Vitamin D and the Metabolic-Associated Steatotic Liver Disease – Type 2 Diabetes Axis: A Scoping-Narrative Review of Global Evidence and Emerging Perspectives for Sub-Saharan Africa

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and Type 2 Diabetes Mellitus (T2DM) are rapidly emerging as twin epidemics in Sub-Saharan Africa (SSA), driven by urbanization and nutritional transition. While global evidence links Vitamin D deficiency (VDD) to the progression of both disorders, data specific to African populations remains fragmented. This review explores the Vitamin D–MASLD–T2DM axis, contrasting global mechanistic insights with the unique genetic, environmental, and infectious disease landscape of SSA. Methods: A hybrid scoping-narrative review was conducted searching PubMed/MEDLINE, Scopus, and Embase for literature published up to 2025. The search targeted mechanistic studies, clinical trials, and regional epidemiological data. Out of 948 initial citations, 59 high-quality studies were prioritized for synthesis. The review integrates molecular evidence of Vitamin D Receptor (VDR) signaling with clinical outcomes and evaluates their applicability to the African context. Results: Mechanistic evidence indicates that Vitamin D exerts potent anti-inflammatory and insulin-sensitizing effects via VDR activation, specifically by downregulating hepatic de novo lipogenesis (SREBP-1c) and suppressing NF-κB signaling in Kupffer cells. Epidemiological data consistently associate VDD with increased liver fibrosis and insulin resistance. However, randomized controlled trials yield conflicting results, likely due to heterogeneity in dosing and baseline status. Uniquely in SSA, the "Vitamin D Paradox" (low total levels with preserved bone health), the rarity of the PNPLA3 genetic risk variant, and the metabolic toxicity of antiretroviral therapy (e.g., Efavirenz) create a distinct pathophysiological environment where standard definitions of deficiency may be inadequate. Conclusion: Vitamin D deficiency is a plausible, modifiable driver of the MASLD–T2DM axis in Sub-Saharan Africa, potentially filling the risk void left by the absence of major genetic drivers like PNPLA3. However, Eurocentric thresholds for deficiency may not apply. Future research must prioritize establishing ancestry-specific reference ranges and conducting region-specific trials that account for the "triple burden" of HIV, urbanization, and dietary transition to inform effective public health interventions such as fortification.