Advancing a causal role of type 2 diabetes and its components in developing macro‐ and microvascular complications via genetic studies

The role of diabetes in developing microvascular and macrovascular complications has been subject to extensive research. Despite multiple observational and genetic studies, the causal inference of diabetes (and associated risk factors) on those complications remains incomplete. In this review, we focused on type 2 diabetes, as the major form of diabetes, and investigated the evidence of causality provided by observational and genetic studies. We found that genetic studies based on Mendelian randomization provided consistent evidence of causal inference of type 2 diabetes on macrovascular complications; however, the evidence for causal inference on microvascular complications has been somewhat limited. We also noted high BMI could be causal for several diabetes complications, notable given high BMI is commonly upstream of type 2 diabetes and the recent calls to target weight loss more aggressively. We emphasize the need for further studies to identify type 2 diabetes components that mostly drive the risk of those complications. Even so, the genetic evidence summarized broadly concurs with the need for a multifactorial risk reduction approach in type 2 diabetes, including addressing excess adiposity.