By Max Bingham, PhD
GWAS Identifies Further Candidate Gene Regions Associated With Fulminant Type 1 Diabetes
A genome-wide association study suggests that a series of specific variations in various genetic regions are associated with fulminant, or very rapid-onset, type 1 diabetes. According to Kawabata et al. (p. ), identifying such variations should now mean it is possible to predict or intervene against this particular form of diabetes—particularly in light of its increased risk when patients undergo cancer immunotherapy. The results come from a study involving 257 Japanese patients with fulminant type 1 diabetes who underwent genotyping for just over 600,000 single nucleotide polymorphisms (SNPs). Control subjects included patients with autoimmune type 1 diabetes and healthy subjects without diabetes. Initial results showed that multiple SNPs in the human leukocyte antigen (HLA) region were associated with fulminant type 1 diabetes, confirming previous reports, with one particular SNP (rs9268853) having the strongest association. In addition, however, 11 SNPs outside the HLA region also showed some evidence of association with the disease. In particular, rs11170445 in the CSAD/lnc-ITGB7 region of chromosome 12q13.13 showed genome-wide significance, and with fine mapping the authors could identify further candidates. Explaining the outcomes, they suggest that alterations in this particular region likely contribute to fulminant type 1 diabetes, particularly via an increase in ITGB7 (which encodes integrin β subunit 7) and with it an acceleration of tissue destruction. Author Hiroshi Ikegami told Diabetes: “Fulminant type 1 diabetes is the most severe subtype of type 1 diabetes, but the etiology of the disease remains largely unknown. The locus identified in this study is associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the ‘fulminant’ phenotype of type 1 diabetes. The information will increase our understanding of the etiology of fulminant type 1 diabetes, leading to effective methods for the prediction, prevention, and treatment of this tragic disease.”
Manhattan plot presenting the P values across the genome. The -log10 P values from 426,851 SNPs in 257 fulminant type 1 diabetes case subjects and 419 control subjects plotted according to their physical positions on successive chromosomes. A SNP associated with fulminant type 1 diabetes with genome-wide significance outside the HLA region is circled.
Manhattan plot presenting the P values across the genome. The -log10 P values from 426,851 SNPs in 257 fulminant type 1 diabetes case subjects and 419 control subjects plotted according to their physical positions on successive chromosomes. A SNP associated with fulminant type 1 diabetes with genome-wide significance outside the HLA region is circled.
FoxOs Implicated in Muscle Atrophy Due to Insulin Deficiency in Diabetes
Loss of muscle mass in patients with diabetes appears to be driven by FoxO transcription factors that are normally suppressed via the action of insulin, according to an analysis by O’Neill et al. (p. ). As a result, they suggest that FoxOs might be potential therapeutic targets to prevent muscle loss in patients with diabetes. Disability due to muscle loss is a particular problem for older patients with type 2 diabetes and also patients with type 1 diabetes. The results come from a series of experiments that focus on a mouse model with a triple knockout of FoxO1, FoxO3, and FoxO4 and controls. Mice were treated with streptozotocin to induce diabetes or vehicle (as a control), and in subsequent days various muscles were examined for development. A series of other histological, physiological, and transcriptomic analyses were also included, as well as an investigation of muscle biopsies taken from volunteers with type 1 diabetes following a short discontinuation of insulin. The authors found that muscle mass decreased significantly in mice with streptozotocin-induced diabetes but that the triple FoxO knockout completely prevented this from happening. This occurred with no effect on hyperglycemia or insulin levels and with no effect on muscle protein synthesis. Further analysis revealed that muscle mass is maintained in the mice with the knockout due to suppression of autophagy-lysosome and ubiquitin-proteasome degradation. Further transcriptomic analysis indicated that transcripts involved in protein degradation pathways were prevented in various muscles in the knockout mice. Largely the same effects were seen or confirmed in muscle biopsies taken from volunteers with type 1 diabetes who were deprived of insulin for ∼8 h. Author C. Ronald Kahn commented: “Loss of muscle mass and weakness are major problems for individuals with poorly controlled diabetes. We hope that our new understanding of this process will provide novel targets for treatment or prevention of this problem.”
