Diabetes mellitus might be a protective factor of glioma

Ting-Ting Ni

doi:10.4103/0973-1482.183184

ORIGINAL ARTICLE

Year : 2018 | Volume : 14 | Issue : 10 | Page : 644-647

Diabetes mellitus might be a protective factor of glioma

Ting-Ting Ni
Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China

Date of Web Publication

24-Sep-2018

Correspondence Address:
Ting-Ting Ni
Putuo Hospital, Shanghai University of TCM, No. 164 Lanxi Road, Shanghai 200062
China

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/0973-1482.183184

> Abstract

Aims: Several studies suggested that diabetes mellitus (DM) was associated with the risk of glioma. However, other studies did not confirm the result. Therefore, I conducted this meta-analysis.
Materials and Methods: I retrieved the PubMed, Embase, and Web of Science database, by adopting keywords “glioma,” and “diabetes,” “DM.” The strength of the associations between DM and the risk of glioma was measured by odds ratios (ORs) with 95% confidence intervals (95% CIs).
Results: Ten relevant studies were identified in the final analysis. A statistically significant association between DM and glioma risk was fond (OR = 0.84; 95% CI, 0.73–0.97; P = 0.02). In the subgroup analysis of age group, young population with DM showed decreased glioma risk (OR = 0.83; 95% CI, 0.70–0.98; P = 0.02), whereas old population with DM did not show a significant association (OR = 0.87; 95% CI, 0.65–1.16; P = 0.34). In the subgroup analysis of gender, male patients with DM showed decreased glioma risk (OR = 0.82; 95% CI, 0.68–0.99; P = 0.04), whereas female population with DM did not show a significant association (OR = 0.93; 95% CI, 0.70–1.24; P = 0.63).
Conclusions: This meta-analysis suggested that DM may be associated with the reduced glioma risk.

Keywords: Association, diabetes mellitus, glioma, meta-analysis

How to cite this article:
Ni TT. Diabetes mellitus might be a protective factor of glioma. J Can Res Ther 2018;14, Suppl S3:644-7

How to cite this URL:
Ni TT. Diabetes mellitus might be a protective factor of glioma. J Can Res Ther [serial online] 2018 [cited 2020 Oct 21];14:644-7. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/644/183184

> Introduction

Diabetes mellitus (DM) is a common chronic disease with tremendous impact on health worldwide. DM is the seventh leading cause of mortality, and is increasing in prevalence. Epidemiologic study suggests that people with diabetes are at significantly higher risk for many forms of cancer and greater cancer mortality.^[1] For example, Michels et al. suggested that women with type 2 diabetes may have a slightly increased risk of breast cancer.^[2] Hu et al. found that diabetes is associated with an increased risk of colorectal cancer in women.^[3] Friberg et al. indicated that DM was associated with a 2-fold increased risk, and combination of DM with obesity and low physical activity was associated with a further increased risk for endometrial cancer.^[4] Wang et al. found recent-onset diabetes may be a complication or an early marker of pancreatic cancer.^[5]

Several studies suggested that DM was associated with the risk of glioma. However, other studies did not confirm the result.^{[6],[7],[8],[9],[10],[11],[12],[13],[14],[15]} Therefore, to derive a more precise estimation of the association between DM and glioma risk, I conducted this meta-analysis.

> Materials and Methods

Publication search

I retrieved the PubMed, Embase, and Web of Science database, by adopting keywords “glioma,” and “diabetes,” “DM.” I also conducted a hand retrieve of the references of the original articles or reviews on this issue for additional studies. All the eligible studies were restricted to humans. I will enroll the reports with largest sample size when more than one reports published the same data or data subsets.

Inclusion and exclusion criteria

Reports were enrolled referring to the following criteria: (a) Reports that assessed the association between DM and glioma risk, (b) case–control study or cohort study. Besides, I will exclude these studies when they were: (a) Case reports, case-only study or reviews, (b) animal studies, and (c) duplicated publications.

Data extraction and quality assessment

The following details should be concerned: The name of the first author, the year of publication, the mean age of each study, the male number of study, the case number of each study, and the covariants. I compared the data.

The Newcastle–Ottawa Scale (NOS) was used to evaluate the methodological quality, which scored studies by the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest. I considered a study awarded 0–3, 4–6, or 7–9 as a low-, moderate-, or high-quality study, respectively. Discrepancies were resolved by consensus and discussion.

Statistical analysis

The strength of the associations between DM and glioma was measured by odds ratios (ORs) with 95% confidence intervals (95% CIs). Between study heterogeneity was assessed by Chi-square test, and was quantified using the I² statistic (ranging from 0% to 100%), which was defined as the percentage of the observed between study variability that is due to heterogeneity rather than chance. A random-effects model (DerSimonian–Laird method) was used. Publication bias was conducted if more than ten studies were included. All statistical tests were performed using RevMan 5.1 software (Nordic Cochrane Center, Copenhagen, Denmark). The value of P < 0.05 was considered significant. All the P values were two-sided.

> Results

Study characteristics

After a comprehensive literature search applying our inclusion criteria, ten relevant studies which comprised 5,829,250 subjects were identified in the final analysis. Six studied provided the data of mean age. All studies were assessed by NOS. The quality scores ranged from 7 to 9, suggesting that the methodological quality was acceptable. The main study characteristics are summarized in [Table 1] and [Table 2].

