Diabetes & Metabolism Journal

Original Articles

Complications
Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus: Jun Ouk Ha, Tae Hee Lee, Chang Won Lee, Ja Young Park, Seong Ho Choi, Hee Seung Park, Jae Seung Lee, Seung Heon Lee, Eun Hee Seo, Young Hwan Kim, Young Woo Kang; Diabetes Metab J. 2016;40(4):297-307. Published online June 8, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.4.297

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Background

Gastrointestinal symptoms are common in patients with type 2 diabetes mellitus (T2DM). The prevalence of gastroesophageal reflux disease (GERD) in Korea appears to be increasing. Some studies have shown that T2DM is a risk factor for symptomatic GERD. However, this possibility is still debated, and the pathogenesis of GERD in T2DM is not yet fully understood. The aim of this study was to analyze the prevalence and risk factors (including autonomic neuropathy) of GERD in patients with T2DM.

Methods

This cross-sectional case-control study enrolled T2DM patients (n=258) and healthy controls (n=184). All participants underwent physical examinations and laboratory tests. We evaluated medical records and long-term diabetes complications, including peripheral and autonomic neuropathy in patients with T2DM. Esophagogastroduodenoscopy was performed in all patients. The Los Angeles (LA) classification was used to grade GERD. GERD was defined as LA grade A (or higher) or minimal change with GERD symptoms. GERD symptoms were examined using a frequency scale. Data were expressed as mean±standard error. Independent t-tests or chi-square tests were used to make comparisons between groups.

Results

The prevalence of GERD (32.6% vs. 35.9%, P=0.266) and GERD symptoms (58.8% vs. 59.2%, P=0.503) was not significantly different between T2DM patients and controls. We found no significant differences between T2DM patients with GERD and T2DM patients without GERD with respect to diabetic complications, including autonomic neuropathy, peripheral neuropathy, duration of DM, and glucose control.

Conclusion

The prevalence of GERD in patients with T2DM showed no difference from that of controls. GERD was also not associated with peripheral and cardiovascular autonomic neuropathy, age, or duration of DM in patients with T2DM.

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Ураження органів травлення при цукровому діабеті
M.O. Borovets , О.М. Radchenko , Kh.A. Moskva , O.Yo. Komarytsya , A.M. Urbanovych
Endokrynologia.2023; 28(3): 270. CrossRef
Metabolic effects of bariatric surgery on patients with type 2 diabetes: a population-based study
Erman O. Akpinar, Ronald S.L. Liem, Simon W. Nienhuijs, Jan Willem M. Greve, Perla J. Marang-van de Mheen, L.M. de Brauw, S.M.M. de Castro, S.L. Damen, A. Demirkiran, M. Dunkelgrun, I.F. Faneyte, G. van ‘t Hof, I.M.C. Janssen, R.A. Klaassen, E.A.G.L. Laga
Surgery for Obesity and Related Diseases.2021; 17(7): 1349. CrossRef
The effect of proton pump inhibitors on glycaemic control in diabetic patients
Muhammad Ali Rajput, Fizzah Ali, Tabassum Zehra, Shahid Zafar, Gunesh Kumar
Journal of Taibah University Medical Sciences.2020; 15(3): 218. CrossRef
Prediabetes and gastrointestinal (GI) symptoms; a cross-sectional study
Akram Ghadiri-Anari, Somaye Gholami, Fariba Zolfaghari, Nasim Namiranian
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2019; 13(1): 844. CrossRef
Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management
Yang T. Du, Christopher K. Rayner, Karen L. Jones, Nicholas J. Talley, Michael Horowitz
Diabetes Care.2018; 41(3): 627. CrossRef
Features of Endoscopic Changes in Gastroesophageal Reflux Disease in Patients with Type II Diabetes Mellitus
Ye. S. Sirchak, M. P. Stan, Yo. I. Pichkar, V. V. Vajs
Ukraïnsʹkij žurnal medicini, bìologìï ta sportu.2018; 3(5): 166. CrossRef
Prevalence and Correlates of Gastroesophageal Reflux Disease in Southern Iran: Pars Cohort Study
Zohre Khodamoradi, Abdullah Gandomkar, Hossein Poustchi, Alireza Salehi, Mohammad Hadi Imanieh, Arash Etemadi, Reza Malekzadeh
Middle East Journal of Digestive Diseases.2017; 9(3): 129. CrossRef
Letter: Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J2016;40:297-307)
Dongwon Yi
Diabetes & Metabolism Journal.2016; 40(5): 418. CrossRef
Response: Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J2016;40:297-307)
Jun Ouk Ha, Tae Hee Lee, Chang Won Lee
Diabetes & Metabolism Journal.2016; 40(5): 420. CrossRef

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.

