Potassium Homeostasis and the Systemic Consequences of Intracellular Potassium Deficiency: From Molecular Mechanisms to Clinical Manifestations

Potassium is the predominant intracellular cation and plays a fundamental role in maintaining membrane potential, cellular metabolism, enzyme activity, protein synthesis, acid–base homeostasis, and mitochondrial bioenergetics. Although hypokalemia is readily identified by decreased serum potassium concentration, serum potassium represents only a small fraction of total-body potassium stores and therefore may not accurately reflect intracellular potassium status. Consequently, chronic total-body potassium depletion and intracellular potassium deficiency may remain clinically unrecognized despite serum potassium concentrations within the reference range. Growing experimental and clinical evidence suggests that disturbances of potassium homeostasis are associated with multiple metabolic abnormalities involving the cardiovascular, neuromuscular, endocrine, renal, and gastrointestinal systems. Intracellular potassium depletion has been associated with mitochondrial dysfunction, oxidative stress, impaired insulin secretion and insulin sensitivity, metabolic alkalosis, chronic low-grade inflammation, and anabolic resistance. However, these relationships are complex and frequently bidirectional, indicating that potassium deficiency should be regarded as one component of an integrated metabolic network rather than an isolated pathogenic mechanism. This narrative review critically summarizes current evidence regarding the physiological regulation of potassium homeostasis, distinguishes hypokalemia from total-body potassium depletion and intracellular potassium deficiency, and discusses the mechanisms through which potassium depletion may contribute to systemic metabolic dysfunction. Particular attention is given to the clinical manifestations, diagnostic evaluation, and current therapeutic approaches to disorders of potassium homeostasis. Finally, important knowledge gaps are highlighted, including the need for reliable biomarkers of intracellular potassium deficiency and prospective studies evaluating whether correction of chronic potassium depletion improves long-term metabolic and clinical outcomes beyond normalization of serum potassium concentration.