Identifying Reversal of Glucotoxicity in the Therapeutic Response to Glucose-Lowering Medications in early Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a chronic condition characterized by high levels of glucose (sugar) in the blood. It arises when the body is unable to make sufficient amounts of a hormone called insulin which helps to keep blood glucose levels in the normal range. This insufficiency is largely determined by an individual’s genes, which cannot be modified. However, early in the course of T2DM, there is a reversible component to this inability to make sufficient insulin. This reversible component is partly due to the adverse (harmful) effect that high levels of blood glucose has on the cells that make insulin.

In patients, it has been suggested that this adverse effect (called glucotoxicity) likely contributes to the variability in the effectiveness of diabetes medications in lowering their blood glucose. However, until now, there has been no way to tell if glucotoxicity impacts the response to diabetes medications in patients. Importantly, we recently introduced a method for identifying patients in whom glucotoxicity has affected their response to treatment with insulin.

We now seek to apply this method to a completed clinical trial in which patients with recently-diagnosed T2DM were treated with one of 3 diabetes medications. In doing so, we seek to determine whether this phenomenon of underlying glucotoxicity is a factor contributing to the known variability of the glucose-lowering effectiveness of diabetes medications in patients. Such a demonstration would provide an explanation for their variable effectiveness in practice and yield insight that could inform more precise targeting of diabetes medications to the individual needs of patients.