Explore the vast range of titles available.

Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identified in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiology, and might lead to serious and potentially lethal consequences in patients with diabetes, particularly in those with more advanced disease and comorbidities. Continuous glucose monitoring systems can provide real‐time glucose information and generate timely alerts on rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability and integration with insulin pump technology, continuous glucose monitoring systems are emerging as critical tools to help prevent serious hypoglycemia and mitigate its consequences in patients with diabetes. This review discusses the current knowledge on IAH and effective diagnostic methods, the relationship between hypoglycemia and cardiovascular autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neuropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use of CGM technologies in patients with type 1 diabetes with IAH. Hypoglycemia can induce hypoglycemia unawareness, which puts patients at higher risk for developing severe hypoglycemia. Hypoglycemia and its relationship with cardiovascular autonomic neuropathy are complex and remain to be further elucidated. Continuous glucose monitoring systems (CGMs) can help reduce hypoglycemia for those with hypoglycemia unawareness.

Objective To determine the associations between individual metabolic syndrome (MetS) components and peripheral neuropathy in a large population‐based cohort from Pinggu, China. Methods A cross‐sectional, randomly selected, population‐based survey of participants from Pinggu, China was performed. Metabolic phenotyping and neuropathy outcomes were performed by trained personnel. Glycemic status was defined according to the American Diabetes Association criteria, and the MetS using modified consensus criteria (body mass index instead of waist circumference). The primary peripheral neuropathy outcome was the Michigan Neuropathy Screening Instrument (MNSI) examination. Secondary outcomes were the MNSI questionnaire and monofilament testing. Multivariable models were used to assess for associations between individual MetS components and peripheral neuropathy. Tree‐based methods were used to construct a classifier for peripheral neuropathy using demographics and MetS components. Results The mean (SD) age of the 4002 participants was 51.6 (11.8) and 51.0% were male; 37.2% of the population had normoglycemia, 44.0% prediabetes, and 18.9% diabetes. The prevalence of peripheral neuropathy increased with worsening glycemic status (3.25% in normoglycemia, 6.29% in prediabetes, and 15.12% in diabetes, P < 0.0001). Diabetes (odds ratio [OR] 2.60, 95% CI 1.77–3.80) and weight (OR 1.09, 95% CI 1.02–1.18) were significantly associated with peripheral neuropathy. Age, diabetes, and weight were the primary splitters in the classification tree for peripheral neuropathy. Interpretation Similar to previous studies, diabetes and obesity are the main metabolic drivers of peripheral neuropathy. The consistency of these results reinforces the urgent need for effective interventions that target these metabolic factors to prevent and/or treat peripheral neuropathy.

Aims/Introduction Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. Materials and Methods Standardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN. Results Participants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut‐off points of ECG‐derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with CARTs‐defined CAN. Combining SDNN and rMSSD optimal cut‐off points does not provide additional predictive power for CAN. Conclusions These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care. Participants with cardiovascular reflex tests‐defined cardiovascular autonomic neuropathy (CAN) had significantly lower standard deviation of normally conducted R‐R intervals and root mean square of successive differences between normal‐to‐normal R‐R intervals compared to those without CAN (P < 0.001). standard deviation of normally conducted R‐R intervals plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistics for standard deviation of normally conducted R‐R intervals was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with cardiovascular reflex tests‐defined CAN.

IntroductionCurrent pharmacological treatment options for painful diabetic neuropathy (PDN) often fail to provide adequate pain relief. However, in the recent SENZA-PDN study, high-frequency 10 kHz spinal cord stimulation (SCS) demonstrated significant long-term improvements in lower limb pain and health-related quality of life (HRQoL) in a PDN population. Furthermore, more than half of 10 kHz SCS recipients showed improved sensory function based on non-blinded clinical assessments in post hoc analysis. We report the design of the PDN-Sensory study, which aims to evaluate changes in pain and neurological function with 10 kHz SCS in the treatment of PDN. The study will include objective measures of neurological function, including the modified Toronto Clinical Neuropathy Score (mTCNS) and intraepidermal nerve fibre density (IENFD).Methods and analysisThis multicentre, prospective, randomised controlled trial will compare conventional medical management (CMM) with 10 kHz SCS+CMM in individuals with diabetes and chronic, intractable lower limb pain due to PDN. Participants will be randomised 1:1 to CMM alone or 10 kHz SCS+CMM, with optional crossover at 6 months. The primary outcome is the proportion of participants at 6 months achieving ≥50% pain relief from baseline. The key secondary endpoint is the proportion of participants at 6 months with a reduction in mTCNS of ≥3 points from baseline (excluding changes in foot pain). Additional endpoints at 6 and 12 months include changes from baseline in mTCNS, IENFD, 7-day averaged pain score, pain-related interference, HRQoL, sleep, psychological outcomes, functional status and metabolic parameters.Ethics and disseminationThe study protocol received central approval from the Western Institutional Review Board (IRB #20230954). Local IRB approval will be required before initiation of the study at each participating clinical site. The study complies with Good Clinical Practice guidelines (ISO 14155), the Declaration of Helsinki, and all applicable national, federal and local regulatory requirements. Dissemination plans include presentations at national and international conferences and publication in a peer-reviewed journal with open access.Trial registration numberNCT05777317.

