The cluster of differentiation 36 (CD36) is a scavenger receptor present on various types of cells and has multiple biological functions that may be important in inflammation and in the pathogenesis of metabolic diseases, including diabetes. Here, we consider recent insights into how the CD36 response becomes deregulated under metabolic conditions, as well as the therapeutic benefits of CD36 inhibition, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with metabolic diseases. To facilitate this process further, it is important to pinpoint regulatory mechanisms that are relevant under physiological and pathological conditions. In particular, understanding the mechanisms involved in dictating specific CD36 downstream cellular outcomes will aid in the discovery of potent compounds that target specific CD36 downstream signaling cascades.

In type 2 diabetes, metabolic stress has a negative impact on pancreatic β-cell function and survival (T2D). Although the pathogenesis of metabolic stress is complex, an imbalance in redox homeostasis causes abnormal tissue damage and β-cell death due to low endogenous antioxidant expression levels in β-cells. Under diabetogenic conditions, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to contributing to β-cell dysfunction. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions by NADPH oxidase, as well as the therapeutic benefits of NOX inhibitors, which may provide clues for understanding the pathomechanisms and developing strategies aimed at the treatment or prevention of metabolic stress associated with β-cell failure.

Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure.

Reductive stress, characterized by excessive reducing equivalents such as NADH, NADPH, and reduced glutathione (GSH), is increasingly recognized as a pathophysiological counterpart to oxidative stress. Chronic hyperinsulinemia and insulin resistance promote this over-reduced state by increasing glucose flux, pentose phosphate pathway activity and de novo lipogenesis, thereby elevating NADPH pools and reshaping cellular lipid composition. While reducing equivalents are essential for biosynthesis and antioxidant defense, persistent over-reduction disrupts redox balance, mitochondrial function and metabolic flexibility. Paradoxically, this reductive metabolic environment may increase susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and failure of glutathione peroxidase 4 (GPX4). Here, we define how reductive stress becomes deregulated in the context of insulin signaling and insulin resistance, and assess whether antioxidant interventions can mitigate ferroptosis, providing a framework for therapeutic strategies to restore redox balance in metabolic disease.