Predicting and understanding the response to short-term intensive insulin therapy in people with early type 2 diabetes

Yury O. Nunez Lopez, Ravi Retnakaran, Bernard Zinman, Richard E. Pratley, Attila A. Seyhan

Short-term intensive insulin therapy (IIT) administered early in the course of type 2 diabetes acutely improves beta-cell function by eliminating glucotoxicity and lipotoxicity. However, this beneficial effect is not seen in all patients. Nunez Lopez et al. have generated an accurate multimodal random forests classifier using serum miRNAs with potential clinical utility for predicting responses to short-term IIT among patients with recently diagnosed type 2 diabetes.

Objective: Short-term intensive insulin therapy (IIT) early in the course of type 2 diabetes acutely improves beta-cell function with long-lasting effects on glycemic control. However, conventional measures cannot determine which patients are better suited for IIT, and little is known about the molecular mechanisms determining response. Therefore, this study aimed to develop a model that could accurately predict the response to IIT and provide insight into molecular mechanisms driving such response in humans.

Methods: Twenty-four patients with early type 2 diabetes were assessed at baseline and four weeks after IIT, consisting of basal detemir and premeal insulin aspart. Twelve individuals had a beneficial beta-cell response to IIT (responders) and 12 did not (nonresponders). Beta-cell function was assessed by multiple methods, including Insulin Secretion-Sensitivity Index-2. MicroRNAs (miRNAs) were profiled in plasma samples before and after IIT. The response to IIT was modeled using a machine learning algorithm and potential miRNA-mediated regulatory mechanisms assessed by differential expression, correlation, and functional network analyses (FNA).

Results: Baseline levels of circulating miR-145-5p, miR-29c-3p, and HbA1c accurately (91.7%) predicted the response to IIT (OR = 121 [95% CI: 6.7, 2188.3]). Mechanistically, a previously described regulatory loop between miR-145-5p and miR-483-3p/5p, which controls TP53-mediated apoptosis, appears to also occur in our study population of humans with early type 2 diabetes. In addition, significant (fold change > 2, P < 0.05) longitudinal changes due to IIT in the circulating levels of miR-138-5p, miR-192-5p, miR-195-5p, miR-320b, and let-7a-5p further characterized the responder group and significantly correlated (|r| > 0.4, P < 0.05) with the changes in measures of beta-cell function and insulin sensitivity. FNA identified a network of coordinately/cooperatively regulated miRNA-targeted genes that potentially drives the IIT response through negative regulation of apoptotic processes that underlie beta cell dysfunction and concomitant positive regulation of proliferation.

Conclusions: Responses to IIT in people with early type 2 diabetes are associated with characteristic miRNA signatures. This study represents a first step to identify potential responders to IIT (a current limitation in the field) and provides important insight into the pathophysiologic determinants of the reversibility of beta-cell dysfunction. identifier: NCT01270789.