Decreased complexity of glucose dynamics preceding the onset of diabetes in mice and rats

Continuous glucose monitoring (CGM) is a platform to measure blood glucose (BG) levels continuously in real time with high enough resolution to document their underlying fluctuations. Multiscale entropy (MSE) analysis has been proposed as a measure of time-series complexity, and when applied to clinical CGM data, MSE analysis revealed that diabetic patients have lower MSE complexity in their BG time series than healthy subjects. To determine if the clinical observations on complexity of glucose dynamics can be back-translated to relevant preclinical species used routinely in diabetes drug discovery, we performed CGM in both mouse (ob/ob) and rat (Zucker Diabetic Fatty, ZDF) models of diabetes. We demonstrate that similar to human data, the complexity of glucose dynamics is also decreased in diabetic mice and rats. We show that low complexity of glucose dynamics is not simply a reflection of high glucose values, but rather reflective of the underlying disease state (i.e. diabetes). Finally, we demonstrate for the first time that the complexity of glucose fluctuations in ZDF rats, as probed by MSE analysis, is decreased prior to the onset of overt diabetes, although complexity undergoes further decline during the transition to frank diabetes. Our study suggests that MSE could serve as a novel biomarker for the progression to diabetes and that complexity studies in preclinical models could offer a new paradigm for early differentiation, and thereby, selection of appropriate clinical candidate molecules to be tested in human clinical trials.