In This Issue of Diabetes

Treatment with inhibitors of DNA demethylation and permissive histone-3 methylation appears to enhance mucosal and dermal healing in the context of diabetes, according to Yang et al. (p. 120). Specifically, high levels of glucose significantly increase interactions between forkhead box O1 (FOXO1) and the matrix metalloproteinase 9 (MMP9) promoter to increase MMP expression, which limits keratinocyte migration, a key step in would healing, and this may set up the mechanism as a route for treating wounds in diabetes and other complications of diabetes. The findings come from mechanistic studies focused mainly on human mucosal keratinocytes to identify how high glucose increases MMP9 production through epigenetic changes, mouse studies to examine the role of these epigenetic changes in the healing process, and studies that confirmed key events in human wounds related to diabetes. The in vitro studies revealed that raised levels of glucose promote an interaction between FOXO1 and the MMP9 promoter and between FOXO1 and RNA polymerase II, which in turn results in high levels of expression of MMP9, which limits the migration of keratinocytes. Specific inhibitors of DNA demethylation or permissive histone-3 methylation then rescue keratinocyte migration. Crucially, the authors replicated the outcomes in mice with diabetes, showing that inhibitors of DNA demethylation or inhibition of permissive histone-3 methylation could completely rescue the negative effects of diabetes on wound repair. Mice with diabetes had twofold larger wounds than control mice without diabetes, but application of the inhibitors significantly improved healing of both mucosal and skin wounds. The authors note that while this is the first evidence that inhibitors of DNA demethylation and histone-3 methylation can help with wound healing in diabetes, it may well have applications in other complications because of the wider role of the transcription factor FOXO1. Commenting further, author Dana T. Graves said, “The use of highly specific epigenetic inhibitors holds promise in treating complications of diabetes, since several of them are linked to common mechanisms of transcriptional dysregulation that contribute to pathogenesis.”

Aerobic, resistance, and combined exercise training are all effective strategies for enhancing insulin sensitivity, but it appears that their effects on intervening metabolic pathways are disparate, according to Pataky et al. (p. 23). Specifically, each type of exercise appears to affect amino and citric acid metabolic pathways and lipidome in different ways but still results in improved cardiometabolic risk and enhanced muscle insulin sensitivity. The authors suggest the findings might lead to more informed exercise prescription to improve insulin sensitivity and are thus highly relevant to reversing the insulin resistance that characterizes type 2 diabetes. The findings come from a study involving 52 healthy individuals without diabetes who underwent baseline testing and muscle biopsies. This was followed by 12 weeks of high-intensity interval training (HIIT), resistance training, or a combination of both, followed by retesting 72 h after the last training session. Researchers then used a combination of RNA sequencing and targeted and untargeted metabolomics to try to decipher the metabolic consequences of each of the training approaches. In the complex picture that emerges, they found that there was a significant association between insulin sensitivity and the branched-chain amino acid metabolic pathway following resistance training and HIIT. Targeted and untargeted metabolomics (including lipidomics) then revealed that levels of many muscle-related amino acid pathway metabolites increased in response to exercise (particularly HIIT). They also found that short-chain C3 and C5 acylcarnitines were reduced by all three exercise approaches. Meanwhile, both HIIT and combined training resulted in increased citric acid cycle metabolites, which the authors suggest indicates greater mitochondrial activity. Conversely, resistance and combined training resulted in greater increases in plasma membrane phospholipids than HIIT, suggesting protection against damage from exercise.

A chimeric mouse strain, termed MNX (for mitochondrial-nuclear exchange), has improved survival and delayed diabetes incidence compared with an unaltered strain susceptible to diabetes, according to Zou et al. (p. 108). Specifically, the mice had nuclear DNA from a strain susceptible to diabetes and mtDNA from nondiabetic mice, which the authors suggest means mtDNA has an outsized influence on the progression of type 1 diabetes. Based on the findings, they suggest the approach will enable development of therapies for type 1 diabetes and possibly even mitochondrial diseases. Prior studies have indicated mitochondria contribute to type 1 diabetes, yet the specific genetic factors involved have remained largely elusive. Central to the study was the generation of the chimeric MNX mouse model via pronuclear transfer and combined nuclear DNA from NOD/ ShiLtJ diabetes-susceptible mice and mtDNA from nondiabetic C57BL/6J mice. The authors then tracked this heteroplasmic mtDNA across multiple generations of mice, finding it mostly followed the mtDNA of the mother and that survival and delay in diabetes onset were generally better in the MNX mice than in the unaltered NOD/ ShiLtJ diabetes-prone mice, which the authors suggest means that mtDNA is implicated in disease progression. Finally, to delineate the functions behind the improvements seen in the MNX mice, the authors hypothesized that changes in components of complex I and complex IV were the most likely candidates based on the differences between C57 and NOD mice. Using enzyme activity assays, they found that NOD/ShiLtJ mice had significant hyperactivity of complex I of the electron transport chain relative to the MNX mice and that a specific mtDNA variant (m.9461T>C) might be responsible for the diabetes seen in the NOD/ShiLtJ mice.

A type of lipid species termed lysophosphatidylinositols, or lysoPIs, is associated with the loss of pancreatic β-cells, according to Jiménez-Sánchez et al. (p. 93). Specifically, it appears that lysoPI levels increase when there is a decline in functional β-cell mass, and the change happens before clinical symptoms of diabetes appear. The findings suggest that lysoPIs act as markers of impending loss of functional β-cell mass and thus could aid in the search for more effective methods of prevention of type 2 diabetes. The findings come from an investigation based on an unbiased lipidomics strategy applied initially to a mouse model of prediabetes. The authors then applied the same approach in patients following pancreaticoduodenectomy (individuals receiving this surgery have ∼50% β-cell loss), patients with established type 2 diabetes, and patients at high risk of developing diabetes. Experiments with the mouse model revealed 340 circulating lipid metabolites across numerous lipid classes, with considerable differentiation between the prediabetic and control mice. However, the only significantly regulated lipid class was lysoPIs, which showed increases in the prediabetic mice. Similar changes occurred in patients following acute reduction of β-cell mass and in type 2 diabetes. Notably, increases in lysoPIs correlated with HbA_1c, fasting glycemia, and an oral disposition index (a measure of insulin secretion) but not insulin resistance or obesity in the context of type 2 diabetes. When exposed to exogenous lysoPIs, cells and islets isolated from mouse and human donors without diabetes did show signs of glucosestimulated and basal insulin secretion. Meanwhile, in islets from mice and humans with diabetes, exogenous lysoPIs partially rescued impaired insulin secretion. On that basis, the authors suggest more research will be needed to explore whether treatment with lysoPIs is an option.“LysoPIs appear to be important as biomarkers for β-cell dysfunction,” says author Charna Dibner. “Their identification may also pave the way for developing nutrient supplements to support insulin secretion,” added author Pierre Maechler.