Membrane remodeling, ion channels, Ca2+ signaling, and stress pathways as molecular links between type 2 diabetes and cancer

Abstract

The interrelationship between type 2 diabetes mellitus (T2DM) and cancer reflects a convergence of molecular disturbances involving metabolism, inflammation, and cellular stress, often underpinned by genetic alterations. This review examines some key shared mechanisms of progression, with a focus on changes in plasma membrane dynamics, ion channel remodeling, Calcium (Ca²⁺) signaling, mitochondrial dysfunction, unfolded protein response, and oxidative stress. Changes in membrane composition, fluidity, lipid raft organization, and glycosylation affect receptor function and intracellular signaling in both diseases. These structural changes often occur in conjunction with the remodeling of ion channels. Ca²⁺ influx, K⁺, and Na⁺ are particularly affected, contributing to dysregulated excitability, proliferation, and immune modulation. Disturbed ion transport leads to intracellular Ca²⁺ overload or oscillatory defects, impairing insulin secretion in diabetes and activating pro-oncogenic pathways in cancer. A sustained Ca²⁺ imbalance further triggers the maladaptive activation of the UPR, while also affecting mitochondrial function. In T2DM, this response promotes β-cell dysfunction and insulin resistance, whereas in cancer, selective UPR engagement supports cell survival, angiogenesis, and immune evasion. Oxidative stress acts as both a trigger and amplifier in this cascade. Lipid peroxidation and mitochondrial dysfunction reinforce membrane instability and propagate damage, accelerating both metabolic decline and tumor progression. Therapeutically, interventions such as membrane lipid replacement and Ca²⁺ channel blockers are being explored for their dual potential in addressing some of these molecular dysfunctions. By integrating molecular and epidemiological perspectives, this review highlights the potential of using precision therapies that target some of the overlapping properties of T2DM and cancer, offering a more unified strategy to confront these global health challenges.