By Max Bingham, PhD

Muscle stem cells, or satellite cells, are likely impaired in type 1 diabetes and as such may contribute to the skeletal muscle atrophy that is often observed as a complication of the disease. This is according to the outcome of a study by D’Souza et al. (p. 3053) in which they investigated the condition of satellite cells in mice with type 1 diabetes and, significantly, human muscle biopsy samples obtained from young adult donors with the disease. According to the authors, mice that naturally develop type 1 diabetes at 4 weeks (Akita mice) had reduced endurance and increased muscle damage following exercise in comparison to controls. An examination of satellite cells in the two groups revealed a more general failure to generate new muscle cells (myogenesis) in the mice with diabetes, and consequently satellite cell content was also reduced. Additional markers of myogenesis were also reduced in the diabetic mice. To then understand the potential pathways involved, the authors investigated Notch signaling on the basis of its well-established role in myogenesis. Persistent activation of the pathway was observed in satellite cells of the diabetic mice, which could also be reversed with a Notch inhibitor. On that basis they suggest such activation impairs satellite cell functionality in diabetic muscle. However, perhaps most significantly, most of these observations were also seen in human type 1 diabetes skeletal muscle samples, lending more support to the observations seen in mice. Commenting more widely on the study, author Thomas J. Hawke told Diabetes: “These impairments in the muscle stem cell population were profound and, more worrisome, were observed in young adulthood. Given the importance of skeletal muscle to our physical abilities and our metabolic health, deficiencies in the satellite cell population would mean a significant reduction in the ability of diabetic muscles to utilize glucose and lipids from the blood and to grow and repair following exercise. Clearly our next steps are about uncovering strategies to reverse these defects.”

D’Souza et al. Decreased satellite cell number and function in humans and mice with type 1 diabetes is the result of altered Notch signaling. Diabetes 2016;65:3053–3061

Wild-type (WT) and Akita mice were eccentrically exercised (ECC EX) to induce mild muscle damage, with exercised Akita mice displaying the greatest indices of muscle damage compared with rested mice. The black arrows identify centrally located nuclei, and the black asterisks identify necrotic tissue.

Wild-type (WT) and Akita mice were eccentrically exercised (ECC EX) to induce mild muscle damage, with exercised Akita mice displaying the greatest indices of muscle damage compared with rested mice. The black arrows identify centrally located nuclei, and the black asterisks identify necrotic tissue.

Muscle disuse (as in spending a week in bed) results in loss of muscle mass and strength and a loss of insulin sensitivity, according to a study by Dirks et al. (p. 2862). Although such effects have been reported before, it is not quite clear why the loss of the insulin sensitivity occurs in conjunction with the loss of muscle mass during extended rest. To investigate, the authors subjected 10 healthy, young males to 1 week of strict bed rest and then comprehensively assessed various measures of muscle mass and function and a whole range of metabolic measures to determine possible links between them and insulin resistance. The 1 week of bed rest resulted in loss of ∼1.4 kg of lean tissue (the authors note that it takes months of intensive training to gain the same amount tissue mass) and a ∼3.2% reduction of thigh muscle cross-sectional area. Strikingly though, bed rest resulted in a ∼30% decrease in insulin sensitivity—an effect the authors say cannot be fully explained by the changes in muscle composition or the usual pathways involved in the development of insulin resistance. Although the mechanisms behind the effect on insulin sensitivity still remain elusive, the authors are clear that the negative effects should be accounted for in treatment strategies that involve bed rest. Injury and illness often necessitate hospitalization and bed rest, with repeated episodes of hospitalization being a particular concern in the elderly. Clearly accounting for this effect on insulin resistance in treatment strategies may have long-term consequences for general health outcomes. Commenting more widely on the study, author Luc J.C. van Loon told Diabetes: “The reduction in insulin-stimulated peripheral glucose uptake following a short period of bed rest should not be simply regarded as a negative health consequence of muscle disuse, as it more likely represents an adaptive response to the lesser energy demands of the muscle. The mechanisms responsible for the shift in glucose flux between tissues may hold the key to understanding the pathophysiology of insulin resistance in type 2 diabetes.”

Dirks et al. One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation. Diabetes 2016;65:2862–2875

Oil Red O staining of skeletal muscle, made by immunofluorescence microscopy with a magnification of ×40. I: Oil Red O. II: Myosin heavy chain-I.III: Laminin. IV: Combined image.

