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Introduction: Elevated plantar pressure (PP) constitutes a risk factor for developing foot ulcers. Once present, elevated PP increases morbidity and mortality in patients with diabetes. Given the high prevalence of overweight and obesity in the Mexican population, this study aimed to describe the magnitudes and the distribution of the PP observed in a sample of newly diagnosed patients with diabetes, adjusting for body mass index (BMI) groups (normal weight, overweight, grade I obesity, and grade II and III obesity)., Materials and Methods: A total of 250 volunteers attending a comprehensive care program for the management of type 2 diabetes received foot assessments that included vascular and neurological evaluation, the identification of musculoskeletal changes, and measurements of PP., Results: Diabetic neuropathy and peripheral arterial disease were present in 21.6% and 11.2% of all participants. Musculoskeletal alterations were present in 70.8% of participants. A positive and significant correlation (p<0.001) was observed between BMI and the peak PP of all anatomical regions assessed. After adjusting for BMI, significant differences (p<0.001) were seen between groups. The metatarsal region, particularly under the third metatarsal head, denoted the highest magnitudes across all BMI., Conclusions: Periodic PP assessment is recommended to identify the distribution of high-pressure points along the plantar surface. However, as a preventive measure, it is suggested to encourage patients with diabetes and overweight or obesity to wear appropriate footwear and pressure-relief insoles to relieve high-pressure areas - often seen in these populations - to help prevent foot complications., (Copyright © 2024 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Accumulation of advanced glycation end-products (AGEs) in the brain contributes significantly to cognitive impairment in patients with diabetes by disrupting the post-mitotic state of neuronal cells, thereby triggering ectopic cell cycle re-entry (CCR) and subsequent neuronal apoptosis. Cinnamaldehyde (CINA), a potential mitigator of cognitive impairment due to its blood glucose-lowering properties, warrants exploration for its role in counteracting diabetes-related neurological damage. In this study, we examined the neuroprotective effect of CINA on AGE-damaged SH-SY5Y human neuroblastoma cells differentiated in vitro. We investigated the impact of CINA on AGE-induced neuronal CCR and apoptosis, finding that it substantially suppressed aberrant DNA replication, precluded cells from entering the mitotic preparatory phase, and diminished apoptosis. Additionally, CINA inhibited the expression of eIF4E without altering S6K1 phosphorylation. These findings indicate that CINA safeguards neuronal cells from AGE-related damage by preventing abnormal CCR, preserving the post-mitotic state of neuronal cells, and reducing AGE-induced apoptosis, potentially through the inhibition of eIF4E-controlled cell proliferation. Our results highlight the prospective utility of CINA in managing diabetic neuropathy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to assess the effectiveness of foot skin protection technology in elderly patients with diabetic peripheral neuropathy., Methods: The foot skin protection technology was developed based on a comprehensive literature review and preliminary research conducted by our research team. Subsequently, 88 elderly patients with diabetic peripheral neuropathy and experiencing foot skin problems were recruited from two community health service centers in Shanghai. Using a random number table, the participants were randomly assigned to either the control group or the experimental group. Patients in the experimental group received foot skin protection technology interventions, while those in the control group received standard community nursing guidance for a duration of 3 months. The incidence, severity, and discomfort associated with foot skin problems were evaluated before and after the intervention period in both groups., Results: The incidence, severity, and discomfort of foot skin problems notably reduced in the experimental group (all P < 0.05)., Conclusion: The foot skin protection technology demonstrates significant potential in enhancing foot skin condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Song, Qin, Jia, Miao and Bai.)

Anethole is a terpenoid with antioxidant, anti-inflammatory, and neuronal blockade effects, and the present work was undertaken to study the neuroprotective activity of anethole against diabetes mellitus (DM)-induced neuropathy. Streptozotocin-induced DM rats were used to investigate the effects of anethole treatment on morphological, electrophysiological, and biochemical alterations of the sciatic nerve (SN). Anethole partially prevented the mechanical hyposensitivity caused by DM and fully prevented the DM-induced decrease in the cross-sectional area of the SN. In relation to electrophysiological properties of SN fibers, DM reduced the frequency of occurrence of the 3rd component of the compound action potential (CAP) by 15%. It also significantly reduced the conduction velocity of the 1st and 2nd CAP components from 104.6 ± 3.47 and 39.8 ± 1.02 to 89.9 ± 3.03 and 35.4 ± 1.56 m/s, respectively, and increased the duration of the 2nd CAP component from 0.66 ± 0.04 to 0.82 ± 0.09 ms. DM also increases oxidative stress in the SN, altering values related to thiol, TBARS, SOD, and CAT activities. Anethole was capable of fully preventing all these DM electrophysiological and biochemical alterations in the nerve. Thus, the magnitude of the DM-induced neural effects seen in this work, and the prevention afforded by anethole treatment, place this compound in a very favorable position as a potential therapeutic agent for treating diabetic peripheral neuropathy.

Background: Diabetic neuropathy (DN) is recognized as a significant complication arising from diabetes mellitus (DM). Pathogenesis of DN is accelerated by endoplasmic reticulum (ER) stress, which inhibits autophagy and contributes to disease progression. Autophagy is a highly conserved mechanism crucial in mitigating cell death induced by ER stress. Chrysin, a naturally occurring flavonoid, can be found abundantly in honey, propolis, and various plant extracts. Despite possessing advantageous attributes such as being an antioxidant, anti-allergic, anti-inflammatory, anti-fibrotic, and anticancer agent, chrysin exhibits limited bioavailability. The current study aimed to produce a more bioavailable form of chrysin and discover how administering chrysin could alter the neuropathy induced by Alloxan in male rats., Methods: Chrysin was formulated using PEGylated liposomes to boost its bioavailability and formulation. Chrysin PEGylated liposomes (Chr-PLs) were characterized for particle size diameter, zeta potential, polydispersity index, transmission electron microscopy, and in vitro drug release. Rats were divided into four groups: control, Alloxan, metformin, and Chr-PLs. In order to determine Chr- PLs' antidiabetic activity and, by extension, its capacity to ameliorate DN, several experiments were carried out. These included measuring acetylcholinesterase, fasting blood glucose, insulin, genes dependent on autophagy or stress in the endoplasmic reticulum, and histopathological analysis., Results: According to the results, the prepared Chr-PLs exhibited an average particle size of approximately 134 nm. They displayed even distribution of particle sizes. The maximum entrapment efficiency of 90.48 ± 7.75% was achieved. Chr-PLs effectively decreased blood glucose levels by 67.7% and elevated serum acetylcholinesterase levels by 40% compared to diabetic rats. Additionally, Chr-PLs suppressed the expression of ER stress-related genes (ATF-6, CHOP, XBP-1, BiP, JNK, PI3K, Akt, and mTOR by 33%, 39.5%, 32.2%, 44.4%, 40.4%, 39.2%, 39%, and 35.9%, respectively). They also upregulated the miR-301a-5p expression levels by 513% and downregulated miR-301a-5p expression levels by 65%. They also boosted the expression of autophagic markers (AMPK, ULK1, Beclin 1, and LC3-II by 90.3%, 181%, 109%, and 78%, respectively) in the sciatic nerve. The histopathological analysis also showed that Chr-PLs inhibited sciatic nerve degeneration., Conclusion: The findings suggest that Chr-PLs may be helpful in the protection against DN via regulation of ER stress and autophagy., (© 2024. The Author(s).)

Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and impacted by the metabolic implications of diabetes. Insulin receptors, glucose transporters, Na + and K + channels, and mitochondria are abundant in nodes, all of which have been linked to the development and progression of Diabetic Peripheral Neuropathy (DPN) and Type 1 Diabetes Mellitus (T1DM)-associated cognitive impairment. Our study aimed to evaluate if the administration of Nigella sativa (NS) and Cassia angustifolia (CA) prevented diabetes-associated nervous system deficits in hyperglycemic mice. We developed T1DM mice through Streptozotocin (STZ) injections and validated the elevations in blood glucose levels. NS and CA were administered immediately upon the induction of diabetes. Behavioral analysis, histopathological evaluations, and assessment of molecular biomarkers (NR2A, MPZ, NfL) were performed to assess neuropathy and cognitive impairment. Improvements in memory, myelin loss, and the expression of synaptic proteins, even with the retention of hyperglycemia, were evident in the mice who were given a dose of herbal products upon the detection of hyperglycemia. NS was more beneficial in preventing memory impairments, demyelination, and synaptic dysfunction. The findings indicate that including these herbs in the diets of diabetic as well as pre-diabetic patients can reduce complications associated with T1DM, notably diabetic peripheral neuropathy and cognitive deficits associated with T1DM., (Copyright ©2024, Yale Journal of Biology and Medicine.)

Diabetes mellitus (DM) is a collection of metabolic disorder that is characterized by chronic hyperglycemia. Recent studies have demonstrated the crucial involvement of oxidative stress (OS) and inflammatory reactions in the development of DM. Curcumin (CUR), a natural compound derived from turmeric, exerts beneficial effects on diabetes mellitus through its interaction with the nuclear factor kappa B (NF-κB) pathway. Research indicates that CUR targets inflammatory mediators in diabetes, including tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), by modulating the NF-κB signaling pathway. By reducing the expression of these inflammatory factors, CUR demonstrates protective effects in DM by improving pancreatic β-cells function, normalizing inflammatory cytokines, reducing OS and enhancing insulin sensitivity. The findings reveal that CUR administration effectively lowered blood glucose elevation, reinstated diminished serum insulin levels, and enhanced body weight in Streptozotocin -induced diabetic rats. CUR exerts its beneficial effects in management of diabetic complications through regulation of signaling pathways, such as calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII), peroxisome proliferator-activated receptor gamma (PPAR-γ), NF-κB, and transforming growth factor β1 (TGFB1). Moreover, CUR reversed the heightened expression of inflammatory cytokines (TNF-α, Interleukin-1 beta (IL-1β), IL-6) and chemokines like MCP-1 in diabetic specimens, vindicating its anti-inflammatory potency in counteracting hyperglycemia-induced alterations. CUR diminishes OS, avert structural kidney damage linked to diabetic nephropathy, and suppress NF-κB activity. Furthermore, CUR exhibited a protective effect against diabetic cardiomyopathy, lung injury, and diabetic gastroparesis. Conclusively, the study posits that CUR could potentially offer therapeutic benefits in relieving diabetic complications through its influence on the NF-κB pathway., (© 2024 John Wiley & Sons Ltd.)

Dyslipidemia has been considered a risk factor for diabetic peripheral neuropathy. Proprotein convertase subtilisin-like/Kexin 9 inhibitor (PCSK9) inhibitors are a new type of lipid-lowering drug currently in clinical use. The role of PCSK9 in diabetic peripheral neuropathy is still unclear. In this study, the effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve in rats with diabetic peripheral neuropathy and its underlying mechanisms were investigated. The diabetic peripheral neuropathy rat model was established by using a high-fat diet combined with streptozotocin injection, and experimental subjects were divided into normal, diabetic peripheral neuropathy, and alirocumab groups. The results showed that Alirocumab improved nerve conduction, morphological changes, and small fiber deficits in rats with DPN, possibly related to its amelioration of oxidative stress and the inflammatory response.

Diabetic peripheral neuropathy occurs in up to 50% of patients with diabetes mellitus and increases the risk of diabetic foot ulcers and infections. Consistent screening and clear communication are essential to decrease disparities in assessment of neuropathic symptoms and diagnosis. Physicians should address underlying risk factors such as poor glycemic control, vitamin B12 deficiency, elevated blood pressure, and obesity to reduce the likelihood of developing neuropathy. First-line drug therapy for painful diabetic peripheral neuropathy includes duloxetine, gabapentin, amitriptyline, and pregabalin; however, these medications do not restore sensation to affected extremities. Evidence for long-term benefit and safety of first-line treatment options is lacking. Second-line drug therapy includes nortriptyline, imipramine, venlafaxine, carbamazepine, oxcarbazepine, topical lidocaine, and topical capsaicin. Periodic, objective monitoring of medication response is critical because patients may not obtain desired pain reduction, adverse effects are common, and serious adverse effects can occur. Opioids should generally be avoided. Nondrug therapies with low- to moderate-quality evidence include exercise and neuromodulation with spinal cord stimulation or transcutaneous electrical nerve stimulation. Peripheral transcutaneous electrical nerve stimulation is well tolerated and inexpensive, but benefits are modest. Other treatments, such as acupuncture, alpha-lipoic acid, acetyl-L-carnitine, cannabidiol, and onabotulinumtoxinA need further study in patients with diabetic peripheral neuropathy.

Background: Diabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN., Methods: Sprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators., Results: PPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1β and ICAM-1)., Conclusion: Collectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni's test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and β-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM., (© 2024. The Author(s).)

Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.