Table 1: Characteristics of the studies

Click here to view

Table 2: Quality scores of studies using Newcastle–Ottawa Scale (maximum score of 9)

Click here to view

Quantitative data synthesis

As shown in [Figure 1], a statistically significant association between DM and glioma risk was fond (OR = 0.84; 95% CI, 0.73–0.97; P = 0.02). In the subgroup analysis of age group, young population with DM showed decreased glioma risk (OR = 0.83; 95% CI, 0.70–0.98; P = 0.02); [Figure 2], whereas old population with DM did not show a significant association (OR = 0.87; 95% CI, 0.65–1.16; P = 0.34). In the subgroup analysis of gender, male patients with DM showed decreased glioma risk (OR = 0.82; 95% CI, 0.68–0.99; P = 0.04); [Figure 3], whereas female population with DM did not show a significant association (OR = 0.93; 95% CI, 0.70–1.24; P = 0.63). Publication bias was not performed because only ten studies were included in this meta-analysis.

Figure 1: Effect of diabetes on the risk of glioma

Click here to view

Figure 2: Subgroup analysis by age on the association between diabetes and risk of glioma

Click here to view

Figure 3: Subgroup analysis by gender on the association between diabetes and risk of glioma

Click here to view

> Discussion

This current meta-analysis of ten studies including 5,829,250 subjects systematically evaluated the association between DM and glioma risk. The results indicated that DM patients had lower risk for developing glioma. In the subgroup analysis by age, glioma risk was decreased in young patients with DM, suggesting a possible influence among age and DM. In the subgroup analysis by age, glioma risk was decreased in male patients with DM, suggesting a possible influence among gender and DM. There were only three or four studies in subgroup analysis. Thus, more studies are needed to confirm if age and gender could influence the glioma risk in DM patients.

Several mechanisms have been proposed to explain links between DM and increased cancer risk, including deregulation of insulin and insulin-like growth factor signaling, obesity and inflammation, and metabolic symbiosis; moreover, ER stress and autophagy have also emerged as important cellular mechanisms linking DM to cancer. However, the reason of why DM could reduce the risk of glioma is not known. Some recent studied suggested that metformin might provide this protective effect. Yu et al. indicated that temozolomide in combination with metformin synergistically inhibits the glioma stem cells proliferation through downregulation of AKT-mammalian target of rapamycin (mTOR) signaling pathway.^[16] Sesen et al. also suggested that metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis, and cell death in vitro with a concomitant activation of AMP-activated protein kinase (AMPK), Redd1 and inhibition of the mTOR pathway.^[17] Sato et al. showed that metformin promoted FOXO3 activation and differentiation via AMPK activation, which was sensitive to extracellular glucose availability.^[18]

The present meta-analysis should be interpreted with caution, several limitations merit consideration. First, due to lacking of the original data of the eligible studies, I could not perform other subgroup analyses based on DM type, life style. Second, the numbers of published studies were not sufficient for a comprehensive analysis, particularly for age. However, our meta-analysis also had some merits. First, I investigated the association between DM and glioma risk in different age group. Second, there was low heterogeneity in this meta-analysis.

This meta-analysis suggested that DM may be associated with the reduced glioma risk. Further studies with a larger sample size are needed to further assess the presence of an association.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

> References

1.	Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, et al. Metformin: Taking away the candy for cancer? Eur J Cancer 2010;46:2369-80.
2.	Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al. Type 2 diabetes and subsequent incidence of breast cancer in the nurses' health study. Diabetes Care 2003;26:1752-8.
3.	Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 1999;91:542-7.
4.	Friberg E, Mantzoros CS, Wolk A. Diabetes and risk of endometrial cancer: A population-based prospective cohort study. Cancer Epidemiol Biomarkers Prev 2007;16:276-80.
5.	Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev 2006;15:1458-63.
6.	Cicuttini FM, Hurley SF, Forbes A, Donnan GA, Salzberg M, Giles GG, et al. Association of adult glioma with medical conditions, family and reproductive history. Int J Cancer 1997;71:203-7.
7.	Schlehofer B, Blettner M, Preston-Martin S, Niehoff D, Wahrendorf J, Arslan A, et al. Role of medical history in brain tumour development. Results from the international adult brain tumour study. Int J Cancer 1999;82:155-60.
8.	Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005;293:194-202.
9.	Schwartzbaum J, Jonsson F, Ahlbom A, Preston-Martin S, Malmer B, Lönn S, et al. Prior hospitalization for epilepsy, diabetes, and stroke and subsequent glioma and meningioma risk. Cancer Epidemiol Biomarkers Prev 2005;14:643-50.
10.	Swerdlow AJ, Laing SP, Qiao Z, Slater SD, Burden AC, Botha JL, et al. Cancer incidence and mortality in patients with insulin-treated diabetes: A UK cohort study. Br J Cancer 2005;92:2070-5.
11.	Stocks T, Rapp K, Bjørge T, Manjer J, Ulmer H, Selmer R, et al. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): Analysis of six prospective cohorts. PLoS Med 2009;6:e1000201.
12.	Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care 2012;35:1835-44.
13.	Kitahara CM, Linet MS, Brenner AV, Wang SS, Melin BS, Wang Z, et al. Personal history of diabetes, genetic susceptibility to diabetes, and risk of brain glioma: A pooled analysis of observational studies. Cancer Epidemiol Biomarkers Prev 2014;23:47-54.
14.	Cahoon EK, Inskip PD, Gridley G, Brenner AV. Immune-related conditions and subsequent risk of brain cancer in a cohort of 4.5 million male US veterans. Br J Cancer 2014;110:1825-33.
15.	Seliger C, Ricci C, Meier CR, Bodmer M, Jick SS, Bogdahn U, et al. Diabetes, use of antidiabetic drugs, and the risk of glioma. Neuro Oncol 2016;18:340-9.
16.	Yu Z, Zhao G, Xie G, Zhao L, Chen Y, Yu H, et al. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget 2015;6:32930-43.
17.	Sesen J, Dahan P, Scotland SJ, Saland E, Dang VT, Lemarié A, et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One 2015;10:e0123721.
18.	Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, et al. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med 2012;1:811-24.