Diabetic Cardiac Autonomic Neuropathy Research Articles

542-P: Association of Cardiac Autonomic Dysfunction with Plasma Lipid Metabolites in Recent-Onset Type 2 Diabetes

Emerging evidence suggests that obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterized by reduced heart rate variability (HRV). In this context we assessed the relationship of 127 biomarkers of lipid metabolism (11 acylcarnitines, 39 free fatty acids, 12 sphingomyelins, 56 phosphatidylcholines, and 9 lysophosphatidylcholines) in plasma using mass spectrometry with HRV indices in individuals with recent-onset type 1 (T1D) or type 2 diabetes (T2D) from the baseline cohort (known diabetes duration (DD) ≤1 year) of the German Diabetes Study (T1D/T2D [mean±SD]: n=126/243; age: 34.5±12.9/53.4±11.0 years; BMI: 24.7±4.3/31.7±6.0 kg/m²; DD: 211±93/198±90 days; HbA1c: 6.8±1.4/6.5±0.9 %). Time domain and frequency domain HRV indices were derived from NN intervals recorded during a 3 h hyperinsulinemic-euglycemic clamp. After adjustment for age, sex, and BMI as well as Bonferroni correction including seven HRV parameters and the number of metabolites of the corresponding lipid class, higher levels of three free fatty acids (myristic acid: β=-0.14, p=0.049; palmitic acid: β=-0.19, p=0.007; palmitoleic acid: β=-0.15, p=0.048), eight phosphatidylcholines (e.g., phosphatidylcholine diacyl (PC aa) C32:0: β=-0.28, p<0.001; phosphatidylcholine acyl-alkyl C34:3: β=-0.20, p<0.004), and two sphingomyelins (sphingomyelin C16:0: β=-0.15, p=0.028; sphingomyelin C16:1: β=-0.18, p=0.020) were inversely associated with the standard deviation of NN intervals (SDNN) in recent-onset T2D but not T1D. PC aa C32:0 was inversely associated with both low (LF) and high frequency (HF) power spectrum in T2D (LF: β=-0.23, p=0.001; HF: β=-0.23, p=0.001). In conclusion, the link between higher plasma levels of specific lipid metabolites and early cardiac autonomic dysfunction in recent-onset type 2 diabetes suggests that plasma lipid panels could be useful to improve the prediction of the development or progression of CAN. Disclosure G.J. Bönhof: None. A. Strom: None. K. Strassburger: None. B. Knebel: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. O.P. Zaharia: None. Y. Karusheva: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. D. Ziegler: None.

Worsening Cardiac Autonomic Neuropathy on Progression to Type 2 Diabetes: Localized vs. Systemic Inflammation

