By Max Bingham, PhD
White Matter Changes Correlate With Mild Cognitive Impairments in Diabetes
Individuals with type 2 diabetes and amnesic mild cognitive impairment (MCI) have widespread microstructural changes in brain white matter, according to Gao et al. (p. ). At the same time, the individuals had worse performance in a battery of psychological tests in comparison to individuals with type 2 diabetes and normal cognition and also individuals with no diabetes. A total of 36 individuals with type 2 diabetes and amnesic MCI were involved in the study, along with 40 individuals with diabetes but normal cognition and 40 healthy control individuals. Each participant underwent diffusion tensor image and T1-weighted MRI scans and a series of cognitive tests. The authors found that the control subjects and individuals with diabetes and normal cognition did not differ in terms of white matter. In contrast, the individuals with diabetes and amnesic MCI had disrupted integrity in several brain regions. In terms of cognitive tests, the groups had considerable variation in numerous cognitive domains, with the best overall performance in individuals without diabetes and the worst in individuals with MCI. For specific brain regions that appeared altered, they highlight a number that correlated with memory and attention function impairment. They go on to discuss some of the potential mechanisms that might link white matter changes to cognitive function in diabetes. They also note that larger studies are needed to confirm their observations and that ultimately the causal relationship between white matter changes and cognitive function in diabetes remains fairly unclear. Commenting further, author Zhanjun Zhang told Diabetes: “The results show that white matter structure is affected in the major white matter tracts in patients with MCI in comparison with their counterparts without MCI and control subjects. These white matter disruptions were related to worse cognitive performance and also to lower gray matter density in the regions that connect to the white matter tracts. Our study provides insights into the pathogenic mechanisms of type 2 diabetes–related cognitive impairment.”
Voxel-wise differences in fractional anisotropy metrics between diabetes groups (T2DM) with either amnesic MCI (aMCI) or normal cognition (NC) and healthy control (HC) subjects. Red-yellow regions represent white matter regions with decreased fractional anisotropy in T2DM-aMCI individuals.
Voxel-wise differences in fractional anisotropy metrics between diabetes groups (T2DM) with either amnesic MCI (aMCI) or normal cognition (NC) and healthy control (HC) subjects. Red-yellow regions represent white matter regions with decreased fractional anisotropy in T2DM-aMCI individuals.
Role of CACNB2 Gene Explored in Proliferative Diabetic Retinopathy
Vuori et al. (p. ) report evidence of a possible association between genetic variations in the CACNB2 gene and proliferative diabetic retinopathy (PDR). In addition, they also report that CACNB2 is likely to regulate vascular endothelial growth factor (VEGF), which is reportedly involved in the early stages of retinopathy. This would also explain the potential efficacy of anti-VEGF therapy that is currently being considered for the complication. The conclusions are the result of genome-wide linkage and association studies involving individuals with type 1 diabetes and also follow-up experiments with relevant cell lines. Focusing on an initial population of 361 individuals, the authors found “suggestive evidence” of a linkage with PDR at chromosome 10p12 or D10S548 in the CACNB2 gene. They also found nearly 200 gene candidates linking to PDR in a much larger population, with the strongest single nucleotide polymorphism being rs11014284, which is reportedly closely located to the original chromosome. Subsequent sequencing of CACNB2 samples uncovered two genetic variants located close to the previous two candidates that were also predicted to affect protein function. Moving to cell line experiments, they found that CACNB2 was expressed at the mRNA level in ARPE19 cells and at the protein level in both ARPE19 and MIO-M1 cells. Human embryonic stem cell–derived retinal pigmented epithelium also had higher expression of the gene’s mRNA. They also found that knocking out CACNB2 via RNA interference resulted in a significant decrease in VEGF in a variety of the cells they used. Based on the findings, they go on to discuss some of the mechanisms involved and also describe some of the strengths and limitations of their study, highlighting that studies continue to address some of the issues surrounding the role of CACNB2 in PDR and whether anti-VEGF therapy has a role to play in treating/preventing the complication.
Regional summary of the association, linkage, and sequencing findings for PDR on chromosome 10p12 CACNB2 locus.
Regional summary of the association, linkage, and sequencing findings for PDR on chromosome 10p12 CACNB2 locus.