The relationship between urinary endothelial growth factor (uEGF) and cardiovascular autonomic neuropathy (CAN) in adults with type 1 diabetes was evaluated. uEGF levels at baseline and standardized CAN measures were collected at baseline and annually for 3 years for type 1 diabetes adults. Linear regression analysis and linear mixed effects model were used for analysis. In this cohort (n = 44, 59% women, mean ± standard deviation age 34 ± 13 years and diabetes duration 14 ± 6 years), lower baseline uEGF levels correlated with lower baseline expiration : inspiration ratios (P = 0.03) and greater annual declines in Valsalva ratios (P = 0.02) in the unadjusted model, and correlated with lower low‐frequency power : high‐frequency power ratios (P = 0.01) and greater annual changes in low‐frequency power : high‐frequency power ratios (P = 0.01) after adjustment for age, sex, body mass index, and hemoglobin A1C. In conclusion, baseline uEGF levels correlate to baseline and longitudinal changes in CAN indices. A large‐scale, long‐term study is needed to validate uEGF as a reliable CAN biomarker. Relationships between baseline urinary endothelial growth factor and baseline and longitudinal changes in cardiovascular autonomic neuropathy indices were observed. A large‐scale, long‐term study is needed to evaluate if urinary endothelial growth factor can serve as a reliable non‐invasive biomarker of cardiovascular autonomic neuropathy.

Diabetic neuropathies (DNs) differ in clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical type being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement. The pathogenesis of diabetic DSP is multifactorial, including increased mitochondrial production of free radicals due to hyperglycemia-induced oxidative stress. Mechanisms that impact neuronal activity, mitochondrial function, membrane permeability, and endothelial function include formation of advanced glycosylation end products, activation of polyol aldose reductase signaling, activation of poly(ADP ribose) polymerase, and altered function of the Na + /K + -ATPase pump. Hyperglycemia-induced endoplasmic reticulum stress triggers several neuronal apoptotic processes. Additional mechanisms include impaired nerve perfusion, dyslipidemia, altered redox status, low-grade inflammation, and perturbation of calcium balance. Successful therapies require an integrated approach targeting these mechanisms. Intensive glycemic control is essential but is insufficient to prevent onset or progression of DSP, and disease-modifying treatments for DSP have been disappointing. Atypical forms of DN include subacute-onset sensory (symmetric) or motor (asymmetric) predominant conditions that are frequently painful but generally self-limited. DNs are a major cause of disability, associated with reduced quality of life and increased mortality.

Diabetic peripheral and autonomic neuropathies are common complications of diabetes with broad spectrums of clinical manifestations and high morbidity. Studies using various agents to target the pathways implicated in the development and progression of diabetic neuropathy were promising in animal models. In humans, however, randomized controlled studies have failed to show efficacy on objective measures of neuropathy. The complex anatomy of the peripheral and autonomic nervous systems, the multitude of pathogenic mechanisms involved, and the lack of uniformity of neuropathy measures have likely contributed to these failures. To date, tight glycemic control is the only strategy convincingly shown to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in some patients with type 2 diabetes. Lessons learned about the role of glycemic control on distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy are discussed in this review.

We performed a cross‐sectional study to determine associations between cognition and MRI‐derived brain outcomes, with obesity, diabetes duration, and metabolic risk factors in 51 Pima American Indians with longstanding type 2 diabetes (T2d) (mean [SD] age: 48.4 [11.3] years, T2d duration: 20.1 [9.1] years). Participants had similar cognition (NIH Toolbox Cognition Battery composite: 45.3 [9.8], p  = 0.64, n  = 51) compared to normative data. T2d duration, but not other metabolic risk factors, associated with decreased cortical thickness (Point Estimate (PE): −0.0061, 95%CI: −0.0113, −0.0009, n  = 45), gray matter volume (PE: −830.39, 95%CI: −1503.14, −157.64, n  = 45), and increased white matter hyperintensity volume (PE: 0.0389, 95%CI: 0.0049, 0.0729, n  = 45).

Aims/hypothesisSmall cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP.MethodsNine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard.ResultsType 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity.Conclusions/interpretationWe established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA 1c concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A 1c [HbA 1c] of <6·0%) or standard (7·0–7·9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1·00, 95% CI 0·88–1·14; p=1·00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0·96, 0·89–1·02; p=0·19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0·95, 95% CI 0·85–1·07, p=0·42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0·95, 0·89–1·01, p=0·12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Six secondary measures at study end favoured intensive therapy (p<0·05). Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.