Patients with Diabetic Kidney Disease (DKD) suffer from various complications of diabetes mellitus, including autonomic neuropathy. Cardiac autonomic nervous system dysfunction is a common disorder in patients with diabetes mellitus and Chronic Kidney Disease (CKD), and is associated with an increased risk of arrhythmias and cardiovascular morbidity and mortality. Although the effects of exercise training have been thoroughly studied in different patient populations with CKD or diabetes mellitus, few studies have investigated the effects of exercise on cardiac autonomic nervous system activity in patients with DKD. This narrative review aims to summarize the evidence regarding the effects of exercise training on cardiac autonomic nervous system modulation in DKD patients.

Cardiac autonomic neuropathy (CAN) is a significant complication in chronic kidney disease (CKD), leading to increased morbidity and mortality. Early detection is essential for managing CKD patients effectively, especially those on hemodialysis. This study evaluated the prevalence CAN in CKD and diagnostic accuracy of Bellavere's Score in predicting CAN in CKD patients, including those undergoing hemodialysis.

This prospective observational study included 200 CKD patients. Cardiac autonomic neuropathy was assessed using Bellavere's Score, calculated through a series of autonomic function tests including heart rate variability and blood pressure responses. Bellavere's Score was measured pre-and post-dialysis in hemodialysis patients. The diagnostic performance of the score was evaluated using receiver operating characteristic (ROC) curves to determine sensitivity, specificity, and likelihood ratios.

Among the patients, 60% were diagnosed with CAN, with 35% having early CAN and 24% severe CAN. Bellavere's Score showed high diagnostic accuracy across CKD stages, with sensitivity ranging from 75 to 89.29% and specificity from 69.09 to 96%. In CKD stage III patients, the sensitivity was 78.57% and specificity 91.4%. In stage V, sensitivity increased to 89.29%, though specificity dropped to 69.09%. For hemodialysis patients, Bellavere's Score exhibited a sensitivity of 79.78% and specificity of 79.28%. The prevalence of CAN decreased significantly from 79.8% pre-dialysis to 64% post-dialysis (p < 0.01).

Bellavere's Score provides a reliable and non-invasive approach for diagnosing CAN in CKD patients, with strong diagnostic performance across different disease stages and in hemodialysis. Larger studies are warranted to further validate its utility.

Cardiovascular autonomic neuropathy (CAN) and inflammation predict more severe outcomes in type 1 diabetes (T1D). However, the link between CAN and inflammation in T1D remains unclear. We examined associations between CAN measures and inflammatory biomarkers in individuals with T1D.

In a cross-sectional study, we measured cardiovascular autonomic reflex tests and heart rate variability (established CAN measures) and a panel of 39 inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), in T1D participants of the TINSAL-T1DN (Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy) trial (n=57, discovery), and the PERL (Preventing Early Renal Loss in Diabetes) trial (n=468, validation). Amongst 39 inflammatory biomarkers measured in TINSAL-T1DN, suPAR levels had the strongest negative correlations with CAN measures: expiration/inspiration (r=-0.48), Valsalva (r=-0.28), 30:15 (r=-0.37), SD of the normal RR interval (r=-0.37), and root mean square of differences of successive RR intervals (r=-0.31) (all P<0.05). Findings were validated in PERL. In unadjusted analyses, median suPAR levels significantly differed between the lowest and highest SD of the normal RR interval tertiles (3.79 versus 3.12 ng/mL, P<0.001) and root mean square of differences of successive RR intervals (3.76 versus 3.17 ng/mL, P<0.001). After adjusting for covariates (age, sex, hemoglobin A1c, and estimated glomerular filtration rate), median suPAR values remained significantly elevated in the lowest tertiles of SD of the normal RR interval (P=0.004) and root mean square of differences of successive RR intervals (P=0.006).

Amongst several inflammatory biomarkers, suPAR, an immune-mediated glycoprotein, has a singular association with CAN measures. The potential of targeting suPAR as a disease-modifying approach for CAN in T1D warrants further exploration.

URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02936843, NCT02017171.