Oil Red O staining of skeletal muscle, made by immunofluorescence microscopy with a magnification of ×40. I: Oil Red O. II: Myosin heavy chain-I.III: Laminin. IV: Combined image.

The benefits of exercise in terms of preventing and treating type 2 diabetes are widely accepted. However, individuals respond in very different ways, and in some, the beneficial impact of training on glucose control and insulin sensitivity fails to occur. According to Böhm et al. (p. 2849), this “nonresponse” in insulin sensitivity can be explained by the upregulation of the transforming growth factor (TGF)-β signaling pathway in some individuals, which in turn leads to an inhibition of genes involved in glucose metabolism and insulin sensitivity. This study focused on 20 individuals reportedly at risk of diabetes who completed an endurance training program over 8 weeks to first identify individuals who responded or not in terms of insulin sensitivity. Using transcriptomics on muscle biopsy samples taken before and after the training period, the authors investigated in detail changes in muscle gene expression that might be related to the response in insulin sensitivity. Follow-up work on primary human muscle cells was used to verify observations from the transcriptomics studies. The results reveal a range of transcriptional changes in skeletal muscle following exercise that differed according to the individual response in insulin sensitivity. Significantly, failure to improve insulin sensitivity following exercise was associated with impaired upregulation of genes important for glucose and fatty acid oxidation and mitochondrial function. The authors suggest that, taken together, the proposed molecular mechanisms likely help explain the nonresponse to exercise and that TGF-β signaling might represent a target for dealing with the issue. Commenting more widely on the study, author Cora Weigert told Diabetes: “Our data show that prolonged activation of TGF-β signaling following exercise can explain the ‘nonresponse’ in terms of insulin sensitivity, but it is not clear what causes TGF-β to be activated in the muscle of some individuals. The data underline the importance of individualized training strategies in type 2 diabetes to avoid unaccustomed muscle activity and to overcome the individual differences in response to exercise interventions.”

Böhm et al. TGF-β contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle. Diabetes 2016;65:2849–2861

Immunostaining of CD56, MYH2 (fast), and MYH7 (slow) in human skeletal muscle cells treated with 1 ng/mL TGF-β1 or TGF-β1 and 10 mmol/L SB431542 (SB) for 7 days. Nuclei are shown in red.

Immunostaining of CD56, MYH2 (fast), and MYH7 (slow) in human skeletal muscle cells treated with 1 ng/mL TGF-β1 or TGF-β1 and 10 mmol/L SB431542 (SB) for 7 days. Nuclei are shown in red.

Skeletal muscle insulin resistance may be associated with diacylglycerol (DAG) accumulation, yet certain data question the link. A study by Serup et al. (p. 2932) suggests that the specific isoform of DAG may be essential to evaluating the role of the compound in lipid-induced insulin resistance. The authors report a mouse study where they compare the effects of exercise on two groups of mice, one being control wild-type mice and the other a set of mice that had the gene for hormone-sensitive lipase (HSL) knocked out. HSL, according to the authors, is a major DAG lipase, and consequently the deletion of the HSL gene results in DAG accumulation and, in theory, insulin resistance. After sending the mice on a run on a treadmill, the HSL knockout mice did accumulate DAG in skeletal muscle but at the same time showed higher insulin-stimulated glucose uptake after exercise in comparison to the wild-type mice. Subsequent deeper analysis revealed the majority of DAG accumulation was due to one specific isomer of DAG, sn-1,3 DAG. Another isomer, sn-1,2 DAG, only accumulated at very low levels in both groups. Further analyses suggested insulin-stimulated glucose uptake could be related to the upregulation of the GLUT4 protein in the HSL knockout mice, which suggested to the authors an increased capacity to take up glucose upon insulin stimulation. Commenting more widely on the study, author Bente Kiens told Diabetes: “Our findings show that DAGs are not always the bad guys in relation to insulin action. Our results suggest that in future research it will be important to investigate not only total DAGs but DAG isoforms and their cellular location to elucidate their importance in insulin action. The study also confirms the importance of exercise in insulin action.”

Serup et al. Partial disruption of lipolysis increases postexercise insulin sensitivity in skeletal muscle despite accumulation of DAG. Diabetes 2016;65:2932–2942

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