-deficient mice. However, the PPARβ/δ agonist decreased levels in skeletal muscle from non-genetically modified mice.
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The results of this study identify new mechanisms by which PPARβ/δ regulates InsRβ protein levels in skeletal muscle. “The research describes new actions of this nuclear receptor that may help explain its beneficial effects on insulin resistance and DM2”, concludes Vázquez-Carrera.