Woman injecting insulin, daily diabetes care during COVID-19
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A comprehensive map of insulin signaling in mice analyzes the influence of both genetics and diet. The team, from University of Sydney in Australia, studied mice with different but well-characterized genetic backgrounds. Impact of a high-fat diet, the researchers found, are strongly controlled by genetics. Insulin resistance is a major precursor of metabolic disease, including type 2 diabetes.

The research was published as a reviewed preprint in eLife. The work sheds light on the interplay between genetic attributes and environmental conditions in shaping insulin signaling in skeletal muscle—a crucial regulator of metabolism. The study also provides a unique tool for assessing the range of phosphorylation in insulin reactions.

“Insulin resistance—the failure of insulin to promote glucose uptake in its target tissues—is triggered by genetic and environmental factors such as family history and high-calorie diets,” says lead author Julian van Gerwen, who was an undergraduate at the School of Life and Environmental Sciences, University of Sydney, as he worked on the study.

Insulin normally prompts the body to absorb glucose from the bloodstream via a signaling pathway. These signals are enabled by phosphorylation. This is the addition of a phosphate group to a protein at a very specific positiona phosphosite. 

Insulin signaling is believed to control thousands of phosphosites, but many are still uncharacterized. In addition, although it is well known that people vary greatly in their physiological response to insulin, it remains unclear how genetics or diet influence the phosphorylation status of cellular proteins—also known as the phosphoproteome. 

This team fed five strains of mice either a normal or high-fat and high-sugar diet, and took samples of their skeletal muscle, which is the site of greatest insulin-triggered glucose uptake after eating. The team they measured phosphorylation of the thousands of proteins present in each muscle sample using mass spectrometry. Their analysis recovered many well-known insulin-regulated phosphosites, and many more novel sites not previously been associated with insulin signaling. 

To explore the influence of genetic and environmental variation, the team developed an algorithm to analyze which changes could be attributed to genetics, diet, or their combination. Almost half of all insulin-regulated phosphosites were affected in the strain of the mice fed a normal diet, either having a stronger or weaker response to insulin. Overall, each genetic background displayed a unique fingerprint of insulin signaling. 

By contrast, although there were changes in insulin signaling caused by diet, the vast majority of these were shaped by the genetic background of the mice. Many phosphosites even changed in the opposite direction between multiple strains, highlighting that the molecular impacts of a high-fat diet are strongly controlled by genetics. 

To explore whether these changes in phosphorylation amounted to an altered insulin response in the mice, the team also measured glucose uptake in the same muscles used for the phosphoproteome analysis. By linking all insulin-regulated phosphosites with the level of glucose uptake, the researchers narrowed down on a set of key phosphosites likely to control the insulin response. “Inspired” by one of these phosphosites, the team found that modulating a specific protein could reverse insulin resistance in a cell-based model.

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