Objective:To answer the question what is the best source or composition of omega-3 polyunsaturated fatty acids (PUFA) that will provide the most favorable and safe outcome for peripheral neuropathy (PN) in an animal model of obesity? Traditionally encapsulated fish oil is the primary source of omega-3 PUFA as a nutritional supplement. However, other sources exist that could be a better environmental, safety, and/or economic choice. Methods:Male Sprague Dawley rats 12 weeks of age were fed a 45% kcal diet to induce obesity and model pre-diabetes. Early and late intervention protocols were used to determine the ability of omega-3 PUFA derived from menhaden (fish) oil, krill oil, algal oils, or ethyl esters to slow the progression or reverse PN associated with pre-diabetes by examining multiple endpoints of sensory nerve function, morphometry and vascular reactivity. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the primary omega-3 PUFA, and a combination exist in fish and krill oil. However, algal oils and ethyl esters are available as EPA, DHA, or EPA & DHA and each were used in this study. Results:We report that multiple sources of omega-3 PUFA are a proactive treatment for PN that occurs with pre-diabetes including improvement in sensory nerve conduction velocity, thermal nociception and cornea sensitivity and corneal nerve fiber length. Improvement in vascular reactivity of epineurial arterioles of the sciatic nerve was observed. We also report that EPA and DHA had different outcomes for these endpoints. Conclusion:We confirm that omega-3 PUFA are an effective treatment to prevent and reverse PN associated with obesity and pre-diabetes. Additional studies will be needed to definitively determine what would be the best and most consistent source of this important nutritional supplement from an environmental and economical viewpoint.

Background and Objectives: We have previously reported that omega-3 polyunsaturated fatty acids (PUFAs) derived from fish oil (FO) is an effective treatment for type 1 and type 2 diabetes neural and vascular complications. As omega-3 PUFAs become more widely used as a nutritional and disease modifying supplement an important question to be addressed is what is the preferred source of omega-3 PUFAs? Methods: Using a type 2 diabetic rat model and early and late intervention protocols we examined the effect of dietary treatment with omega-3 PUFAs derived from menhaden (fish) oil (MO), krill oil (KO), algal oils consisting primarily of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or combination of EPA + DHA, or pharmaceutical-derived ethyl esters of EPA, DHA or combination of EPA + DHA. Nerve related endpoints included motor and sensory nerve conduction velocity, heat sensitivity of the hind paw, intraepidermal nerve density, cornea nerve fiber length, and cornea sensitivity. Vascular reactivity to acetylcholine and calcitonin gene-related peptide by epineurial arterioles that provide blood to the sciatic nerve was also examined. Results: The dose of each omega-3 PUFA supplement increased the content of EPA, docosapentaenoic acid (DPA), and/or DHA in red blood cell membranes, serum and liver. Diabetes caused a significant decrease of 30–50% of neural function and fiber occupancy of the skin and cornea and vascular reactivity. Treatment with MO, KO or the combination of EPA + DHA provided through algal oil or ethyl esters provided significant improvement of each neural endpoint and vascular function. Algal oil or ethyl ester of EPA alone was the least effective with algal oil or ethyl ester of DHA alone providing benefit that approached combination therapies for some endpoints. Conclusions: We confirm that omega-3 PUFAs are an effective treatment for DPN and sources other than fish oil are similarly effective.

