Diabetes & Metabolism Journal

Original Article

Clinical Diabetes & Therapeutics
Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea: Sol Jae Lee, Su Jin Jeong, Yu Chang Lee, Yong Hoon Lee, Jung Eun Lee, Chong Hwa Kim, Kyung Wan Min, Bong Yun Cha; Diabetes Metab J. 2017;41(4):275-283. Published online July 6, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.4.275

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Background

Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV).

Methods

In 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.

Results

Most 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.

Conclusion

Although 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.

Citations

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Effect of Ramipril on Cardiac Autonomic Neuropathy in Patients With Type II Diabetes Mellitus
Chaitali A Chindhalore, Ganesh N Dakhale, Prathamesh H Kamble, Bharatsing D Rathod, Sunita Kumbhalkar, Mrunal S Phatak
Cureus.2023;[Epub] CrossRef
Evaluating treatment options for cardiovascular autonomic neuropathy in patients with diabetes mellitus: a systematic review
Jasmine KaiLi Goh, Leroy Koh
Diabetology International.2023; 14(3): 224. CrossRef
The effects of alpha lipoic acid (ALA) supplementation on blood pressure in adults: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials
Mahdi Vajdi, Nooshin Noshadi, Shirin Hassanizadeh, Atefeh Bonyadian, Hooria Seyedhosseini-Ghaheh, Gholamreza Askari
Frontiers in Cardiovascular Medicine.2023;[Epub] CrossRef
Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway
George J. Dugbartey, Quinsker L. Wonje, Karl K. Alornyo, Louis Robertson, Ismaila Adams, Vincent Boima, Samuel D. Mensah
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Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: a systematic review and dose–response meta-analysis of randomized trials
Aliyu Tijani Jibril, Ahmad Jayedi, Sakineh Shab-Bidar
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Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet
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Alpha-lipoic acid (ALA) supplementation effect on glycemic and inflammatory biomarkers: A Systematic Review and meta- analysis
Mehran Rahimlou, Maryam Asadi, Nasrin Banaei Jahromi, Anahita Mansoori
Clinical Nutrition ESPEN.2019; 32: 16. CrossRef
Response: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J 2017;41:275-83)
Chong Hwa Kim, Sol Jae Lee, Bong Yun Cha
Diabetes & Metabolism Journal.2017; 41(5): 420. CrossRef
Letter: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J2017;41:275-83)
Jeongmin Lee, Jae Hyoung Cho
Diabetes & Metabolism Journal.2017; 41(5): 417. CrossRef

Review

Pathophysiology
Morphologic Changes in Autonomic Nerves in Diabetic Autonomic Neuropathy: Heung Yong Jin, Hong Sun Baek, Tae Sun Park; Diabetes Metab J. 2015;39(6):461-467. Published online December 11, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.6.461

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Diabetic neuropathy is one of the major complications of diabetes, and it increases morbidity and mortality in patients with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Because the autonomic nervous system, for example, parasympathetic axons, has a diffuse and wide distribution, we do not know the morphological changes that occur in autonomic neural control and their exact mechanisms in diabetic patients with diabetic autonomic neuropathy (DAN). Although the prevalence of sympathetic and parasympathetic neuropathy is similar in T1DM versus T2DM patients, sympathetic nerve function correlates with parasympathetic neuropathy only in T1DM patients. The explanation for these discrepancies might be that parasympathetic nerve function was more severely affected among T2DM patients. As parasympathetic nerve damage seems to be more advanced than sympathetic nerve damage, it might be that parasympathetic neuropathy precedes sympathetic neuropathy in T2DM, which was Ewing's concept. This could be explained by the intrinsic morphologic difference. Therefore, the morphological changes in the sympathetic and parasympathetic nerves of involved organs in T1DM and T2DM patients who have DAN should be evaluated. In this review, evaluation methods for morphological changes in the epidermal nerves of skin, and the intrinsic nerves of the stomach will be discussed.

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Original Articles

Relationship between the Korean Version Survey of the Autonomic Symptoms Score and Cardiac Autonomic Neuropathy Parameters in Patients with Diabetic Peripheral Neuropathy: Sun Hee Kim, Kyung Ae Lee, Heung Yong Jin, Hong Sun Baek, Tae Sun Park; Diabetes Metab J. 2014;38(5):349-355. Published online October 17, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.5.349

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Background

The Survey of Autonomic Symptom (SAS) scale was reported as an easy instrument to assess the autonomic symptoms in patients with early diabetic neuropathy. In this study, we investigated the relationship between the SAS scale and the parameters of cardiac autonomic neuropathy (CAN) in Korean patients with diabetic peripheral neuropathy (DPN).

