Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

Abstract

Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

Figure 1

Strategies for β-cell regenerative therapies. β-cell replenishment through exogenous transplantation of pancreas or pancreatic islet cells or stem cell-derived β-cells and endogenous expansion of β-cells via cell proliferation or transdifferentiation. Both pancreatic endocrine cells, such as islet α-cells, δ-cells, and γ-cells, acinar cells, duct cells, and gastrointestinal tract cells, can be reprogramed into insulin-producing β-like cells. Stem cell-derived β-cells have positioned hPSCs, typically including ESCs and iPSCs, as a promising and theoretically unlimited source of insulin-producing cells. ESCs: Embryonic stem cells; hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells.