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Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses

  • Authors:
    • Dono Indarto
    • Tri N. Susilawati
    • Yuliana H. Suselo
    • Purwo S. Rejeki
    • Yuxi Feng
    • Yohanes C. Wibowo
    • Melani R. Mahanani
  • View Affiliations / Copyright

    Affiliations: Department of Physiology, Faculty of Medicine, Sebelas Maret University, Surakarta, Central Java 57126, Indonesia, Department of Microbiology, Faculty of Medicine, Sebelas Maret University, Surakarta, Central Java 57126, Indonesia, Physiology Division, Department of Physiology and Medical Biochemistry, Faculty of Medicine, Airlangga University, Surabaya, East Java 60115, Indonesia, Experimental Pharmacology Mannheim, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, D‑68167 Mannheim, Germany, Heidelberg Institute of Global Health, Medical Faculty Heidelberg, Heidelberg University, D‑69120 Heidelberg, Germany
    Copyright: © Indarto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 54
    |
    Published online on: December 16, 2025
       https://doi.org/10.3892/etm.2025.13049
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Abstract

The present systematic review and meta‑analysis aimed to explore the associations between four diabetic‑related genes [dipeptidyl peptidase‑4 (DPP4), glucagon‑like peptide‑1 receptor (GLP1R), protein tyrosine phosphatase non‑receptor type 1 (PTPN1) and CD36] and the risk of type 2 diabetes mellitus (T2DM) across different body weight categories. A comprehensive search for all available evidence was conducted on the associations between these four genes and T2DM, up to March 31, 2024, and 11 meta‑analyses were performed on genetic polymorphisms that had been examined in >2 studies. A total of 36 studies were identified, investigating the association between the four genes of interest and T2DM risk. Notably, the 11 meta‑analyses on polymorphisms in GLP1R, PTPN1 and CD36 did not reveal any significant associations between the specific genetic variants and T2DM risk. Specifically, the meta‑analysis on the CD36 rs1761667 polymorphism showed no significant association with T2DM, either in the overall population or when stratified by body weight category. The funnel plots and results from the Egger's test indicated some variation. Furthermore, while the leave‑one‑out analyses of the GLP1R and PTPN1 polymorphisms showed some differences compared with the overall estimates, these may be a part of a broader sensitivity analysis, rather than definitive evidence of an impact. Despite the extensive systematic review and meta‑analysis of data from multiple studies, the evidence for an influence of various polymorphisms in key metabolic genes on T2DM risk was not statistically significant. Future research should focus on larger and more diverse populations, potentially examining additional genetic variants and their interactions with other risk factors to improve the understanding of the complex nature of T2DM.
View Figures

Figure 1

Preferred Reporting Items for
Systematic Review and Meta-Analysis flow chart.

Figure 2

Associations between GLP1R
rs3765467 polymorphism and risks of T2DM. (A) Forest plot of the
pooled association with the OR on the x-axis and the study
identifiers on the y-axis, and (B) funnel plot with the OR on the
x-axis and the standard error on the y-axis; Egger's test:
z=-2.9233, P=0.0035. GLP1R, glucagon-like peptide-1
receptor; T2DM, type 2 diabetes mellitus; OR, odds ratio; CI,
confidence interval.

Figure 3

Associations between PTPN1
polymorphisms and risks of T2DM. Polymorphisms of PTPN1 (A)
rs3787345; (B) rs3787335; (C) rs941798; (D) rs1570179; (E)
rs754118; (F) rs2282147; (G) rs718050; and (H) rs3787348 and their
association with the risk of T2DM. PTPN1, protein tyrosine
phosphatase non-receptor type 1; T2DM, type 2 diabetes mellitus;
OR, odds ratio; CI, confidence interval.