Cardiac autonomic neuropathy (CAN) occurs early in the course of diabetes with significant cardiovascular risks. While linked to hyperglycemia, current understanding extends CAN development to pre‐diabetes. The instigating cause of CAN, its temporal progression, and responsiveness to treatment remain ill‐defined. Here, we used a rat model of mild metabolic challenge with delayed development of hyperglycemia to trace these parameters in different disease stages.Male Sprague Dawley rats (5–6 weeks old) were fed a mild hypercaloric diet (4.035 vs. 3 KCal/g) leading to hyperinsulinemia after 12 weeks, representing the prediabetic stage. Type 2 diabetes was induced by two consecutive injections of low‐dose streptozotocin (40 mg/kg) at weeks 8 and 9. Drug treatment (metformin 100 mg/Kg/day, pioglitazone 2.5 mg/Kg/day, insulin titrated to control glucose levels, or their combination) was started at week 10. CAN was assessed by estimating baroreceptor sensitivity using the vasoactive method. ELISA, immunohistochemistry, and western blotting were used to examine markers of structural deterioration, inflammation, and autophagy in serum, heart, and brainstem.CAN was detected in the prediabetic state as blunted bradycardic reflex to phenylephrine stimulation reflected by a decrease in the slope of the DMAP vs. DHR line. It progressed with the transition to diabetes to further parasympathetic deterioration and de novo sympathetic insult. Interestingly, diabetic sympathetic dysfunction was readily reversed by insulin treatment. While prediabetic parasympathetic dysfunction responded to treatment with non‐hypoglycemic, anti‐inflammatory doses of metformin or pioglitazone, this was not the case in diabetic rats. Worsened parasympathetic function in diabetic rats was only restored by combination treatments, with insulin and Met/Pio. Notably, whereas prediabetic dysfunction was associated with localized perivascular adipose inflammation, the exaggerated CAN observed in diabetes was accompanied by significant systemic inflammation manifesting as elevated serum IL‐1b levels. This was concomitant with centralization of inflammation presenting in the brainstem along with microglial activation and autophagy suppression. Significantly, only combination treatment produced a considerable decrease in serum IL‐1b, consistent with their corrective effect on CAN in diabetes. Moreover, hyperglycemic rats showed signs of focal cardiac ischemia and left ventricular dysfunction which were ameliorated with combination treatments. In a cellular framework, we showed that systemic inflammation, rather than metabolic stress, induced neuronal damage. Differentiated PC12 cells simulating sympathetic neurons only replicated the central manifestations observed in diabetic rats when exposed to diabetic rat serum as opposed to the altered serum insulin, glucose, and lipid levels.Our results highlight a temporal framework whereby deteriorating metabolic state leads to exaggerated CAN possibly related to the progression of localized adipose inflammation to a systemic inflammatory state affecting brainstem and cardiac function.Support or Funding InformationFunding by AUB‐FM grant #320148

Osthole relieves diabetics cardiac autonomic neuropathy associated with P2X3 receptor in ratstellate ganglia

Diabetic cardiac autonomic neuropathy (DCAN) is a serious complication of diabetes mellitus, which often leads to cardiac dysfunction and even threatens patients’ life. Osthole, a natural coumarin derivative, has anti-inflammatory, anti-oxidant and antihypertensive effects. The P2X3 receptor is related to DCAN. The objective of this study will investigate whether osthole relieves DCAN associated with the P2X3 receptor in the stellate ganglia of diabetic rats. A type 2 diabetes mellitus rat model was induced by a combination of diet and streptozotocin. Our results showed that osthole improved the abnormal changes of blood pressure, heart rate, and heart rate variability in diabetic rats and significantly reduced the up-regulated expression levels of the P2X3 receptor, tumor necrosis factor-α and interleukin-1β in stellate ganglia of diabetic rats. Meanwhile, osthole significantly decreased the elevated serum adrenaline concentration and phosphorylation level of extracellular regulated protein kinase 1/2. In addition, the molecular docking result indicated that osthole was a perfect fit for interacting with the P2X3 receptor. Overall, osthole alleviates the sympathetic relative excitation via inhibiting the expression of P2X3 receptors in the stellate ganglia, to achieve a balance between sympathetic and parasympathetic nerves, relieves the DCAN.

Diagnosis of diabetic cardiac autonomic neuropathy

Cardiac autonomic neuropathy (CAN) is a common complication in type 1 and 2 diabetes and is defined as the impairment of autonomic control of the cardiovascular system. CAN is strongly associated with increased mortality, and in some studies with morbidity of vascular complications, such as stroke, coronary artery disease and myocardial infarction. At the early stages, CAN can be subclinical and it becomes clinically evident as the disease progresses. Subclinically, the disease is defined by cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and ischemia, and increased mortality. Although very common and serious, CAN is a frequently overlooked complication of diabetes. Because the progression of cardiovascular denervation is partly reversible or can be slowed down in the early stages of the disease, recent guidelines strongly recommend screening for CAN in patients with diabetes. In this review we summarize the diagnostic tools suggested in the screening for diabetic CAN. Orv Hetil. 2019; 160(35): 1366-1375.

