Chicoric and chlorogenic acids (CRA and CGA), two caffeic acid derivatives found in a large variety of plants, particularly in Asteraceae, are known to modulate glucose-6-phosphatase (G6Pase) in hepatic and muscle cells. The aim of the present study is to use CRA/CGA to explore the modulation role and molecular mechanism of endocrine pancreatic beta-cells’ insulin secretion. The G6Pase enzyme activity influenced by caffeic and derivatives alone or in combination was assessed on microsomal fractions of INS1-beta-cells and hepatocytes. Overall, our results show inverse effects of CGA/CRA, allowing us to investigate the G6Pase activity modulation under low and high glucose concentrations. Our data strongly suggests the existence of two putative forms of the G6Pase enzyme. Based on these observations, we formulate the hypothesis of an adaptative bi-conformational model of G6Pase enzyme activity modulation depending on the level of the beta-cell glucose exposure.

Protein inhibitor of neuronal NO synthase (PIN) or dynein light chain 8 (LC8) is a highly conserved protein interacting with multiple partners, like neuronal NO synthase (nNOS) or myosin Va to modulate a variety of cellular functions. As PIN is expressed in skeletal muscle, our aim was to investigate a possible role of PIN in glucose uptake in L6 and primary muscle cells. PIN overexpression resulted into a decrease in glucose uptake with reduced GLUT4 expression and translocation at the plasma membrane, similarly to the pharmacological blockade of nNOS with L-NAME. PIN effect is mediated by a reduction in nNOS protein level and a direct interaction with nNOS leading to a reduced NO production in L6 myocytes. Surprisingly, a siRNA targeting PIN decreased glucose uptake and GLUT4 translocation, suggesting the involvement of nNOS-independent effects. We therefore focused on myosin Va which interacts with PIN in L6 myocytes. Myosin Va silencing provoked a decrease in glucose uptake. As PIN siRNA also reduced myosin Va expression, this confirms the essential role of myosin Va in the observed effects of PIN silencing on glucose uptake. We conclude that PIN modulates glucose uptake and GLUT4 translocation in rat muscle cells, through NO-dependent and -independent mechanisms.