REVIEW article
Front. Endocrinol.
Sec. Clinical Diabetes
ESSENTIAL MICRONUTRIENTS AND BIGUANIDES (METFORMIN) SYNERGISTIC AND ANTAGONISTIC INTERACTIONS ON NEUROCOGNITIVE OUTCOMES IN TYPE TWO DIABETES MELLITUS: A SYSTEMATIC REVIEW OF PRECLINICAL AND CLINICAL EVIDENCE
Provisionally accepted
- 1Department of Physiology, School of Medicine, Kabale University, Kabale, Uganda
- 2Department of Mental Health, Kabale University School of Medicine, Kabale, Uganda
- 3Department of Pharmacology, School of Medicine, Kabale University, Kabale, Uganda
- 4Department of Pharmacology, Kabale University School of Medicine, Kabale, Uganda
- 5Department of Physiology, Kabale University School of Medicine, Kabale, Uganda
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Background: Type 2 diabetes mellitus (T2DM) represents a systemic disease that extends beyond metabolic dysfunction to include accelerated neurocognitive decline driven by oxidative stress, inflammation, and insulin resistance. Emerging evidence suggests that essential micronutrients may interact synergistically or antagonistically with biguanides, particularly metformin, to influence neurocognitive function. This systematic review synthesized preclinical and clinical evidence on the interactions between essential micronutrients and biguanides (notably metformin) in modulating neurocognitive outcomes in T2DM. Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, and Scopus for studies published between 2010 and 2025. After screening 226 records in Rayyan, 40 studies met the inclusion criteria. Both preclinical and clinical studies were analyzed descriptively to identify patterns of mechanistic and functional outcomes. Extracted data covered intervention types, doses, duration, biomarkers, and cognitive outcomes. Results: Of the 40 studies, 27 (67.5%) were preclinical and 13 (32.5%) were clinical, spanning 14 countries. Most interventions involved vitamin D, zinc, magnesium, vitamin E, or polyphenols, either alone or combined with metformin. Synergistic effects were observed in 77.5% of studies, with significant improvements in fasting plasma glucose, HbA1c, insulin sensitivity, and oxidative balance. Key molecular pathways involved AMPK, PI3K/Akt, GSK3β, and Nrf2–CREB, which mediated enhanced glucose utilization, mitochondrial function, and synaptic plasticity. Antagonistic effects (10%) were mainly linked to metformin-induced vitamin B12 depletion, which impaired neurotrophic signaling and elevated homocysteine levels. Across studies, neuroprotective benefits correlated with increased BDNF, PSD-95, and SIRT1 expression, and reduced IL-6, TNF-α, and MDA levels. Conclusion: Most (75%) of the studies showed a synergistic interaction between biguanides (metformin) and micronutrients save a few that showed antagonistic interaction. Integrating micronutrient supplementation particularly vitamin D, zinc, and antioxidant compounds into T2DM management enhances both metabolic control and cognitive function. These findings support a paradigm shift toward combined nutraceutical–pharmacologic therapy within clinical and public health frameworks. Future research should focus on dose optimization, mechanistic validation, and long-term clinical evaluation to develop evidence-based, nutrition-sensitive diabetes care models.
Keywords: AMPK, BDNF, Metformin, Micronutrients, neurocognition, Oxidative Stress, type 2 diabetes mellitus
Received: 09 Dec 2025; Accepted: 29 Jan 2026.
Copyright: © 2026 Ninsiima, Ainamani, Ayebazibwe, Matovu and Eze. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: HERBERT Izo Ninsiima
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.