Early diagnosis of diabetic cardiac autonomic neuropathy by method of high-frequency ultrasonic dopplerography

Introduction. Diabetic neuropathy is the most wide-spread complication of diabetes mellitus and neuropathy is steadily progressing even with compensation of the underlying disease. The search of the new methods of treatment and diagnosis of neuropathy is required. Diabetic autonomic neuropathy lies in the base of early morbidity and mortality of diabetic patients.We estimated the potential of High-frequency Ultrasonic Dopplerography for diagnosis of autonomic neuropathy. Material and methods. 26 diabetic patients with sensorimotor neuropathy were examined. Microvascular blood flow of finger skin was assessed at rest as well as in functional tests: with cold impact and occlusion (cuff). Cardiac autonomic neuropathy was assessed using several cardiovascular autonomic reflex tests as a gold standard of diagnosis. Diagnostic values of microvascular blood flow test in detecting of cardiac autonomic neuropathy staging were evaluated in comparing with traditional modalities.Results. Cardiac autonomic neuropathy was found for all patients and definite/confirmed staging in 61.5 % cases. Initial parameters of microvascular blood flow velocity were significantly decreased in all patients in comparing with control (Vam= = (1.9±0.22); (1.7±0.51) and (6.7±0.51) sm/s in patients with early cardiac autonomic neuropathy, definite/confirmed staging and control subjects respectively, p<0.05). Microvascular blood flow functional testes had great informational content for diagnosis of autonomic neuropathy (sensitivity – 100 and 58 %, specify – 50 and 80 % respectively). The algorithm of diabetic patients examination was offered for early diagnosis of autonomic neuropathy staging.Conclusions. High-frequency Ultrasonic Dopplerography allowed to separate of cardiac autonomic neuropathy stages. This study is necessary to continue for revealing of all method possibilities.

Physical activity and dietary interventions in diabetic neuropathy: a systematic review.

Diabetic neuropathy is a common and disabling disorder, and there are currently no proven effective disease-modifying treatments. Physical activity and dietary interventions in patients with diabetes and diabetic neuropathy have multiple beneficial effects and are generally low risk, which makes lifestyle interventions an attractive treatment option. We reviewed the literature on the effects of physical activity and dietary interventions on length-dependent peripheral neuropathy and cardiac autonomic neuropathy in diabetes. The electronic database PubMed was systematically searched for original human and mouse model studies examining the effect of either dietary or physical activity interventions in subjects with diabetes, prediabetes, or metabolic syndrome. Twenty studies are included in this review. Fourteen studies were human studies and six were in mice. Studies were generally small with few controlled trials, and there are no widely agreed upon outcome measures. Recent research indicates that dietary interventions are effective in modifying diabetic neuropathy in animal models, and there are promising data that they may also ameliorate diabetic neuropathy in humans. It has been known for some time that lifestyle interventions can prevent the development of diabetic neuropathy in type 2 diabetes mellitus subjects. However, there is emerging evidence that lifestyle interventions are effective in individuals with established diabetic neuropathy. In addition to the observed clinical value of lifestyle interventions, there is emerging evidence of effects on biochemical pathways that improve muscle function and affect other organ systems, including the peripheral nerve. However, data from randomized controlled trials are needed.

Alpha-lipoic acid and diabetic cardiac autonomic neuropathy

Alpha-lipoic acid (ALA) supplementation may provide benefits in the prevention of diabetes-related vascular and neuronal comorbidities. The mechanism of ALA influence on diabetic neuropathies pathogenesis is not well-known. Thus, further investigations aimed to understand the mechanism of action and for confirmation of the beneficial effect of ALA on biochemical parameters, dynamics of independent cardiovascular tests daily, monitoring of electrocardiography, arterial wall stiffness parameters among patients with type 2 diabetes mellitus, diabetic neuropathies and its associated comorbidities may be needed to validate this clinical findings.

NONRATT021972 long-noncoding RNA: A promising lncRNA in diabetes-related diseases.

