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A novel protein complex may influence diabetes development

Scientists discovered a new complex of proteins that regulate the function of insulin-producing β (beta) cells and may influence the development of type 1 and type 2 diabetes. Hormones—signaling molecules that act on distant tissues and organs—regulate many physiological and behavioral processes, so elucidating their roles is critical to understanding health and disease. A previously identified hormone, fatty-acid-binding protein 4 (FABP4), has been shown to be released by fat cells (adipocytes) during times of starvation as these cells break down their stored fat for use as energy for the body, and FABP4 levels have been strongly associated with cardiometabolic disease. FABP4’s exact role, however, has been unclear.

In this new study, scientists discovered that FABP4 joins with two other proteins—adenosine kinase and nucleoside diphosphate kinase—to form a novel complex they named “Fabkin.” To determine the role of Fabkin, the scientists used two mouse models of diabetes. In a model of type 1 diabetes, they observed that Fabkin increased both shortly before and during disease development, suggesting that it may have a role in β-cell failure and disease pathogenesis. Interestingly, blocking Fabkin preserved β-cell mass and function, protecting against development of type 1 diabetes. In a mouse model of type 2 diabetes, blocking Fabkin improved control of blood glucose (sugar) and prevented the disease. To determine whether Fabkin had a role in diabetes in humans, the investigators looked at its levels and found that serum Fabkin was increased in individuals with new-onset type 1 diabetes compared to individuals without diabetes. In older people with type 1 diabetes with various durations of disease, serum Fabkin correlated with levels of hemoglobin A1c (HbA1c; a measure of blood glucose levels over time), suggesting that it is associated with glycemic control. Additional experiments to understand the underlying mechanisms of how Fabkin exerts its effects suggested that the hormone complex couples energy levels with a metabolic response to regulate the function of β cells.

This important discovery of Fabkin and its novel mechanism to integrate energy status with regulation of metabolism has revealed a promising new therapeutic target to combat metabolic diseases, including type 1 and type 2 diabetes. Further research on Fabkin and its impacts on human health and disease will be required to capitalize on these exciting results.

Prentice KJ, Saksi J, Robertson LT,…Hotamisligil GS. A hormone complex of FABP4 and nucleoside kinases regulates islet function. Nature 600: 720-726, 2022.

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