The Neuronal and Non-Neuronal Pathways of Sodium-Glucose Cotransporter-2 Inhibitor on Body Weight-Loss and Insulin Resistance

Abstract

With the emergence of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the treatment of type 2 diabetes mellitus (T2DM) has achieved a new milestone, of which the insulin-independent mechanism could produce weight loss, improve insulin resistance (IR) and exert other protective effects. Besides the well-acknowledged biochemical processes, the dysregulated balance between sympathetic and parasympathetic activity may play a significant role in IR and obesity. Weight loss caused by SGLT-2i could be achieved via activating the liver–brain–adipose neural axis in adipocytes. We previously demonstrated that SGLT-2 are widely expressed in central nervous system (CNS) tissues, and SGLT-2i could inhibit central areas associated with autonomic control through unidentified pathways, indicating that the role of the central sympathetic inhibition of SGLT-2i on blood pressure and weight loss. However, the exact pathway of SGLT2i related to these effects and to what extent it depends on the neural system are not fully understood. The evidence of how SGLT-2i interacts with the nervous system is worth exploring. Therefore, in this review, we will illustrate the potential neurological processes by which SGLT2i improves IR in skeletal muscle, liver, adipose tissue, and other insulin-target organs via the CNS and sympathetic nervous system/parasympathetic nervous system (SNS/PNS).

A multicentre, double‐blind, placebo‐controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add‐on therapy in type 2 diabetic patients treated with metformin and dapagliflozin

“…In the present study, we showed that addition of low‐dose pioglitazone to background SGLT2 inhibitor therapy decreased fasting insulin and HOMA‐IR levels and increased adiponectin levels significantly, compared to placebo treatment. These data suggest that we can expect an insulin‐sensitizing effect with addition of TZD on top of SGLT2 inhibitors, which also have significant efficacy in reducing insulin resistance 1,4,24 . We also found that female sex, high BMI, and high HbA1c levels at baseline were independent predictors for a good response to pioglitazone therapy in the multivariate regression analysis.…”

“…These data suggest that we can expect an insulin-sensitizing effect with addition of TZD on top of SGLT2 inhibitors, which also have significant efficacy in reducing insulin resistance. 1,4,24 We also found that female sex, high BMI, and high HbA1c levels at baseline were independent predictors for a good response to pioglitazone therapy in the multivariate regression analysis. The improvements of these glucose regulation parameters by pioglitazone therapy were more pronounced in people with people with obesity or overweight (Table S2).…”

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

“…By lowering calories and improving hypothalamic insulin response, SGLT2i treatment might cause adipocytes in perivascular adipose tissues to become smaller and promote them to spend more energy. Significant weight loss would follow, along with reductions in visceral fat, subcutaneous fat, and overall adiposity (98)(99)(100). But SGLT2i treatment-induced weight loss was limited.…”

Sodium- glucose cotransporter inhibitors and the brain

“…Канаглифлозин усиливал симпатическую иннервацию и секрецию норэпинефрина в жировой ткани через сигнальный путь цАМФ-протеинкиназа A, что, в свою очередь, снижало ИР у мышей, получавших диету с высоким содержанием жиров [18]. Таким образом, в настоящее время предполагается, что иНГЛТ-2 активирует ось мозг-жировая ткань и вызывает потерю жировой массы, уменьшая инсулинорезистентность [19].…”