Diabetes mellitus (DM) is a principal health problem with increasing incidence worldwide. It can be associated with various systemic diseases. Long non-coding RNA (lncRNA), a member of non-coding RNA has been newly linked with various human diseases. Recent evidence from animal experiments has shown that the incidence and development of type 2 diabetes are contributed by the atypical expression of lncRNA in which the biomarker with capable clinical potential was lncRNA NONRATT021972. In this review, we demonstrated the numerous functions of NONRATT021972 in different diabetes-related diseases including diabetic neuropathy, diabetic cardiac autonomic neuropathy, myocardial ischemia, and hepatic glucokinase dysfunction. The emerging evidence shows that the role of NONRATT021972 in diabetic-related disease is novel and therapeutic. These results direct us to conclude that NONRATT021972 is a potential diagnostic and future targeted therapy for diabetes-associated diseases.

High-Frequency Ultrasonic Dopplerography May be used to Screen for Diabetic Cardiac Autonomic Neuropathy

High-Frequency Ultrasonic Dopplerography May be used to Screen for Diabetic Cardiac Autonomic Neuropathy

Omega-3 Polyunsaturated Fatty Acids Improved Arterial Stiffness Parameters in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy

Abstract Background and Aims: Diabetic cardiac autonomic neuropathy (DCAN) in type 2 diabetes (T2D) is among the strongest and independent risk markers for future global and cardiac mortality. Material and Methods: Thirty-six patients suffering from T2D and confirmed DCAN were enrolled in this investigation. Depending on the prescribed therapy, patients were allocated into two groups: group 1 was comprised of 15 patients to whom standard hypoglycemic treatment was prescribed (control group), the second received standard hypoglycemic treatment and omega-3 polyunsaturated fatty acids (ω-3 PUFAs, n = 21). The duration of the study was three month. Results: In subjects with T2D and DСAN prescription of ω-3 PUFAs was associated with a significant decrease of aorta augmentation index (AIxao), pulse wave velocity (PWV) during the active period of the day and decrease of AIxao, brachial augmentation index and PWV during the passive period of the day compared with the control group. Therefore, three month of ω-3 PUFAs supplementation to patients with confirmed DCAN and T2D promotes to improvement of arterial stiffness indices. Conclusions: In patients with T2D and СAN treatment with ω-3 PUFAs improved arterial stiffness parameters. The effectiveness of ω-3 PUFAs is not connected with optimization of glycemic control, but is rather the result of a direct drug action on the studied parameters.

Cochlear dysfunction and microvascular complications in patients with type 1 diabetes mellitus

Sensorineural hearing impairment has been associated with DM, and it is probably linked to the same pathophysiological mechanisms as well-established in microvascular diabetes complications. The study of otoacoustic emissions (OAEs) is useful to identify subclinical cochlear dysfunction. Therefore, the aim of this study was to evaluate the association between abnormal OAEs responses, diabetic kidney disease (DKD) and diabetic cardiac autonomic neuropathy (CAN). We performed a cross-sectional study with 37 type 1 DM patients without auditory symptoms, submitted to the study of Distortion Product Otoacoustic Emissions (DPOAEs) and screened for DKD and CAN. The otoacoustic emissions responses were considered abnormal in 27/37 (73%) patients. A correlation was found between abnormal OAEs responses and presence of DKD (r = 0.36, p < 0.05), and 14/16 (88%) patients with a lower amplitude of OAEs in 8 kHz frequency band presented DKD. Abnormal OAEs responses in the 6 kHz frequency band were correlated with the presence (r = 0.41, p = 0.01) and severity of CAN (r = 0.44, p < 0.001). Additionally, 7/9 (78%) patients with abnormal OAE responses in this frequency also presented abnormal CAN scores. Our results suggest that abnormal otoacoustic emissions responses in high frequency bands are associated with diabetes microvascular complications and could be a risk marker for DKD and CAN, presenting low sensitivity and high specificity. Therefore, assuming that hearing impairment is a pre-clinical stage of hearing loss, performing distortion product otoacoustic emissions in T1DM patients with microvascular complications could be useful to identify those who would be benefit with regular audiologic follow up and tighter diabetes control.