Figure 4

Funnel plot of PTPN1
meta-analyses, separated according to polymorphisms with the
observed outcome on the x-axis and the standard error on the
y-axis. Funnel plots of the PTPN1 polymorphisms (A)
rs3787345, Egger's test: z=0.7744, P=0.4387; (B) rs3787335, Egger's
test: z=-0.2818, P=0.7781; (C) rs941798, Egger's test: z=1.3135,
P=0.1890; (D) rs1570179, Egger's test: z=0.8535, P=0.3934; (E)
rs754118, Egger's test: z=-0.0047, P=0.9963; (F) rs2282147, Egger's
test: z=-0.8002, P=0.4236; (G) rs718050, Egger's test: z=-0.4236,
P=0.6719; (H) rs3787348, Egger's test: z=0.7685; P=0.4422.
PTPN1, protein tyrosine phosphatase non-receptor type 1.

Figure 5

Associations between CD36
rs1761667 polymorphism and risks of T2DM. (A) Forest plot of the
pooled association overall and separated by body weight category,
with the odds ratio on the x-axis and the study identifiers on the
y-axis, and (B) funnel plot of the association between CD63
rs1761667 polymorphism and T2DM, with the observed outcome on the
x-axis and the standard error on the y-axis. Egger's test:
z=-1.5423, P=0.1230. T2DM, type 2 diabetes mellitus; OR, odds
ratio; CI, confidence interval.

Figure 6

Associations between CD36
rs3211867 polymorphism and risks of T2DM. (A) Forest plot of the
pooled association with the OR on the x-axis and the study
identifiers on the y-axis, and (B) funnel plot of the association
between CD36 rs3211867 polymorphism and T2DM, with the
observed outcome on the x-axis and the standard error on the
y-axis. T2DM, type 2 diabetes mellitus; OR, odds ratio; CI,
confidence interval.
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Copy and paste a formatted citation
Spandidos Publications style
Indarto D, Susilawati TN, Suselo YH, Rejeki PS, Feng Y, Wibowo YC and Mahanani MR: Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses. Exp Ther Med 31: 54, 2026.
APA
Indarto, D., Susilawati, T.N., Suselo, Y.H., Rejeki, P.S., Feng, Y., Wibowo, Y.C., & Mahanani, M.R. (2026). Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses. Experimental and Therapeutic Medicine, 31, 54. https://doi.org/10.3892/etm.2025.13049
MLA
Indarto, D., Susilawati, T. N., Suselo, Y. H., Rejeki, P. S., Feng, Y., Wibowo, Y. C., Mahanani, M. R."Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses". Experimental and Therapeutic Medicine 31.2 (2026): 54.
Chicago
Indarto, D., Susilawati, T. N., Suselo, Y. H., Rejeki, P. S., Feng, Y., Wibowo, Y. C., Mahanani, M. R."Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses". Experimental and Therapeutic Medicine 31, no. 2 (2026): 54. https://doi.org/10.3892/etm.2025.13049
Copy and paste a formatted citation
x
Spandidos Publications style
Indarto D, Susilawati TN, Suselo YH, Rejeki PS, Feng Y, Wibowo YC and Mahanani MR: Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses. Exp Ther Med 31: 54, 2026.
APA
Indarto, D., Susilawati, T.N., Suselo, Y.H., Rejeki, P.S., Feng, Y., Wibowo, Y.C., & Mahanani, M.R. (2026). Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses. Experimental and Therapeutic Medicine, 31, 54. https://doi.org/10.3892/etm.2025.13049
MLA
Indarto, D., Susilawati, T. N., Suselo, Y. H., Rejeki, P. S., Feng, Y., Wibowo, Y. C., Mahanani, M. R."Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses". Experimental and Therapeutic Medicine 31.2 (2026): 54.
Chicago
Indarto, D., Susilawati, T. N., Suselo, Y. H., Rejeki, P. S., Feng, Y., Wibowo, Y. C., Mahanani, M. R."Metabolic gene polymorphisms and type 2 diabetes mellitus risk: A systematic review and meta‑analyses". Experimental and Therapeutic Medicine 31, no. 2 (2026): 54. https://doi.org/10.3892/etm.2025.13049
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