Diabetic nephropathy, as a severe microvascular complication of diabetes, manifests in four clinical types: classic, albuminuria regression, a rapid decline in kidney function (RDKF), and non-proteinuric or non-albuminuric DKD. Rapidly progressive diabetic nephropathy advances to end-stage renal disease more swiftly than the typical form, posing significant risks. However, a comprehensive understanding of rapidly progressive diabetic nephropathy is currently lacking. This article reviewed latest developments in genetic and clinical risk factors associated with rapidly progressive diabetic nephropathy, aiming to broad perspectives concerning the diagnosis and interventions of this condition.

Cardiovascular autonomic neuropathy (CAN) is known to affect patients with diabetes mellitus (DM) and cause adverse renal outcomes. We aimed to analyze the association between CAN and diabetic kidney disease (DKD).

We enrolled 254 DM patients (mean age, 56.7 ± 15.2 years; male: female ratio, 1.17:1) with 19 (7.5%) type 1 DM patients and 235 (92.5%) type 2 DM patients. All patients had undergone cardiovascular autonomic function tests between January 2019 and December 2021 in a tertiary hospital in Korea. Cardiovascular autonomic neuropathy was categorized as normal, early, or definite after measuring three heart rate variability parameters. Diabetic kidney disease refers to a persistently elevated urinary albumin-creatinine ratio (uACR ≥30 mg/g) or reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2). Logistic and Cox regression analyses were performed.

Patients with elevated uACR (n=107) and reduced eGFR (n=32) had a higher rate of definite CAN. After adjusting for covariates, definite CAN was associated with elevated uACR (OR=2.4, 95% CI 1.07-5.36) but not with reduced eGFR (OR=3.43, 95% CI 0.62-18.90). A total of 94 patients repeated uACR measurements within 2 years (mean follow-up, 586.3 ± 116.8 days). Both definite and early CAN were independent risk factors for elevated uACR (HR=8.61 and 8.35, respectively; both p<0.05). In addition, high-density lipoprotein cholesterol, ACE inhibitors/angiotensin receptor blockers and glucagon-like peptide-1 receptor agonists were independent protective factors for elevated uACR (HR=0.96, 0.25, and 0.07, respectively; all p<0.05).

Cardiovascular autonomic neuropathy is a potential indicator of DKD. Comprehensive management of DKD in the early stages of CAN may prevent microalbuminuria.

Cardiac autonomic neuropathy (CAN) is a severe complication of type 1 diabetes mellitus (T1DM). This meta-analysis aimed to synthesize relevant literature on the prevalence of CAN and its risk factors in individuals with T1DM.

We screened relevant literature from databases based on predefined search criteria until June 28, 2022. Data extraction and quality assessment were conducted independently by two reviewers. A meta-analysis was conducted to determine the prevalence of CAN and its risk factors in individuals with T1DM using a random-effects model. A subgroup analysis was conducted to assess variations in CAN prevalence based on diabetes duration, diagnostic criteria, study quality, study design, and geographic region of the participants.

A total of 21 studies provided information on the prevalence of CAN, while 18 studies explored the potential risk factors for CAN. The overall estimated prevalence of CAN in individuals with T1DM was 25.8% (95% confidence interval (95% CI): 0.208-0.307), with no significant differences observed among the five regions. Additionally, smoking, lipid abnormalities, hypertension, duration of diabetes, increased body mass index, elevated glycated haemoglobin concentrations, and presence of chronic complications of diabetes, such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy, were associated with a higher prevalence of CAN in individuals with diabetes.

CAN is prevalent in individuals with T1DM worldwide. Efforts should be made to improve early screening and intervention for CAN, as well as to implement strategies aimed at improving or controlling early risk factors associated with CAN.

Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes.

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.

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.

Impaired kidney function and albuminuria are associated with increased risk of heart failure (HF) in patients with type 2 diabetes (T2D). We investigated whether rapid kidney function decline over time is an additional determinant of increased HF risk in patients with T2D, independent of baseline kidney function, albuminuria, and other HF predictors.

Included in the study were 7,539 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with baseline urinary albumin-to-creatinine ratio (UACR) data, who had completed 4 years of follow-up and had ≥ 3 eGFR measurements during that period (median eGFR/year = 1.9, IQR 1.7-3.2). The association between rapid kidney function decline (eGFR loss ≥ 5 ml/min/1.73 m2/year) and odds of HF hospitalization or HF death during the first 4 years of follow-up was estimated by logistic regression. The improvement in risk discrimination provided by adding rapid kidney function decline to other HF risk factors was evaluated as the increment in the area under the Receiving Operating Characteristics curve (ROC AUC) and integrated discrimination improvement (IDI).

