Effect of insulin insufficiency on ultrastructure and function in skeletal muscle.

BACKGROUND: Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with ß-cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. METHODS: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional ß-cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (ß-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. RESULTS: RNA transcripts were significantly altered in ß-DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in ß-DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the ß-DKO mice. Supplementation of ß-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. CONCLUSIONS: Insulin insufficiency due to ß-cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

The association between lipid levels and leukocyte count: A cross-sectional and longitudinal analysis of three large cohorts.

Background: Relationships between dyslipidaemia and leukocyte counts have been investigated in several studies, demonstrating limited evidence of associations in humans. As such, studying a diverse range of cohorts will ensure evidence is robust. This study focused on investigating cross-sectional and longitudinal relationships in three large-scale cohorts. Methods: The cross-sectional analysis included a total of 27,566 participants with valid data on lipid measures and leukocyte counts from three study cohorts: National Health and Nutrition Survey (NHANES), Korean National Health and Nutrition Survey (KNHANES) and Treating to New Targets (TNT) trial. The longitudinal analysis included 9323 participants with valid data on lipid measures and leukocyte counts at baseline and one year with statin treatment. Associations between lipid levels and leukocyte counts were analysed by multivariable linear regression and adjusted for basic demographic and cardiovascular risk factors. Results: Cross-sectional data from NHANES demonstrated the association of lower high-density lipoprotein (HDL) cholesterol and higher triglycerides with higher leukocyte count (0.9% lower and 0.3% higher count per 10 mg/dL increase in HDL cholesterol and triglycerides respectively, both p < 0.001). Similar trends were found in TNT trial (both p < 0.001), but not in KNHANES. In the TNT trial, 10 mg/dL increase in triglycerides over one year was also associated with a 0.09 × 103/µL increase in leukocyte count over the same period. Conclusions: The findings of this study are consistent with those of previous human studies, supporting weak yet noteworthy associations between dyslipidaemia and leukocytosis.