Diabetes and gastric cancer: The potential links

Table 1 Main findings in four meta-analyses on the association between diabetes and incidence or mortality of gastric cancer

Ref.	Studies included	Summary RR (95%CI)		Notes and comments for specific studies	Limitations common to the meta-analysis studies
		Overall	Subgroup analysis
Ge et al[33], 2011	4 case-control and 17 cohort	1.09 (0.98-1.22)	Women: 1.18 (1.01-1.39)Men: 1.04 (0.94-1.15)Duration of follow-up < 10 yr: 0.95 (0.72-1.26)Duration of follow-up ≥ 10 yr: 1.14 (1.01-1.29)	Evaluating incidence and mortality togetherA mixture of incidence and mortality studies may not be appropriateEthnicity differences not considered	Heterogeneity in terms of study design, population demographics, diabetes ascertainment, duration of follow-up, and confoundersType 1 and type 2 diabetes not distinguished in most studiesCardia and non-cardia gastric cancer not discerned in most studiesConfounding effects of H. pylori, smoking and diet are not considered in most studiesNumbers of studies in subgroup analyses varied and may be too small for some analysesMost studies included in meta-analyses were conducted in developed western countries and not primarily designed for evaluating the association between diabetes and gastric cancerPublication bias is possible
Marimuthu et al[34], 2011	20 population-based cohort	Incidence: 1.01 (0.90-1.11)Mortality: 1.62 (1.36-1.89)	Type 1 diabetes (incidence): 1.60 (0.56-2.64)Asians (mortality): 1.98 (1.57-2.39)	Evaluating incidence and mortality separately in overall analysisConsidering type 1 diabetes and ethnicity differences in subgroup analyses
Tian et al[35], 2012	7 case-control and 18 cohort	Incidence: 1.11 (1.00-1.24) Mortality: 1.29 (1.04-1.59)	Asians: 1.19 (1.07-1.32)Cohort design: 1.14 (1.01-1.30) Type 2 diabetes: 1.16 (1.01-1.33) Studies adjusted for more confounders: 1.16 (1.03-1.30)	Evaluating incidence and mortality separately in overall analysisSubgroup analysis was conducted with a mixture of incidence and mortality
Yoon et al[36], 2013	6 case-control and 11 cohort	1.19 (1.08-1.31)	Cohort design: 1.20 (1.08-1.34)Case-control design: 1.12 (0.87-1.45)East Asian countries: 1.19 (1.02-1.38)Western countries: 1.18 (1.03-1.36)Men: 1.10 (0.97-1.24)Women: 1.24 (1.01-1.52)Studies adjusted for smoking: 1.17 (1.01-1.34)Studies adjusted for infection of H. pylori: 2.35 (1.24-4.46)Cardia cancer: 1.39 (0.72-2.69)Noncardia cancer: 1.19 (0.80-1.77)	Evaluating only incidenceStrengths include considering subgroup analyses in studies with adjustment for smoking and H. pylori infectionSubgroup analyses on cardia and noncardia cancer are available, but only 2 studies are included

H. pylori: Helicobacter pylori.

Table 2 Explanations on the putative mechanisms linking diabetes and gastric cancer and the limitations of current studies

Factors	Explanations/limitations
Shared risk factors	Explanations: Diabetes and gastric cancer may share common risk factors such as obesity, insulin resistance, hyperinsulinemia and smoking Limitations: These shared risk factors are known to cause cancer. Therefore, if these shared risk factors are in play, they may also increase the risk of other types of cancer, like colorectal cancer and lung cancer. As demonstrated in some studies, the link between diabetes and gastric cancer may be independent of smoking. Evidence for such an effect in humans needs to be fortified by further studies
Hyperglycemia	Explanations: Hyperglycemia is associated with pro-inflammatory status, oxidative stress, impaired immune function and increased insulin secretion. All of these may contribute to the development of gastric cancer. Epidemiological studies conducted in Japan support hyperglycemia as a risk factor for gastric cancer, and an interaction between hyperglycemia and H. pylori infection. Such a link may also be supported by findings from in vitro studies Limitations: Confirmation of such a link in other ethnicities is necessary
H. pylori infection	Explanations: Diabetes and H. pylori infection may be mutually causative. Patients with diabetes may have a higher infection rate, a lower eradication rate, and/or a higher reinfection rate of H. pylori. On the other hand, the inflammatory process induced by H. pylori infection may also increase the risk of diabetes Limitations: Findings in epidemiological studies are controversial with regards to the higher infection rate of H. pylori in patients with diabetes. Detection bias can not be excluded because patients with diabetes may suffer from more gastrointestinal symptoms leading to the diagnosis of H. pylori infection and gastric cancer
Salt intake	Explanations: A synergistic effect between H. pylori infection and salt intake on gastric cancer is supported by recent human studies and by in vivo and in vitro studies. Patients with diabetes may consume more salt because of loss of sensitivity to taste Limitations: Patients with diabetes may also be advised to take less salt especially in those with hypertension, kidney disease or congestive heart failure. Epidemiological studies evaluating the link between salt intake and gastric cancer in patients with diabetes are lacking
Medications	Explanations: Insulin and sulfonylureas may increase the risk of cancer. On the other hand, metformin, aspirin and statin may potentially reduce the risk of gastric cancer. Patients who repeatedly use antibiotics may have a lower risk of infection with H. pylori Limitations: Research of well quality on the use of medications and gastric cancer risk is lacking
Comorbidities	Explanations: Patients with diabetes may have multiple comorbidities including obesity, hypertension, dyslipidemia, vascular complications and heart failure. All of these may affect the development of gastric cancer, either positively or negatively, through the use of medications and changes in lifestyle, salt intake, dietary components, and the metabolism of drugs Limitations: A detection bias on H. pylori infection or gastric cancer is possible in patients with multiple comorbidities. Studies clarifying such links are still lacking

H. pylori:Helicobacter pylori.