Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

Abstract

Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs.

The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure

“…Initiation of a low-carbohydrate diet induces similar dynamic metabolic changes. However, renal gluconeogenesis is also modulated following SGLT2 inhibition [17] and this may affect glucose control in the post-absorptive state, as gluconeogenesis-derived glucose is normally provided in almost equal amounts by the proximal tubule and the liver.…”

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Both canagliflozin and empagliflozin have been shown to upregulate SIRT1, and both empagliflozin and dapagliflozin induce the expression of HIF‐1α . Interestingly, in the renal tubules, there appears to be an inverse relationship between the activity of SGLT2 and the expression of both SIRT1 and HIF‐1α . Hypoxia causes simultaneous downregulation of SGLT2 but upregulation of HIF‐1α, whereas high levels of renal tubular glucose promotes the expression of SGLT2 but reduces the expression of SIRT1 .…”

Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

“…SGLT2 is a biological indicator of nutrient excess, and therefore there is an inverse relationship between the activity of SGLT2 and the expression of SIRT1 and AMPK in the kidney. High levels of renal tubular glucose promote the expression of SGLT2 but reduce the expression of SIRT1; increases in SGLT2 promote oxidative stress in the kidney . Hypoxia causes simultaneous downregulation of SGLT2 but upregulation of AMPK .…”