Inter and Intra-Rater Reliability of Short-Term Measurement of Heart Rate Variability on Rest in Diabetic Type 2 Patients.

Heart rate variability (HRV) among other methods can be used to assess diabetic cardiac autonomic neuropathy by cardiac intervals were recorded. However, the amount of error depending on this measurement methodology is unclear. To evaluate the intra- and inter-rater reliability to calculate HRV indices, comparing different times and by different trained examiners in patients with type 2 diabetes mellitus (T2DM). Thirty individuals of both genders, aged between 18 and 45years, with T2DM. The RR interval (RRi) were recorded during a 10min period on supine position using a portable heart rate monitor (Polar® S810i model). HRV indices were calculated by the software Kubios® HRV analysis (version 2.2). Linear (Mean RRi; STD RR; Mean HR; rMSSD; RR Tri; TINN LF; HF; total power) and non-linear (SD1; SD2; DFα1; DFα2, ApEn and, SampEn) indices were calculated by two examiners with an interval of one week between them. Substantial to excellent was found for reliability of the intra-examiner, with intraclass correlation coefficient (ICC) values ranging from 0.79 to 0.99, standard error of measurement (SEM) between 0.02 and 123.49 (inpercentage: 1.83 and 16.67), and minimum detectable change (MDC) between 0.07 and 342.30. Regarding the inter-examiner reliability, substantial to excellent reliability was found, with ICC values ranging from 0.73 to 0.97, SEM between 0.04 and 178.13 (in percentage: 3.26 and 24.18), and MDC between 0.11 and 493.77. The use of the portable heart rate monitor to measure HRV showed acceptable intra and inter reliability in individuals with T2DM, supporting the use of this method of evaluation in research and clinical practice.

Knockdown the P2X3 receptor in the stellate ganglia of rats relieved the diabetic cardiac autonomic neuropathy

Diabetic cardiac autonomic neuropathy (DCAN) is a common and serious complication of diabetes mellitus (DM), is manifested by nerve fiber injury in the sympathetic and parasympathetic nerve of the autonomic nervous system, and causes hypertension, cardiac arrhythmias, silent myocardial infarction, and sudden death. Our previous study observed that P2X3 receptor in superior cervical ganglia in rat was associated with sympathetic neuropathy caused by myocardial ischemia. However, whether the P2X3 receptor is involved in the diabetic cardiac autonomic neuropathy and the underlying mechanisms remain unclear. The aim of this research was explored the effect of P2X3 short hairpin RNA (shRNA) on information transmission of sympathetic nerve induced by DCAN. Sprague-Dawley (SD) male rats were randomly divided into four groups: Control, DM, DM treated with P2X3 shRNA and DM treated with scramble shRNA. Blood pressure, heart rate and heart rate variability were measured in each group. The expression of P2X3 in stellate ganglion (SG) was detected by immunohistochemistry, western blotting and QPCR. Results showed that P2X3 shRNA alleviated blood pressure and heart rate, improved heart rate variability, decreased the up-regulated expression levels of P2X3, interleukin-1beta and tumor necrosis factor alpha in stellate ganglion (SG) of diabetic rats. P2X3 shRNA also reduced the incremental concentration of serum epinephrine and the phosphorylation level of extracellular regulated protein kinases1/2 in diabetic rats. These results indicated that P2X3 shRNA could decrease sympathetic activity via inhibiting P2X3 receptor in the SG to alleviate DCAN.

