Therefore, [Ca2+]i modulates insulin-mediated glucose transport in skeletal muscle in two opposite ways: a permissive effect as long as [Ca2+]i remains at optimal concentration and an inhibitory effect, caused by chronic reduction or elevation of muscle [Ca2+]i, which inhibits insulin-mediated glucose uptake causing muscle insulin resistance and hyperinsulinemia, as observed in RYR1-p.R163C and db/db mice. The gene discussed is INS; the disease is hyperinsulinism.