Calcium Signaling Dysregulation in Diabetic Cardiomyopathy: Roles of STIM and Orai Channels.

Abstract

Diabetes mellitus is a major metabolic disorder that significantly increases the risk of cardiovascular disease. Altered calcium (Ca²⁺) homeostasis, particularly through store-operated calcium entry (SOCE), has emerged as a critical pathway linking diabetes with cardiac dysfunction. Evidence indicates that SOCE is dysregulated in diabetes, but findings remain controversial. Some studies report reduced SOCE due to downregulation or impaired coupling of STIM1 and Orai1, leading to altered Ca²⁺ homeostasis and cardiac dysfunction. Others demonstrate enhanced SOCE linked to Orai and STIM isoforms upregulation, contributing to mitochondrial dysfunction, maladaptive hypertrophy, and metabolic remodeling in diabetic cardiomyopathy. Recent work also highlighted an unexpected role of STIM1 in fatty acid metabolism, linking Ca²⁺ signaling with energy substrate preference in the diabetic heart. This chapter synthesizes current evidence on the molecular mechanisms of STIM and Orai proteins in the regulation of SOCE under diabetic conditions, highlighting their roles in heart dysfunction.