Type 2 diabetes is a growing epidemic, and is recognized as one of the most serious metabolic disease worldwide. A multifactorial disease, type 2 diabetes is a perfect example of metabolic miscommunication between different organs resulting in a pathological outcome. According to CDC in the United States, 29.1 million people in the United States have diabetes, and 8.1 million may be undiagnosed. The disease affects more than 1 in every 10 adults, and seniors aged 65 and above are most affected. What makes the disease morbid are the secondary complications associated with it; atherosclerosis and cardiomyopathy are the leading cause of death in people diagnosed with type 2 diabetes. The need for an effective treatment has become a global health priority.

Glucose stimulation, promotes β cell proliferation and survival by modulating growth factor signaling pathways (Insulin/IGF-1). However, downregulation of one or more proteins of the Insulin/IGF-1 pathway results in reduced β cell mass, ultimately leading to defects in insulin secretion. Impaired insulin secretion and β cell dysfunction are characteristic features in the pathogenesis and progression of Type 2 diabetes and result in chronic hyperglycemia. Thus, increasing β cell proliferation to generate functional insulin-secreting cells can be a promising approach to treating Type 2 diabetes.

The islet β cell is among the most differentiated mammalian cell types, with the adult β cell being largely quiescent. To date, researchers studying β cell proliferation have generally focused on mechanisms that kick off the cell cycle to try and coax quiescent β cells into active cell division. Unfortunately, many of the β cells that re-enter the cell cycle do not complete it due to faulty regulatory signals. Investigators at Joslin Diabetes Center sought to understand the failure of β cells to divide. Using β cells modified to lack Insulin/IGF-1 receptor, they previously demonstrated that these cells do not divide as efficiently as normal β cells. To determine what underlies the inability of these β cells to divide, the authors attempted to explore the link between growth factor signaling pathways and the mitotic checkpoint in β cells.

In their recent research article published in Cell Metabolism, the researchers studied two cell cycle proteins, namely centromere protein A (CENP-1) and polo-like kinase-1 (PLK-1), essential players in chromosomal segregation. The authors reported that β cells lacking insulin receptor had significantly reduced expression of CENP-1 and PLK-1 compared to normal β cells. Further, mice lacking CENP-1 exhibited a higher propensity to develop insulin resistance when exposed to physiological states demanding adaptive β cell compensation, such as aging, high-fat diet, and pregnancy. The number of mitotic β cells was also attenuated. Human β cells from diabetic donors were also found to have lower levels of CENP-1 and PLK-1 proteins compared to cells from healthy donors. On the other hand, mice with islet hyperplasia had increased expression of CENP-1 and PLK-1.

To gain a deeper understanding of growth factor-mediated mechanisms underpinning β cell proliferation, the researchers investigated a pathway involving the transcription factor FOXM1. FOXM1 regulates the transcription of genes that drive cell proliferation. The authors discovered that insulin signaling was critical in FOXM1-mediated regulation of PLK-1 and CENP-1 in both mouse and human β cells. However, β cells with disrupted insulin signaling demonstrated loss of FOXM1 binding, leading to β cell apoptosis. This phenomenon was specific to the β cells.

These findings provide novel insights into the role of Insulin/IGF-1 signaling in cell cycle regulation, with implications for β cell loss being secondary to aberrant cell cycle regulation in Type 2 diabetes. The Insulin/IGF-1->FOXM1->PLK1->CENP-1 axis thus serves as an important pathway in β cell adaptation to delay and/or prevent progression to Type 2 diabetes. Understanding the nature of failure of physiologic and metabolic processes leading to insufficient insulin release and subsequent diabetes is essential for the development of novel anti-diabetic therapeutics.

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