Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2025; 16(2): 94861
Published online Feb 15, 2025. doi: 10.4239/wjd.v16.i2.94861
Effect of SPTLC1 on type 2 diabetes mellitus
Bo Yi, Yan Bao, Zhong-Yuan Wen
Bo Yi, Yan Bao, Zhong-Yuan Wen, Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
Author contributions: Yi B designed the study and wrote the manuscript; Bao Y performed the research and analyzed the data; Wen ZY contributed analytic tools and revised the manuscript; All authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Clinical Research Ethics Commission of Renmin Hospital of Wuhan University, No. WDRY2023-K119.
Institutional animal care and use committee statement: The study did not need the statement of animal care and use.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bo Yi, MD, PhD, Doctor, Department of Endocrinology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan 430060, Hubei Province, China. 1227yb@whu.edu.cn
Received: March 26, 2024
Revised: September 10, 2024
Accepted: November 21, 2024
Published online: February 15, 2025
Processing time: 278 Days and 17.8 Hours
Abstract
BACKGROUND

Although numerous single nucleotide polymorphism in multiple genes involve in the risk of type 2 diabetes mellitus (T2D), the single gene defects of T2D with strong family history is not clear yet. SPTLC1 are causative for hereditary sensory and autonomic neuropathy, which is clinical overlapping with diabetic peripheral neuropathy. Mice with adipocyte-specific deletion of SPTLC1 had impaired glucose tolerances and insulin sensitivity. Thus, it is necessary to investigate the SPTLC1 mutations in adult-onset T2D with strong family history.

AIM

To analyze the role of SPTLC1 mutation on adult-onset T2D with strong family history.

METHODS

By whole-exome sequence analysis of a patient with T2D and his family members, an uncertain variant in SPTLC1 was identified. Bioinformation analysis was used to evaluate the influence of mutation, rare variant gene-level associations for SPTLC1 in T2D, and the relationship between SPTLC1 mRNA and T2D in human islets from GSE25724. The effect of G371R of SPTLC1 on the characteristics of inflammatory cytokines and apoptosis was also tested on human embryonic kidney (HEK) 293 cells.

RESULTS

A single nucleotide variation in SPTLC1 (c.1111G>A: p.G371R) was identified in a family with T2D. The deleterious variant was predicted by functional analysis through hidden Markov models and mendelian clinically applicable pathogenicity software. This pathogenicity might be derived from the different amino acid properties. In HEK 293T cells, p.G371R of SPTLC1 induced the expression of tumor necrosis factor-α and the percent of apoptosis. Meanwhile, rare variant gene-level associations for SPTLC1 also refer to the high risk of T2D (the overall odds ratio = 2.4968, P = 0.0164). Data from GSE25724 showed that SPTLC1 mRNA was lower in pancreatic islets from T2D human islets (P = 0.046), and was associated with the decreased level of insulin mRNA expression (Spearman r = 0.615, P = 0.025).

CONCLUSION

The study classified SPTLC1 p.G371R mutation as the likely pathogenic mutation from an adult-onset T2D patients with strong family history T2D.

Keywords: Apoptosis; Diabetic peripheral neuropathy; Gene mutation; Inflammation; SPTLC1; Type 2 diabetes mellitus

Core Tip: The single gene defects of type 2 diabetes mellitus (T2D) with strong family history is not clear yet. We identified SPTLC1 p.G371R mutation as the likely pathogenic mutation from an adult-onset T2D patients with family history. This mutation induced the expression of tumor necrosis factor-α and the percent of apoptosis in human embryonic kidney 293T cells. Moreover, data from Accelerating Medicines Partnership T2D knowledge showed a positive correlation between rare variant gene-level associations for SPTLC1 and the risk of T2D. This study provides a novel perspective to understand the pathology of T2D.