SGLT-2 inhibition and glucagon: Cause for alarm?

Abstract

Recent studies raised the alarm that the inhibition of sodium-coupled glucose transporter type-2 in humans increases endogenous glucose production rates by an unclear mechanism. Surprisingly, a potential explanation may be linked directly to the alpha-cell. Is this a mechanistic spoiler or an added benefit?

Keywords: HNF4alpha; SGLT-2 inhibitors; alpha-cell; glucagon; glucose production.

Figure 1. Beta-cells and alpha-cells both use glucose metabolism and K_ATP channel closure to regulate secretion

In both cell types glucose oxidation rates are set by glucokinase and cytosolic glucose is not rate-limiting [8]. In beta-cells glucose uptake is via the low-affinity (high K_m) GLUT2 transporter. In alpha cells the high-affinity (low K_m) GLUT1 and newly reported low-affinity (high K_m) SGLT-2 transporter both may transport glucose [7]. The MODY-1 gene, HNFα, in beta-cells regulates GLUT2 expression as well as other proteins in the glucose sensing pathway. A new role for HNFα is identified in the alpha-cell where it is proposed to regulate SGLT-2, though it is unclear if either GLUT1 or GLUT2 are similarly regulated [7, 10].