Obesity and Diabetes — 14

Of note, the Mass General Brigham health system in Boston has started implementing array-based polygenic risk scores in their patient population for more than thirty-six thousand multiancestry participants. They found 8.4 percent fit into a high-risk category for type 2 diabetes, with an overall odds ratio of 1.75, and 1.93 for those of European ancestry. Nearly one in ten with nearly double the risk! Other studies have shown how blood proteins predict risk of type 2 diabetes better than a polygenic risk score of Hemoglobin A1c. Such informative data about high risk should be made available to everyone since there are so many ways to prevent this condition. Once type 2 diabetes takes hold, it is difficult, but not impossible, to turn the table back and achieve durable normal glucose control. The severity and chronicity of the disease is linked to many end-organ complications that include retinopathy, heart and vascular disease, kidney disease, strokes, neuropathy, increased risk of cancers, and Alzheimer’s disease. The burden of diabetes was quantified by a population study of forty-six million people in England: “By the age of 50 years, one-third of those with diabetes have at least three conditions, spend more than 20 years with them, and die 11 years earlier than the general population.” Simply put—nothing good. Even worse than obesity.

Your family history of type 2 diabetes is a factor, but your polygenic risk score provides valuable information because it is possible that the combination of variants you derived from your mother and your father is quite different from the set of variants either parent had alone, or their lineage. The hundreds of gene variants associated with type 2 diabetes are quite different from those linked to obesity, which adds to the notion that the biologic underpinnings for these two chronic conditions are distinct, and that type 2 diabetes can occur as a consequence of obesity, or on its own.

So much for the genomics of type 2 diabetes, let’s move on to its treatment. In all of medicine there is no malady with a longer list of medications. Last count it had fifteen classes of them, including metformin, sulfonylureas, meglitinides, amylin analogs, alpha-glucosidase inhibitors, thiazolidinediones (TZDs), dipeptidyl peptidase (DPP-4) inhibitors, dopamine-2 agonists, bile acid sequestrants, insulin, symlin, pramlintide, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and GLP-1 receptor (e.g., semaglutide) or dual GLP-1/GIP agonists (e.g., tirzepatide).