Methods

The SAS scale was tested in 30 healthy controls and 73 patients with DPN at Chonbuk National University Hospital, in Korea. The SAS score was compared to the parameters of the CAN test and the total symptom score (TSS) for DPN in patients with DPN.

Results

The SAS symptom score and total impact score were increased in patients with DPN compared to the control group (P=0.01), particularly in sudomotor dysfunction (P=0.01), and vasomotor dysfunction (P=0.01). The SAS score was increased in patients with CAN compared to patients without CAN (P<0.05). Among the diverse CAN parameters, the valsalva ratio and postural hypotension were associated with the SAS score (P<0.05). However, there was no association between the SAS scale and TSS for DPN, and TSS for DPN did not differ between patients with and without CAN.

Conclusion

SAS is a simple instrument that can be used to assess autonomic symptoms in patients with diabetes and can be used as a screening tool for autonomic neuropathy, particularly for CAN.

Citations

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Autonomic neuropathic symptoms in patients with diabetes: practical tools for screening in daily routine
Ana Raquel Souza de Azevedo Vieira, Lara Benigno Porto-Dantas, Flaviene Alves do Prado Romani, Patrícia Souza Carvalho, Rodica Pop-Busui, Hermelinda Cordeiro Pedrosa
Diabetology & Metabolic Syndrome.2023;[Epub] CrossRef
Symptomatic diabetic autonomic neuropathy in type 1 diabetes (T1D): Findings from the T1D exchange
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Eun Bin Cho, Ki-Jong Park
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Peripheral Nerve Conduction And Sympathetic Skin Response Are Reliable Methods to Detect Diabetic Cardiac Autonomic Neuropathy
Xiaopu Lin, Chuna Chen, Yingshan Liu, Yu Peng, Zhenguo Chen, Haishan Huang, Lingling Xu
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Hou Yee Lai, Li Lian Foo, Siu Min Lim, Chen Fei Yong, Pui San Loh, Sook Hui Chaw, Mohd Shahnaz Hasan, Chew Yin Wang
Clinical Autonomic Research.2020; 30(1): 53. CrossRef
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Vincenza Spallone
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Validation of the Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes
C. Greco, F. Di Gennaro, C. D'Amato, R. Morganti, D. Corradini, A. Sun, S. Longo, D. Lauro, G. Pierangeli, P. Cortelli, V. Spallone
Diabetic Medicine.2017; 34(6): 834. CrossRef
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Jae-Seung Yun, Seon-Ah Cha, Tae-Seok Lim, Eun-Young Lee, Ki-Ho Song, Yu-Bae Ahn, Ki-Dong Yoo, Joon-Sung Kim, Yong-Moon Park, Seung-Hyun Ko
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American Journal of Ophthalmology.2016; 170: 15. CrossRef
Screening of Autonomic Neuropathy in Patients with Type 2 Diabetes
Bo Kyung Koo
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Assessment of Diabetic Polyneuropathy and Autonomic Neuropathy Using Current Perception Threshold in Korean Patients with Diabetes Mellitus: Bo Kyung Koo, Jung Hun Ohn, Soo-Heon Kwak, Min Kyong Moon; Diabetes Metab J. 2014;38(4):285-293. Published online August 20, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.4.285

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Background

The current perception threshold (CPT) could be quantified by stimulating Aβ and C fibers at 2,000 and 5 Hz, respectively. C fibers play a role in the autonomic nervous system and are involved in temperature and pain sensation. We evaluated the usefulness of CPT for diagnosing distal polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in diabetic patients.

Methods

The CPT was measured in the index finger (C7 level) and in the third toe (L5 level) in diabetic patients aged 30 to 69 years. We assessed DPN according to the neuropathy total symptom score-6 (NTSS-6) and 10-g monofilament pressure sensation. Subjects with a NTSS-6 >6 or with abnormal 10-g monofilament sensation were defined to have DPN. CAN was evaluated by spectral analysis of heart rate variability and by Ewing's traditional tests.

