The overwhelming majority of type 2 diabetics are insulin resistant, which means their bodies are unable to respond to and use the insulin they produce. Two new papers recently published in the Proceedings of the National Academy of Sciences by researchers from Penn Medicine's Institute for Diabetes, Obesity, and Metabolism advance understanding of this complicated condition.
Pancreas Islet Cells. Credit: Doris Stoffers, MD, PhD.
Of the many prevalent theories on the development of insulin resistance, one of the leading ideas is that activation of a part of the immune response called innate immunity is responsible. Senior author Morris Birnbaum, MD, PhD, the Rhoda and Willard Ware Professor of Metabolic Diseases at Penn, and colleagues have activated the immune response in fruit flies either genetically or by infection, thereby producing insulin resistance. This result provides a plausible explanation of why such a maladaptive process would ever evolve. They suggest that the connection between the two systems evolved to protect the organism from infection by shifting energy from growth to the immune response. “We have created a genetically tractable system for tying together the immune system-insulin relationship to identify new genes or drugs for diabetes and related metabolic diseases,” says Birnbaum.
Pancreatic beta cells compensate for insulin resistance, usually associated with obesity, by increasing both beta-cell number and beta-cell function. In type 2 diabetes, it is the failure of these beta cells to compensate for insulin resistance that underlies the progression to overt diabetes. The lab of Doris Stoffers, MD, PhD, professor of Medicine, determined that Pdx1, a protein that regulates beta-cell identity, is required for the ability of beta cells to increase their function and number in response to obesity-induced insulin resistance. What’s more, they found that Pdx1 deficiency enhances beta-cell susceptibility to death by impairing the function of the endoplasmic reticulum (ER), a part of the inner cell responsible for the initial synthesis and processing of insulin. The association of Pdx1 mutations with type 2 diabetes in humans and low levels of Pdx1 with beta cell dysfunction in experimental models of diabetes points to Pdx1 regulation of ER homeostasis as a potential therapeutic target for type 2 diabetes.
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