Over 4 years of follow-up, 1,573 participants (20.9%) experienced rapid kidney function decline and 255 (3.4%) experienced a HF event. Rapid kidney function decline was associated with a ~ 3.2-fold increase in HF odds (3.23, 95% CI, 2.51-4.16, p < 0.0001), independent of baseline CVD history. This estimate was not attenuated by adjustment for potential confounders, including eGFR and UACR at baseline as well as at censoring (3.74; 95% CI 2.63-5.31). Adding rapid kidney function decline during follow-up to other clinical predictors (WATCH-DM score, eGFR, and UACR at study entry and end of follow-up) improved HF risk classification (ROC AUC = + 0.02, p = 0.027; relative IDI = + 38%, p < 0.0001).

In patients with T2D, rapid kidney function decline is associated with a marked increase in HF risk, independent of starting kidney function and/or albuminuria. These findings highlight the importance of serial eGFR measurements over time to improve HF risk estimation in T2D.

Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.

The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.

Heart failure is the most common cardiovascular complication of chronic kidney disease (CKD) and foreshadows a high morbidity and mortality rate. Baroreflex impairment likely contributes to cardiovascular mortality. We aimed to study the associations between CKD, heart failure, and baroreflex sensitivity (BRS) and their association with cardiovascular outcomes.

We retrospectively analyzed data from a cohort of 247 individuals with moderate to severe HF. All subjects underwent BRS measurements after intravenous phenylephrine along with electrocardiography, echocardiography, and laboratory measurements. We used logistic regression models to assess the association of CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m²) with BRS using iterative models. Cox proportional hazards models were used to assess associations of binary BRS and subgroups according to categorizations of CKD and BRS with cardiovascular mortality.

Median eGFR among individuals with CKD was 52 (IQR 44-56) ml/min per 1.73 m². eGFR was lower in those with depressed BRS (65 [IQR 54-76] ml/min per 1.73 m²) compared with those with preserved BRS (73 [IQR 64-87] ml/min per 1.73 m²; P≤0.001). The majority of individuals with CKD had depressed BRS compared with those without CKD (60% versus 29%; P=0.05). In regression models, CKD and BRS were independently associated. Cardiovascular mortality was significantly increased in individuals with or without CKD and depressed BRS compared with those with preserved BRS and CKD.

Cardiac BRS is depressed in patients with mild to moderate CKD and HF and associated with cardiovascular mortality. Additional study to confirm its contribution to cardiovascular mortality, particularly in advanced CKD, is warranted.

The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers.

The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development.

This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes.

This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Cardiac autonomic neuropathy (CAN) may contribute to vascular complications in diabetes. We hypothesized that adolescents with CAN are at greater risk of diabetic retinopathy and early kidney dysfunction.

In this prospective longitudinal study of 725 adolescents with type 1 diabetes without retinopathy and albuminuria at baseline, early CAN was defined as one or more abnormalities in seven heart rate tests derived from a 10-min electrocardiogram. Retinopathy was defined as the presence of one or more microaneurysms, early kidney dysfunction as an albumin excretion rate (AER) >7.5 μg/min, and albuminuria as an AER >20 μg/min. Multivariable generalized estimating equations were used to examine the association between CAN and retinopathy or early kidney dysfunction. Cox proportional hazards regression analysis was used to assess cumulative risks of incident retinopathy and albuminuria.

At baseline, the mean age of the sample was 13.6 ± 2.6 years, 52% were male, and mean diabetes duration was 6.1 ± 3.3 years. Over a median follow-up of 3.8 (interquartile range 2.2-7.5) years, the complication rate 27% for retinopathy, 16% for early kidney dysfunction, and 3% for albuminuria. The mean study HbA1c was 72.3 ± 16 mmol/mmol (8.6 ± 1.4%). CAN predicted incident retinopathy (odds ratio 2.0 [95% CI 1.4, 2.9]) and early kidney dysfunction (1.4 [1.0, 2.0]) after adjusting for HbA1c and diabetes duration. CAN also predicted retinopathy (hazard ratio 1.57 [95% CI 1.09, 2.26]) and albuminuria (2.30 [1.05, 5.04]) independently of HbA1c.

