Association between metabolic dysfunction-associated steatotic liver disease, vitamin D3, and diabetic gastric motility disorders in type 2 diabetes mellitus

Abstract

This letter comments on a study linking metabolic dysfunction-associated steatotic liver disease (MASLD), vitamin D3, and severe gastric autonomic neuropathy (diabetic gastric motility disorders) in type 2 diabetes mellitus (T2DM). We question the necessity of excluding patients with severe cataract (unable to complete fundus exams), as the focus on T2DM-MASLD correlation may render other T2DM complications less relevant. We emphasize vitamin D3’s multifaceted relevance: It associates with T2DM (high-dose supplementation reduces onset risk), MASLD (serum levels predict risk), smooth muscle function, immunity, and T2DM-related fractures via advanced glycation end products. We propose correlating MASLD severity with vitamin D3 levels and diabetic gastric motility disorders in validation analyses (e.g., correlation, area under the curve) to refine factor analysis. Additionally, based on the authors’ note of vitamin D3-tryptophan metabolism links, we call for deeper integration of metabolic pathways to clarify vitamin D3’s role in smooth muscle electrophysiology, leveraging the team’s prior research insights.

Key Words: Diabetic gastric motility disorders; Metabolically-dysfunction-associated steatotic liver disease; Vitamin D3; Type 2 diabetes mellitus; Smooth muscle; Electrophysiological function

Core Tip: This letter discusses a study linking metabolic dysfunction-associated steatotic liver disease, vitamin D3, and diabetic gastric motility disorders in type 2 diabetes mellitus, suggests refining exclusion criteria, highlights vitamin D3’s roles in metabolism and smooth muscle function, and proposes correlating metabolic dysfunction-associated steatotic liver disease severity with vitamin D3 and motility disorders, while anticipating deeper exploration of vitamin D3’s physiological functions via metabolic pathways.

TO THE EDITOR

This is a well-designed study with significant findings, and we would like to express our respect to the authors. To the best of our knowledge, this is the first article focusing on the association between metabolic dysfunction-associated steatotic liver disease (MASLD), vitamin D3 (25-hydroxyvitamin D), and severe gastric autonomic neuropathy in type 2 diabetes mellitus (T2DM)[1]. We present our comments on some aspects of this study.

First, the exclusion criteria included “patients with severe cataract and unable to complete fundus examination”, which is somewhat confusing to us. Since this study focuses on the correlation between T2DM and MASLD, patients with T2DM-related complications should not be excluded. Previous studies have reported that the expression of diabetes-induced aldo-keto reductase family 1 member B1, an enzyme whose expression is altered at an early stage, is closely linked to diabetes-induced cataractogenesis, as demonstrated by Balestri et al[2]. Notably, this critical enzyme exhibits systemic upregulated expression across multiple organs and tissues. Our team’s research has further revealed that short-term high fructose intake induces upregulated expression of AMP-activated protein kinase in smooth muscle cells while antagonizing aldo-keto reductase family 1 member B1 expression. Additionally, Kitazawa et al[3] have shown that AMP-activated protein kinase modulates calcium ion flux and rhythmicity in gastrointestinal smooth muscle cells. Collectively, these findings suggest that there may be shared pathogenic factors underlying the development of cataracts and gastrointestinal electrophysiological dysfunction, which should not be excluded from consideration.

Second, we are particularly interested in the inclusion of vitamin D3 among the biochemical parameters. In recent years, research on the associations of vitamin D3 with T2DM, MASLD, and smooth muscle function has been increasing, making it a hot topic in the field of diabetes mellitus. A literature review[4] reveals that patients with T2DM have nearly twice the fracture incidence of the general population, which is attributed to the accumulation of advanced glycation end products. Advanced glycation end products impair osteoblast function, increase collagen cross-linking, and induce a pro-inflammatory senescent phenotype. Additionally, the elevated incidence of microvascular disease and increased risk of vitamin D deficiency collectively reduce bone quality, thereby enhancing bone fragility. Moreover, vitamin D3 has been proven to directly correlate with smooth muscle cell function and immune function[5], and high-dose vitamin D3 supplementation can reduce the risk of T2DM development[6]. Recent studies also indicate that serum vitamin D3 Levels can serve as a risk predictor for MASLD[7].

Therefore, both MASLD and T2DM may influence the occurrence of diabetic gastric motility disorders by regulating vitamin D3 expression. In correlation and area under the curve analysis, it might be valuable to correlate the severity of MASLD with vitamin D3 Levels and diabetic gastric motility disorders, which could yield more accurate factor analysis results. According to the latest guideline recommendations[8], magnetic resonance imaging proton density fat fraction is recommended as the optimal modality for grading non-pathological MASLD. This recommendation is provided for authors to reference in their further investigations.

It is even more encouraging that the authors have noted the correlation between vitamin D3 and tryptophan metabolism. Our research suggests that this metabolic pathway may affect the electrophysiological function of smooth muscle. Huang et al[9] have demonstrated that indole-3-aldehyde, a tryptophan-derived metabolite of gut microbiota, effectively inhibits the phenotypic switching of contractile vascular smooth muscle cells to the synthetic phenotype, thereby improving survival outcomes in aortic dissection. Concurrently, Lin et al[10] have revealed that gut-derived tryptophan-modified bile acids can trigger the release of glucagon-like peptide-1 via the orphan receptor Mas-related G protein-coupled receptor member E expressed in intestinal L cells, thus ameliorating impaired glucose tolerance. We look forward to a more in-depth interpretation of the physiological functions of vitamin D3 by integrating metabolic pathways in future studies.

ACKNOWLEDGEMENTS

We are deeply grateful to Professor Zhou and Professor Duan for their guidance on this letter. As authoritative experts in oncology and metabolomics, their insightful suggestions have significantly enhanced the academic rigor and professional depth of this manuscript.