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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
Diabetes & Metabolism Journal.2018; 42(6): 519. CrossRef
Association between Pain Sensitivity, Central Sensitization, and Functional Disability in Adolescents With Joint Hypermobility
Elizabeth A. Bettini, Ki Moore, Yunfei Wang, Pamela S. Hinds, Julia C. Finkel
Journal of Pediatric Nursing.2018; 42: 34. CrossRef
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

The Effect of Alpha-Lipoic Acid on the Protection of Epidermal Nerve Fibers and Microcapillaries in the Streptozotocin-Induced Diabetic Rats.: Ming Han Piao, Heung Yong Jin, Sun Kyung Song, Seun Mi Kang, So Young Kim, Ji Hyun Park, Hong Sun Baek, Tae Sun Park; Korean Diabetes J. 2007;31(6):488-497. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.488

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Abstract PDF: BACKGROUND
Diabetic neuropathy is associated with risk factors for macrovascular diseases and other microvascular complications. Alpha-lipoic acid (ALA) administration has been reported to improve metabolic abnormalities and ameliorate peripheral polyneuropathy in diabetic patients. In addition, ALA improves endoneurial nutritive neural blood flow and nerve conduction velocity in diabetic rats. But it is not clear whether ALA has a preservation effect on microvasculature in addition to the effect on intraepidermal nerve fibers (IENFs). We investigated the effect of ALA on intraepidermal nerve fiber density (numbers/mm) and cutaneous capillary length in streptozotocin-induced diabetic rats. METHODS: The rats were randomly divided into 3 groups: diabetes without diet control, diabetes with diet control, and diabetes with ALA treatment. Diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg) and the effect of ALA treatment was assessed by IENF immunostained with protein gene product 9.5 and by quantification of total cutaneous capillary length with mouse anti-rat reca-1 immunostaining. RESULTS: The value of IENF density significantly increased in ALA treatment group compared with other groups (P < 0.05). Quantification of microvascularity was also significantly increased in ALA treatment group compared with other groups (P < 0.05). CONCLUSION: The results of this study suggest that ALA administration in diabetic rats may be beneficial in the prevention of peripheral neuropathy associated with improvement of microvascularity. And the symptomatic amelioration after ALA treatment may be attributed to this morphological improvement.

The Association of Aldose Reductase Gene Polymorphisms with Neuropathy in Patients with Type 2 Diabetes.: In Kyong Jeong, Kyong Soo Park, Min Kyong Moon, Jae Hyeon Kim, Chan Soo Shin, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2007;31(3):274-283. Published online May 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.3.274

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BACKGROUND
Previous studies have suggested that polymorphisms in and around the aldose reductase (AR) gene are associated with the development of diabetic microvascular disease. This study explored the hypothesis that the polymorphisms of the (A-C)n dinucleotide repeat sequence, located at 2.1 kilobase (kb) upstream of the transcription start site of AR gene, modulate the risk of diabetic neuropathy (DN). METHODS: 66 patients with DN, 30 without microvascular complications (MC) after 20 years of diabetes, and 87 normal healthy controls were studied. To test highly polymorphic microsatellite marker 2.1 kb upstream of the initiation site of the AR gene, we performed polymerase chain reaction using the primer labeled with fluorescent dye and GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0. RESULTS: Seven alleles (Z-6, Z-4, Z-2, Z, Z+2, Z+4 and Z+6) were identified. Z-2 allele was more frequently observed in patients with DN (77.3%) than in those without MC (43.3%, P = 0.007). The subgroup of patients who developed DN within 5 years after the diagnosis of diabetes also had higher frequency of Z-2 allele (91.7%) compared to those without MC (43.3%, P = 0.028). On the contrary, Z+6 allele tended to be more frequent in patients without MC (10.0%) than in those with DN (0%, P = 0.063). CONCLUSION: These results support the hypothesis that environmental-genetic interactions may modulate the risk of neuropathy in patients with diabetes. Particularly, the Z-2 allele, in the presence of diabetes, may be associated with the development of DN.

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The Association between Serum GGT Concentration and Diabetic Peripheral Polyneuropathy in Type 2 Diabetic Patients
Ho Chan Cho
Korean Diabetes Journal.2010; 34(2): 111. CrossRef

The Effects of Alpha-Lipoic Acid on Epidermal Nerve Preservation in the Diabetic Neuropathy of OLETF Rats.: Ming Han Piao, Ji Hyun Park, Hong Sun Baek, Tae Sun Park; Korean Diabetes J. 2006;30(3):170-176. Published online May 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.3.170