In 2022, the Center for Disease Control and Prevention reported that 11.3% of the United States population, 37.3 million people, had diabetes and 38% of the population had prediabetes. A large American study conducted in 2021 and supported by many other studies, concluded that about 47% of diabetes patients have peripheral neuropathy and that diabetic neuropathy was present in 7.5% of patients at the time of diabetes diagnosis. In subjects deemed to be pre-diabetes and impaired glucose tolerance there was a wide range of prevalence estimates (interquartile range (IQR): 6%-34%), but most studies (72%) reported a prevalence of peripheral neuropathy ≥10%. There is no recognized treatment for diabetic peripheral neuropathy (DPN) other than good blood glucose control. Good glycemic control slows progression of DPN in patients with type 1 diabetes but for patients with type 2 diabetes it is less effective. With obesity and type 2 diabetes at epidemic levels the need of a treatment for DPN could not be more important. In this article I will first present background information on the “primary” mechanisms shown from pre-clinical studies to contribute to DPN and then discuss mono- and combination therapies that have demonstrated efficacy in animal studies and may have success when translated to human subjects. I like to compare the challenge of finding an effective treatment for DPN to the ongoing work being done to treat hypertension. Combination therapy is the recognized approach used to normalize blood pressure often requiring two, three or more drugs in addition to lifestyle modification to achieve the desired outcome. Hypertension, like DPN, is a progressive disease caused by multiple mechanisms. Therefore, it seems likely as well as logical that combination therapy combined with lifestyle adjustments will be required to successfully treat DPN.

Changes in the anterior segment of the eye due to type 2 diabetes mellitus (T2DM) are not wellcharacterized, in part due to the lack of a reliable animal model. This study evaluated changes in the anterior segment, including crystalline lens health, corneal endothelial cell density, aqueous humor metabolites, and ciliary body vasculature, in a rat model of T2DM compared with human eyes. Male Sprague-Dawley rats were fed a high-fat diet (45% fat) or normal diet, and rats fed the high-fat diet were injected with streptozotocin intraperitoneally to generate a model of T2DM. Cataract formation and corneal endothelial cell density were assessed using microscopic analysis. Diabetes-related rat aqueous humor alterations were assessed using metabolomics screening. Transmission electron microscopy was used to assess qualitative ultrastructural changes ciliary process microvessels at the site of aqueous formation in the eyes of diabetic rats and humans. Eyes from the diabetic rats demonstrated cataracts, lower corneal endothelial cell densities, altered aqueous metabolites, and ciliary body ultrastructural changes, including vascular endothelial cell activation, pericyte degeneration, perivascular edema, and basement membrane reduplication. These findings recapitulated diabetic changes in human eyes. These results support the use of this model for studying ocular manifestations of T2DM and support a hypothesis postulating blood-aqueous barrier breakdown and vascular leakage at the ciliary body as a mechanism for diabetic anterior segment pathology. (Am J Pathol 2024, 194: 1090-1105; https://doi.org/10.1016/j.ajpath.2024.02.004)

BACKGROUND Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF. OBJECTIVE The purpose of this study was to investigate the role of calpain in diabetes-associated AF, fibrosis, and calcium handling dysfunction. METHODS DM-associated AF was induced in wild-type (WT) mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet feeding followed by low-dose streptozotocin injection (75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophageal atrial pacing. Intracellular Ca21 transients, spontaneous Ca21 release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy. RESULTS WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca21 handling dysfunction relative to control treated animals. CAST-OE mice with DM had a similar level of hyperglycemia as diabetic WT littermates but lacked significant atrial fibrosis and AF susceptibility. DM-induced atrial calpain activity and downregulation of the calpain substrate junctophilin-2 were prevented by CAST-OE. Atrial myocytes of diabetic CAST-OE mice exhibited improved T-tubule membrane organization, Ca21 handling, and reduced spontaneous Ca21 release events compared to littermate controls. CONCLUSION This study confirmed that DM promotes calpain activation, atrial fibrosis, and AF in mice. CAST-OE effectively inhibits DM-induced calpain activation and reduces atrial remodeling and AF incidence through improved intracellular Ca21 homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients.

