By Max Bingham, PhD

Endothelial nitric oxide (NO) signaling is important in limiting insulin resistance and inflammation in obesity and, according to new data in this issue of Diabetes (p. 2836), it appears to do this by polarizing liver macrophages towards their more anti-inflammatory M2 phenotype. Combining data from both mouse models and cell studies, Lee et al. report a series of experiments that implicate signaling via NO and a crucial protein called VASP (vasodilator-stimulated phosphoprotein) as key determinants of macrophage polarization and that signaling via this pathway is required to prevent hepatic inflammation and insulin resistance. For example, mice that overexpress endothelial nitric oxide synthase (eNOS) did develop obesity when exposed to a high-fat diet but did not develop associated inflammation and insulin resistance (whereas controls did). Crucially, this effect was associated with reduced M1 and increased M2 activation in Kupffer cells (liver macrophages). Follow-up work replicated these findings in cells and identified the key role of VASP. Transplantation of bone marrow from VASP-deficient mice to normal mice resulted in inflammation and insulin resistance normally associated with obesity even though they were fed a low-fat diet that would not normally induce obesity. As the authors suggest, the clinical relevance of this work is that the M1 polarization of macrophages is crucial in obesity and diabetes, and thus targeting this M1/M2 polarization might be an option for treatment. NO-VASP signaling might be the route to achieve this. Commenting on the implications of the study, author Francis Kim told us: “Macrophage NO-VASP signaling seems to be an important control mechanism of macrophage polarization during obesity and may well represent a new target for therapeutic intervention.”

Lee et al. M2 macrophage polarization mediates anti-inflammatory effects of endothelial nitric oxide signaling. Diabetes 2015;64:2836–2846

The rate of weight loss over longer periods of obesity may depend on how energy is expended in the short term following fasting or overfeeding according to new clinical data that appear in this issue of Diabetes (p. 2859). In a small study of obese but otherwise healthy volunteers, Reinhardt et al. identify “thrifty” and “spendthrift” energy expenditure phenotypes which, they suggest, may predict the likely outcome of longer-term caloric restriction. It appears that energy-thrifty individuals lose weight less rapidly than spendthrift individuals despite receiving identical calorie-restricted diets. “Thrifty” refers to energy expenditure increases that are small following overfeeding and decreases that are large following fasting. “Spendthrift” refers to the opposite response. The phenomenon explains how species—and particularly humans—respond to ecological variability (e.g., times of plenty vs. times of plight). The concept has received quite a bit of attention from the perspective of obesity in recent years. Using detailed measurement approaches and in-patient settings, the authors show that there is clear interindividual variation in weight loss following caloric restriction. This was not due to adherence issues or measurement inaccuracies but real biological variation between individuals in terms of rates of energy expenditure. The study, while small, goes some way toward explaining why the response to weight loss interventions (i.e., dietary and lifestyle interventions) may vary considerably between individuals on the same caloric restriction. Commenting more widely on the study, lead author Martin Reinhardt told us: “It is important to know that all volunteers, regardless of their phenotype, lost a significant amount of weight during the 6-week calorie restriction period. Our study shows that weight loss is possible despite inherent biological differences. However, key to our findings was the carefully controlled in-patient setting and the detailed measurements of energy intake, energy expenditure, waste, and physical activity that permitted us to identify real biologic differences in response to caloric restriction. We are currently looking for other more easily measurable markers to identify people with varying metabolic responses to caloric restriction or caloric excess, which one day might help direct weight loss or weight maintenance efforts.”

Reinhardt et al. A human thrifty phenotype associated with less weight loss during caloric restriction. Diabetes 2015;64:2859–2867

The existence of a strain of Staphylococcus aureus that colonizes diabetic foot ulcers but has very low virulence is reported in this issue of Diabetes (p. 2991). Using comparative genomic strategies, Messad et al. show that the strain has a very stable phage insertion that attenuates virulence, promotes colonization via biofilm formation, and has a noninvasive character, which is significant because most S. aureus strains are invasive and infectious in many diabetic foot ulcers. The strain seems to offer some level of protection against infection from more virulent S. aureus strains and, in a sense, suggests that the presence of the phage effectively forces the strain to become commensal and in some ways protective. The authors also note that in testing for the presence of the phage sequence in other S. aureus strains isolated in different clinical situations in France, it was almost exclusively only found in instances of colonizing diabetic foot ulcers. Further experiments showed that the absence of the phage restored virulence and dented its ability to form biofilms. Commenting on the wider implications of the work, author Jean-Philippe Lavigne said: “This is an important advance in the understanding of tissue colonization by bacteria and highlights alternative ways to fight pathogens in particular by using bacteriophage therapy. From a clinical prospective, the stability of the phage and the very low potential for virulence of the strain suggest we can rapidly detect its presence via molecular approaches and that this could lead to better use of antibiotics since it seems it is not necessary to treat this S. aureus. As knowledge grows around the organization of bacterial communities associated with chronic wounds, it seems wise to revisit classic dogma such as Koch’s postulates or the single pathogen paradigm [of infections] especially in the light of new molecular biology data. In the future, understanding of crosstalk between pathogenic and nonpathogenic bacteria in different functionally equivalent groups will allow for the best management of these wounds.”

Messad et al. Existence of a colonizing Staphylococcus aureus strain isolated in diabetic foot ulcers. Diabetes 2015;64:2991–2995

According to the outcomes of a new analysis that appears in this issue of Diabetes (p. 2969), the CXCR4 antagonist plerixafor can mobilize hematopoietic stem cells (HSCs) in patients with diabetes, which is likely to be significant from the perspective of successful HSC blood transplantations. Reporting on both a small prospective study and larger retrospective studies, Fadini et al. show that plerixafor was able to mobilize HSCs in individuals with and without diabetes, while historic data suggested that granulocyte colony-stimulating factor (G-CSF) was less effective in patients with diabetes, confirming previous observations. Usually G-CSF is used for mobilization of HSC prior to HSC transplants that are used to treat a variety of cancers plus potentially other conditions. However, hyperglycemia associated with diabetes causes damage in bone marrow and changes the way HSCs are mobilized. The ability of G-CSF to mobilize such cells in particular is severely impaired. In the retrospective studies, patients with diabetes undergoing HSC transplantations were associated with poorer mobilization when they only received G-CSF, but this was not the case when they received G-CSF plus plerixafor. As the authors state, this could have major implications for the care of patients with diabetes requiring stem cell mobilization and transplantation. Although not specifically tested for in this study, the authors also allude to the idea that bone marrow may contain subsets of vascular progenitor cells, including endothelial progenitor cells, suggesting that such a transplantation approach might also be relevant to cardiovascular disease, a major complication of diabetes. Commenting on the wider implications of this work, author Gian Paolo Fadini told us: “The differential mobilizing effects of the CXCR4 antagonist plerixafor versus G-CSF in patients with diabetes give us important clues about the molecular mechanisms whereby the diabetic bone marrow and stem cell mobilization are affected. This is a very new and stimulating area of research with terrific therapeutic potential.”

Fadini et al. Diabetes limits stem cell mobilization following G-CSF but not plerixafor. Diabetes 2015;64:2969–2977