Results

The subjects with DPN had significantly higher CPT at all of the frequencies than the subjects without DPN (P<0.05). Abnormal 10-g monofilament sensation and NTSS-6 >6 could be most precisely predicted by CPT at 2,000 and 5 Hz, respectively. However, only 6.5% and 19.6% of subjects with DPN had an abnormal CPT at 2,000 Hz at the C7 and L5 levels. Although CPT at 5 Hz showed a negative correlation with the power of low and high frequency in the spectral analysis (P<0.05), only 16.7% of subjects with CAN exhibited an abnormal CPT at the same frequency.

Conclusion

Although the CPT is significantly associated with neuropathic symptoms or signs corresponding to the nerve fiber stimulated, it provides little additional information compared with conventional evaluations.

Citations

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New Perspective in Diabetic Neuropathy: From the Periphery to the Brain, a Call for Early Detection, and Precision Medicine
Heng Yang, Gordon Sloan, Yingchun Ye, Shuo Wang, Bihan Duan, Solomon Tesfaye, Ling Gao
Frontiers in Endocrinology.2020;[Epub] CrossRef
Patterns of Nerve Conduction Abnormalities in Patients with Type 2 Diabetes Mellitus According to the Clinical Phenotype Determined by the Current Perception Threshold
Joong Hyun Park, Jong Chul Won
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Elizabeth A. Bettini, Ki Moore, Yunfei Wang, Pamela S. Hinds, Julia C. Finkel
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The impact of neuropathic pain and other comorbidities on the quality of life in patients with diabetes
Vesna Dermanovic Dobrota, Pero Hrabac, Dinko Skegro, Ranko Smiljanic, Savko Dobrota, Ingrid Prkacin, Neva Brkljacic, Kristijan Peros, Martina Tomic, Vesna Lukinovic-Skudar, Vanja Basic Kes
Health and Quality of Life Outcomes.2014;[Epub] CrossRef

Influence of Visceral Adiposity on Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus: Eun-Hee Jang, Na-Young Kim, Yong-Moon Park, Mee-Kyoung Kim, Ki Hyun Baek, Ki-Ho Song, Kwang Woo Lee, Hyuk-Sang Kwon; Diabetes Metab J. 2012;36(4):285-292. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.285

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Background

The aim of this study was to investigate the influences of visceral adiposity on cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus.

Methods

Two hundred eleven patients with type 2 diabetes participated in this study. Anthropometric and metabolic parameters were measured, and the visceral fat area was assessed using computed tomography. CAN was diagnosed using a cardiovascular reflex test. We analyzed the correlation between the visceral fat area and each parameter in this test.

Results

The mean age, body mass index (BMI), and duration of diabetes of the study population were 60±14 years (mean±standard deviation), 25.1±4.2 kg/m², and 12.3±8.9 years, respectively. The visceral fat area showed positive correlations with age, BMI, waist circumference, and subcutaneous fat area. There was no statistically significant difference in the cardiovascular reflex test outcome between genders. Univariate linear regression analysis showed that an increased visceral fat area diminished good heart rate response to a Valsalva maneuver (R²=4.9%, P=0.013 in an unadjusted model), but only in women. This statistical association was preserved after adjusting for age and BMI (R²=9.8%, P=0.0072).

Conclusion

The results of this study suggest that visceral adiposity contributes to an autonomic imbalance to some degree, as demonstrated by the impaired cardiovascular reflex test among women with type 2 diabetes.

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Excessive generalized and visceral adiposity is associated with a higher prevalence of diabetic retinopathy in Caucasian patients with type 2 diabetes
Andrea Tumminia, Agostino Milluzzo, Nunzia Carrubba, Federica Vinciguerra, Roberto Baratta, Lucia Frittitta
Nutrition, Metabolism and Cardiovascular Diseases.2024; 34(3): 763. CrossRef
Obesity, Metabolic Syndrome and the Risk of Microvascular Complications in Patients with Diabetes mellitus
Niki Katsiki, Panagiotis Anagnostis, Kalliopi Kotsa, Dimitrios G. Goulis, Dimitri P. Mikhailidis
Current Pharmaceutical Design.2019; 25(18): 2051. CrossRef
Morphologic Comparison of Peripheral Nerves in Adipocyte Tissue from db/db Diabetic versus Normal Mice
Kyung Ae Lee, Na Young Lee, Tae Sun Park, Heung Yong Jin
Diabetes & Metabolism Journal.2018; 42(2): 169. CrossRef
Gender differences in the perception of difficulty of self-management in patients with diabetes mellitus: a mixed-methods approach
Hideyo Tsutsui, Kyoko Nomura, Masataka Kusunoki, Tetsuya Ishiguro, Takayoshi Ohkubo, Yoshiharu Oshida
Diabetology International.2016; 7(3): 289. CrossRef
Contribution of subcutaneous abdominal fat on ultrasonography to carotid atherosclerosis in patients with type 2 diabetes mellitus
Chan-Hee Jung, Bo-Yeon Kim, Kyu-Jin Kim, Sang-Hee Jung, Chul-Hee Kim, Sung-Koo Kang, Ji-Oh Mok
Cardiovascular Diabetology.2014;[Epub] CrossRef