Introduction: Density of sub-epithelial corneal nerves have been promoted as a surrogate marker for early diagnosis of DPN. As an alternative, we developed an objective functional test of corneal sensitivity (Invest Ophthalmol Vis Sci. 2016, 57: 2412-9). In this study we provide verification of this methodology in human subjects with DPN. Methods: Following verification of DPN, response to a drop of isotonic vs. 5% NaCl (hypertonic) solution was recorded (primary endpoint). Ratio of time that the eyelids were closed from 10s to 60s following application of each solution were quantified using an image analysis program. Results: We examined 24 subjects with type 2 diabetes and 12 age-matched controls. The presence of DPN in diabetes vs. control subjects was verified by completing the Michigan Neuropathy Screening Instrument questionnaire and lower extremity examination including amplitude and conduction velocity of the sural nerve. The presence of eye discomfort was examined for each subject by completing the DEQ5 and Ocular Surface Disease Index (OSDI) questionnaires. DPN was confirmed in all subjects with diabetes as well as presence of mild to moderate ocular surface disease. Two control subjects had mild ocular surface disease but no peripheral neuropathy. Cochet-Bonnet filament esthesiometer examination revealed significant corneal sensitivity impairment in subjects with diabetes vs. control subjects (5.64 ± 0.08 vs. 5.97 ± 0.03 cm, respectively). Corneas of subjects with diabetes were also significantly less sensitive vs. controls to application of hypertonic solution (0.18 ± 0.01 vs. 0.29 ± 0.04, respectively). Data is presented as mean ± S.E.M. There was no difference in sensitivity to the isotonic solution. Conclusion: Corneal nerves that penetrate the epithelium and sprout near the surface of the eye and are the first to exhibit the "dying-back" phenomenon associated with DPN. Clinical evaluation of the sensitivity of these nerves could be a valuable method for early detection of DPN. Disclosure M.A.Yorek: Consultant; Novo Nordisk. M.Correia: Research Support; Eli Lilly and Company, Novartis, Novo Nordisk. R.Kardon: None. P.Poolman: Stock/Shareholder; FaceX LLC. Funding U.S. Department of Veterans Affairs (RX000889)

Introduction: We have shown that omega-3 polyunsaturated fatty acids (PUFA) derived from fish oil (FO) was an effective treatment for diabetes vascular and neural complications. However, is FO the best source of omega-3 PUFA for treating diabetic peripheral neuropathy (DPN)? Methods: To address this question we used a rat model of type 2 diabetes and a late intervention protocol. After 10 weeks of hyperglycemia, diabetic rats were treated for 12 weeks via diet with omega-3 PUFA derived from a variety of sources including menhaden (fish) oil (MO), krill oil (KO), oils derived from algae that produce primarily eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or combination of EPA and DHA, or commercial ethyl esters of EPA, DHA or combination of EPA and DHA. Primary endpoints were motor (MNCV) and sensory (SNCV) nerve conduction velocity, intraepidermal and cornea nerve fiber density, thermal and cornea sensitivity, and vascular reactivity of epineurial arterioles that provide circulation to the sciatic nerve. The omega-3 index, and serum fatty acid levels were also determined. Results: The dose of each omega-3 PUFA supplement was customized to create a healthy omega-3 index. Defined as the sum of EPA and DHA as a percentage of total fatty acids in red blood cells, range for healthy level 8 - 12%. Following 22 weeks of untreated diabetes neural and vascular endpoints were significantly impaired compared to control rats. Treatment with MO provided the greatest improvement for all neural endpoints followed by KO and algal oils or ethyl esters containing a combination of EPA and DHA. Algal oil or ethyl ester of EPA alone was the least effective. The greatest improvement in vascular reactivity of epineurial arterioles to acetylcholine was realized following treatment with MO with less benefit from the other omega-3 PUFA sources. Conclusion: These pre-clinical studies suggest that in a clinical trial for DPN the best outcome may be obtained by using FO as the source for omega-3 PUFA. Disclosure M.A.Yorek: Consultant; Novo Nordisk. Funding U.S. Department of Veterans Affairs (RX003826-01)