CAN predicted incident retinopathy and kidney dysfunction in adolescents with type 1 diabetes, likely reflecting autonomic microvascular dysregulation contributing to complications. Therefore, screening and interventions to reduce CAN may influence the risk of complications.

The aim of the study was to identify the demographic and clinical features in an urban cohort of people with type 1 diabetes who developed a ≥50% decline in estimated glomerular filtration rate (eGFR).

We evaluated 5,261 people with type 1 diabetes (51% female, 13.4% African Caribbean) with baseline eGFR >45 mL/min/1.73 m2 between 2004 and 2018. The primary end point was an eGFR decline of ≥50% from baseline with a final eGFR <30 mL/min/1.73 m2. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

Of the cohort, 263 (5%) reached the primary end point. These individuals were more likely to be of African Caribbean ethnicity, be older, have a longer duration of diabetes, have higher systolic blood pressure and HbA1c, have more prevalent retinopathy, and have higher albuminuria (all P < 0.05). In multivariable Cox regression models, African Caribbean ethnicity emerged as a significant risk factor for the primary end point (hazard ratio 1.57, 95% CI 1.19, 2.08) compared with other ethnicities and independent of established risk factors (P < 0.01). The incidence rate for the primary end point in African Caribbean people was double that in non-African Caribbean people (16 vs. 7.7 per 1000 patient-years, P < 0.001). A similar significant independent impact of African Caribbean ethnicity for secondary end points (≥40% and ≥30% fall in eGFR) was observed.

We report a novel observation that African Caribbean ethnicity increased the risk of kidney function loss in people with type 1 diabetes, an effect that was independent of traditional risk factors. Further studies are needed to examine the associated pathophysiology that may explain this observation.

This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.

Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum metabolites and CAN in persons with type 1 diabetes (T1D).

Cardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders.

Participants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA_1c 63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4-deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p<0.05). Upon adjustment, positive associations with the CAN diagnoses were retained for hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, citric acid, and phenols (P<0.05).

Metabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives are associated with the CAN diagnosis in T1D. These pathway may be part of the pathogeneses leading to CAN and may be modifiable risk factors for the complication.

Evidence on the relationship between heart rate variability (HRV) and albumin-to-creatinine ratio (ACR) combined with estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus (T2DM) is rare. Thus, this study aimed to investigate the relationship between heart rate variability and the risk of diabetic kidney disease (DKD) progression in diabetes patients.

Overall, 747 T2DM patients who were admitted to the Second Affiliated Hospital of Nanchang University underwent 24-hour dynamic electrocardiograms for HRV analysis. Time-domain HRV measures included mean heart rate, standard deviation of the R-R interval (SDNN), SDNN index, root mean squared difference of successive RR intervals (RMSSD), and percent of adjacent RR intervals with a difference greater than 50 ms (PNN50). Frequency-domain measures included low frequency (LF), very low frequency (VLF), high frequency (HF) components and LF-to-HF ratio. The risk of DKD progression was determined by combining ACR and eGFR and stratified as low risk (Group A), moderately increased risk (Group B), high risk (Group C), and very high risk (Group D) based on the Kidney Disease: Improving Global Outcomes guidelines.

There were significant differences in HRV parameters among the four risk groups (SDNN: 113 ms vs 109 ms vs 101 ms vs 81 ms, P<0.01; LF: 240.2 ms² vs 241.1 ms² vs 155.2 ms² vs 141.9 ms², P<0.01; LF-to-HF ratio: 1.70 vs 1.24 vs 1.12 vs 0.93, P<0.01; VLF: 723.7 ms² vs 601.1 ms² vs 446.4 ms² vs 356.3 ms², P<0.01). A very high risk of DKD progression was significantly associated with a lower SDNN (β=-19.5, 95% CI: -30.0 to -10.0, P<0.01), and moderately increased, high, and very high risks were associated with lower LF-to-HF ratio and VLF (P<0.05). Logistic regression analysis showed that group D had a higher risk of reduced SDNN, LF-to-HF ratio, and VLF compared with group A after adjusting for systolic blood pressure, glycated haemoglobin, haemoglobin, high-density lipoprotein cholesterol, and age (odds ratio (95% CI): 0.989 (0. 983-0.996), 0.674 (0.498-0.913), and 0.999 (0.999-1.000), respectively).

Cardiac autonomic dysfunction is associated with a risk of DKD progression in adults with T2DM, and reduced heart rate variability increased such risk. Thus, HRV screening may be necessary in patients with T2DM, especially those with high proteinuria.

