Studies of Rare Human Diseases Lead to Insights Into Regulation of Human Beta-Cell Proliferation

Maureen Gannon
Endocrinology, Volume 165, Issue 4, April 2024, bqae019
https://doi.org/10.1210/endocr/bqae019

Abstract

Recently, unrelated analyses of mutations that lead to rare overgrowth diseases such as Beckwith-Wiedemann syndrome (BWS; occurring in approximately 1 in 11 000 births) and genes showing reduced expression in human insulinomas (1%–2% of all pancreatic neoplasias) have converged on a known cell cycle inhibitor gene, CDKN1C, encoding p57^KIP2. Loss of CDKN1C removes an important brake, leading to increased beta-cell proliferation. One of the phenotypic characteristics of BWS is neonatal hypoglycemia due to hyperinsulinemia caused by expanded beta-cell mass; characteristics also associated with human insulinomas. Human beta cells have been shown to be more resistant to proliferative stimuli and to express more cell cycle inhibitors compared with rodent beta cells, potentially contributing to decreased adaptability in the face of metabolic challenges, and increased risk for diabetes with age and weight gain. Therapeutic manipulation of cell cycle inhibitor activity could potentially expand functional beta-cell mass and ameliorate diabetes. Indeed, small molecules that inhibit DYRK1A have been identified as human beta-cell regenerative drugs, and these drugs repress CDKN1C in human beta cells.

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