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Abstract PDF: BACKGROUND
Alpha-Lipoic acid (ALA) administration has been reported to ameliorate some of symptoms of peripheral polyneuropathy in diabetic patients and to improve endoneurial nutritive neural blood flow and nerve conduction velocity in diabetic rats. But it is not clear whether ALA has the preservation effect on epidermal nerve fibers (ENFs) density. METHODS: We tested the efficacy of ALA in preserving current perception thresholds (CPTs) and ENFs (numbers/mm) in OLETF (Otsuka Long-Evans Tokushima Fatty) rats, an animal model of type 2 diabetes, which were fed with sucrose until diabetes mellitus developed. Thereafter, one group of OLETF rats was fed with ALA and the other was not for 40 weeks. Diabetic rats were administered with ALA (80 mg/kg of body weight/day) by oral feeding for 40 weeks. The effect of ALA treatment on ENFs preservation was assessed by protein gene product 9.5 immunostaining. Quantification of neuropathic symptoms on the dorsum of hind paws of rat was measured by CPT test every 4 weeks. RESULTS: Numbers of ENF significantly decreased in OLETF rats fed without ALA compared with OLETF rats fed with ALA (P < 0.01). The thresholds at 2000, 250 and 5 Hz in OLETF rats fed with ALA did not increased and OLETF rats without ALA significantly increased at 80 weeks (P < 0.01). CONCLUSION: These observations suggest that administrations of ALA may be useful for preserving ENFs and CPTs in OLETF rats dorsum of hind paws skin.

Randomized Controlled Trial

The Comparison of Efficacy with alpha-lipoic Acid Treatment Methods in Diabetic Polyneuropathy.: Hyejin Lee, Kyung Wan Min, Kyung Ah Han; Korean Diabetes J. 2006;30(2):112-121. Published online March 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.2.112

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Abstract PDF: BACKGROUND
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Antioxidant treatment has been shown to prevent nerve dysfunction, providing a rationale for a potential therapeutic value in diabetic patients. The safety and efficacy of alpha-lipoic acid (ALA) given intravenously were proved in many studies, but the oral treatment remains to be established. Therefore we compare the efficacy and safety of ALA given intravenously followed by oral treatment and given only orally. METHODS: 45 outpatients were randomly assigned to sequential treatment with ALA intravenously for 2 weeks, followed by orally for 10 weeks (group 1, n = 21); ALA orally for 12 weeks (group 2, n = 24). The primary end point was change of the sum score of severity and duration of total symptom score (TSS). HbA1c and safety parameters were determined at baseline and after 12 weeks. RESULTS: The TSS was significantly decreased from baseline to 2 week and 12 week in both groups. But no significant differences between the two groups were noted at 2 week and 12 week. There were no significant changes in HbA1c and safety parameters between baseline and 12 week. The rate of adverse events were 47.6% in group 1 and 12.5% in group 2. CONCLUSION: We conclude that both methods of ALA treatment are effective to improve the symptoms of diabetic polyneuropathy, and the safety was probably superior in oral treatment method

Original Articles

Effect of 12-week Oral Treatment with alpha-lipoic acid on the Nerve Conduction in Symptomatic Diabetic Neuropathy.: Tae Seo Sohn, Jung Min Lee, Sang Ah Chang, Hyun Shik Son, Bong Youn Cha, Ho Young Son, Kwang Woo Lee, Sung Ku Kang; Korean Diabetes J. 2005;29(6):533-539. Published online November 1, 2005

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Abstract PDF: BACKGROUND
Diabetic peripheral neuropathy is multifactorial disorder arising from hyperglycemia and insulin deficiency. It has been suggested that oxidative stress resulting from enhanced free-radical formation and defects in antioxidant defence plays a major role among the putative pathogenic mechanisms of diabetic neuropathy. As alpha-lipoic acid, a natural antioxidant, has been suggested to improve symptoms of diabetic neuropathy, we assessed the efficacy of alpha-lipoic acid on neuropathic symptoms and peripheral nerve conduction in patients with type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: A cohort of 30 type 2 diabetic patients with symptomatic polyneuropathy received a daily dose of 600 mg alpha-lipoic acid, and was followed for 3 months. Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) of the feet were scored at monthly interval and summarized as a Total Symptom Score (TSS). Nerve conduction study was done before and after 3 month treatment of alpha-lipoic acid. RESULTS: Treatment of alpha-lipoic acid given 600 mg per oral for 12 weeks improved the symptoms of diabetic polyneuropathy. Effects of alpha-lipoic acid on nerve conduction study were that in the motor nerve, the amplitudes of median nerve and tibial nerve and the conduction velocity of tibial nerve improved after 12 weeks treatment. In the sensory nerve, the conduction velocities of median nerve, ulnar nerve, and sural nerve improved after 12 weeks. CONCLUSION: alpha-Lipoic acid was effective in the treatment of diabetic peripheral polyneuropathy improving both clinical manifestations and nerve conduction. The improvement of clinical manifestations may be due to improved conduction velocity of sensory fibers.

