Muscle glucose uptake, glycogen synthase activity, and insulin signaling were investigated in response to a physiological hyperinsulinemic (600 p m o l / l ) -e u g l y c e m i c clamp in young healthy subjects. Four hours before the clamp, the subjects performed one-legged exercise for 1 h. In the exercised leg, insulin more rapidly activated glucose uptake (half activation time [t 1 / 2 ] = 11 vs. 3 4 min) and glycogen synthase activity (t 1 / 2 = 8 vs. 17 min), and the magnitude of increase was two-to fourfold higher compared with the rested leg. However, prior exercise did not result in a greater or more rapid increase in insulin-induced receptor tyrosine kinase ( I RTK) activity (t 1 / 2 = 50 min), serine phosphorylation of Akt (t 1 / 2 = 1-2 min), or serine phosphorylation of glycogen synthase kinase-3 (GSK-3) (t 1 / 2 = 1-2 min) or in a larger or more rapid decrease in GSK-3 activity (t 1 / 2 = 3-8 min). Thirty minutes after cessation of insulin infusion, glucose uptake, glycogen synthase a c t i v i t y, and signaling events were partially reversed in both the rested and the exercised leg. We conclude the following: 1) physiological hyperinsulinemia induces sustained activation of insulin-signaling molecules in human skeletal muscle; 2) the more distal insulinsignaling components (Akt, GSK-3) are activated much more rapidly than the proximal signaling molecules (1). In human skeletal muscle, the effects of exercise per se on muscle glucose transport are relatively short-lived (2-4 h), whereas the enhanced sensitivity for glucose transport activation by insulin has been observed >48 h after an exercise bout in human subjects (3-5). In rat skeletal muscle, it has been demonstrated that there is a marked increase in insulin sensitivity for both glucose transport and glycogen synthase activation after exercise (2,6). These changes facilitate glycogen resynthesis, and they may be the mechanism by which muscle glycogen storage is increased above pre-exercise values, known as "supercompensation" (7,8). Whether prior exercise also increases the sensitivity for glycogen synthase activation by insulin in human skeletal muscle is unknown.We have previously hypothesized that an upregulation of insulin signaling is involved in the increased insulin sensitivity after exercise (9). However, if humans are subjected to physiological hyperinsulinemia or if rat muscles are incubated in the presence of insulin 3-4 h after exercise, insulin receptor tyrosine kinase (IRTK) a c t i v i t y, insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol (PI) 3-kinase activity are not enhanced in skeletal muscle (9,10). This suggests that exercise may modulate insulin signaling further downstream or affect processes directly involved in glucose transporter translocation and activation.Signaling involving D-3 phosphorylated inositol lipids, generated by the action of PI 3-kinases, has been suggested to lead to the metabolic effects of insulin, including the activation of glucose transport and glycogen sy...
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BackgroundObesity is a major area of public health concerns, since it is associated with a wide range of se-rious health complications, including diabetes type 2, musculoskeletal disorders, sleep apnea, depression, asthma, hypertension, and cancer. Consequently, obese children are more likely to receive drug treatment than their normal weight peers. Further, obesity is known to be associated with changes in pharmacokinetics of drugs (1–5). Dosing overweight (OW) and obese (OB) children by the use of traditional paediatric dosage strategies (e.g. mg per kilogram or fixed dose by age) may therefore result in a potential risk of sub-or supra-therapeutic doses. We aimed to investigate currently applied dosage strategies in OW/OB children, in a clinical treatment facility. In par-ticular, whether dosage guidelines were used and metrics of body size applied with special attention to drugs with a narrow therapeutic interval and/or loading dose of clin-ical importance.MethodsA retrospective cohort study conducted at the Children’s Obesity Clinic in Denmark, in the period 2008–2015. OW/OB children≤18 years, having at least one drug prescribed, were included. 200 patient records were reviewed. The study was approved by the Data Protection Agency (BBH-2014–045, I-suite 03045)Drug treatments/prescriptions were registered with ref-erence to the Anatomical Therapeutic Chemical (ATC) Classification System. Dosage strategies were registered as dosage by total body weight (TBW), fixed dose by age (years), use of adjusted weight measures (e.g. IBW, ABW) or dose estimation by other strategies.ResultsA total number of 455 prescriptions were iden-tified, primarily distributed in ATC groups N, A, R and J. Guidelines for dosage of OW/OB children were not avail-able in the clinic, for any of the recorded drugs. Only one prescription of gentamicin was adjusted by weight (ABW) using metrics of body size. Otherwise, gentamicin was dosed after three different dosage regimens. In 35/455 prescriptions, dose was adjusted by an undocumented dosage strategy. Dose was primarily limited to the max-imum recommended adult dose, when dose (mg/kg) exceeded adult dose, i.e. acetaminophen.ConclusionThis study highlights the shortage of dos-age guidelines in OW/OB children. We found as suspect-ed a large inter-individual variability in dosage regimens even in drugs with narrow therapeutic intervals or drugs which has loading doses important for clinical effects. The clinicians are left with ‘best practice’, as evidence based dosage regimens are missing for several drugs prescribed during childhood.
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