Volume 5 Issue 2, February 2023

MacDonald and Rorsman discuss the physiological role of glucagon, regulation and dysregulation of its secretion from alpha cells, and the potential of glucagon as a therapeutic target for diabetes and associated metabolic diseases.

Some individuals with obesity have a healthy metabolic profile and are not at increased risk for diabetes or cardiovascular disease. The mechanisms behind this phenomenon are poorly understood, but recent work now characterizes the biological underpinnings of the metabolically healthy obese phenotype.

Identifying mechanistic pathways that link obesity with COVID-19 severity provides targets for interventions to reduce the high risk of severe outcomes owing to obesity. The authors of a recent study use genomics and proteomics to show that nephronectin could be involved in one of these pathways.

Dai and colleagues show that activation of AMPK by glucose starvation leads to phosphorylation of GATOR2 and affects nutrient-dependent activation of mTORC1.

Cell division is a highly regulated process and requires a concurrent supply of energy and nutrients. Shin et al. provide critical insights into the allosteric mechanisms by which UTP regulates CAD activity and pyrimidine synthesis during the cell cycle.

Lactate build up in the tumour microenvironments is thought to dampen anti-tumour immunity, but in vitro pre-conditioning T cells with lactate enhances anti-tumour activity in vivo in pre-clinical mouse models.

The alternative splicing landscape of pancreatic islets is dominated by an evolutionarily conserved program of microexons. These short exons encode only a few extra amino acids in genes related to hormone secretion. Microexons are important to islet function, affecting glycaemic control and the risk of type 2 diabetes.

We show that the retinal pigment epithelium (RPE) — the outermost layer of the retina — is a local source of insulin that is modulated by starvation and phagocytosis, separate from pancreatic insulin. Further, this RPE-derived insulin has functional relevance in retinal physiology, retinal metabolic homeostasis and in limiting retinal disease.

Retinal pigment epithelial cells are identified as a local source of insulin in the retina, which is stimulated by phagocytosis of photoreceptor outer segments and starvation and has the potential to influence retinal physiology and disease.

In this study, Juan-Mateu et al. discover microexons that modulate insulin secretion in the pancreas in response to glucose levels in beta cell lines and mouse islets. Human genetic variants modulating these islet microexons are associated with type 2 diabetes risk.

Coral et al. characterize genetically determined discordance between obesity and type 2 diabetes, identifying discordant genes that may convey protection against type 2 diabetes in obesity.

How obesity contributes to COVID-19 severity is not fully understood. In this study, Yoshiji et al. found that the plasma protein nephronectin partially mediates the effect of obesity on the risk of COVID-19 severity using a two-step Mendelian randomization approach and omics analyses.

Dai et al. show that in response to low glucose levels, AMP-activated protein kinase-mediated phosphorylation of WDR24, a component of the GATOR2 complex, leads to suppression of mTORC1 activation.

Shin et al. gain structural insight into how pyrimidine synthesis is coupled to cell cycle regulation through the modulation of CAD activity, and identify allostery as a major means to regulate de novo pyrimidine biosynthesis during the mammalian cell cycle.

Takhaveev et al. use single-cell methods and mathematical modeling to reveal distinct waves in the synthesis rates of proteins, lipids and polysaccharides during the budding yeast cell cycle and relate them to flux changes in primary metabolism.

Prolonged exposure to acid is shown to reprogram T cell intracellular methionine metabolism to preserve T cell stemness and increase anti-tumor efficacy.

The authors provide evidence in mice and humans showing that parenteral nutrition impairs glucose and insulin homeostasis by altering the gut microbiota and its metabolites.