We investigated the association between cardiovascular autonomic neuropathy (CAN) and decline in kidney function in type 1 diabetes.

We included 329 persons with type 1 diabetes. CAN was assessed by cardiovascular reflex tests (CARTs): heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuvre. Two or more pathological CARTs defined CAN diagnosis. Outcomes were yearly change in albuminuria or yearly change in estimated glomerular filtration rate (eGFR). An endpoint of eGFR decline >30%, development of end-stage kidney disease (ESKD) or death was examined.Associations were assessed by linear and Cox regression.

Participants were aged 55.2 (9.4) years, 52% were male, with a diabetes duration of 40.1 (8.9) years, HbA_1c of 7.9% (62.5 mmol/mol), eGFR 77.9 (27.7) mL/min/1.73 m², urinary albumin excretion rate of 14.5 (7-58) mg/24 hours, and 31% were diagnosed with CAN.CAN was associated with a 7.8% higher albuminuria increase per year (95% CI: 0.50% to 15.63%, p=0.036) versus no CAN. The endpoint of ESKD, all-cause mortality and ≥30% decline in eGFR was associated with CAN (HR=2.497, p=0.0254).

CAN and sympathetic dysfunction were associated with increase in albuminuria in individuals with type 1 diabetes suggesting its role as a potential marker of diabetic kidney disease progression.

Cardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-β-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy.

This cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimate the severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed.

The association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; P=0.031). Total CAN score was positively associated with loguNAG (β=0.261, P=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV.

This study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.

Several nontraditional risk factors have been the focus of research in an attempt to understand the disproportionately high cardiovascular morbidity and mortality in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) populations. One such category of risk factors is cardiovascular autonomic dysfunction. Its true prevalence in the CKD/ESKD population is unknown but existing evidence suggests it is common. Due to lack of standardized diagnostic and treatment options, this condition remains undiagnosed and untreated in many patients. In this review, we discuss current evidence pointing toward the role of autonomic nervous system (ANS) dysfunction in CKD, building off of crucial historical evidence and thereby highlighting the areas in need for future research interest.

There are several key mediators and pathways leading to cardiovascular autonomic dysfunction in CKD and ESKD. We review studies exploring the mechanisms involved and discuss the current measurement tools and indices to evaluate the ANS and their pitfalls. There is a strong line of evidence establishing the temporal sequence of worsening autonomic function and kidney function and vice versa. Evidence linking ANS dysfunction and arrhythmia, sudden cardiac death, intradialytic hypotension, heart failure and hypertension are discussed.

There is a need for early recognition and referral of CKD and ESKD patients suspected of cardiovascular ANS dysfunction to prevent the downstream effects described in this review.There are many unknowns in this area and a clear need for further research.

Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short-duration type 1 diabetes. Our aims were to examine these interventions and changes in autonomic function in individuals with long-duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy.

Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter 'the combination'). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models.

Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (-1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results.

Autonomic function is improved transiently in individuals with long-duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention.

Cardiovascular autonomic neuropathy (CAN) is a common and deadly complication of diabetes mellitus, which is frequently overlooked in clinical practice due to its characteristic subtle presentation earlier in disease. Yet, timely detection of CAN may help implementation of tailored interventions to prevent its progression and mitigate the risk of associated complications, including cardiovascular disease (CVD), cardiac arrhythmias, myocardial dysfunction leading to congestive heart failure and all-cause mortality. This review highlights current CAN epidemiology trends, novel mechanisms linking CAN with other diabetes complications and current recommendations for diagnosis and management of the disease in the clinical setting.

Serum angiopoietin 2 levels have been associated with endothelial dysfunction and diabetic kidney disease. Derangements in autonomous nervous system lead to increased production of vasoconstrictory and angiogenic mediators such as norepinephrine and neuropeptide Y and are associated with increased risk of microvascular complications.

To investigate associations between angiopoietin 2, neuropeptide Y and diabetic kidney disease in patients with type 1 diabetes mellitus.

289 patients with type 1 diabetes mellitus duration > 1 year were included. Patients were stratified according to presence of diabetic nephropathy (macroalbuminuria, estimated glomerular filtration rate<60 ml/min/1.73 m² or end-stage renal disease). Angiopoietin 2 was measured by Luminex technology. Neuropeptide Y was measured by ELISA.