Aim: To validate neuroprotective effect of pectin against neuropathic pain in diabetic rodents., Material and Method: Pectin was isolated and characterised from different sources to validate its neuroprotective effect against T2DM associated neuropathic pain. The antioxidant activity of pectins was done by the DPPH method. Type-2 diabetes mellitus (T2DM) was induced in Wistar albino rats by high-fat diet and high-fat emulsion feeding for 2 weeks followed by a single i.p. of Sterptozotocin in 3rd week. The animals were grouped as positive control and Citrus sinensis (L.) Osbeck peel pectin (CSL-OP) as test group and treated for the next 4 weeks. Body weight and blood glucose were measured up to 8 weeks; however, behavioural assessment was done at the end of 5th to 8th week., Result: CSL-OP restored the reduced body weight and elevated blood glucose with increased pain threshold and improved walking performance., Conclusion: CSL-OP prevented progression of early diabetic neuropathy with anti-oxidant activity.

Oxidative stress, imbalanced antioxidants, and dysregulated renal lipids are closely linked with diabetic nephropathy and eventual cause of end-stage renal failure. This study was performed to investigate the protective effect of bacoside-A on markers of lipid peroxidation, renal lipids, and markers of renal function in diabetic rats. Experimental diabetes was induced in Wistar rats by a single dose of streptozotocin [40 mg/kg body weight (BW)] via intraperitoneal injection. Oral administration of bacoside-A (10 mg/kg BW) and glibenclamide, a reference drug, continued for 45 days. Diabetic rats showed a significant increase in the levels of plasma glucose, renal lipids, markers of renal lipid peroxidation, and plasma biomarkers of renal function such as urea, uric acid, and creatinine. A significant decrease in the levels of plasma insulin, nonenzymatic antioxidants, and the activity of enzymatic antioxidants was seen compared with the normal controls. Bacoside-A (10 mg/kg BW) and glibenclamide (600 μg/kg BW) administered to diabetic rats resulted in a significant decrease in plasma glucose and renal lipids but a significant increase in the plasma insulin level. In addition, bacoside-A achieved a remarkable increase in the activity of enzymatic antioxidants and the levels of nonenzymatic antioxidants in the renal tissue of diabetic rats, along with significant decreases in the markers of lipid peroxidation and those of renal function, consequently substantiating the protecting effectiveness of bacoside-A in a diabetic state. These biochemical observations were supported by a histopathological study of the renal tissue. The present study suggested that bacoside-A, a triterpenoid, offers a higher renoprotective effect to counter abnormal parameters of renal function in diabetes-induced renal injury., (Copyright © 2023 Copyright: © 2023 Saudi Journal of Kidney Diseases and Transplantation.)

Diabetic neuropathic pain is one of the microvascular complications of diabetes mellitus characterized by symmetrical pain and sensory abnormalities. A steroidal lactone isolated from the datura innoxa plant, withametelin (WMT), exhibited significant neuroprotective, anti-inflammatory, antioxidant, and anticancer properties. The current study aimed to investigate anti-neuropathic pain activity and the molecular mechanism of WMT against streptozotocin (STZ)-induced diabetic neuropathy. Rats were given a single injection of STZ (60 mg/kg, intraperitoneally (i.p.)) for induction of diabetes on the first day of the study. After the onset of diabetic neuropathy, pregabalin (10 mg/kg, i.p.) and WMT (0.1 and 1 mg/kg, i.p.) treatments were started from day 14 up to day 42. It was found that STZ-induced neuropathic pain behaviors were markedly reduced by WMT. It inhibited the STZ-associated histopathological changes and genotoxicity in the sciatic nerve and spinal cord. Additionally, Fourier transforms infrared (FTIR) spectroscopy results revealed that STZ-induced alterations in the biochemical components of the sciatic nerve's myelin sheath were inhibited by WMT. In the spinal cord, it markedly reduced the immunoreactivity of mitogen-activated protein kinases (MAPKs) signaling components such as p38-MAPK, c-Jun N-terminal kinase (JNK), extracellular-signal-regulated-kinase (ERK), and activator-protein 1 (AP-1). It also reduced the expression levels of nuclear factor-kappa-B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The production of inflammatory cytokines was considerably reduced by WMT. This study provides convincing evidence that WMT treatment attenuated STZ-induced diabetic neuropathic pain by inhibition of MAPK/NF-κB signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Diabetes and hypertension stand as the major non-infectious diseases affecting 34.2 million and 1.28 billion people respectively. The literature on the impact of diabetes on hypertension and vice versa is evolving. The major objectives of this review were to compile the evolving literature establishing the role of hypertension in diabetic neuropathy, derive the exact mechanisms for its pathogenesis, and describe evidence-based precise individualized management of diabetic neuropathy in patients having diabetes complicated by hypertension. A systematic review was conducted by searching databases of PubMed, Embase, and Scopus covering the literature from inception to 2022. We included all observational and experimental studies, including both human and animal studies looking into the correlation between diabetic neuropathy and hypertension. Hypertension poses to be the leading modifiable risk factor for the development of diabetic neuropathy, especially distal symmetrical polyneuropathy, producing abnormal nerve conduction parameters and increased vibration perception threshold in patients with diabetes mellitus. Thus, we advocate that good glycemic control in patients with diabetes needs to be supported with strict blood pressure control for preventing and delaying the onset of diabetic neuropathy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate the AMPK pathway-mediated effect of alpha-lipoic acid (ALA) on the dorsal root ganglia (DRGs) of rats with diabetic peripheral neuropathy (DPN) and to attempt to elucidate the underlying mechanism., Methods: Sprague-Dawley rats (n = 15) were randomly divided into three groups. The control group was fed a standard diet, and the other groups were fed a high-carbohydrate/high-fat diet. Diabetes was established by a single streptozotocin (STZ) (30 mg/kg) injection, and control rats were injected with an equal volume of citrate buffer. ALA (60 mg/kg/day) was administered for 12 weeks. The nerve conduction velocity (NCV) of the sciatic nerve was measured. Glutathione (GSH) and malondialdehyde (MDA) concentrations in serum were measured with the thiobarbituric acid method and biochemistry. Pathological changes in the rat DRGs were observed. AMPK, phospho-AMPK (p-AMPK), nuclear factor erythroid-2-related factor 2 (Nrf2), phospho-nuclear factor erythroid-2-related factor 2 (p-Nrf2), heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1), Forkhead box O3 (FoxO3a), phospho-Forkhead box O3 (p-FoxO3a), and Bcl-2 interacting mediator of cell death (Bim) expression levels were assessed by immunohistochemistry and western blotting., Results: ALA improved the motor NCV (MNCV) and sensory NCV (SNCV) of rats with DPN and reduced their mechanical pain threshold. ALA increased serum GSH concentrations and decreased serum MDA concentrations. Additionally, AMPK was activated by ALA. Nrf2, p-Nrf2, HO-1, and NQO1 expression was upregulated, while FoxO3a, p-FoxO3a, and Bim expression was downregulated. ALA reduced oxidative stress and apoptosis in DRG., Conclusion: ALA alleviates DPN and improves peripheral nerve function. ALA reduces oxidative stress by activating Nrf2 through AMPK and inhibits FoxO3a and Bim thereby reducing neuronal apoptosis., (© 2022. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Peripheral neuropathy, peripheral arterial disease and diabetes-related foot ulcers are the most important risk factors for future amputation. Up to 50% of people with diabetes have distal symmetrical polyneuropathy as a complication of diabetes. Distal symmetrical polyneuropathy results in loss of protective sensation in the feet, increasing the risk of diabetes-related foot ulceration., Objective: The aim of this article is to provide structured guidance for detecting diabetes-related peripheral neuropathy, appropriate referral based on risk assessment and prevention of diabetes‑related foot ulceration., Discussion: As a result of the often-asymptomatic nature of diabetes-related peripheral neuropathy, general practice is an ideal location for screening all adults with diabetes for loss of protective sensation. Loss of protective sensation in a person with diabetes indicates an at-risk foot. Increased frequency of foot examination, education in self-care, appropriate footwear and referral to podiatry for non‑ulcerative foot problems can reduce the development of diabetes-related foot ulcers.

