Insulin signalling articles from across Nature Portfolio

IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.

Hees et al. identify a mechanism that integrates insulin signalling with distal mitochondrial quality control in neurons via AMPK/PINK1, with implications for mitochondrial dysfunction in the context of insulin resistance in neurons.

The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here, the authors show in a mice model that insulin action in the gut may play a protective role in the development of NASH and HCC in diabetes.

Direct conversions offer an alternative approach to generate insulin-producing cells for cell therapy in diabetes. A study reports a method to convert human stomach-derived gastric stem cells into functional insulin-producing cells through a unique differentiation path.

A new paper reports that the protein isthmin 1 is secreted by mature adipocytes and triggers a signalling cascade similar to that of insulin. The novel adipokine acts through an unidentified receptor tyrosine kinase and, at pharmacological doses in mice, isthmin 1 ameliorates metabolic disturbances associated with type 2 diabetes mellitus, including hyperglycaemia and liver steatosis.

A new study has reported genetic evidence that MEK–ERK signalling is needed by β-cells, both for maintenance of β-cell mass and for optimization of insulin release. Their results point towards a new challenge of disentangling ERK signalling across multiple time scales.

Exhaustion of pancreatic beta cells in the face of prolonged insulin resistance results in the development of type II diabetes. Ansarullah et al. now describe an inhibitor of beta-cell insulin signalling that, on removal, increases beta-cell mass and improves beta-cell function, with potential as a new way to address beta-cell failure.