Patients with diabetic nephropathy had significantly increased levels of angiopoietin 2 (4020.5 (2172.4-5778.1) pg/ml vs. 2001.0 (1326.7-2862.7) pg/ml) and neuropeptide Y (18.22 (14.85-21.85) ng/ml vs. 12.91 (9.96-17.07) ng/ml). Higher levels of angiopoietin 2 and neuropeptide Y were observed also in patients with arterial hypertension. Angiopoietin 2 and neuropeptide Y correlated significantly (ρ=0.245, p<0.001). Both biomarkers were significant predictors of estimated glomerular filtration rate and diabetic nephropathy in univariate regression models. In the fully adjusted regression models and after application of a stepwise selection regression method, angiopoietin 2 demonstrated a stronger predictive power for diabetic nephropathy compared to neuropeptide Y.

Diabetic nephropathy is associated with increased serum concentrations of angiopoietin 2 (marker of endothelial dysfunction) and neuropeptide Y (marker of sympathetic activity) in type 1 diabetes. Angiopoietin 2 is a more potent predictor of diabetic nephropathy compared to neuropeptide Y.

While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA_1c 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels-asparagine and glutamine-correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA_1c, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.

Nondipping heart rate (NHR) is a condition reported to be associated with cardiovascular events and cardiovascular mortality recently. We aimed to search whether there is difference among hypertensive patients with and without chronic kidney disease (CKD) in terms of NHR pattern and the factors associated with NHR in patients with CKD.

The study included 133 hypertensive patients with normal kidney functions, 97 hypertensive patients with predialysis CKD, and 31 hypertensive hemodialysis patients. Heart rate, blood pressure and pulse wave velocity (PWV) were measured by 24-h ambulatory blood pressure monitorization. NHR was defined as a decrease of less than 10% at night mean heart rate when compared with daytime values.

NHR pattern was established as 26.3% in non-CKD hypertensive group, 43.3% in predialysis group and 77.4% in dialysis group. Among patients with CKD, when NHR group was compared with dipper heart rate group, it was seen that they were at older age, there were higher prevalence of diabetes mellitus and more female sex, and while the value of urea, creatinine, phosphorus, intact parathyroid hormone, and PWV were significantly higher, the value of hemoglobin, albumin and calcium were significantly lower. By multivariate analysis, hemoglobin [odds ratio (OR) 0.661; 95% CI 0.541-0.806; p < 0.001] and PWV (OR 1.433; 95% CI 1.107-1.853; p = 0.006) were established as independent determinants of NHR pattern.

NHR pattern is significantly more frequently seen in hypertensive CKD patients than in hypertensive patients with non-CKD. Anemia and increased arterial stiffness are seen independently associated with NHR in CKD patients.

The aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications.

CAN was assessed in 95 patients with T1DM, aged 18-29 years, using standard cardiovascular reflex tests - heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests.

The prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A1c (HbA1c) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA1c level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, P&lt;0.001 for TP).

CAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.

The burden of diabetic cardiovascular autonomic neuropathy (CAN) is expected to increase due to the diabetes epidemic and its early and widespread appearance. CAN has a definite prognostic role for mortality and cardiovascular morbidity. Putative mechanisms for this are tachycardia, QT interval prolongation, orthostatic hypotension, reverse dipping, and impaired heart rate variability, while emerging mechanisms like inflammation support the pervasiveness of autonomic dysfunction. Efforts to overcome CAN under-diagnosis are on the table: by promoting screening for symptoms and signs; by simplifying cardiovascular reflex tests; and by selecting the candidates for screening. CAN assessment allows for treatment of its manifestations, cardiovascular risk stratification, and tailoring therapeutic targets. Risk factors for CAN are mainly glycaemic control in type 1 diabetes mellitus (T1DM) and, in addition, hypertension, dyslipidaemia, and obesity in type 2 diabetes mellitus (T2DM), while preliminary data regard glycaemic variability, vitamin B12 and D changes, oxidative stress, inflammation, and genetic biomarkers. Glycaemic control prevents CAN in T1DM, whereas multifactorial intervention might be effective in T2DM. Lifestyle intervention improves autonomic function mostly in pre-diabetes. While there is no conclusive evidence for a disease-modifying therapy, treatment of CAN manifestations is available. The modulation of autonomic function by SGLT2i represents a promising research field with possible clinical relevance.

