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How Eating and Fasting Regulate Insulin

Overhead view of person eating a meal while reading a book

Scientists discovered that eating and fasting prompt cells in mice to ramp up or tamp down insulin secretion by changing the activity of various genes, and that similar insulin adjustments in human cells may be affected by type 2 diabetes, with potential implications for future therapy. Insulin-producing β (beta) cells, which reside in clusters called islets in the pancreas, release more insulin when needed for the body to use nutrients such as glucose (sugar) from food, and less insulin in periods of fasting. This regulation of insulin secretion is critical, as insufficient insulin can result in high blood glucose levels characteristic of diabetes, while excess insulin can lead to dangerously low blood glucose. However, it was not known how islet cells adapt their insulin secretion to nutrient conditions. To investigate this, scientists explored whether these insulin adjustments may result from changes in gene activity and changes to the epigenome, which includes proteins that interact with and package genes along the genome. One of the ways cells can influence gene activity is by chemically modifying these proteins.

The researchers began by analyzing insulin secretion, genes, and the epigenome from islets of mice that had been fed compared to those that had been fasted. They observed higher insulin secretion in islets from fed mice within just a few hours after providing the food. They then identified numerous genes that differed in activity between islets of fed and fasted mice, including genes with roles in nutrient sensing and metabolism, which may help link insulin secretion to feeding. Additionally, feeding increased chemical modifications to epigenomic proteins, consistent with the increased gene activity. Investigating further, they discovered that a different protein, called Lsd1, has a key role in changing epigenomic modifications and gene activity in β cells in response to nutrient status, leading to reduced insulin secretion during fasting. Finally, the researchers discovered that Lsd1 similarly affects insulin secretion and gene activity in human islets, acting at multiple sites across the genome—including sites where type 2 diabetes genetic variants have been found. The researchers suggest that these diabetes-associated variants might affect nutrient-based regulation of gene activity and resulting insulin secretion.

This study sheds light on how β cells adapt insulin secretion to the body’s needs, and how type 2 diabetes may disrupt this process. Future research on this pathway of insulin regulation may lead to new approaches for diabetes treatment.

Wortham M, Liu F, Harrington AR,...Sander M. Nutrient regulation of the islet epigenome controls adaptive insulin secretion. J Clin Invest 133: e165208, 2023.
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