Clinical Significance of the Presence of Autonomic and Vestibular Dysfunction in Diabetic Patients with Peripheral Neuropathy: Soo Kyoung Kim, Kyeong Ju Lee, Jong Ryeal Hahm, Sang Min Lee, Tae Sik Jung, Jung Hwa Jung, Sungsu Kim, Deok Ryong Kim, Seong-Ki Ahn, Won-Hee Choi, Soon Il Chung; Diabetes Metab J. 2012;36(1):64-69. Published online February 17, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.1.64

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Background

We investigated the prevalence of diabetic autonomic neuropathy (DAN) and vestibular dysfunction (VD) in diabetic patients with peripheral neuropathy.

Methods

Thirty-five diabetic patients with peripheral neuropathy were enrolled from August 2008 to July 2009. All subjects underwent autonomic function tests. Nineteen of the patients (54.3%) underwent videonystagmography.

Results

Diabetic autonomic neuropathy was observed in 28 patients (80%). A mild degree of autonomic failure was observed in 18 patients (64.3%), and a moderate degree of autonomic failure was observed in ten patients (35.7%). Factors related to DAN included diabetic nephropathy (P=0.032), degree of chronic kidney disease (P=0.003), and duration of diabetes (P=0.044). Vestibular dysfunction was observed in 11 of 19 patients (57.9%). There was no significant association between DAN and VD.

Conclusion

Diabetic autonomic neuropathy was observed in 28 diabetic patients (80%) with peripheral neuropathy. Vestibular dysfunction was observed in nearly 60% of diabetic patients with peripheral neuropathy who complained of dizziness but showed no significant association with DAN. Diabetic patients who complained of dizziness need to examine both autonomic function and vestibular function.

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Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus.: Seung Hyun Ko, Hyuk Sang Kwon, Jung Min Lee, Sung Rae Kim, Jae Hyung Cho, Ki Dong Yoo, Yong Moon Park, Won Chul Lee, Ki Ho Song, Kun Ho Yoon, Bong Yun Cha, Ho Young Son, Yu Bai Ahn; Korean Diabetes J. 2006;30(3):226-235. Published online May 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.3.226

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Abstract PDF

BACKGROUND
Diabetic autonomic neuropathy has a significant negative impact on survival and quality of life in type 2 diabetic patients. Especially cardiovascular autonomic neuropathy (CAN) is clinically important, because of its correlation to cardiovascular death. Therefore, we investigated the prevalence of CAN in Korean type 2 diabetic patients. METHODS: 1798 type 2 diabetic patients, 727 males and 1071 females, visited Diabetes Clinic at St. Vincent Hospital, Korea, were included from January 2001 to December 2005. Clinical evaluation, laboratory test and assessment of diabetic complication were completed. Standard test for CAN were performed: 1) heart rate variability (HRV) during deep breathing (E/I ratio) 2) Valsalva maneuver 3) 30:15 ratio 4) blood pressure response to standing. CAN score was determined according to the results of the test as following: 0 = normal, 1 = abnormal. RESULTS: Mean age and diabetic duration of patients were 56.7 +/- 10.9, and 9.4 +/- 7.5 years. Normal and abnormal CAN were detected in 815 (45.3%) and 983 (54.7%) of the patients, respectively. Abnormal E/I, valsalva, and 30:15 ratio were found in 333 (18.5%), 717 (39.9%), and 546 (30.4%) patients, respectively. Age, diabetic duration, postprandial hyperglycemia, HbA1c, C-reactive protein, and microalbumuria levels were significantly different between normal and abnormal CAN groups. 49 (6.0%) patients of normal and 100 (10.2%) patients of abnormal CAN group showed previous attack of stroke (P = 0.004). In addition, diabetic foot was more frequent in patients with CAN (normal vs. abnormal, 14 (1.7%) vs. 73 (7.4%), P < 0.05). CONCLUSION: CAN is frequently found in Korean type 2 diabetic patients. It was associated with diabetic duration, uncontrolled diabetes, increased albumin excretion rate, presence of retinopathy, postprandial hyperglycemia.