Cardiovascular autonomic dysfunction is closely related to increased mortality in patients with diabetes. Previous studies have proved that cystatin C (CysC) is an important predictor of both peripheral neuropathy and cardiovascular events. However, whether CysC is also associated with cardiovascular autonomic dysfunction remains unclear. Therefore, the aim of this study was to investigate the relationship between CysC and cardiovascular autonomic dysfunction in type 2 diabetic patients without renal dysfunction.

A total of 161 type 2 diabetic patients with normal serum creatinine (less than 133 μmol/l) and estimated glomerular filtration rate (eGFR) higher than 60 ml/min per 1.73 m² were recruited in our study. Cardiovascular autonomic dysfunction was determined by heart rate variability (HRV) measured by a 24-hour Holter monitor. Serum CysC was tested by particle-enhanced turbidimetric immunoassay, and subjects were divided into three groups based on the tertiles of CysC. Pearson correlation analysis was used to evaluate the association between different indexes, and the association of CysC with HRV indexes was assessed by multivariate linear regression analysis.

The HRV parameters were lower in the group with the highest CysC concentration than in the groups with lower levels of CysC (P < 0.05). Pearson correlation analysis showed a negative relationship between CysC and the HRV parameters, including SDNN (r = -0.31, P < 0.001), SDANN (r = -0.25, P = 0.002), and logLF (r = -0.18, P = 0.023). Furthermore, multivariate linear regression analysis revealed that CysC was independently correlated with SDNN (β = -24.11, P = 0.015) and SDANN (β = -19.88, P = 0.047) after adjusting for the confounding factors of gender, age, blood pressure, body mass index, eGFR, and hemoglobin A1c.

Serum CysC levels are associated with cardiovascular autonomic dysfunction; furthermore, CysC may be a reliable and convenient biomarker for detecting cardiovascular autonomic dysfunction.

This review considers the relationship between abnormal blood pressure (BP) variability and autonomic dysfunction through an attempt to answer questions about its clinical relevance and pertinence to diabetes and cardiovascular autonomic neuropathy (CAN) and which therapeutic measures can lessen its cardiovascular impact.

Office, ambulatory, and home BP monitoring identify posture-related, circadian, short-term, and long-term BP variabilities. Abnormal BP variability is a risk marker for organ damage, mortality, and cardiovascular events. Moreover, BP variability changes are common in diabetes and associated with CAN and possibly exacerbated by comorbidities like nephropathy, obstructive sleep apnoea syndrome, and chronic pain. The prognostic role of nondipping and reverse dipping is well documented in diabetes. Some findings suggest the possibility of restoring dipping with the dosage time of antihypertensive agents. Diabetes is a favorable scenario for altered BP variability, which might mediate the harmful effects of CAN. Preliminary data suggest the protective effect of targeting BP variability. However, further longitudinal outcome studies are needed. In the meantime, BP variability measures and practical expedients in antihypertensive treatment should be implemented in diabetes.

IN BRIEF Distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are prevalent diabetes complications with high morbidity, mortality, and amputation risks. The diagnosis of DSPN is principally a clinical one based on the presence of typical symptoms combined with symmetrical, distal-to-proximal stocking-glove sensory loss. CAN is an independent risk factor for cardiovascular mortality, arrhythmia, silent ischemia, major cardiovascular events, and myocardial dysfunction. Screening for CAN in high-risk patients is recommended. Symptoms of gastroparesis are nonspecific and do not correspond with its severity. Diagnosis of gastroparesis should exclude other factors well documented to affect gastric emptying such as hyperglycemia, hypoglycemia, and certain medications. There is a lack of treatment options targeting the neuropathic disease state. Managing neuropathic pain also remains a challenge. Given the high risk of addiction, abuse, psychosocial issues, and mortality, opioids are not recommended as first-, second-, or third-line agents for treating painful DSPN.

Obesity is associated with an increased risk of cardiovascular morbidity in adults with diabetes.

To examine the predictive role of body mass index (BMI) and adiposity on cardiac autonomic function in childhood onset type 1 diabetes.

Two hundred and fifty-three participants with type 1 diabetes (aged 8-30 years) were assessed for diabetes complications at a tertiary hospital, and followed over 7 years (total 922 visits).