Morphine is a drug of choice for the treatment of severe and chronic pain, but tolerance to the antinociceptive effect limits its use. The development of tolerance to morphine has recently been associated with neuronal apoptosis. In this study, our aim was to investigate the effects of metformin on morphine-induced neuronal apoptosis and antinociceptive tolerance in diabetic rats. Three days of cumulative dosing were administered to establish morphine tolerance in rats. The antinociceptive effects of metformin (50 mg/kg) and test dose of morphine (5 mg/kg) were considered at 30-min intervals by thermal antinociceptive tests. To induce diabetic neuropathy, streptozotocin (STZ, 65 mg/kg) was injected intraperitoneally. ELISA kits were used to measure caspase-3, bax, and bcl-2 levels from dorsal root ganglion (DRG) tissue. Semi-quantitative scoring system was used to evaluate apoptotic cells with the the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. The findings suggest that co-administration of metformin with morphine to diabetic rats showed a significant increase in antinociceptive effect compared to morphine alone. The antinociceptive tests indicated that metformin significantly attenuated morphine antinociceptive tolerance in diabetic rats. In addition, metformin decreased the levels of apoptotic proteins caspase 3 and Bax in DRG neurons, while significantly increased the levels of antiapoptotic Bcl-2. Semi-quantitative scoring showed that metformin provided a significant reduction in apoptotic cell counts in diabetic rats. These data revealed that metformin demonstrated antiapoptotic activity in diabetic rat DRG neurons and attenuated morphine tolerance. The antiapoptotic activity of metformin probably plays a significant role in reducing morphine tolerance., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes., Methods: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m 2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons., Results: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group., Conclusions: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.)., (Copyright © 2022 Massachusetts Medical Society.)

Diabetic neuropathy is a common complication of diabetes mellitus, posing a challenge in treatment. Previous studies have indicated the protective role of mesenchymal stem cells against several disorders. Although they can repair nerve injury, their key limitation is that they reduce viability under stress conditions. We recently observed that overactivation of the carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP) considerably rescued cell viability under hyperglycemic stress and played an essential role in promoting the beneficial effects of Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Thus, the present study was designed to unveil the protective effects of CHIP-overexpressing WJMSCs against neurodegeneration using in vivo animal model based study. In this study, western blotting observed that CHIP-overexpressing WJMSCs could rescue nerve damage observed in streptozotocin-induced diabetic rats by activating the AMPKα/AKT and PGC1α/SIRT1 signaling pathway. In contrast, these signaling pathways were downregulated upon silencing CHIP. Furthermore, CHIP-overexpressing WJMSCs inhibited inflammation induced in the brains of diabetic rats by suppressing the NF-κB, its downstream iNOS and cytokines signaling nexus and enhancing the antioxidant enzyme system. Moreover, TUNEL assay demonstrated that CHIP carrying WJMSCs suppressed the apoptotic cell death induced in STZ-induced diabetic group. Collectively, our findings suggests that CHIP-overexpressing WJMSCs might exerts beneficial effects, which may be considered as a therapeutic strategy against diabetic neuropathy complications., (© 2022 Wiley Periodicals LLC.)

Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages., Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined., Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly., Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ishibashi, Kosaka and Tavakoli.)

Purpose: Neuropathy is one of the most important complications of diabetes. According to recent advances, vitamin D deficiency might play a role in the development and progression of diabetic neuropathy. Moreover, therapeutic vitamin D supplementation has the potential to improve this condition. The aim of the present review was to summarize new data available in this area., Methods: The PubMed database was searched for articles written in English and published through September 2021, using combinations of the following key words: vitamin D, diabetes, diabetes mellitus, diabetic neuropathy, polyneuropathy, peripheral neuropathy, cardiac autonomic neuropathy, supplementation, and therapy., Findings: A number of studies have suggested that vitamin D deficiency can play a significant role in the development of peripheral neuropathy, diabetic foot ulcers, as well as cardiovascular autonomic neuropathy in patients with type 2 diabetes. Vitamin D supplementation might serve as an effective adjuvant therapy for neuropathic pain and may slow or stop the progression of neural damage., Implications: Vitamin D therapy for diabetic complications could be a reliable option; however, further studies are needed to confirm this notion., Competing Interests: DECLARATION OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Axon degeneration in diabetic peripheral neuropathy (DPN) is associated with impaired NAD + metabolism. We tested whether the administration of NAD + precursors, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), prevents DPN in models of Type 1 and Type 2 diabetes. NMN was administered to streptozotocin (STZ)-induced diabetic rats and STZ-induced diabetic mice by intraperitoneal injection at 50 or 100 mg/kg on alternate days for 2 months. mice The were fed with a high fat diet (HFD) for 2 months with or without added NR at 150 or 300 mg/kg for 2 months. The administration of NMN to STZ-induced diabetic rats or mice or dietary addition of NR to HFD-fed mice improved sensory function, normalized sciatic and tail nerve conduction velocities, and prevented loss of intraepidermal nerve fibers in skin samples from the hind-paw. In adult dorsal root ganglion (DRG) neurons isolated from HFD-fed mice, there was a decrease in NAD + levels and mitochondrial maximum reserve capacity. These impairments were normalized in isolated DRG neurons from NR-treated mice. The results indicate that the correction of NAD + depletion in DRG may be sufficient to prevent DPN but does not significantly affect glucose tolerance, insulin levels, or insulin resistance.

SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.

Background: Diabetic neuropathy is a condition that is prevalent among type 2 diabetic patients. Some physicians prescribe vitamin B12 or vitamin B complex supplements to improve symptoms, but studies have shown that there is little to no evidence of vitamin B12 being an effective treatment for diabetic neuropathy. Thus, this study aims to investigate local physicians' knowledge and tendency to prescribe vitamin B12 or vitamin B complex for the treatment or prevention of diabetic peripheral neuropathy., Methods: It was a cross-sectional study, conducted between May and November of 2019, in several primary healthcare centers in different cities of Saudi Arabia. A total of 412 physicians with a minimum of three years of experience answered a three-part questionnaire on their demographic information, prescribing behavior, and knowledge of the relationship between vitamin B12 or vitamin B complex and diabetic neuropathy., Results: The study found that only 42% of the physicians believed that vitamin B12 supplementation did not prevent diabetic neuropathy, while only 52.7% found it to be an ineffective treatment for this condition. Moreover, 58.7% stated that they had certainly prescribed vitamin B12 or multivitamins as a form of treatment or prevention of diabetic neuropathy. 47.8% of the patients requested a vitamin B12 prescription 1-6 times from their physicians, while 31.6% of them requested it ≥ 7 times, with 42.5% of physicians agreeing that their prescriptions of vitamin B12 had been a result of patient demand more than clinical justification. Likewise, 43% of respondents were aware that vitamin B12 levels should be tested annually. Furthermore, a higher proportion of consultants chose not to prescribe vitamin B12 to prevent or treat diabetic neuropathy than any other rank., Conclusion: The findings of this study indicate a tendency of unnecessarily prescribing vitamin B12 supplementation for the prevention or treatment of diabetic neuropathy as well as a lack of knowledge on the matter among doctors in primary care hospitals in Saudi Arabia. The study has also shown that there are patients who often request this prescription, adding pressure on their physicians to comply. Future studies should investigate most of the hospitals in Saudi cities and include less experienced residents and medical students., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Globally, diabetes has assumed epidemic proportions with the neuropathic complications attributed to the malady emerging as a substantial burden on patients and society. DNP has greatly affected the daily life of patients, the effect of traditional treatment methods is not ideal, and it is easy to produce drug resistance. This work is aimed at scrutinizing the effect of upregulating the expression of TNFAIP3 on diabetic neuralgia in mice. This work entailed ascertaining the effects of TNFAIP3 on a murine DNP system. This inspired us to observe the analgesic effect via high expression of lentivirus-mediated TNFAIP3 by intrathecal injection in the animal model to explore its regulatory impacts, symptom relief, and mechanistic role in pain. The results displayed an attenuation of hind paw pain hypersensitivity by LV-TNFAIP3 in the animals. The spinal cord and dorsal root ganglion of mice with neuropathic pain displayed an evident dip in TNFAIP3. Inhibition of the ERK/NF- κ B signaling pathway employing LV-TNFAIP3 conspicuously suppressed this pathway while the diabetic pain hypersensitivity was quelled. This effect was also seen with insulin treatment evidently. In conclusion, according to the above analyses, the interaction between DNP and extracellular signal-regulated kinase signal transduction pathway is one of the key factors of pathogenesis., Competing Interests: The author declares that there are no competing economic interests., (Copyright © 2021 Yang Liu et al.)

Background: The application of nanomedicine to antiretroviral drug delivery holds promise in reducing the comorbidities related to long-term systemic exposure to highly active antiretroviral therapy (HAART). However, the safety of drugs loaded with silver nanoparticles has been debatable. This study is aimed at evaluating the effects of HAART-loaded silver nanoparticles (HAART-AgNPs) on the behavioural assessment, biochemical indices, morphological, and morphometric of the hippocampus in diabetic Sprague-Dawley rats., Methods: Conjugated HAART-AgNPs were characterized using FTIR spectroscopy, UV spectrophotometer, HR-TEM, SEM, and EDX for absorbance peaks, size and morphology, and elemental components. Forty-eight male SD rats (250 ± 13 g) were divided into nondiabetic and diabetic groups. Each group was subdivided into ( n = 8) A (nondiabetic+vehicle), B (nondiabetic+HAART), C (nondiabetic+HAART-AgNPs), D (diabetic+vehicle), E (diabetic+HAART), and F (diabetic+HAART-AgNPs). Morris water maze, Y-maze test, and weekly blood glucose levels were carried out. Following the last dose of 8-week treatment, the rats were anaesthetized and euthanized. Brain tissues were carefully removed and postfixed for Nissl staining histology., Results: 1.5 M concentration of HAART-AgNPs showed nanoparticle size 20.3 nm with spherical shape. HAART-AgNPs revealed 16.89% of silver and other elemental components of HAART. The diabetic control rats showed a significant increase in blood glucose, reduced spatial learning, positive hippocampal Nissl-stained cells, and a significant decrease in GSH and SOD levels. However, administration of HAART-AgNPs to diabetic rats significantly reduced blood glucose level, improved spatial learning, biochemical indices, and enhanced memory compared to diabetic control. Interestingly, diabetic HAART-AgNP-treated rats showed a significantly improved memory, increased GSH, SOD, and number of positive Nissl-stained neurons compared to diabetic-treated HAART only., Conclusion: Administration of HAART to diabetic rats aggravates the complications of diabetes and promotes neurotoxic effects on the experimental rats, while HAART-loaded silver nanoparticle (HAART-AgNP) alleviates diabetes-induced neurotoxicity., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Sodiq Kolawole Lawal et al.)

