Cellular stress regulates β-cell dysfunction in type 2 diabetes

By Heather Caslin

A close-up of a printed page that describes type 2 diabetes. A pair of reading glasses sitting on the page are magnifying the text, “Diabetes type 2."
Approximately 30 million Americans have type 2 diabetes. The majority are over 45 years old. © Vitalii Vodolazskyi, stock.adobe.com

Within the pancreas, β-cells produce insulin that delivers energy to tissues through glucose. People with type 2 diabetes have smaller, less functional β-cells; however, the mechanisms that drive these cellular differences are not completely understood. A recent Diabetes paper from the lab of Mark Magnuson, professor of molecular physiology and biophysics, shows that two forms of cellular stress drive distinct but additive genetic changes in β-cells.

Excitotoxicity occurs when excess fatty acids and glucose over-activate cells and lead to a build-up of intracellular calcium. In turn, overnutrition occurs when the levels of fatty acids in the blood exceed cells’ energy requirements and the excess is stored inappropriately. Both processes can lead to cellular stress and dysfunction. The current study investigated the effects of excitotoxicity and overnutrition on β-cell function.

To model excitotoxicity, lead author Anna Osipovich and colleagues used mice without Abcc8, a gene that helps regulate potassium and calcium channel activity. The team modeled overnutrition by feeding the mice a high-fat diet. Together, the excitotoxicity and overnutrition models impaired the normal response to an injection of glucose in mice. Treatment with a calcium channel blocker reversed this effect.

The Magnuson group further studied β-cells in culture to determine how excitotoxicity and overnutrition influence β-cell function. Both stressors caused similar, but distinct, changes in gene expression for pathways controlling cell metabolism, insulin secretion, and cell maintenance, with some additive effects. The combined stressors increased mitochondrial energy production and impaired the metabolic response to glucose, suggesting that excitotoxicity and overnutrition impair the cell’s flexibility to use different fuel sources. Moreover, male mice had greater stress-induced impairments than female mice for both models of cellular stress, suggesting sex-specific differences.

Together, these findings indicate that multiple stress pathways drive similar but distinct metabolic dysfunction in β-cells. The researchers propose that targeting excitotoxicity with calcium channel blockade could help improve β-cell function in type 2 diabetes.

This research was supported by institutional and philanthropic funds provided by Vanderbilt University.