Heart rate variability (HRV) measures assessed by 10-minute electrocardiography recording using LabChart Pro were standard deviation of RR intervals, time between consecutive QRS complexes, [SDNN], root mean squared difference of successive RR intervals (RMSSD), triangular index (TI), and low to high frequency ratio [LF:HF]. Multivariable generalized estimating equations were used to model the longitudinal associations between HRV measures and clinical variables (BMI standard deviation scores [SDS], waist:height ratio, total daily insulin dose/kg (TDD) and hemoglobin A1c [HbA1c]).

At baseline, mean age was 14.4 ± 2.7 years, diabetes duration 7.1 ± 3.7 years, HbA1c 8.3% ± 1.5% (67 ± 16 mmol/mol), and 33% were overweight/obese (BMI ≥85th percentile). At final visit, mean age was 18.5 ± 2.7 years, duration 11.3 ± 3.9 years, HbA1c 9.0% ± 1.8% (75 ± 20 mmol/mol), and 40% were overweight/obese. Adiposity (higher BMI SDS or waist: height ratio) was a significant predictor of worse HRV (lower SDNN, RMSSD; P < .05), while higher HbA1c and TDD predicted all adverse HRV measures (lower SDNN, RMSSD, TI; P < .05) and abnormal sympathovagal balance (higher LF:HF ratio; P < .05).

Higher BMI and central adiposity are associated with cardiac autonomic dysfunction in childhood onset type 1 diabetes, after adjusting for HbA1c. Interventions targeting overweight/obesity during adolescence may optimize long-term vascular health in type 1 diabetes.

To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study.

The study included 1646 subjects with type 1 diabetes (age 18 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.1 ± 1.9%, 76% non-Hispanic Whites) and 252 with type 2 diabetes (age 22 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.2 ± 3.0%, 45% non-Hispanic Blacks). Cross-sectional and longitudinal risk factors were assessed at baseline and follow-up visits. Area under the curve (AUC) was used to assess the longitudinal glycemic exposure and cardiovascular risk factors. CAN was assessed by time and frequency domain indices of heart rate variability (HRV). CAN was defined as the presence of ≥3 of 5 abnormal HRV indices.

The prevalence of CAN was 12% in adolescents and young adults with type 1 diabetes and 17% in those with type 2 diabetes. Poor long-term glycemic control (AUC HbA1c), high blood pressure, and elevated triglyceride levels were correlates of CAN in subjects with type 1 diabetes. In those with type 2 diabetes, CAN was associated with elevated triglycerides and increased urinary albumin excretion.

The prevalence of CAN in this multiethnic cohort of adolescents and young adults with type 1 and type 2 diabetes are comparable to those reported in adults with diabetes. Suboptimal glycemic control and elevated triglycerides were the modifiable risk factors associated with CAN.

To compare the cardiovascular autonomic reflex tests (CARTs) with cardiac sympathetic innervation imaging with ¹²³I-metaiodobenzylguanidine (MIBG) in patients with type 1 diabetes mellitus (T1DM).

Forty-nine patients (29 males, mean age 36 ± 10 years, mean T1DM duration 19 ± 6 years) without cardiovascular risk factors were prospectively enrolled. Participants were evaluated for autonomic dysfunction by assessing the mean circular resultant (MCR), Valsalva maneuver (Vals), postural index (PI), and orthostatic hypotension (OH). Within one month from the performance of these tests, patients underwent cardiac MIBG imaging and the ratio of the heart to upper mediastinum count density (H/M) at 4 hours postinjection was calculated (abnormal values, H/M < 1.80).

Twenty-nine patients (59%) had abnormal CARTs, and 37 (76%) patients had an H/M_4 < 1.80 (p = 0.456). MCR, PI, Vals, and OH were abnormal in 29 (59%), 8 (16%), 5 (10%), and 11 (22%) patients, respectively. When using H/M_4 < 1.80 as the reference standard, a cutoff point of ≥2 abnormal CARTs had a sensitivity of 100% but a specificity of only 33% for determining CAN.

CARTs are not closely associated with ¹²³I-MIBG measurements, which can detect autonomic dysfunction more efficiently than the former. In comparison to semiquantitative cardiac MIBG assessment, the recommended threshold of ≥2 abnormal CARTs to define cardiovascular autonomic dysfunction is highly sensitive but of limited specificity and is independently determined by the duration of T1DM.