Citations

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Prolonged QT Interval and the BMI, Systolic BP and HDL-Cholesterol in Type 2 Diabetic Patients.: Chunggu Cho, Hye Jung No, Hyo Jeong Oh, Bong Joon Yang, Ha Young Kim, Byoung Hyun Park; Korean Diabetes J. 2005;29(3):215-222. Published online May 1, 2005

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Abstract PDF: BACKGROUND
A prolonged QT interval is considered as an indicator of an increased risk of coronary heart disease, malignant ventricular arrhythmias and/or sudden death. QT interval prolongation has been reported to be a common finding in patients with obesity and diabetic autonomic neuropathy and it is well known that both leptin and insulin stimulate sympathetic activity. The waist to hip ratio and the plasma insulin levels were recently reported to be correlated with the QT intervals and the sympathovagal balance. The aim of the present study was to evaluate the association of the features of metabolic syndrome and the QT interval in type 2 diabetic patients. METHODS: We studied 114 type 2 diabetes(45 males and 69 females). The QT intervals were measured by a software program and then the QTc was calculated. The fasting glucose, total cholesterol, triglyceride and high-density lipoprotein(HDL)-cholesterol, HbAIC and Cpeptide were measured. All the patients received clinical tests for cardiovascular autonomic dysfunction by the Ewing's method. RESULTS: A significant difference was found in the mean QT interval between the patients with an autonomic score>=1 and the patients who were without cardiac autonomic neuropathy(autonomic score=0). On Pearson's simple regression analysis, the QT interval showed positive correlations with the BMI, fasting C-peptide, systolic blood pressure(sBP), and age. The QT interval also showed negative correlation with the HDL-cholesterol. The associations of the QTc with triglyceride, fasting glucose, and the autonomic score did not reach statistical significance. On the multiple regression analysis, the QT interval was independently correlated with BMI, systolic BP and HDL-cholesterol but not with the other variables that we tested(c-peptide, autonomic score, diastolic blood pressure, glycated hemoglobin, triglyceride and cholesterol). CONCLUSION: Our results suggest that a variety of features of metabolic syndrome are associated with QT interval prolongation in the type 2 diabetic patients

Case Report

A Case of Acute Multifocal Bacterial Nephritis Associated with Diabetic Autonomic Neuropathy.: Eun Kyung Park, Jae Hak Lee, Ji Sung Yoon, Ji O Mok, Yeo Joo Kim, Hyeong Kyu Park, Chul Hee Kim, Sang Jin Kim, Dong Won Byun, Kyo Il Suh, Myung Hi Yoo; Korean Diabetes J. 2003;27(4):379-384. Published online August 1, 2003

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Abstract PDF: Acute multifocal bacterial nephritis is a severe form of acute renal infection in which a heavy leukocytic infiltrate occurs throughout the kidney. It is also an early phase of renal corticomedullary abscess. Clinically, patients have evidence of a severe urinary tract infection secondary to a gram-negative organism and there are frequently signs of sepsis. About half of the reported patients have been diabetics. Urinary tract infections are more common in diabetic women than in non-diabetic women. A variety of factors may contribute. The most important predisposing factor may be bladder dysfunction as a result of diabetic neuropathy and cystopathy. Diabetic cystopathy begins as decreased bladder sensation and decreased reflex detrusor activity caused by neuropathy affecting sympathetic and parasympathetic afferent fibers. Impaired bladder sensation results in bladder distention and increased residual urine volume. Long-term effects may eventually be vesicoureteral reflux and recurrent upper urinary tract infection. However, until now no diabetic patient with acute multifocal bacterial nephritis has been reported in Korea. Acute multifocal bacterial nephritis can be diagnosed by clinical manifestations and on radiologic grounds, including abdominal computed tomography showing multiple, wedge shaped, poorly defined areas of decreased contrast enhancement in multiple renal lobes. Therefore, we report the first Korean case of acute multifocal bacterial nephritis associated with diabetic autonomic neuropathy and review the literatures.