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia

Background/Aims: Chronic diabetic hyperglycemia can damage various of organ systems and cause serious complications. Although diabetic cardiac autonomic neuropathy (DCAN) is the primary cause of death in diabetic patients, its pathogenesis remains to be fully elucidated. Baicalin is a flavonoid extracted from Scutellaria baicalensis root and has antibacterial, diuretic, anti-inflammatory, anti- metamorphotic, and antispasmodic effects. Our study explored the effects of baicalin on enhancing sympathoexcitatory response induced by DCAN via the P2Y12 receptor. Methods: A type 2 diabetes mellitus rat model was induced by a combination of diet and streptozotocin. Serum epinephrine was measured by enzyme-linked immunosorbent assay. Blood pressure and heart rate were measured using the indirect tail-cuff method. Heart rate variability was analyzed using the frequency-domain of electrocardiogram recordings. The expression levels of P2Y12, interleukin-1beta (IL-1β), tumor necrosis factor alpha (TNF-α), and connexin 43 (Cx43) were determined by quantitative real-time reverse transcription-polymerase chain reaction and western blotting. The interaction between baicalin and P2Y12 determined using by molecular docking. Results: Baicalin alleviated elevated blood pressure and heart rate, improved heart rate variability, and decreased the elevated expression levels of P2Y12, IL-1β, TNF-α, and Cx43 in the stellate ganglia of diabetic rats. Baicalin also reduced the elevated concentration of serum epinephrine and the phosphorylation of p38 mitogen-activated protein kinase in diabetic rats. Conclusion: Baicalin decreases sympathetic activity by inhibiting the P2Y12 receptor in stellate ganglia satellite glial cells to maintain the balance between sympathetic and parasympathetic nerves and relieves DCAN in the rat.

Diabetic cardiac autonomic neuropathy and arterial stiffness-which comes first?

Diabetic cardiac autonomic neuropathy and arterial stiffness-which comes first?

Combination of Ewing test, heart rate variability, and heart rate turbulence analysis for early diagnosis of diabetic cardiac autonomic neuropathy

The aim of this study was to compare and analyze Ewing test, heart rate variability (HRV), and heart rate turbulence (HRT) in the diagnosis of cardiac autonomic neuropathy (CAN) in diabetic patients.Ninety diabetic patients (age 18–78) and 20 nondiabetic control subjects were studied. Standard Ewing test and 24-hour Holter was performed in all participants to evaluate CAN. Patients with Ewing score ≥2 were classified as CAN+.The rate of CAN+ in diabetic patients [44.4% (40/90)] was higher than that in the controls [5% (1/20)] (P < .05). Using the HRV analysis and HRT analysis, rates of CAN+ in diabetic patients were 56.67% (51/90) and 52.22% (47/90), respectively. SD of all normal-to-normal (NN) intervals (SDNN), SD of the average NN intervals calculated over 5-minute periods of the entire recording (SDANN), low frequency power (LF), and turbulence slope (TS) were significantly correlated negatively with Ewing scores. TS (r = −0.68, P < .05) and SDNN (r = −0.58, P < .05) had the strongest correlation with Ewing scores among relevant factors. Combining TS with SDNN as diagnostic criteria for CAN, the diagnostic sensitivity can be increased to 98%.Parameters used for evaluating parasympathetic functions in Ewing test, HR variability, and HR turbulence were found to significantly decrease in CAN+ group. The combination of SDNN and TS showed greater diagnostic value than Ewing test, HRV analysis, or HRT analysis alone.

Electrochemical Skin Conductance May Be Used to Screen for Diabetic Cardiac Autonomic Neuropathy in a Chinese Population with Diabetes.

