Regulation of Adipose Tissue Insulin Resistance and Diabetic Parameters in Drug Naïve Subjects with Type 2 Diabetes Treated with Canagliflozin Monotherapy

Abstract

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.

Diverse Strategies for Modulating Insulin Resistance: Causal or Consequential Inference on Metabolic Parameters in Treatment-Naïve Subjects with Type 2 Diabetes

“…HOMA-R exceeding 2.5 generally signifies the presence of insulin resistance [ 10 , 15 ], while HOMA-B below 30% indicates low beta-cell function [ 10 , 15 ]. Obesity is defined as BMI above 25 [ 8 ]. Considering these contextual factors, it is postulated that newly diagnosed, untreated Japanese patients with T2DM exhibit characteristics of high insulin resistance, relatively preserved beta-cell function, modest overweight status, and poor glycemic control.…”

“…SGLT-2 inhibitors reduce both weight and insulin resistance. However, previous findings have suggested that specific populations treated with SGLT-2 inhibitors may not experience weight loss, and correlations between changes in insulin resistance and weight are not consistently observed [ 8 ]. A TZD drug, such as pioglitazone, reduces insulin resistance but contributes to weight gain [ 4 , 6 ].…”

“…The precise mechanism behind weight gain with pioglitazone remains unclear, but it has been hypothesized that the activation of PPARγ leads to an increase in the number and size of fat cells, resulting in increased fat storage [ 20 ]. In addition, the improvement in insulin sensitivity with this drug (referred to as group X in this paper) is accompanied by an increase in weight due to heightened lipogenesis [ 8 ]. These could contribute to an overall gain in body fat, leading to increased body weight.…”

“…As anticipated from their mechanism of action, SGLT-2 inhibitors induce weight loss [ 5 ]. Furthermore, SGLT-2 inhibitors are recognized for their favorable effects on insulin resistance, beta-cell function, and specific lipid profiles [ 5 , 8 ]. Intriguingly, it has been demonstrated that the weight loss induced by one SGLT-2 inhibitor, canagliflozin, is not inherently associated with insulin-sensitizing properties or glycemic efficacy [ 8 ].…”