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The objective of this study is to investigate the link between the baseline/changes of body weight and those of diabetic parameters during treatment with an SGLT-2 inhibitor. Drug naïve subjects with T2DM received canagliflozin monotherapy for 3 months. Adipo-IR was selected as the significant factor responsible for the changes of (Δ)BMI with this drug. While no correlations were noted between ΔBMI and ΔFBG, ΔHbA1c, ΔHOMA-R or ΔQUICKI, significant negative correlations were observed between ΔBMI and Δadipo-IR (R=−0.308). The subjects were divided into two groups with baseline BMI<25 (n=31, group alpha) or≥25 (n=39, group beta). Baseline levels of FBG, HbA1c, T-C, TG, non-HDL-C, LDL-C showed no differences between group alpha and beta. The subjects were also divided into two equal numbers of subjects (n=35 each) based on the changes of weight: the lower half (−3.6%, p<0.00001, group A) and the upper half (0.1%, n.s., group B) of ∆BMI. FBG, HbA1c or HOMA-R significantly, similarly decreased, while QUICKI increased in group A and B. TG significantly decreased, while HDL-C increased in group A. HOMA-B significantly increased, while adipo-IR insignificantly decreased in group B. Collectively, these results suggest that 1) adipose tissue insulin resistance is responsible for the weight changes with canagliflozin. 2) baseline levels of glycemic and some lipid parameters were similar between obese and non-obese populations. 3) weight changes with canagliflozin were not associated with its glycemic or insulin sensitizing efficacies but were linked to adipose-tissue insulin resistance, some lipids, and beta-cell function.

Objectives This work is to investigate the regulation of adipose tissues insulin resistance with DPP-4 inhibitors in relation to other diabetic parameters in treatment naïve subjects with T2DM. Methods The subjects received alogliptin 12.5–25 mg/day (n = 55), sitagliptin 25–50 mg/day (n = 49) or teneligliptin 10–20 mg/day (n = 43) monotherapy for 3 months. Changes of adipo-IR and some diabetic parameters were analyzed. Results Among these drugs, only alogliptin could significantly reduce adipo-IR (-25.9%) and lipid parameters including LDL-C (-7.8%), T-C/HDL-C (-6.8%), log(TG)/HDL-C (-6.8%), non-HDL-C/HDL-C (-8.7%), LDL-C/HDL-C (-11.2%). The subjects in alogliptin group were divided into two similar numbers of groups with distinct changes (Δ) of adipo-IR (group A: Δadipo-IR=-56.5%, p < 0.00001, n = 28; group B: Δadipo-IR = 19.1%, p = 0.055, n = 27). Comparable, significant reductions of FBG (-14.1%, -15.5%) or HbA1c (10.26–8.93%, 11.04–9.08%) were observed in group A and B, respectively. Significant reductions of HOMA-R (-25.7%), T-C/HDL-C (-10.3%), TG (-18.1%), log(TG)/HDL-C (-11.3%), non-HDL-C/HDL-C (-13.1%), LDL-C/HDL-C (-12.8%) or FFA (-28.9%), and increases of QUICKI (5.9%) or HDL-C (6.9%) were seen in group A. By contrast, significant reductions of QUICKI (-3.8%) or LDL-C (-9.2%), and increases of HOMA-R (28.4%), insulin (55.1%), HOMA-B (106.3%), C-peptide (16.5%) or CPR-index (39.8%) were observed in group B. Conclusion These results indicate that 1) alogliptin, but not other DPP-4 inhibitors, could down-regulate adipo-IR and some atherogenic lipids. To date, this is the first report showing that a DPP-4 inhibitor regulates adipose tissue insulin resistance. 2) adipo-IR is associated with non-LDL-C lipid parameters, but not with glycemic control during treatment of alogliptin. 3) glycemic efficacy of alogliptin is determined by modulation of insulin resistance and beta-cell function.