By Max Bingham, PhD

Successful healing of diabetic foot ulcers might be predictable in the early weeks of treatment by counting specific circulating stem cells in the bloodstream. That is according to a clinical investigation by Thom et al. (p. 486) who examined 100 patients with diabetes and foot ulcers. They found that more stem cells entered circulation in the early weeks of the study in patients who healed at 16 weeks than those that did not heal. They now suggest that assays for these stem cells during the first few weeks of treatment might “provide insight into how well wounds will respond and may aid with decisions on the use of adjunctive measures.” According to the authors, the management of diabetic foot ulcers remains a major clinical problem with success rates typically remaining at ∼30% after 16 weeks. Indeed, their success rate was 37/100 patients at 16 weeks. Thom et al. suggest that stem cells are mobilized following wounding and, in their case, they suspect that debridement (i.e., removal of dead, dying, or damaged tissue) may have been the stimulus that triggered increases in circulating stem cells. In cases where this occurred and subsequently achieved wound healing, there was no increase in stem cell counts in later weeks. Also, the level of increase seemed to correlate with the level of wounding. Where wound healing did not occur at all, there was no increase in stem cells. According to author Stephen R. Thom: “We are excited by the clinical implications of our study. If validated in larger patient samples, counting stem cells and the pattern of changes over weeks could aid greatly with patient management decisions. Further, we think that our findings regarding differences in the ratio of hypoxia-inducible factors (HIFs) within the stem cells from patients who healed versus those who did not heal has important scientific implications. Because HIFs play such an important role in stem cell functions—especially with regard to neovascularization—the differences may reflect unappreciated problems in certain patients.”

Thom et al. Measurements of CD34+/CD45-dim stem cells predict healing of diabetic neuropathic wounds. Diabetes 2016;65:486–497

Representative confocal microscope images of wound margin tissue.

Representative confocal microscope images of wound margin tissue.

The concept of β-cell rest, where pancreatic β-cells are literally given a rest from producing insulin, is addressed this month with Alarcon et al. (p. 438) reporting a set of studies in mice that might well help revive the treatment strategy for obesity-linked diabetes. In a series of experiments, the authors demonstrate that β-cells in obese mice have a morphology that is likely suited to the maximization of the production and early secretion of (pro)insulin, which at the same time depletes the ability of the cells to store any insulin. This suggests that the consistent exposure to glucose in the obese environment effectively means the cells lose the ability to efficiently deal with spikes in glucose exposure with the result being insulin resistance and hyperglycemia. Significantly, however, the authors were also able to demonstrate that once the glucose environment was returned to normal (i.e., nonobese), the cells could undergo rapid adjustments in morphology and revert back to something akin to regular insulin production and storage. Exposure to spikes in glucose (i.e., the equivalent of a meal) then resulted in the usual insulin response. The authors suggest that the effect is an adaptive plasticity of β-cells that is likely designed to deal with the regular in vivo demand for insulin. However, they warn that this plasticity only goes so far, thereby suggesting that the obese environment, with its continual demand for insulin, eventually exhausts the cells into failure. Commenting more widely on the work, author Christopher J. Rhodes stated: “The key is translating these in vitro β-cell ‘reversibility’ findings into the in vivo setting. Will taking the pressure off of the β-cell (by alleviating insulin resistance, hyperglycemia, hyperlipidemia, etc.) restore β-cell function in vivo? I believe it will. If so, it should change the philosophy for treating type 2 diabetes to fix everything else, and the β-cell should fix itself. However, there is an important proviso: to make sure that type 2 diabetes is diagnosed early enough so that there are enough remaining β-cells to fix. The adaptive plasticity of the β-cell is amazing. Let’s take therapeutic advantage of that.”

Alarcon et al. Pancreatic β-cell adaptive plasticity in obesity increases insulin production but adversely affects secretory function. Diabetes 2016;65:438–450

Representative immunofluorescent images of 10-week-old KSdb/db mouse pancreatic sections.