Current treatments for type 2 diabetes fail to prevent the development of peripheral neuropathy. To examine insulin degludec’s effect on peripheral neuropathy in rats, we tested insulin 700, an analog identical to insulin degludec with the same pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but with the absence of the terminal threonine on the B-chain. Rats were fed a high fat diet for 8 weeks and then treated with a low dose of streptozotocin to induce hyperglycemia. After 2 weeks, diabetic rats were treated with I700 or a control basal insulin (IC) with similar PK twice daily for 18 weeks. A healthy reference group fed a chow diet and not subjected to streptozotocin treatment was also included. The endpoints evaluated included sensory and motor nerve conduction velocity, allodynia using von Frey’s test, thermal sensitivity using Hargreaves test and corneal sensitivity. We evaluated innervation of sensory nerves using corneal confocal microscopy and, in the skin, using histological methods. We also tested vascular reactivity of epineurial arterioles using pressure myography. The insulin analogues were equally effective at correcting hyperglycemia as determined by HbA1C levels of 4.1±0.1 and 4.1±0.1% for I700 and IC, respectively. Both insulin analogues improved all neuropathy related parameters. However, I700 was more effective in that by the end of the treatment period there was no difference in thermal sensitivity, corneal sensitivity, corneal nerve fiber length and sensory and motor nerve conduction velocity between the group treated with I700 and the healthy reference rats. Interestingly, vascular relaxation to acetylcholine improved more with IC treatment. In conclusion, this study demonstrates that I700 (a degludec-like insulin analog) is a more effective treatment for diabetic peripheral neuropathy than a comparable control insulin, independent of glycemic control. Disclosure T.C.A.Åkerström: Employee; Novo Nordisk. L.Andreasen: Employee; Novo Nordisk. E.Nishimura: Employee; Novo Nordisk A/S. M.A.Yorek: Consultant; Novo Nordisk.

According to the American Diabetes Association, in 2015, 9.4% of the United States population had diabetes and about 50% of these patients will or already have developed peripheral neuropathy. Furthermore, peripheral neuropathy is detectable in about 30% of subjects with pre-diabetes and impaired glucose tolerance. The only treatment recognized for diabetic peripheral neuropathy is glycemic control, which slows progression in patients with type 1 diabetes but is less effective in subjects with type 2 diabetes. With the occurrence of obesity and type 2 diabetes at epidemic levels there is a critical need of a treatment. Diabetic peripheral neuropathy has a complex etiology with at least six major pathways involved in its development: metabolic, vascular, immunologic, neurohormonal growth factor deficiency, genetic, and extracellular matrix remodeling. In light of this complicated etiology any effective treatment for diabetic peripheral neuropathy will likely require a combination of lifestyle and therapeutic interventions. However, before an effective treatment strategy can be developed a more comprehensive understanding of the factors contributing to neurovascular and neural dysfunction in diabetes is needed. This article will address some of the major mechanisms including aldose reductase pathway, non-enzymatic glycation, hexosamine and protein kinase C pathways, oxidative and nitrosative stress, inflammatory stress, and proteases thought to contribute to the development and progression of diabetic peripheral neuropathy.

Current treatments for type 2 diabetes fail to prevent the development of peripheral neuropathy. To examine insulin degludec’s effect on peripheral neuropathy in rats, we tested insulin 700, an analog identical to insulin degludec with the same pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but with the absence of the terminal threonine on the B-chain. Rats were fed a high fat diet for 8 weeks and then treated with a low dose of streptozotocin to induce hyperglycemia. After 2 weeks, diabetic rats were treated with I700 or a control basal insulin (IC) with similar PK twice daily for 18 weeks. A healthy reference group fed a chow diet and not subjected to streptozotocin treatment was also included. The endpoints evaluated included sensory and motor nerve conduction velocity, allodynia using von Frey’s test, thermal sensitivity using Hargreaves test and corneal sensitivity. We evaluated innervation of sensory nerves using corneal confocal microscopy and, in the skin, using histological methods. We also tested vascular reactivity of epineurial arterioles using pressure myography. The insulin analogues were equally effective at correcting hyperglycemia as determined by HbA1C levels of 4.1±0.1 and 4.1±0.1% for I700 and IC, respectively. Both insulin analogues improved all neuropathy related parameters. However, I700 was more effective in that by the end of the treatment period there was no difference in thermal sensitivity, corneal sensitivity, corneal nerve fiber length and sensory and motor nerve conduction velocity between the group treated with I700 and the healthy reference rats. Interestingly, vascular relaxation to acetylcholine improved more with IC treatment. In conclusion, this study demonstrates that I700 (a degludec-like insulin analog) is a more effective treatment for diabetic peripheral neuropathy than a comparable control insulin, independent of glycemic control. Disclosure T.C.A.Åkerström: Employee; Novo Nordisk. L.Andreasen: Employee; Novo Nordisk. E.Nishimura: Employee; Novo Nordisk A/S. M.A.Yorek: Consultant; Novo Nordisk.

