Effect of Sphingosine-1-Phosphate Receptor Modulators on Insulin Resistance: A Review

Abstract

Objective:

The objective is to review the potential impact of sphingosine-1-phosphate (S1P) receptor modulators on insulin resistance in patients with multiple sclerosis, including underlying mechanisms and clinical evidence.

Data sources:

A literature search was conducted in PubMed for publications from inception through November 2025. Additional sources, including therapeutic positioning reports and official product information (Summary of Product Characteristics), were also reviewed.

Study selection and data extraction:

Relevant English and Spanish language articles were extracted and evaluated.

Data synthesis:

Sphingosine-1-phosphate receptors (S1PR) regulate both immunological and metabolic functions, representing a key therapeutic target in multiple sclerosis. Agents such as fingolimod, siponimod, ozanimod and ponesimod bind to these receptors, thereby preventing lymphocyte migration into the central nervous system. Preclinical evidence suggests that S1P signaling participates in insulin receptor and Akt pathways, affecting glycogen synthesis, glucose uptake and β-cell survival. Clinical experience, including a case of a patient with type 1 diabetes and multiple sclerosis treated with ponesimod, indicates potential increases in insulin requirements and hyperglycemia, although formal human studies are lacking.

Relevance to patient care and clinical practice:

Clinicians should monitor glycemic control in patients with multiple sclerosis receiving S1PR modulators, especially those with pre-existing metabolic disorders. Awareness of potential insulin resistance may guide drug selection and metabolic management. Further prospective studies are warranted to clarify clinical implications.

Conclusions:

S1PR modulators are effective disease-modifying therapies in multiple sclerosis, but emerging evidence suggests a possible impact on insulin signaling and glucose metabolism. Vigilance in metabolic monitoring is recommended, particularly in patients with diabetes or other risk factors for insulin resistance.