By Max Bingham, PhD

Previous clinical trials have shown that atrasentan, an endothelial A receptor blocker, can reduce albuminuria in type 2 diabetes, thus making it attractive for managing diabetic nephropathy. However, mechanisms of action behind the experimental drug have been debated ever since the drug emerged in the early 1990s. According to Boels et al. (p. 2429), the key to the reduced albuminuria may relate to the ability of the drug to stabilize the glomerular endothelial glycocalyx, a mesh-like structure that limits the filtration of macromolecules and particularly negatively charged molecules, such as albumin. Specifically, they tested whether atrasentan (7.5 mg/kg/day for 4 weeks) could stabilize the glycocalyx in diabetic apolipoprotein E (apoE)–deficient mice. In comparison to controls, the drug in the study reduced the urinary albumin:creatinine ratio by 26% in the diabetic mice while on an atherogenic diet, but there were no changes in glomerular morphology, systemic blood pressure, or blood glucose. Using high resolution transmission electron microscopy, the authors report atrasentan treatment increased glycocalyx coverage from ∼40 to 80%. Follow-up in vitro experiments with endothelial cells confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness, while in the presence of a diabetic milieu. Commenting more widely on the study, author Margien G.S. Boels said: “Our findings emphasize the importance of an intact and healthy glycocalyx to prevent proteinuria. Although the role of the endothelial glycocalyx in general vascular health and particularly the glomerular barrier function has long been underestimated, nowadays more research points toward this role as an important layer in endothelial function. We still do not fully understand how we best stabilize the glycocalyx in diabetes, but we show once again that stabilization of the glycocalyx is key in the prevention of proteinuria. For future research, it would be important to assess exactly what endothelial glycocalyx health encompasses and how to test this in a noninvasive manner in patients. This may help to identify treatment effects early on and can help to personalize drug therapy.”

Boels et al. Atrasentan reduces albuminuria by restoring the glomerular endothelial glycocalyx barrier in diabetic nephropathy. Diabetes 2016;65:2429–2439

Representative fluorescent images of cathepsin-L (CTSL) expression in apoE knockout (KO) mice (ApoE), nontreated diabetic apoE KO mice (DM), and diabetic apo KO mice treated with atrasentan (DM + A).

Representative fluorescent images of cathepsin-L (CTSL) expression in apoE knockout (KO) mice (ApoE), nontreated diabetic apoE KO mice (DM), and diabetic apo KO mice treated with atrasentan (DM + A).

Hyaluronan, an extracellular matrix component, is proposed this month by Bogdani (p. 2105) to play a role in type 1 diabetes pathogenesis. Specifically, altered content and structure of hyaluronan in diabetic human islets may help guide immune cell migration into islets and control immune cell phenotype with the result being chronic islet inflammation and increased vulnerability of β-cells to inflammatory insult. The proposal, made as part of a Perspective article in this issue of Diabetes, examines the composition and properties of the extracellular matrix, highlighting that it likely has a role that goes much further than being just the scaffolding between cells. In particular, this role likely extends to the inflammatory processes and that available evidence suggests accumulation of hyaluronan precedes or coincides with an influx of inflammatory cells in a variety of diseases, including type 1 diabetes. Based on a variety of evidence, Bogdani proposes a hypothesis that islet hyaluronan “guides immune cell migration into the islets and regulates the immune cell phenotype and that alterations in islet hyaluronan contribute to the increased vulnerability of the β-cells to inflammatory insult.” Commenting more widely on the article, Marika Bogdani told Diabetes: “This Perspective highlights recent work pertaining to the involvement of the islet extracellular matrix in human type 1 diabetes. Although the triggering mechanisms of immune cell attack of the pancreatic β-cells and the initial islet lesion in type 1 diabetes are still unknown, hyaluronan may be involved in the regulation of key steps in the pathogenesis of the disease, such as leukocyte migration, inflammatory gene expression, and β-cell death. The nature of hyaluronan during the development of human insulitis and its role in type 1 diabetes pathogenesis should be explored further. Future studies investigating islet hyaluronan in prediabetes will provide new insight on the role of this extracellular matrix component in early phases of insulitis, and fill in gaps in our understanding of the initial islet lesion in human insulitis.”