Original Articles

Factors Determining Circadian Blood Pressure Rhythm in Normotensive Patients with Type 2 Diabetes.: Jae Hong Kim, Jin Ho Kim, Mi Jung Eun, Si Hyung Lee, Kyeong Cheol Shin, Kyu Chang Won, Ihn Ho Cho, Hyoung Woo Lee; Korean Diabetes J. 2002;26(5):416-430. Published online October 1, 2002

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Abstract PDF: BACKGROUND
Within healthy subjects, there exists the so-called 'dipper phenomenon', where the circadian blood pressure rhythm, that is the systolic and diastolic blood pressures values, are lower at night than during the day. The loss of nocturnal dipping in BP has prognostic value with regard to end-organ damage and vascular events in both hypertension and diabetic patients. A blunted nocturnal decrease in BP has been described in diabetic patients, and has been associated with autonomic neuropathy or nephropathy, but much controversy relating to this still exists. This study was designed to evaluate the factors that influence abnormal circadian blood pressure rhythm. METHODS: 24hr blood pressure monitoring was applied to 99 normotensive type 2 diabetes patients,comprising of 55 males and 44 females, with a mean age: 56 3 years, who visited our hospital between March 2000 and February 2002 for measurement of 24hr systolic and diastolic blood pressures. The control groups was 21 white coat hypertension type 2 diabetic patients, comprising of 15 males and 6 females, with a mean age of 53 4 years. The controls were subgrouped according to their standard cardiovascular autonomic function test(CAN) or nephropathy stage. All patients divided dipper, mean(day time night time) systolic BP/mean(day time-night time) diastolic BP above 10mmHg/5mmHg, and non-dipper groups. RESULTS: The prevalence of non-dipper phenomenon was much greater in the type 2 diabetes patients than in the control groups(p<0.05). There was a significant difference between the dipper and non-dipper groups in the 24hr total urine protein and CAN(p<0.05). In the type 2 diabetes patients, sub-grouped according to their nephropathy stage, there was a significant difference between the microalbuminuric and proteinuric groups relating to the prevalence of the non-dipper phenomenon (p<0.05). The circadian blood pressure, according to the nephropathy stage, the CAN in the normoalbuminuria group, the albumin excretion in the microalbuminuria group, CAN and 24hr total urine protein in the proteinuric group, may useful in determining abnormal circadian rhythm (p<0.05). There was no significant difference between the dipper and non-dipper groups with regard to neuropathy and retinopathy (p<0.05). CONCLUSION: In the early stage of diabetic nephropathy, autonomic dysfunction may have a relatively dominant influence on abnormal circadian blood pressure rhythm. Nephropathy was progressed in diabetic patients: therefore diabetic nephropathy may itself have an influence on abnormal circadian blood pressure rhythm.

Diastolic Dysfunction of Left Ventricle by Cardiovascular Autonomic Neuropathy in Type 2 Diabetic Patients Without Cardiovascular Symptom.: Duk Kyu Kim, Mi Kyoung Park, Do Young Kang; Korean Diabetes J. 2001;25(3):230-239. Published online June 1, 2001

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Abstract PDF: BACKGROUND
We investigated the effect of cardiovascular autonomic neuropathy for left ventricular function in cardiovascular symptom-free type 2 diabetic patients without other major risk factors known to cause cardiac dysfunction, especially diastolic dysfunction. METHODS: Forty seven patients (M:F=20:27, 53+/-10 years) with type 2 DM were enrolled in this study. None of the subjects had the macrovascular diabetic complications, hypertension, hypertrophic cardiomyopathy, valvular heart disease, alcoholic heart disease, congenital heart disease and older age (> 65 years). The patients were tested for cardiovascular autonomic neuropathy using five non-invasive tests of autonomic function. The response to each test was graded as 0, 0.5, 1. A patient was classified as having definite cardiovascular autonomic neuropathy if total score was 2 or more. Using these criteria, 26 patients (Group A) were determined to have cardiovascular autonomic neuropathy. Others were 21 patients (Group B). Tc-99 m RBC gated blood pool scintigraphy was performed as routine standard protocol. RESULTS: The degree of age, sex, body mass index (BMI), duration of diabetes, level of insulin, C-peptide, fructosamine, fasting plasma glucose, total cholesterol (TC), triglyceride (TG), HDL, LDL, BUN, creatinine and incidence of retinopathy, microalbuminuria were not different between group A and B. Heart rate response to Valsalva maneuver, heart rate response to standing were different between Group A and B (p=0.008, p=0.001, respectively). Ejection fraction of left ventricle were normal (> 50%) in all of patients. Maximal filling rate, average filling rate, maximal ejection rate and average ejection rate were increased in patients with cardiac autonomic neuropathy (p=0.03, p=0.05, p=0.02, p=0.04, respectively). Total score of autonomic function was significantly correlated with maximal filling rate (r=0.38, p=0.01), with average filling rate (r=0.37, p=0.01) and with maximal ejection rate (r=0.37, p=0.01). Maximal filling rate was most correlated with resting pulse (r=0.58, p<0.01). CONCLUSION: Cardiovascular autonomic neuropathy as single factor may result in diastolic dysfunction of left ventricle in cardiovascular symptom-free type 2 diabetic patients without other major factor known to cause cardiac diastolic dysfunction.