Diabetic neuropathy is a neurodegenerative disorder that may alter both the somatic and autonomic peripheral nervous systems in the context of diabetes mellitus (DM). It is a prevalent and burdensome chronic complication of DM, that requires timely management. Optimized glycemic control (mainly for type 1 DM), multifactorial intervention (mainly for type 2 DM), with lifestyle intervention/physical exercise, and weight loss represent the basis of management for diabetic distal symmetrical polyneuropathy, and should be implemented early in the disease course. Despite better understanding of the pathogenetic mechanisms of diabetic peripheral neuropathy, there is still a stringent need for more pathogenetic-based agents that would significantly modify the natural history of the disease. The paper reviews the available drugs and current recommendations for the management of distal symmetrical polyneuropathy, including pain management, and for diabetic autonomic neuropathy. Evaluation of drug combinations that would perhaps be more efficient in slowing the progression of the disease or even reversing it, and that would provide a better pain management is still needed., Competing Interests: Declaration of competing interest SC discloses the following: Payment for lectures from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Servier Pharma and for Steering Committee meetings from TIMI Study Group. Consultant fees for Advisory Board from AstraZeneca. Support for participating to professional societies congresses from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Wörwag Pharma. IR discloses the following: Advisory Board: AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., Sano+. Consultant: AstraZeneca, Insuline Medical, Medial EarlySign Ltd., CamerEyes Ltd., Exscopia, Orgenesis Ltd., BOL, Glucome Ltd., DarioHealth, Diabot. Speaker's Bureau: AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., Sano+. Stock/Shareholder: Glucome Ltd., Orgenesis Ltd., DarioHealth, CamerEyes Ltd., Diabot, BOL., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Dental pulp stem cells (DPSCs) are suitable for use in regenerative medicine. Cryopreserved human DPSCs (hDPSCs) ameliorate diabetic polyneuropathy, and the effects of hDPSC transplantation are related to VEGF and NGF secretion. This study evaluated the long-term effects of a single transplantation of hDPSCs on diabetic polyneuropathy. hDPSCs were obtained from human third molars extracted for orthodontic treatment, which were then transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocin injection in nude mice. The effects of hDPSC transplantation were analyzed at 16 weeks post-transplantation. DPSC transplantation significantly improved delayed nerve conduction velocity, decreased blood flow, and increased sensory perception thresholds. Furthermore, the hDPSC-conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons. In conclusion, the therapeutic effects of hDPSC transplantation with a single injection last for prolonged periods and may be beneficial in treating long-term diabetic polyneuropathy.

Aims/introduction: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control., Materials and Methods: This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only., Results: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain., Conclusions: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Microvascular complications of diabetes present a significant challenge due to their diverse presentations, significant morbidity, and as strong predictors of cardiovascular disease. Prevention and management strategies should focus on lifestyle modification, education and awareness, systematic screening for early complications, and intensive management of modifiable risk factors. This review discusses the microvascular complications of diabetes, including diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy, and provides best practice clinical care recommendations to guide health care professionals to better manage people with these conditions., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Aims: The study aimed to evaluate the effects of foot-ankle flexibility and resistance exercises on the recurrence rate of plantar foot diabetic ulcers, HbA1c levels, diabetic neuropathy examination (DNE) scores, ankle brachial index (ABI), and walking speed within 12 and 24weeks., Methods: We conducted a double-blind randomized clinical trial. Fifty patients with recently healed plantar foot diabetic ulcers were randomized to an intervention group that performed foot-ankle flexibility and resistance exercise three times a week in their home (n=25) or a control group (n=25). Both groups were given foot care education. Outcomes were assessed at plantar foot diabetic ulcer recurrence or at 12 and 24weeks whichever came first. Outcome measures included plantar foot diabetic ulcer recurrence, changes of HbA1c levels, DNE scores, ankle brachial index ABI, and walking speed., Results: There were significant difference between groups in ulcer recurrence at either 12weeks (intervention 8%, control 68%, RR 0.288; 95% CI 0.156-0.534, P=0.000) within 12weeks. or 24weeks (intervention 16%, control 72%, RR 0.222; 95% CI 0.088-0.564, P=0.000).). There were significant differences in the DNE score delta (P=0.000) and walking speed delta (P=0.000), but there were no significant differences in the HbA1c delta and ABI delta between groups at either 12 or 24weeks., Conclusions: Foot-ankle flexibility and resistance exercises can reduce the recurrence of plantar foot diabetic ulcer incidence and improve diabetic neuropathy and walking speed. Clinical trial number: NCT04624516., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Diabetic microvascular complications are a major cause of morbidity and are related to glycaemic control and cardiovascular risk factors., Aims: We sought to determine the association of microvascular complications in relation to control of glycemia, blood pressure and lipids in T2DM patients attending secondary care in Qatar., Methods: This is a cross-sectional study undertaken in patients with T2DM attending Qatar's National Diabetes Centres. Patients underwent assessment of glycemia, blood pressure and lipids and prevalence of diabetic peripheral neuropathy (DPN), retinopathy and microalbuminuria., Results: We included 1114 subjects aged 52.1 ± 11.3 years with a duration of diabetes 10.0 ± 7.6 years and had a prevalence of 25.8% for DPN, 34.3% for painful DPN, 36.8% for microalbuminuria and 25.1% for retinopathy. Patients who achieved an HbA1c ≤ 7.0% compared to >7% had a significantly lower prevalence of DPN (P < 0.01), painful DPN (P < 0.01), retinopathy (P < 0.01) and microalbuminuria (P < 0.007). Patients who achieved a systolic BP ≤ 140 mmHg compared to >140 mmHg had a significantly lower prevalence of DPN (P < 0.001), painful DPN (P < 0.001), retinopathy (P < 0.001) and microalbuminuria (P < 0.001). Patients who achieved an LDL ≤2.6 mmol/l compared to >2.6 mmol/l had a significantly higher prevalence of DPN (P < 0.03), but no difference in other outcomes. There was no difference in microvascular complications between those who achieved a HDL-C ≥ 1.02 mmol/l, and among those who achieved triglycerides ≤1.7 mmol/l., Conclusions: Optimal control of glycemia and blood pressure, but not lipids is associated with a lower prevalence of diabetic microvascular complications., Competing Interests: Declaration of competing interest The authors report no conflict of interest in relation to this manuscript., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Aims: Vitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model., Main Methods: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways., Key Findings: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function., Significance: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis., (Copyright © 2021. Published by Elsevier Inc.)

Rheum ribes L., known as Syrian rhubarb, is used in traditional Lebanese folk medicine for the treatment of diabetes. The present study aims to investigate the activities of R. ribes aqueous extract for glucose homeostasis, in vivo antioxidant and diabetic neuropathy protection in mice. The acute and the subacute effects of various doses of R. ribes on blood glucose and in vivo antioxidant activity utilizing serum catalase level (CAT) were studied in alloxan-diabetic mice. The high doses significantly lowered glucose level and increased serum CAT in alloxan-diabetic mice. Pretreatment with the extract prior to alloxination, protected the mice from acquiring diabetes and diabetic neuropathy. Treatment with the extract for 8 weeks alleviated hyperalgesia in diabetic mice. Our findings provide clinicians with promising drugs intended for the management of the symptoms of diabetic complications. The protective activity of R. ribes against acquiring diabetes and diabetic neuropathy might pave the way for preparing a prophylactic treatment for diabetes risk groups., (© 2014. The Pharmaceutical Society of Korea.)