INTRODUCTION:Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent to which this information has been adapted for the human condition will be the subject of this review article.METHODS:A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review.RESULTS:Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature, which contribute to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes, which contributes to a lesser extent in type 2 diabetes, whereas insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models, representing pre-diabetes in the absence of hyperglycemia.CONCLUSION:This complexity complicates the successful treatment of diabetic peripheral neuropathy, and results in the poor outcome of translating successful treatments from animal studies to human clinical trials.

Objective:Feeding mice a diet containing high fat and high sucrose has been promoted as a good model for type 2 diabetes. This study sought to determine the effect of feeding mice a high fat and high sucrose diet on neuropathy compared to mice fed only a high fat diet and mice fed a high diet and treated with streptozotocin.Methods:C57Bl/6J mice were divided into five groups and fed the following diets for 20 weeks: Normal (Control); Sucrose enriched (Control + Sucrose), High Fat (Diet-induced obesity (DIO)), High Fat and High Sucrose (DIO + sucrose) and High Fat diet/streptozotocin treated (Diabetic). The endpoints evaluated included motor and sensory nerve conduction velocity, thermal and mechanical sensitivity and innervation of sensory nerves in the cornea and skin.Results:Diabetic mice were hyperglycemic at the end of the study and along with DIO mice with or without Sucrose had impaired glucose utilization. DIO mice had slowed sensory nerve conduction velocity, mechanical allodynia and decreased innervation of the cornea and skin. DIO + Sucrose and to a greater extent diabetic mice were thermal hypoalgesic, had mechanical allodynia, reduced motor and sensory nerve conduction velocities and decrease innervation of the cornea and skin.Conclusions:Development of peripheral neuropathy was more severe in High Fat and High Sucrose fed mice compared to high fat fed mice but fasting hyperglycemia and impaired glucose utilization was similar for these two models. Peripheral neuropathy was most severe in diabetic mice.

To rigorously explore the role of omega-3 polyunsaturated fatty acids (PUFA) in the treatment of diabetic peripheral neuropathy (DPN), we have created a transgenic mouse utilizing a Cre-lox promoter to control overexpression of human 15-lipoxygenase-1 (15-LOX-1). In this study, we sought to determine the effect of treating type 2 diabetic wild-type mice and transgenic mice ubiquitously overexpressing 15-LOX-1 with menhaden oil on endpoints related to DPN. Wild-type and transgenic mice on a C57Bl/6J background were divided into three groups. Two of each of these groups were used to create a high-fat diet/streptozotocin model for type 2 diabetes. The remaining mice were control groups. Four weeks later, one set of diabetic mice from each group was treated with menhaden oil for twelve weeks and then evaluated using DPN-related endpoints. Studies were also performed using dorsal root ganglion neurons isolated from wild-type and transgenic mice. Wild-type and transgenic diabetic mice developed DPN as determined by slowing of nerve conduction velocity, decreased sensory nerve fibers in the skin and cornea, and impairment of thermal and mechanical sensitivity of the hindpaw compared to their respective control mice. Although not significant, there was a trend for the severity of these DPN-related deficits to be less in the diabetic transgenic mice compared to the diabetic wild-type mice. Treating diabetic wild-type and transgenic mice with menhaden oil improved the DPN-related endpoints with a trend for greater improvement or protection by menhaden oil observed in the diabetic transgenic mice. Treating dorsal root ganglion neurons with docosahexanoic acid but not eicosapentaenoic acid significantly increased neurite outgrowth with greater efficacy observed with neurons isolated from transgenic mice. Targeting pathways that will increase the production of the anti-inflammatory metabolites of omega-3 PUFA may be an efficacious approach to developing an effective treatment for DPN.