Representative immunofluorescent images of 10-week-old KSdb/db mouse pancreatic sections.

An investigation into platelet activation and aspirin use in patients with type 1 diabetes suggests that while platelet activation is likely enhanced in such patients, responsiveness to aspirin is not altered in comparison to healthy control subjects. This means that while adults with type 1 diabetes are likely to have an increased risk for atherothrombosis, the benefits of low-dose aspirin for the primary prevention of blood clots may well remain the same as the general population, which is in contrast to type 2 diabetes where benefits from aspirin might be reduced. The research by Zaccardi et al. (p. 503) used a cross-sectional study and a short-term intervention study to uncover the dynamics of platelet and endothelial activation and then the responsiveness to aspirin intervention. The authors found that platelet activation was persistently enhanced but that the levels of prostacyclin were comparable to those in healthy control subjects. Despite these metabolic disturbances, responsiveness to aspirin did not differ from those of healthy control subjects. According to author Bianca Rocca: “The study demonstrates that thromboxane-dependent platelet activation in vivo is persistently enhanced in type 1 diabetes, particularly in women. This abnormality is not counterbalanced by an increase in the biosynthesis of prostacyclin, an important mechanism of endothelial thromboresistance. Because the pharmacodynamics of low-dose aspirin is unimpaired in type 1 diabetes, the balance of benefits and risks of antiplatelet prophylaxis might be more favorable in patients with type 1 diabetes than in patients with type 2 diabetes, given the younger age of patients with type 1 diabetes and therefore, a lower underlying bleeding risk as compared with patients with type 2 diabetes. Therefore, the efficacy and safety of low-dose aspirin warrants further investigation in this setting.”

Zaccardi et al. In vivo platelet activation and aspirin responsiveness in type 1 diabetes. Diabetes 2016;65:503–509

Gaseous signaling molecules—or so-called gasotransmitters—are the subject of an extensive Perspective by van den Born et al. this month (p. 331) where the authors explore the roles of nitric oxide, carbon monoxide, and hydrogen sulfide in the vascular complications of diabetes. Covering both microvascular and macrovascular complications, the authors describe a mix of roles for the different gases but that they share the common capacity to reduce oxidative stress and induce angiogenesis and vasorelaxation. In diabetes, however, the bioavailability of the gases appears to be reduced. It is this issue that the authors focus on in their article, along with the potential roles of the gases in microvascular complications including retinopathy, neuropathy, and nephropathy. In terms of macrovascular issues, they cover cerebrovascular, coronary artery, and peripheral arterial diseases. The authors suggest that such transmitters “appear to have both inhibitory and stimulatory effects in the course of vascular disease development.” Finally, van den Born et al. discuss potential options for gasotransmitter-based interventions for the treatment of vascular complications in diabetes, pointing out that while some options are available for using nitric oxide–based treatment interventions, carbon monoxide and hydrogen sulfide are not currently used clinically but may well be highly promising candidates. Urging some caution, however, they point out that such gases in high concentrations can be toxic but that, at the same time, all are produced endogenously suggesting that with prudence such interventions may well be safe. Commenting more widely on the topic, author Jan-Luuk Hillebrands said: “Diabetes is associated with reduced gasotransmitter bioavailability and yet, the underlying mechanism(s) are however still to be unraveled. Knowledge on these mechanisms is important since we believe that maintaining endogenously derived gasotransmitter levels in patients with (pre)diabetes will reduce associated cardiovascular risk and subsequent development of vascular complications. Future studies to reveal underlying mechanisms are therefore warranted. In addition, possibilities for gasotransmitter-based interventions (in particular hydrogen sulfide) should be further explored. Increasing plasma gasotransmitter levels by exogenous administration of hydrogen sulfide or its metabolites is predicted to attenuate initiation and progression of diabetes-associated vascular disease and improve long-term outcome.”

van den Born et al. Gasotransmitters in vascular complications of diabetes. Diabetes 2016;65:331–345