A Glycemic Threshold above which the Improvement of Beta-cell Function and Glycemia in Response to Insulin Therapy is Amplified in early Type 2 Diabetes:The Reversal of Glucotoxicity
OBJECTIVE: Alleviation of unrecognized glucotoxicity, with resultant recovery of beta-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed amongst patients with T2DM. However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve beta-cell function in early T2DM. Thus, for evidence of recovery of glucotoxicity-associated beta-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both beta-cell function and glycemia is amplified.
RESEARCH DESIGN AND METHODS: One-hundred-and-eight adults with T2DM (mean duration 1.8±1.4 years) received 3-weeks of IIT (glargine, lispro). Oral glucose tolerance tests before and after IIT enabled assessment of beta-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-IR. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/l, we modelled the difference in IIT-induced percentage change in beta-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 beta-cell function was non-linear. Instead, this relationship was best fit by cubic regression model with inflection (amplification) at fasting glucose 9.3 mmol/l. Moreover, baseline fasting glucose 9.3 mmol/l also identified the inflection point at which non-linear reductions in fasting glucose and 2-hour glucose, respectively, were both amplified.
CONCLUSION: The respective improvements in beta-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.