Aims: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D., Methods: Pilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period., Results: Forty-five T2D participants on metformin monotherapy (mean age 57 ± 8 years, duration 7 ± 6 years, HbA1c 7.8 ± 1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride., Conclusions: Short term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN., Clinical Trial Registration: NCT02973477., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It well known that long-lasting hyperglycaemia disrupts neuronal function and leads to neuropathy and other neurodegenerative diseases. The α-ketoglutarate analogue (DMOG) and the caspase-inhibitor "Ac-LETD-CHO are potential neuroprotective molecules. Whether their protections may also extend glucotoxicity-induced neuropathy is not known. Herein, we evaluated the possible cell-protective effects of DMOG and Ac-LETD-CHO against hyperglycaemia-induced reactive oxygen species and apoptosis in ND7/23 neuronal cells. The impact of glucotoxicity on the expression of HIF-1α and a panel of micro-RNAs of significance in hyperglycaemia and apoptosis was also investigated.ND7/23 cells cultured under hyperglycaemic conditions showed decreased cell viability and elevated levels of ROS production in a dose- and time-dependent manner. However, presence DMOG (500 µM) and/or Ac-LETD-CHO (50 µM) counteracted this effect and increase cell viability concomitant with reduction in ROS production, DNA damage and apoptosis. AcLETD-CHO suppressed hyperglycaemia-induced caspase 3 activation in ND7/23 cells. Both DMOG and Ac-LETD-CHO increased HIF-1α expression paralleled with the suppression of miR-126-5p, miR-128-3p and miR-181 expression and upregulation of miR-26b, 106a-5p, 106b-5p, 135a-5p, 135b-5p, 138-5p, 199a-5p, 200a-3p and 200c-3p expression.We demonstrate a mechanistic link for the DMOG and Ac-LETD-CHO protection against hyperglycaemia-induced neuronal dysfunction, DNA damage and apoptosis and thereby propose that pharmacological agents mimicking these effects may represent a promising novel therapy for the hyperglycaemia-induced neuropathy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.

Background: Cardiac autonomic neuropathy is a common complication of type 2 diabetes mellitus (T2DM), that can be measured through heart rate variability (HRV)-known to be decreased in T2DM. Physical exercise can improve HRV in healthy population, however results are under debate in T2DM. We conducted a systemic review and meta-analysis to assess the effects of physical exercise on HRV in T2DM patients., Method: PubMed, Cochrane, Embase, and ScienceDirect databases were searched for all studies reporting HRV parameters in T2DM patients before and after exercise training, until September 20th 2020, without limitation to specific years. We conducted random-effects meta-analysis stratified by type of exercise for each of the HRV parameters: RR-intervals (or Normal to Normal intervals-NN), standard deviation of RR intervals (SDNN), percentage of adjacent NN intervals varying by more than 50 milliseconds (pNN50), root mean square of successive RR-intervals differences (RMSSD), total power, Low Frequency (LF), High Frequency (HF) and LF/HF ratio. Sensitivity analyses were computed on studies with the highest quality., Results: We included 21 studies (9 were randomized) for a total of 523 T2DM patients: 472 had an exercise training and 151 were controls (no exercise). Intervention was endurance (14 studies), resistance (2 studies), endurance combined with resistance (4 studies), and high intensity interval training (HIIT) (4 studies). After exercise training, all HRV parameters improved i.e. an increase in SDNN (effect size = 0.59, 95%CI 0.26 to 0.93), RMSSD (0.62, 0.28 to 0.95), pNN50 (0.62, 0.23 to 1.00), HF (0.58, -0.16 to 0.99), and a decrease in LF (-0.37, -0.69 to -0.05) and LF/HF (-0.52, -0.79 to -0.24). There were no changes in controls. Stratification by type of exercise showed an improvement in most HRV parameters (SDNN, RMSSD, pNN50, LF, HF, LF/HF) after endurance training, whereas mostly LF/HF was improved after both resistance training and HIIT. Supervised training improved most HRV parameters. Duration and frequency of training did not influence the benefits on HRV., Conclusion: Exercise training improved HRV parameters in T2DM patients which may reflect an improvement in the activity of the autonomic nervous system. The level of proof is the highest for endurance training. Supervised training seemed beneficial., Competing Interests: The authors have declared that no competing interests exist.

High glucose (HG)-induced nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome activation leads to diabetic neuropathic pain. We recently showed that salidroside could suppress NLRP3 inflammasome activation in hepatocytes exposed to HG. The aim of this study was to evaluate the analgesic effect of salidroside on diabetic rats and to explore its underlying mechanisms. Rat models with diabetic neuropathic pain were induced by high-fat diet feeding combined with low dose streptozotocin injections. Doses of salidroside at 50 and 100 mg.kg -1 .day -1 were administered by gavage to diabetic rats for 6 weeks. Mechanical allodynia test, thermal hyperalgesia test and biochemical analysis were performed to evaluate therapeutic effects. Primary dorsal root ganglion (DRG) cells exposed to HG at 45 mM were used to further study the effects of salidroside on the AMP-activated protein kinase (AMPK)-NLRP3 inflammasome axis and insulin sensitivity in vitro. Salidroside administration improved hyperglycemia, ameliorated insulin resistance, and alleviated neuropathic pain in diabetic rats. Moreover, salidroside induced AMPK activation and suppressed NLRP3 inflammasome activation in the DRGs of diabetic rats. In addition, salidroside treatment relieved oxidative stress, improved insulin sensitivity and regulated the AMPK-NLRP3 inflammasome axis in HG-treated DRGs in vitro. Furthermore, AMPK inhibition in vivo or AMPK silencing in vitro abolished the beneficial effects of salidroside on diabetic neuropathic pain. Together, these results indicate that salidroside alleviates diabetic neuropathic pain through its regulation of the AMPK-NLRP3 inflammasome axis in DRGs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diabetic neuropathy serves as a major complication for diabetic patients across the world. The use of effective treatment is integral for reducing the health complications for diabetic patients. This study has evaluated the carvedilol potential neuroprotective effect on diabetic neuropathy. An in vitro model of diabetic neuropathy was used, including dorsal root ganglia (DRG) that were cultured from male adult mice C57BL. These were incubated for about twenty-four hours in high glucose (HG) media (45 mM). Some cells were incubated with carvedilol (10  μ M). Neuronal viability, neuronal morphology, and activating transcription factor 3 (AFT3) were measured. The cell viability was decreased, along with neuronal length, soma area, and soma perimeter with HG media. Also, there was an overexpression of ATF3, which is a neuronal stress response marker. The pretreatment with carvedilol increased the viability of DRG as compared to HG-treated cells. Also, it significantly protected the DRG from HG-induced morphology changes. Though it shows a decrease in AFT3 expression, the statistical results were insignificant. The current study demonstrates the neuroprotective effect of carvedilol against HG-induced DN using an in vitro model. This could be through carvedilol antioxidant effects., Competing Interests: The author declares that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Rania M. Magadmi et al.)

