The Relationship between Diabetes Mellitus and Gastric Cancer and the Potential Benefits of Metformin: An Extensive Review of the Literature

The objective of this review is to summarize the findings of published research that investigated the relationship between diabetes mellitus and gastric cancer (GCa) and the potential benefits of metformin on GCa. Related literature has been extensively reviewed, and findings from studies investigating the relationship between diabetes mellitus and GCa suggest that hyperglycemia, hyperinsulinemia and insulin resistance are closely related to the development of GCa. Although not supported by all, most observational studies suggest an increased risk of GCa in patients with type 2 diabetes mellitus, especially in women and in Asian populations. Incidence of second primary malignancy diagnosed after GCa is significantly higher in diabetes patients. Diabetes patients with GCa may have more complications after gastrectomy or chemotherapy and they may have a poorer prognosis than patients with GCa but without diabetes mellitus. However, glycemic control may improve in the diabetes patients with GCa after receiving gastrectomy, especially after procedures that bypass the duodenum and proximal jejunum, such as Roux-en-Y gastric bypass or Billroth II reconstruction. The potential links between diabetes mellitus and GCa may involve the interactions with shared risk factors (e.g., obesity, hyperglycemia, hyperinsulinemia, insulin resistance, high salt intake, smoking, etc.), <i>Helicobacter pylori</i> (HP) infection, medications (e.g., insulin, metformin, statins, aspirin, proton pump inhibitors, antibiotics, etc.) and comorbidities (e.g., hypertension, dyslipidemia, vascular complications, heart failure, renal failure, etc.). With regards to the potential benefits of metformin on GCa, results of most observational studies suggest a reduced risk of GCa associated with metformin use in patients with T2DM, which can be supported by evidence derived from many in vitro and animal studies. Metformin use may also reduce the risk of HP infection, an important risk factor of GCa. In patients with GCa, metformin users may have improved survival and reduced recurrence. More studies are required to clarify the pathological subtypes/anatomical sites of GCa associated with type 2 diabetes mellitus or prevented by metformin, to confirm whether GCa risk can also be increased in patients with type 1 diabetes mellitus and to explore the possible role of gastric microbiota in the development of GCa.