The Relation of QTc dispersion and Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus.: Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee; Korean Diabetes J. 1998;22(3):410-418. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The diabetic patients with cardiovascular autonomic neuropathy(CAN) have disturbance of repolarization due to sympathetic imbalance resulting in arrhythmogenesis, and finally leading to sudden death. QTc dispersion may provide regional variation in myocardial recovery time. Thus the hypothesis of this study was that QTc dispersion may be a useful tool in the assessment of arrhythmogenic potential in diabetic patients with CAN depending upon a severity of CAN. METHODS: Ninty-five patients with type 2 diabetes mellitus and 20 normal control subjects were studied. QTc interval and QTc dispersion was calculated from 12 lead ECG leads. QT dispersion was defined as difference between maximum and minimum QT interval and was corrected for heart rate using Bazzets formula. Cardiovascular autonomic neuropathy test(including resting heart rate, Valsalva maneuver, deep breathing, lying to standing, orthostatic hypotension) were assessed in all subjects. RESULTS: Among 95 diabetic patients, 43 patients (37%) had CAN. QTc interval and QT(QTc) dispersion were significantly greater in patients with CAN (p <0.05). There was no correlation between QTc interval and QTc dispersion. There was a statistically significant(r=0.48, p<0.001) correlation between systolic blood pressure response to standing and QTc dispersion. CONCLUSION: These results suggest that QTc dispersion may be an additional non-invasive diagnostic tool in the assessment of arrhythmogenic potential in diabetic patients with cardiovascular autonomic neuropathy.

Association Between QTc Dispersion and Cardiovascular Autonomic Dysfuction in Non-insulin Dependent Dabetes Mellitus.: Jung Guk Kim, Hun Sik Park, Jick Hwa Nam, Byoung Ho Sin, Seong Mo Koo, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 1998;22(2):173-181. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetic patients with autonomic dysfunction have worse prognosis, including an increased incidence, of sudden death, than those without autonomic dysfunction. This event may be due to sympathetic imbalance causing disturbances of ventricular repolarization. QT dispersion have recently been demonstrated to reflect dispersion of ventricular refractoriness and is a marker of arrhythmogenic potential. METHODS: Sixty diabetic patients and 31 normal subjects were studied. All patients had clinical test for cardiovascular autonomic dysfunction by Ewings method and defined as normal, early involved, definitely involved, severely involved and atypical group for 5 validated tests. Resting standard 12-lead electrocardiograms were recorded for measurement of QT dispersion, defined as the difference of longest QT interval and shortest QT interval, and corrected for heart rate using Bazetts formula. RESULTS: Twenty-seven dIiabetic patient were abnormal in cardiovascular autonomic function tests. In these patients corrected QT dispersion (QTc) were significantly longer compared to that 33 patients without autonomic dysfunction(47.4+14.7 vs 22.6+ 8.1msec p<0.001). And also there was significant difference of QTc dispersion between normal subject and diabetic patients with autonomic neuropathy group(20.5+9.2 vs 47.4+14.7msec p<0.001). But there was no difference between normal control and diabetic patients without autonomic neuropathy group. And QTc dispersion was not related to the presence ot nephropathy, retinopathy or peripheral polyneuropathy. We also found that there was no relationship between the severity of autonomic neuropathy and degree of Q7c dispersion. CONCLUSION: We concluded that QTc dispersion may be a good method for evaluation of cardiovascular autonomic neuropathy and increased QTc dispersion may be one of the markers of arrhythmia in diabetic patients with autonomic neuropathy.