Bupivacaine (Bup) has a certain research basis in pain-related diseases, but it has not been studied in painful diabetic neuropathy. In this study, we investigated the role of Bupivacaine in painful diabetic neuropathy. Mouse model with painful diabetic neuropathy was established, and then treated with different concentrations of Bupivacaine. The blood glucose level in the tail vein and the changes in body weight was measured. The mechanical allodynia, thermal hyperalgesia and thermal allodynia was assessed by pain behavioral tests. Microglia were treated with high glucose (HG) and different concentrations of Bupivacaine. The levels of inflammatory cytokines were detected by using Enzyme-linked immunosorbent assays. Dual luciferase reporter assay explored the relationship between miR-23a and phosphodiesterase 4 B (PDE4B). The results displayed that Bupivacaine ameliorated the mechanical allodynia, thermal hyperalgesia, and thermal allodynia in mice with painful diabetic neuropathy, and is more effective at low concentration. Moreover, low concentration of Bupivacaine inhibited inflammation and promoted miR-23a expression in mice with painful diabetic neuropathy and in microglia induced by HIGH GLUCOSE. Overexpression of miR-23a reduced the levels of inflammatory cytokines by down-regulating PDE4B expression. Knockdown of miR-23a reversed the inhibition effect of Bupivacaine on microglial inflammation. These results revealed that low concentration of Bupivacaine inhibited microglial inflammation through down-regulating PDE4B via miR-23a, thereby attenuated painful diabetic neuropathy., (Copyright © 2020. Published by Elsevier B.V.)

Alpha-lipoic acid (ALA) is a substantial antioxidant in the prevention of diabetes and diabetes complications. It can regenerate other antioxidants like vitamin E, vitamin C, Coenzyme Q10 and glutathione and is often known as a universal antioxidant. Antioxidants play a role in diabetes treatment due to hyperglycemia-induced stimulation of the polyol pathway and formation of advanced glycation end products (AGE) and reactive oxygen species (ROS). Clinical trials examining alpha-lipoic acid supplementation on diabetic neuropathy, nephropathy, cardiomyopathy and erectile dysfunction display positive results, particularly in pain amelioration in neuropathy, asymmetric dimethylarginine reductions in nephropathy and improved oscillatory potential and contrast sensitivity in retinopathy. In diabetic cardiomyopathy (DCM), ALA offers protection through inhibition of NF-kB activation, reduction of fas-ligand and decrease in matrix metalloproteinase-2. This comprehensive review summarises and provides an understanding of the importance of alpha- lipoic acid supplementation to prevent diabetes complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin-induced diabetic rats., Methods: In total, 112 adult Sprague-Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot-plate) and mechanical (tail-pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy., Results: After 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect ( P  < .001) in reducing blood glucose levels and showed increased hot-plate and tail-flick latencies compared with the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated ( P  < .001)., Conclusions/interpretations: These data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: Painful diabetic neuropathy (PDN) is a common complication secondary to diabetes mellitus. Nav1.8 is an isoform of voltage-gated sodium channels and its expression regulation is closely related with PDN. MicroRNA-145 (miR-145) is involved in the occurrence and development of neuropathic pain. TargetScan software has revealed that Nav1.8 (SCN10A) is the major target of miR-145. However, its function between miR-145 and Nav1.8 in PDN is unknown., Objectives: We aim to explore the regulatory effect of miR-145 on the expression and function of Nav1.8, which plays a pivotal role in precluding the advancement of neuropathic mechanical hyperalgesia in diabetic pain., Study Design: An experimental, animal study., Setting: An animal research facility at Nanjing Maternal and Child Health Institute, China., Methods: The paw mechanical withdrawal threshold (PMWT) of rats was assessed with the von Frey test. The adverse regulation of Nav1.8 by miR-145 was confirmed by a dual luciferase detection system in HEK293T cells. The mRNA level and expression of Nav1.8 in dorsal root ganglion (DRG) neurons were assessed with real-time polymerase chain reaction (real-time PCR), western blotting and immunofluorescence assays following intrathecal injection of agomiR-145 in vitro and in vivo. Whole-cell patch-clamping was applied to assess alterations in the tetrodotoxin-resistant (TTX-R) sodium current (Nav1.8) in DRGs., Results: The PMWT was significantly decreased in rats following streptozotocin (STZ) injection on Day 7 and was maintained at a lower level on Day 28; this change was accompanied by changes in the expression of Nav1.8 in DRG neurons, which was increased 3 days after STZ injection and reached a maximal level on Day 14. The early knockdown of Nav1.8 with siRNA or agomiR-145 treatment on Day 8 effectively precluded the deterioration of pain behaviors in STZ-treated rats. The luciferase intensity was significantly decreased in HEK293T cells expressing wild-type SCN10A infected with miR-145 mimic. In addition, Nav1.8 overexpression was significantly repressed via overexpression of miR-145 in cultured DRG neurons, and neuronal hyperexcitability was concomitantly decreased. Furthermore, the intrathecal administration of agomiR-145 elicited a significant decrease in Nav1.8 expression in DRG neurons from STZ-treated rats on Day 14., Limitations: The causes of PDN are likely to be multifactorial and inflammatory markers, such as IL-6, IL-2, and TNF-?, are elevated in hyperglycemia and might be the precipitating factors that contribute to miR-145 dysregulation. The curative effect of miR-145 upregulation in reversal of pain behaviors at the stage of well-established PDN wasn't investigated in this study., Conclusion: Early infection with a lentiviral vector overexpressing miR-145 adversely regulated the expression and function of TTX-resistant Nav1.8 and abrogated the development of PDN. Therefore, miR-145 might be a potential therapeutic target for preventing PDN in the near future.