Aims. This study aimed to assess whether the electrochemical skin conductance (ESC) could be used to screen for diabetic cardiac autonomic neuropathy (DCAN) in a Chinese population with diabetes. Methods. We recruited 75 patients with type 2 diabetes mellitus (T2DM) and 45 controls without diabetes. DCAN was diagnosed by the cardiovascular autonomic reflex tests (CARTs) as gold standard. In all subjects ESCs of hands and feet were also detected by SUDOSCAN™ as a new screening method. The efficacy was assessed by receiver operating characteristic (ROC) curve analysis. Results. The ESCs of both hands and feet were significantly lower in T2DM patients with DCAN than those without DCAN (67.33 ± 15.37 versus 78.03 ± 13.73, P = 0.002, and 57.77 ± 20.99 versus 75.03 ± 11.41, P < 0.001). The ROC curve analysis showed the areas under the ROC curve were both 0.75 for ESCs of hands and feet in screening DCAN. And the optimal cut-off values of ESCs, sensitivities, and specificities were 76 μS, 76.7%, and 75.6% for hands and 75 μS, 80.0%, and 60.0% for feet, respectively. Conclusions. ESC measurement is a reliable and feasible method to screen DCAN in the Chinese population with diabetes before further diagnosis with CARTs.

Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea.

BackgroundDiabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV).MethodsIn this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes.ResultsMost of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by −3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms2 in the ALA group, whereas it declined by −15.04 ms2 in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by −0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events.ConclusionAlthough a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.

Co-expression changes of lncRNAs and mRNAs in the cervical sympathetic ganglia in diabetic cardiac autonomic neuropathic rats.

Cardiac autonomic neuropathy in Type 2 diabetes (T2D) is often a devastating complication. Long non-coding RNAs (lncRNAs) have important effects on both normal development and disease pathogenesis. In this study, we explored the expression profiles of some lncRNAs involved in inflammation which may be co-expressed with messenger RNA (mRNA) in superior cervical and stellate ganglia after type 2 diabetic injuries. Total RNA isolated from 10 pairs of superior cervical and stellate ganglia in diabetic and normal male rats was hybridized to lncRNA arrays for detections. Pathway analysis indicated that the most significant gene ontology (GO) processes that were upregulated in diabetes were associated with immune response, cell migration, defense response, taxis, and chemotaxis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that most of the target genes of the lncRNAs were located in cytokine-cytokine receptor interactions, the chemokine signaling pathway and cell adhesion molecules, which were involved in T2D. Gene co-expression network construction showed that the co-expression network in the experimental rats consisted of 268 regulation edges among 105 lncRNAs and 11 mRNAs. Our studies demonstrated the co-expression profile of lncRNAs and mRNAs in diabetic cardiac autonomic ganglia, suggesting possible roles for multiple lncRNAs as potential targets for the development of therapeutic strategies or biomarkers for diabetic cardiac autonomic neuropathy. © 2016 Wiley Periodicals, Inc.

The U-shaped relationship between fibroblast growth factor 21 and microvascular complication in type 2 diabetes mellitus

AimsThe aim of this study was to investigate the relationship between serum FGF21 level and all microvascular complication including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM). MethodsA total 227 T2DM patients were enrolled and serum FGF21 levels were assessed. Diabetic retinopathy, nephropathy, peripheral neuropathy (DPN), and CAN were evaluated. ResultsThe prevalence of retinopathy and nephropathy among the FGF21 tertiles was significantly different (p=0.001, p=0.006, respectively), whereas no difference was found in the prevalence of DPN and CAN. In multivariate analysis, the odds ratio (OR) for the presence of retinopathy was 0.08 for the FGF21 second tertile when compared with the first tertile (p=0.029). OR of retinopathy in third tertile group was lower than first tertile and higher than second tertile, but statistically insignificant. Crude OR for nephropathy was 0.34 for the second FGF21 tertile, when compared with the first tertile (p=0.015). However, FGF21 level was not significantly associated with nephropathy after multivariable adjustment. ConclusionsIn the present study, there was no association between diabetic nephropathy, DPN, and CAN and serum FGF21 levels. However, we found a U-shaped relationship between both lower and higher serum FGF21 levels and diabetic retinopathy. This result suggests that the very low serum FGF21 level itself may associate with diabetic retinopathy and also relatively elevated serum FGF21 level may be a compensatory increase to protect against microvascular injury.