ABSTRACT
AIMS: The purpose of this study is to investigate the regulation of adipose tissue insulin resistance with DPP-4 inhibitors in treatment-naive subjects with T2DM and to examine its relation to other diabetic parameters. SUBJECTS AND METHODS: A total of 147 subjects were treated with 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 in adipo-IR, a mathematical model used to evaluate adipose tissue insulin resistance, and various diabetic parameters were analyzed in this prospective, non-randomized observational study. RESULTS: Among these three drugs, only alogliptin significantly reduced adipo-IR (-25.9%, p < 0.004) and some lipid parameters, such as LDL-C, T-C/HDL-C, log(TG)/HDL-C, non-HDL-C/HDL-C, and LDL-C/HDL-C. Subjects in the alogliptin group were divided into two groups with distinct changes in adipo-IR. Group A had a significant decrease in adipo-IR (-56.5%, p < 0.00001, n = 28), whereas group B had an insignificant increase (19.1%, p = 0.055, n = 27). Significant reductions in FBG or HbA1c were observed in groups A and B, respectively. Group A also showed significant reductions in HOMA-R, T-C/HDL-C, TG, log(TG)/HDL-C, non-HDL-C/HDL-C, LDL-C/HDL-C, and FFA, as well as increases in QUICKI or HDL-C. In contrast, group B showed significant reductions in QUICKI or LDL-C, and increases in HOMA-R, insulin, HOMA-B, C-peptide, or CPR-index. CONCLUSIONS: In contrast to other tested DPP-4 inhibitors, alogliptin demonstrated the ability to down-regulate insulin resistance in adipose tissue, as well as certain atherogenic lipids. This study provides the initial evidence of a DPP-4 inhibitor's potential to regulate adipose tissue insulin resistance. Furthermore, adipo-IR is associated with non-LDL-C lipid parameters instead of glycemic control in those receiving alogliptin.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Insulin Resistance , Humans , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Prospective Studies , Blood Glucose , Glycated Hemoglobin , Hypoglycemic Agents , Sitagliptin Phosphate , Lipids , Adipose TissueABSTRACT
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.