Bogdani. Thinking outside the cell: a key role for hyaluronan in the pathogenesis of human type 1 diabetes. Diabetes 2016;65:2105–2114

Hyaluronan (HA) accumulates in human pancreatic islets (islet is delineated with the white dashed line in panel C). Syn, synaptophysin; T1D, type 1 diabetes.

Hyaluronan (HA) accumulates in human pancreatic islets (islet is delineated with the white dashed line in panel C). Syn, synaptophysin; T1D, type 1 diabetes.

The therapeutic effects of dipeptidyl peptidase-4 (DPP-4) inhibition may not be completely mediated by glucagon-like peptide 1 (GLP-1), according to Nauck et al. (p. 2440), suggesting that other mediators might explain the insulin-raising effects of the treatment. DPP-4 enzyme inhibitors can increase circulating levels of GLP-1 by stopping the ability of the enzyme to breakdown GLP-1. The significance of this is that GLP-1 can stimulate insulin production and therefore reductions in blood glucose. However, to what extent GLP-1 mediates the effects of DPP-4 inhibition is open to question—the DPP-4 enzyme is widely regarded as rather indiscriminate in terms of substrate usage. To quantify the likely contribution of GLP-1, the authors report on a crossover study of patients with type 2 diabetes (n = 32) and healthy age- and weight-matched control subjects (n = 29) in which the participants received vildagliptin, a DPP-4 inhibitor, or placebo for 10 days. At days 9 or 10, the participants received a meal with or without a dose of exendin [9-39], a GLP-1 receptor blocker. Various measurements for glucose, insulin, glucagon, C-peptide, GLP-1, and other markers were then taken before, during, and after the meal. According to the authors, the rationale for the design was as follows: the meal with exendin but no DPP-4 inhibition (i.e., vildagliptin prior to the meal) would define insulin secretion due to mediators other than GLP-1, while the reverse would define the effects due to both GLP-1 and non–GLP-1–mediated components. The outcome, according to the authors, was an estimation that approximately half of the therapeutic effect of DPP-4 inhibition was mediated by GLP-1. The other half was likely a range of gut hormones that cannot be inhibited by exendin—and are still unidentified. According to Michael A. Nauck: “There is no doubt about the clinical effectiveness of DPP-4 inhibitors in the treatment of type 2 diabetes, but the exact mechanism of action is still not known. Our results make it likely that other mediators, different from the well-known gut incretin GLP-1, can be identified as novel targets for the therapy of type 2 diabetes.”

Nauck et al. Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9-39] as a GLP-1 receptor agonist. Diabetes 2016;65:2440–2447

It is becoming increasingly apparent that type 2 diabetes can lead to cognitive decline in some individuals and that as diabetes worsens, cognitive outcomes can become particularly bad. While understanding changes in physical brain structures might explain some outcomes, very little is known about the effects of diabetes on the underlying functional brain networks. According to van Bussel et al. (p. 2404), it seems to be the case that patients with type 2 diabetes—and to a lesser extent, prediabetes—do display some alterations in brain network organization. The researchers found hints of elevated local network efficiency (in comparison to control subjects) that might represent the reorganization of networks prior to future cognitive decline. To uncover these patterns, the study identified 47 individuals with diabetes, 47 with prediabetes, and 45 age-/sex-matched control subjects from the Maastricht Study and compared cognition and outcomes from functional MRI (fMRI) studies. While the cognitive tests revealed few differences between the groups, graph theoretical network analysis on fMRI outcomes did reveal subtle but significant differences in network measures that suggest alterations were already present in prediabetes and type 2 diabetes. According to the authors, enhanced efficiency seems counterintuitive when considered alongside eventual cognitive decline. However, the researchers report that the well-controlled nature of diabetes in the groups they studied likely implies compensatory mechanisms at play in response to the early stages of structural brain damage. The subtle effects hint at network alterations, but to really test their hypothesis, they suggest similar analyses are needed in patients with diabetes and severe complications. Commenting more widely on the potential impact, Jacobus F.A. Jansen stated: “The fact that subtle alterations in functional connectivity are already detectable before cognitive decrements manifest themselves opens the avenue to therapeutic/lifestyle interventions to avoid cognitive impairment in persons with diabetes. Furthermore, the surprisingly more efficient networks in diabetes are indicative of the mystifying, intricate protection mechanisms of the brain.”

van Bussel et al. Functional brain networks are altered in type 2 diabetes and prediabetes: signs for compensation of cognitive decrements? The Maastricht Study. Diabetes 2016;65:2404–2413