QTc Interval and QT Dispersion Prolongation in NIDDM Patients with Diabetic Autonomic Neuropathy.: Yong Kyun Cho, Seung Won Lee, Won Tae Seo, Yoon Sang Choi, Jin Ho Kang, Man Ho Lee, Sang Jong Lee; Korean Diabetes J. 1998;22(1):93-102. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It has been reported that QTc interval and QT dispersion prolongation on 12 lead EKG reflects predictability and diagnosis of cardiovascular complications induced by autonomic nervous system abnormalities. We have investigated in NIDDM patients whether severity of cadiovascular autonomic neuropathy(CAN) evaluated by conventional standard cardiovascular autonomic function test is correlated with prolongation of QT, QTc interval and QT dispersion. In addition, whether these prolonagtion can reflect CAN and if any other clinical variables related to pralongatian exist. METHODS: Eighty patients(39 male, 41 female) treated with oral hypoglycemic agents or insulin after diagnosis of NIDDM in our hospital were included in the study. These patients were devided into three groups (Group I, 13 subjects: No CAN, Group II, 20 subjects: Borderline CAN, Group III, 47 subjects: Definite CAN) according to the score of standard catdiovascular autonomic function test(Deep breathing test, Lying to standing test, Heart ration on Valsalva manuever, Postural BP drop test). The measured QT, QTc interval and QT disp rsion of eaeh diabetic group and control group were analyzed. RESULTS: l. Statistically significant prolongation of QT,QTc, QT dispersion was observed in NIDDM tients as compared with those of control group(p=0.015, 0,021, 0.001). 2. Severity of autonomic neuropathy has shown positive correlation with only prolongation of QT dispersion(p<0.05) in three diabetic subgroups. 3. Statistically significant difference was not ob::rved in HbAlc and BMI between each patients groups of NIDDM(p>0.05) but both HbAlc and BMI showed weak positive correlation with prologation of QT dispersion(r=0.262, r=0.267 repectively). CONCLUSION: QTc interval and QT dispersion are considered easily accessible factors to predict and evaluate the degree of cardiovascular autonomic function abnormalities in NIDDM patients, yet further long term follow up and study in large group should be carried out to decide if these factor can predict and reflect severity of cardiovascular abnormalities such as ventricular arrhythmia, and sudden cardiac death. In additian, prolonged QT dispersion has shown weak positive correlation with both HbAlc and BMI and some other influential factors are suggested to play a role in autonomic neuropathy in NIDDM patients.

Relationship between Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in Non-Insulin Dependent Diabetics.: Sung Woo Ha, Hyun Jeong Lee, Jeung Hun Han, Sang Won Jung, Jick Hwa Nam, Byoung Ho Sin, Seong Mo Koo, Jung Guk Kim, Sam Kwon, Bo Wan Kim; Korean Diabetes J. 1997;21(4):476-483. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Autonomic neuropathy was detected in some diabetics with symmetric peripheral neuropathy, a common complication of diabetes mellitus that may be associated with considerable morbidity. There has been known to be similarity of pathogenic mechanism in two neuropathies. Then we examined nerve conduction velocity and cardiovascular autonomic function tests. We studied relationship between peripheral and cardiovascular autonomic neuropathy in non-insulin dependent diabetics. METHODS: We studied 166 patients with or witbout peripheral neuropathy who had been diagnosed as non-insulin dependent diabetes mellitus. We examined nerve conduction tests to assess diabetic peripheral neuropathy and classified them into 4 groups aecording to neuropathic symptoms and results of nerve conduction tests. We examined five cardiovascular autonomic function tests by Ewing's methods. RESULTS: 1. The duration of diabetes mellitus was significantly longer in the group of cliabetics with neuropathic symptoms and abnormal findings in the nerve conduction velocity tests than the other groups. The level of blood glucose was significantly higher in the group of diabetics with neuropathic symptoms and findings than the other groups. 2. In the 5 cardiovascular autonomic function tests, heart rate response to deep breathing and Valsalva maneuver had significant differences between the diabetic group with peripheral neuropathy and the other groups. 3. The frequency and severity of autonomic neuropathy were higher in the group with peripheral neuro-pathic symptoms and findings than the other groups without neuropathic syrnptoms and findings. There was an overall significant relationship between sensorirnotor neural function and autonomic function. 4. There was no association between peripheral neuropathy and nephropathy although peripheral neuropathy was related with retinopathy. CONCLUSION: Diabetic peripheral neuropathy accompanies autonomic neuropathy. Then, this result suggests that there is the relationship between peripheral and cardiovascular autonomic neuropathy.

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