Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH + ) of T2D; and family history-negative control individuals (FH -). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH + groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH + and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.
ObjectUpper cervical spine injuries in the pediatric age group have been recognized as extremely unstable from ligamentous disruption and as potentially lethal. Few measurement norms have been published for the pediatric upper cervical spine to help diagnose this pathological state. Instead, adult measurement techniques and results are usually applied inappropriately to children. The authors propose using high-resolution reconstructed CT scans to define a range of normal for a collection of selected upper cervical spine measurements in the pediatric age group.MethodsSagittal and coronal reformatted images were obtained from thin axial CT scans obtained in 42 children (< 18 years) in a 2-month period. There were 25 boys and 17 girls. The mean age was 100.9 months (range 1–214 months). Six CT scans were obtained for nontrauma indications, and 36 were obtained as part of a trauma protocol and later cleared for cervical spine injury. Six straightforward and direct linear distances—basion-dental interval (BDI); atlantodental interval (ADI); posterior atlantodental interval (PADI); right and left lateral mass interval (LMI); right and left craniocervical interval (CCI); and prevertebral soft-tissue thickness at C-2—that minimized logistical and technical distortions were measured and recorded. Statistical analysis including interobserver agreement, age stratification, and sex differences was performed for each of the 6 measurements.ResultsThe mean ADI was 2.25 ± 0.24 mm (± SD), the mean PADI was 18.3 ± 0.07 mm, the mean BDI was 7.28 ± 0.10 mm, and the mean prevertebral soft tissue width at C-2 was 4.45 ± 0.43 mm. The overall mean CCI was 2.38 ± 0.44 mm, and the overall mean LMI was 2.91 ± 0.49 mm. Linear regression analysis demonstrated statistically significant age effects for PADI (increased 0.02 mm/month), BDI (decreased 0.02 mm/month), and CCI (decreased 0.01 mm/month). Similarly significant effects were found for sex; females demonstrated on average a smaller CCI by 0.26 mm and a smaller PADI by 2.12 mm. Moderate to high interrater reliability was demonstrated across all parameters.ConclusionsAge-dependent and age-independent normal CT measurements of the upper cervical spine will help to differentiate physiological and pathological states in children. The BDI appears to change significantly with age but not sex; on the other hand, the LMI and ADI appear to be age-independent measures. This preliminary study suggests acceptable levels of interrater reliability, and further expanded study will aim to validate these measurements to produce a profile of normal upper cervical spine measurements in children.
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