A purinergic mechanism underlying metformin regulation of hyperglycemia

The P2Y2 receptor mediates terminal adipocyte differentiation and insulin resistance: Evidence for a dual G-protein coupling mode

“…However, no proven mechanisms have been reported concerning how extracellular ATP suppresses insulin-induced glucose transport in adipocytes since then. We recently reported that extracellular ATP through P2Y 2 R activation in human hepatocytes blocks insulin signaling to the AKT pathway by decreasing PIP3 generation ( 35 ), consistent with our earlier findings in human skeletal muscle cells ( 36 ). Thus, it seems to be a general mechanism for P2Y 2 R control of insulin-AKT signaling in significant metabolic tissues or cells.…”

“…Intracellular PIP3 levels were evaluated as we previously reported ( 35 ). Briefly, preadipocytes were seeded in the black 96-well plate with clear bottom and differentiated into mature adipocytes.…”

Sex-specific effect of P2Y2 purinergic receptor on glucose metabolism during acute inflammation

“…P2Y 2 receptor signaling may interact with the insulin signaling pathway to affect the ability of insulin to signal glucose uptake in peripheral tissues, making the P2Y 2 R -/- males less insulin sensitive. A recent study showed that, in cultured hepatocytes, P2Y 2 activation reduced insulin-dependent signaling, ultimately reducing glucose uptake there ( 6 ), illustrating that P2Y 2 R and insulin signaling pathways intersect to regulate glucose homeostasis locally. Of course, P2Y 2 R may also reduce the levels of insulin released during glucose challenge.…”

“…Studies that systematically address sex-dependent regulation provide crucial insights into an inclusive understanding of physiological processes, dysregulation, and treatment. Indeed, recent evidence suggests that metformin, a common pharmaceutical treatment for insulin resistance, may exert its regulation primarily through P2Y 2 R ( 6 ). P2Y 2 receptor agonist have been approved to treat dry eye in some countries, and purinergic signaling is an enticing drug target for treatment of many conditions, including immune and infection-related disease ( 32 ).…”

“…While insulin dependent trafficking of GLUT4 through the insulin receptor (INSR) is an important regulator of glucose absorption, a dysregulation of GLUT4 and INSR expression has been noted in adipose tissue from P2Y 2 R null mice fed a high fat diet (4). A role for P2Y 2 R receptor activation in regulation of insulin signaling was recently confirmed when activation of P2Y 2 R in hepatocytes disrupted insulin dependent signaling, likely through competition for phosphatidylinositol 4,5-bisphosphate (PIP 2 ), an intermediate required for both signaling pathways (6).…”