Table 1.

Potential mechanisms explaining a higher risk of gastric cancer in diabetes patients.

Potential Mechanisms	Explanations
I.  Direct effect
Hyperglycemia and insulin resistance promote GCa	In in vitro and in vivo studies, high glucose levels promote GCa cell growth and proliferation and induce chemoresistance to 5-fluorouracil. Insulin resistance and hyperinsulinemia may lead to an over-stimulation of the tumorigenic pathways of insulin, leading to the development of GCa. In human epidemiological studies, high glucose levels or insulin resistance biomarkers are associated with an increased incidence of or mortality from GCa. Some meta-analyses suggest a significantly higher risk of GCa in diabetes patients and in people with prediabetes.
Ⅱ.  Indirect links
Shared risk factors	GCa and type 2 diabetes mellitus share some important risk factors, such as obesity, hyperglycemia, hyperinsulinemia, insulin resistance, smoking etc.
2.Salt intake	High salt intake is a potential risk factor of GCa. Diabetes patients may have loss or impairment of taste, leading to a higher intake of salt. On the one hand, diabetes patients may have been advised to restrict salt intake because of heart or kidney diseases.
3.Helicobacter pylori infection	Helicobacter pylori infection is known to cause GCa. A cellular study supports the role of hyperglycemia in maintaining the growth and viability of Helicobacter pylori. Diabetes patients are prone to have a higher infection rate and a lower eradication rate of Helicobacter pylori infection.
4.Medications	Some drugs commonly used by diabetes patients may affect GCa risk. Metformin, aspirin and statins are associated with a lower risk of GCa. Insulin and proton pump inhibitors are associated with a higher risk of GCa. Antibiotics may affect the infection rate of Helicobacter pylori.
5.Comorbidities	Comorbidiites such as hypertension and dyslipidemia are also associated with insulin resistance. Patients with vascular complications such as heart failure and renal failure may have changed their lifestyle, daily activity, salt intake and dietary pattern. Patients with liver or kidney disease may have altered drug metabolism and they may be treated with medications that affect GCa risk. Detection bias because of a higher tendency to receive extra laboratory examination.
Ⅲ.  Screening effect
Screening program	A Korean study suggests that diabetes patients are less likely to receive GCa screening. Screening can lead to a higher incidence but early intervention may reduce the mortality rate.

GCa: gastric cancer.