Impaired Wound Healing in Type 1 Diabetes due to Aberrant NF-κB Activation
The key to resolving bone injuries in type 1 diabetes may lie with skeletal stem cells (SSC) and their ability to resolve inflammation, according to Ko et al. (p. ). Specifically, they show that diabetes causes a dysregulation of nuclear factor-κB (NF-κB) in SSCs that leads to inflammation and poor bone healing and that NF-κB inhibition reverses the inflammation and improves healing. Using a series of experiments in mice and cells, the authors focus on genetic approaches to manipulate, rescue, and inhibit SSCs and NF-κB to examine downstream effects in terms of mechanisms and also wound healing in mice with and without streptozotocin-induced diabetes. They found that specific ablation of SSCs in fractures led to persistent inflammation and that diabetes affected fracture healing through a reduction in the numbers of SSCs and also enhanced inflammation. In both cases, this was the result of enhanced levels of NF-κB. Specific inhibition of NF-κB in SSCs via a genetic deletion reversed diabetes-induced apoptosis and prevented the loss of SSCs, which resulted in enhanced tissue regeneration. In terms of more detailed mechanisms, they found that aberrant NF-κB activation impaired the ability of SSCs to express TGF-β1 and subsequently the formation of M2 macrophages. This shifted the balance to the more inflammatory M1 macrophage and away from the more proresolving M2 macrophage. Crucially, they go on to show that the impact of diabetes on wound healing could be reversed by increasing TGF-β1 levels. Although they focus on type 1 diabetes in the experiments, they suggest the findings are likely also applicable to type 2 diabetes and may even represent a general mechanism underlying many diabetes complications. Commenting more widely, author Dana T. Graves told Diabetes: “Many diabetic complications are linked to increased and prolonged inflammation. The loss of stem cells of mesenchymal origin caused by diabetic conditions may represent a key to understanding this increase since they regulate a switch from an M1 to M2 macrophage phenotype that resolves inflammation and promotes healing.”
Representative images of day 6 fracture wounds from control mice (left) and SSC-ablated mice (right) stained with Safranin O/Fast Green to show cartilage growth. Scale bars, 1 mm.
Representative images of day 6 fracture wounds from control mice (left) and SSC-ablated mice (right) stained with Safranin O/Fast Green to show cartilage growth. Scale bars, 1 mm.
Sarm1: Potential Treatment Target for Diabetic Peripheral Neuropathy
Inhibiting the expression of the gene Sarm1 could form the basis for a therapeutic approach toward diabetic peripheral neuropathy, according to Cheng et al. (p. ). They suggest that with more investigations, it should be possible to identify key structural features of SARM1 involved in axon degeneration and possibly even small molecules that are capable of interfering with the normal function of the gene. Axon degeneration is a key early feature of diabetic peripheral neuropathy, but efforts to alter and treat progression in humans have largely failed despite some success in animal studies. The conclusions are the result of a series of experiments with mice that had a knockout for Sarm1 and involved comparing the effects of streptozotocin-induced diabetes on various measures of neuropathy and also genetic changes. They found that the mice with the knockout did not have altered glucose metabolism or pain sensitivity compared to wild-type controls. They also found that while diabetes resulted in diabetic neuropathy in the control mice, the Sarm1 deletion alleviated hypoalgesia, intraepidermal nerve fiber loss, axon degeneration, and various other indicators of neuropathy. Turning to genetic analyses, they found that Sarm1 deficiency reduced changes in the gene expression profile of the sciatic nerve following streptozotocin administration. In addition to identifying a number of genes that might be interesting from a therapeutic perspective, they also suggest the genes could provide clues for uncovering potential molecular mechanisms. They go on to discuss potential pathways and ultimately conclude that it should be possible to target Sarm1 to slow down axon degeneration and hence the development of diabetic peripheral neuropathy. Commenting more widely, author Qiwei Zhai told us: “We have started to screen small molecules to inhibit Sarm1, and hopefully we will find a good candidate to combat diabetic peripheral neuropathy, which might finally benefit millions of patients.”
Representative images of intraepidermal nerve fiber profiles in wild-type (WT) and Sarm1–/– mice treated with vehicle or streptozotocin (STZ). Scale bar, 35 µm.
Representative images of intraepidermal nerve fiber profiles in wild-type (WT) and Sarm1–/– mice treated with vehicle or streptozotocin (STZ). Scale bar, 35 µm.
