Organelle-specific crosstalk between calcium and redox signaling in pancreatic β-cells in physiology and type 2 diabetes.

Two of the main intracellular signaling molecules in pancreatic β-cells are calcium (Ca2+) and reactive oxygen species (ROS). Ca2+ signaling is essential for regulating energy metabolism, insulin secretion, and the modulation of key factors involved in β-cell survival and function. In parallel, redox signaling also affects energy metabolism and enhances glucose-stimulated insulin secretion. Imbalances in Ca2+ and redox signaling may contribute to the development of various pathological conditions, including type 2 diabetes mellitus (T2D). T2D is one of the most prevalent diseases worldwide and is characterized by a progressive decline in insulin secretion, typically in the context of obesity and insulin resistance in target tissues. Insulin resistance and poor glycemic control lead to the development of several complications, such as retinopathy, kidney dysfunction, and neuropathy, which negatively impact both quality and life expectancy. Understanding how Ca2+ and ROS are modulated during the progression of T2D may aid in the development of pharmacological strategies aimed at preventing β-cell dysfunction or promoting their functional recovery. The two main intracellular Ca2+ stores in β-cells are the endoplasmic reticulum (ER) and mitochondria, while two important sources of ROS are mitochondria and NADPH oxidase (NOX) enzymes. It is also known that ROS and Ca2+ interact bidirectionally: Ca2+ can stimulate oxidative phosphorylation, increasing mitochondrial ROS production; some mitochondrial Ca2+ channels are redox-sensitive; certain Ca2+-dependent enzymes respond to redox signals; and some NOX isoforms are activated by Ca2+. Thus, ROS can modulate Ca2+ signaling, while Ca2+ signaling is essential for ROS production, establishing a feedback loop that affects β-cell function and survival. The aim of this review is to summarize the main findings on Ca2+ and ROS in pancreatic β-cells, addressing each of these signaling systems separately in physiological conditions and in T2D, and subsequently discussing their functional interaction and how these mechanisms function within the islet network. We also highlight the integration of the different intracellular compartments involved in these processes, namely, the ER, mitochondria, and NOX enzymes.