In This Issue of Diabetes

Sphingosine kinase 1 (SK1) likely plays a crucial role in the revascularization of islet cells following transplantation, according to Rojas-Canales et al. (p. 1301). As such, the authors say it could represent a novel clinical target for improving transplant outcomes by reducing the extensive β-cell death that occurs with current transplantation approaches. Their study focuses on gene knockout mice deficient in SK1 and compares the effect of the deletion on a variety of characteristics of donor islet cells and ultimately whether it can cure diabetes in mice following transplantation. The authors found that mice deficient in SK1 had pancreatic islets with reduced numbers of intraislet vascular endothelial cells in comparison to wild-type controls. These cells are reportedly crucial for islet function, providing a conduit for blood delivery and direct regulatory and supportive factors to β-cells. They go on to demonstrate in vitro that the main product of SK1, sphingosine-1-phosphate, also controls the migration of intraislet endothelial cells, suggesting that the pathway does indeed have a central role in the revascularization of transplanted islets. To prove the case, the authors report that control mice rendered diabetic via streptozotocin that subsequently received transplanted islets had a 55% recovery rate in terms of reversing diabetes after 28 days. The otherwise equivalent SK1 knockout mice only had a 13% recovery rate. Commenting more widely on the study, authors Claudine S. Bonder and Claire F. Jessup told Diabetes: “Our findings that the deletion of SK1 in donor pancreatic islets reduces their curative potential highlight the potent effect that local perturbation of common sphingolipid pathways may have on whole-body glycemic control. In the future, enhancement of SK1 activity (or media supplementation with sphingosine-1-phosphate) may be utilized in the clinic to prime donor islets for swift engraftment following human islet transplantation. To achieve this, further consideration of the interplay of the SK axis with the well-characterized immune pathways that underlie the development of type 1 diabetes will be required.”

Rojas-Canales et al. Local sphingosine kinase 1 activity improves islet transplantation. Diabetes 2017;66:1301–1311

The reprogramming of pancreatic islet cells to produce insulin is a potential route for treating type 1 diabetes. In principal, the remaining islet cell types, such as α-cells, can be reprogrammed to become β-cells and thus produce insulin, counteracting the effects of type 1 diabetes and the loss of insulin-generating capacity. Matsuoka et al. (p. 1293) have now identified key β-cell–enriched transcription factors that are likely critical for the conversion of α-cells to β-like cells. The authors suggest that their insights might now be used to reprogram the transcription factor networks in the residual type 1 diabetic islet cells that do not normally produce insulin. The authors used a variety of immunohistochemical and molecular approaches in the analysis of mouse models embryonically producing the transcription factors Pdx1, Mafa, or combinations of the two in either Ngn3-positive islet cell progenitors or later glucagon-positive cell populations. They suggest that Mafa enables Pdx1 to produce insulin-positive β-like cells from α-cells while potentiating the ability of Pdx1 to generate insulin-positive cells when coexpressed in islet progenitor cells. In particular, they suggest that it might be possible to switch islet cell identity by manipulating the expression of essential islet cell transcriptional regulators, such as Mafa and Pdx1. Author Taka-aki Matsuoka commented: “Elegant studies cited within our article have illustrated the plasticity and potential reprogrammable nature of embryonic and adult islet α-cells to β-like cells. However, the essential factors regulating this change in islet cell identity have not been defined completely. Here, we illustrate the importance of Mafa in facilitating insulin-positive cell production from islet cell progenitors and later committed α-cells. These results not only highlight the fundamental role of Mafa production in generating functional β-cells but also shed light into the therapeutic mechanisms necessary for converting noninsulin-producing islet cell types in the treatment of type 1 diabetes.”

Matsuoka et al. Mafa enables Pdx1 to effectively convert pancreatic islet progenitors and committed islet α-cells into β-cells in vivo. Diabetes 2017;66:1293–1300

Drugs used to treat patients with painful diabetic neuropathy can have highly variable, limited, and sometimes disappointing efficacy. Identifying sites that contribute most to the pain may allow targeted therapy with better pain relief. Along this line, Marshall et al. (p. 1380) have reportedly identified rate-dependent depression (RDD) of the Hoffman reflex as a possible way to distinguish patients with spinally mediated painful diabetic neuropathy. As such, they suggest this should provide a means to identify those patients who would benefit optimally from therapies that can modulate spinally mediated pain, e.g., duloxetine. According to the authors, the study initially identified impaired RDD in rats with either type 1 or 2 diabetes and allodynia (a type of pain associated with neuropathy). They then showed that impaired RDD could be rapidly corrected via spinal injection of duloxetine and that it was acting via 5-hydroxytryptamine type 2A receptors, thus suggesting that the pain was arising from spinal disinhibition. Subsequent studies in patients with type 1 diabetes indicated deficits in RDD and a reduction in corneal nerve density in a proportion of patients with painful diabetic neuropathy, which was not found in patients with painless neuropathy or healthy control subjects. As a result, they say that the approach may prove useful in identifying patients with spinally mediated painful diabetic neuropathy and thus might offer a more selective approach to the drugs used to treat such patients. Author Rayaz A. Malik said: “We believe our studies exemplify truly translational research by identifying a novel approach to target patients with spinal and peripherally mediated pain, utilizing RDD and corneal confocal microscopy to implement ‘personalized or precision medicine’ in the treatment of painful diabetic neuropathy. It also represents a novel paradigm where future clinical trials of drugs for painful diabetic neuropathy could utilize RDD or corneal confocal microscopy to identify patients who will respond maximally to drugs acting at spinal or peripheral sites, increasing the likelihood of approval.”

Marshall et al. Spinal disinhibition in experimental and clinical painful diabetic neuropathy. Diabetes 2017;66:1380–1390