Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-13 C]glucose, [2-13 C]glycerol, [1-2 H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 M). In livers of S4048-treated rats (0.5 mg kg ؊1 min ؊1 ; 8 h) Glc-6-P content increased strongly (؉440%), and massive glycogen accumulation (؉1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 ؎ 2.0 versus 33.2 ؎ 2.9 mol kg ؊1 min ؊1 in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 ؎ 1 versus 38 ؎ 1%; p < 0.001) to glycogen synthesis (35 ؎ 5% versus 65 ؎ 5%; p < 0.005) by S4048. This was associated with a strong inhibition (؊82%) of the flux through glucokinase and an increase (؉83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (ϳ9-fold), Glc-6-P translocase (ϳ4-fold), glycogen synthase (ϳ7-fold) and L-type pyruvate kinase (ϳ 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.

Background: Prolonged high ischial tuberosities pressure (IT pressure), decreased regional blood flow (BF) and oxygenation (%SO2) are risk factors for developing pressure ulcers (PUs) in patients with spinal cord injury (SCI). Electrical stimulation (ES)-induced gluteal and hamstring muscle activation may improve pressure distribution by changing the shape of the buttocks while sitting and also increase BF and %SO2. Objective: To compare acute effects of ES-induced gluteal and hamstring muscle activation with pressure relief movements (PRMs) on IT pressure, BF and %SO2. Participants and methods: Twelve men with SCI performed PRMs -push-ups, bending forward and leaning sideward -and received surface ES (87±19 mA) to the gluteal and hamstring muscles while sitting in their wheelchair. Ischial tuberosities pressure was measured using a pressure mapping system; (sub)cutaneous BF and %SO2 were measured using reflection spectroscopy and laser Doppler, respectively. Results: Compared with rest (156±26 mm Hg), IT pressure was significantly lower during all other conditions (push-ups 19±44; bending forward 56±33; leaning sideward 44±38; ES 67±45 mm Hg). For the whole group, all PRMs significantly augmented BF ( þ 39 to À96%) and %SO2 ( þ 6.0 to À7.9%-point), whereas ES-induced muscle activation did only for peak BF. In all, 63% of the participants showed an increased BF (average 52%) with ES. Conclusion: PRMs acutely reduced IT pressure and improved oxygenation and BF in SCI. The currently used ES method cannot replace PRMs, but it may be used additionally. ES-induced muscle activation is not as effective for acute pressure relief, but the frequency of stimulation is much higher than the performance of PRMs and can therefore be more effective in the long term.