Abstract
SGLT2 inhibitors reduce renal glucose uptake through an insulin-independent mechanism. They also increase glucagon concentration, although the extent to which this is due to a direct effect on pancreatic alpha cells remains unclear. In the present work, αTC1 cells treated with the SGLT2 inhibitor dapagliflozin (Dapa) were analyzed for glucose transporters, molecular mediators of hormone secretion, glucagon and GLP-1 release, and the effects of somatostatin. Data were validated in murine and human pancreatic islets. SLC5A2 (the SGLT2-encoding gene) was nearly undetectable in αTC1 cells, not even by a digital PCR technique using different probes. In contrast, SLC5A1 (the SGLT1-encoding gene) was constitutively abundant in αTC1 cells and in islets, and increased with Dapa. This was associated with greater glucagon release, preceded by increased expression of preproglucagon and HNF4α. Looking at the candidate intracellular signalling pathway, reduced PASK and increased AMPK-α2 expression were also detected. GLUT1 and GLUT2, as well as regulators of glucagon release and alpha-cell phenotype (chromogranin A, paired box 6, proprotein convertase 1/2, synaptophysin), were unaffected by Dapa, as were GLP-1 receptor expression and GLP-1 r...Continue Reading
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