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.

ApoA-I and Diabetes.

ApoA-I-the main apolipoprotein constituent of the HDL (high-density lipoprotein) fraction of human plasma-is of therapeutic interest because it has several cardioprotective functions. Recent reports have established that apoA-I also has antidiabetic properties. In addition to improving glycemic control by increasing insulin sensitivity, apoA-I improves pancreatic ß-cell function by amplifying expression of transcription factors that are essential for ß-cell survival and increasing insulin production and secretion in response to a glucose challenge. These findings indicate that increasing circulating apoA-I levels may be of therapeutic value in patients with diabetes in whom management of glycemic control is suboptimal. This review summarizes current knowledge of the antidiabetic functions of apoA-I and the mechanistic basis of these effects. It also evaluates the therapeutic potential of small, clinically relevant peptides that mimic the antidiabetic functions of full-length apoA-I and describes potential strategies for development of these peptides into innovative options for treatment of diabetes.

Impact of Impaired Cholesterol Homeostasis on Neutrophils in Atherosclerosis.

Atherosclerosis is complex chronic disease characterized by intimal cholesterol accumulation and vascular inflammation. There is a well-established relationship of hypercholesterolemia and inflammation with atherosclerosis. However, the link between inflammation and cholesterol is not completely understood. Myeloid cells, in particular, monocytes, macrophages, and neutrophils play essential roles in the pathogenesis of atherosclerotic cardiovascular disease. It is well known that macrophages accumulate cholesterol, forming foam cells, which drive atherosclerosis-associated inflammation. However, the interaction between cholesterol and neutrophils remains poorly defined-an important gap in the literature given that neutrophils represent up to 70% of total circulating leukocytes in humans. Elevated levels of biomarkers of neutrophil activation (myeloperoxidase and neutrophil extracellular traps) and higher absolute neutrophil counts are both associated with increased rates of cardiovascular events. Neutrophils contain the necessary machinery to uptake, synthesize, efflux and esterify cholesterol; yet, the functional consequence of dysregulated cholesterol homeostasis on neutrophil activity remains poorly defined. Preclinical animal data suggest a direct link between cholesterol metabolism and hematopoiesis, although current evidence in humans has been unable to corroborate such findings. This review will explore the impact of impaired cholesterol homeostasis neutrophils and draw focus on the discordant data from animal models and atherosclerotic disease in humans.