OBJECTIVE

Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified.

RESEARCH DESIGN AND METHODS

IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it.

RESULTS

The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified.

CONCLUSIONS

The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.

Clinical trial reg. no. NCT02192424, clinicaltrials.gov

This article contains supplementary material online at https://doi.org/10.2337/figshare.26866417.

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