Previous work by ourselves and others showed that mitoquinone (mitoQ) reduced oxidative damage and prevented hepatic fat accumulation in mice made obese with high-fat (HF) feeding. Here we extended these studies to examine the effect of mitoQ on parameters affecting liver function in rats treated with HF to induce obesity and in rats treated with HF plus streptozotocin (STZ) to model a severe form of type 2 diabetes. In prior reported work, we found that mitoQ significantly improved glycemia based on glucose tolerance data in HF rats but not in the diabetic rats. Here we found only non-significant reductions in insulin and glucose measured in the fed state at sacrifice in the HF mice treated with mitoQ. Metabolomic data showed that mitoQ altered several hepatic metabolic pathways in HF-fed obese rats toward those observed in control normal chow-fed non-obese rats. However, mitoQ had little effect on pathways observed in the diabetic rats, wherein diabetes itself induced marked pathway aberrations. MitoQ did not alter respiration or membrane potential in isolated liver mitochondria. MitoQ reduced liver fat and liver hydroperoxide levels but did not improve liver function as marked by circulating levels of aspartate and alanine aminotransferase (ALT). In summary, our results for HF-fed rats are consistent with past findings in HF-fed mice indicating decreased liver lipid hydroperoxides (LPO) and improved glycemia. However, in contrast to the HF obese mice, mitoQ did not improve glycemia or reset perturbed metabolic pathways in the diabetic rats.

Purpose: Determine whether density of nerve fibers in the cornea and corneal function are valid markers for early detection and treatment of peripheral neuropathy in rat models of prediabetes and type 2 diabetes. Methods: Rat models for prediabetes and type 2 diabetes were created and longitudinally studied for loss of structure and function of sensory nerves in the cornea and skin as well as nerve conduction velocity and vascular reactivity of epineurial arterioles. Reversibility of neuro and vascular pathology was also examined in these models following chronic obesity or type 2 diabetes after dietary intervention with menhaden oil a natural source of long chain omega-3 polyunsaturated fatty acids. Results and Conclusions: Our longitudinal study demonstrated that vascular and neural dysfunction associated with obesity or type 2 diabetes occur early and are progressive. Decrease in cornea nerve fiber length and function were valid markers of disease in both the prediabetic and diabetic rat models and were more sensitive than decrease in intraepidermal nerve fiber density of the skin and thermal nociception of the hindpaw. Late intervention with menhaden oil reversed both vascular and peripheral damage induced by chronic obesity or type 2 diabetes. These studies provide support for examination of corneal structure and function as an early marker of peripheral neuropathy in prediabetes and diabetes. Furthermore, we demonstrate that omega-3 polyunsaturated fatty acids derived from fish oil as an effective treatment for peripheral neuropathy that occurs with chronic obesity or type 2 diabetes. Disclosure M.A. Yorek: Consultant; Self; Novo Nordisk Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK107339); U.S. Department of Veterans Affairs (RX000889)

Objective: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy. Methods: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium. Results: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation. Conclusions: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism. (C) 2020 The Authors. Published by Elsevier GmbH.

Journal of Diabetes Research is delighted to announce the installation of Dr. Mark Yorek as the new Chief Editor for the journal. In this Editorial, Dr. Yorek discusses his research background, his ideas for the journal’s development, and his views on the direction of the field of diabetes.