Induction of autophagy-lysosomal markers is prevented in STZ FoxO-TKO muscle. Immunofluorescent staining of LC3A and myosin IIa in tibialis anterior muscle cross sections from control, STZ-Diabetes, M-FoxO-TKO, and STZ FoxO-TKO mice (scale bar = 50 µm) (n = 5–6).
Induction of autophagy-lysosomal markers is prevented in STZ FoxO-TKO muscle. Immunofluorescent staining of LC3A and myosin IIa in tibialis anterior muscle cross sections from control, STZ-Diabetes, M-FoxO-TKO, and STZ FoxO-TKO mice (scale bar = 50 µm) (n = 5–6).
Multimodal Imaging Identifies Different Disease Pathways in Early Stages of Diabetic Retinopathy
The initial stages of diabetic retinopathy are likely characterized by different phenotypes of disease progression, according to Marques et al. (p. ). Specifically, they show that eyes characterized as being at the same level of development of diabetic retinopathy may show signs of neurodegeneration, edema, and/or decreases in vessel density. However, they seem to occur in different degrees in different eyes, suggesting that the predominant mechanisms involved may differ between patients—a phenomenon that would have implications for the management of diabetic retinopathy. The findings come from a retrospective cross-sectional study in which eyes of 142 patients with type 2 diabetes were examined and rated according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and then grouped (three groups) according to disease severity. A full ophthalmological exam was administered, including color fundus photography and two types of optical coherence tomography. The authors found that vessel density (indicative of ischemia) varied significantly between the groups, with eyes in a more severe stage of the disease having reduced vessel density. Retinal thickness did not differ between the groups. Vessel density remained a significant factor in multivariate regression analysis even after adjusting for numerous factors. However, there were no differences between the groups in various other measures linked to neurodegeneration or edema. As a result, they suggest the approach has clinical value in that eyes at increased risk for progression to more severe stages of retinopathy can be identified earlier and treated accordingly, despite having diabetic retinopathy scores that might indicate otherwise. Author José Cunha-Vaz commented: “It is becoming clear now that only a subset of patients with diabetes who develop retinal changes are at risk for progression to vision loss. These patients can be identified, in the initial stages of the disease, by the presence of retinal capillary closure.”
Prostaglandin Signaling Implicated in Gastroparesis Associated With Type 2 Diabetes
Excessive prostaglandin signaling appears to result in altered gastric motility, at least in mice with type 2 diabetes. According to Blair et al. (p. ), this might point toward a novel treatment for gastroparesis (delayed gastric emptying) that can occur in patients with diabetes. The conclusions come from a study involving Lepob mice in which the authors examined the gastric antrums to understand the pathophysiological consequences of the mice having type 2 diabetes. In addition to using a variety of functional, morphological, and molecular approaches, they included video analyses and force measurements to more fully characterize stomach condition and peristalsis. Wild-type mice were used as controls. The authors found that in the Lepob mice, antral contractions were of higher frequency but were less robust in comparison to those in the control mice. Equally, electrical pacemaker activity was reduced while frequency increased in comparison to controls. Electrical recordings at several antral recording sites also indicated that slow waves were reduced in some Lepob mice and could not be resolved in others, effectively indicating that peristalsis and mechanical breakdown of food was inhibited or had ceased. Based on previous observations, the authors then hypothesized that the altered patterns may be the consequence of prostaglandin E2 overproduction. While they did not find any changes in neurons and various other cell populations, multiple components, including enzymes and receptors of the prostaglandin pathway, were upregulated. Conversely, application of the prostaglandin inhibitor valdecoxib increased slow wave amplitudes and reduced their frequency, effectively confirming the role of prostaglandin signaling in gastroparesis in type 2 diabetes in mice. As a result, they suggest that treating gastroparesis via the inhibition of prostaglandins might be possible.
