100 YEARS OF INSULIN: Towards improved precision and a new classification of diabetes mellitus.

Type 2 diabetes (T2D) is one of the fastest increasing diseases worldwide. Although it is defined by a single metabolite, glucose, it is increasingly recognized as a highly heterogeneous disease with varying clinical manifestations. Identification of different subtypes at an early stage of disease when complications might still be prevented could hopefully allow for more personalized medicine. An important step toward precision medicine would be to target the right resources to the right patients, thereby improving patient health and reducing health costs for the society. More well-defined disease populations also offer increased power in experimental, genetic and clinical studies. In a recent study, we used six clinical variables (glutamate decarboxylase autoantibodies, age at onset of diabetes, glycated hemoglobin, BMI and simple measures of insulin resistance and insulin secretion (so called HOMA estimates) to cluster adult-onset diabetes patients into five subgroups. These subgroups have been robustly reproduced in several populations worldwide and are associated with different risks of diabetic complications and responses to treatment. Importantly, the group with severe insulin-deficient diabetes had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes group has the highest risk for diabetic kidney disease (DKD) and fatty liver. This emphasizes the key role of insulin resistance in the pathogenesis of DKD and fatty liver in T2D. In conclusion, this novel subclassification, breaking down T2D in clinically meaningful subgroups, provides the prerequisite framework for expanded personalized medicine in diabetes beyond what is already available for monogenic and to some extent type 1 diabetes.