Evaluation of the Indicator Test(NeurocheckTM) in the Diagnosis of Peripheral Neuropathy among Type 2 Diabetic Patients.: Tae Seo Sohn, Hyun Shik Son, Jae Myung Yu, Bong Soo Cha, Kyung Wan Min, Sei Hyun Baik; Korean Diabetes J. 2005;29(3):247-253. Published online May 1, 2005

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Abstract PDF: BACKGROUND
Eighty-five percent of the lower-limb amputations that are done for patients with diabetes are preceded by foot ulceration, and this suggests that prevention and the appropriate management of foot lesions are of paramount importance. Ulceration is caused by several factors acting together, but they are particularly caused by neuropathy. Various aspects of the neurovascular function can be evaluated with specialized tests, but these tests have generally not been well standardized and they have limited clinical utility. A new indicator test(NeurocheckTM) that utilizes the water-induced color change of a cobaltII compound from blue to pink has been introduced. The aim of the present study was to evaluate this new indicator test in the diagnosis of peripheral neuropathy among type 2 diabetic patients. METHOD: This study included 124 diabetic patients(45 men and 79 women) who were recruited from 5 diabetic centers in Korea. The presence of diabetic neuropathy was diagnosed by nerve conduction study. The degree of the patient's symptom was checked as the total symptom score(TSS). Autonomic sudomotor neuropathy was assessed by means of the new indicator test(NeurocheckTM). The degree of color change in 10 minutes was assessed as a complete color change, an incomplete color change or no color change. RESULTS: Of the 124 diabetics patients we investigated, 109 patients were proven to have peripheral neuropathy by nerve conduction study. Autonomic sudomotor neuropathy by NeurocheckTM was diagnosed in 94 patients with peripheral neuropathy(86.2%) and in 6 patients(40%) without peripheral neuropathy. The overall measure of agreement between NeurocheckTM and the electrodiagnostic test was 0.3673(0.1547, 0.58). The sensitivity and specificity of NeurocheckTM was higher in women(91.2% and 63.6%, respectively) than in men(78.0% and 50.0%, respectively). The measure of agreement in women was 0.5093(0.2396, 0.9601) and in the men it was 0.1567(-0.1423, 0.4588). CONCLUSION: The new indicator test has a high sensitivity for the diagnosis of peripheral neuropathy among diabetic patients, especially in women. It is likely that the new indicator test is useful clinically as a screening and diagnostic tool for diabetic neuropathy. Since the specificity of the test is somewhat low, the patients with a high total symptom score and who are without sudomotor neuropathy may need further diagnostic evaluation on neuropathy

Differences in Dynamic Plantar Pressure in Type 2 Diabetics with or without Peripheral Neuropathy.: Gui Hwa Jeong, Ju Young Lee, Shin Won Lee, Chang Hoon Choi, Soon Hee Lee, Jung Guk Kim, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2002;26(6):481-489. Published online December 1, 2002

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Abstract PDF: BACKGROUND
Foot ulcers, and lower-extremity amputations, are relatively common complications of diabetes mellitus and their clinical management is very important. High plantar pressure is known to be a major risk factor of foot ulceration in diabetic patients. The EMED-system is used for the assessment of pressure distribution for the identification of focal areas at high risk of ulceration that merit protection from preventive footwear. However, a potential relationship between diabetic neuropathy and the plantar pressure has not been fully evaluated. Changes in the plantar pressure were measured in diabetic patients, both with and without peripheral polyneuropathy, using the EMED - AT system to clarify if diabetic neuropathy increases the plantar pressure. METHODS: Ninety seven patients with type 2 diabetes were divided into two groups on the basis of their peripheral polyneuropathy. No patient had a past history of foot ulceration. The clinical characteristics of 2 groups were analyzed, and their plantar pressures was measured using the EMED - AT system. These results were analyzed, with the EMED software program, after their division into ten masks for a so-called "regional analysis". The pressure time (PTI) and force- time (FTI) integrals were analyzed for each mask on both feet. RESULTS: The diabetic neuropathy (DN) group showed significantly higher FTI levels in both masks 05 (area of the 1st metatarsal head) and masks 08 (area of the hallux) than the diabetic control (DC) group. The PTI was also higher in right the mask 08 of the DN group than in the DC group. CONCLUSION: These results suggest that peripheral neuropathy to be an important risk factor, and predictor of diabetic foot ulcers, due to the increasing plantar pressure in some areas of the foot. Measurement of the plantar pressure may be a useful method for the diagnosis and monitoring of foot disorders in diabetic patients with peripheral neuropathy.

Detection of Diabetic Autonomic Neuropathy by 24-Hour Heart Rate Variability Analysis in Type 2 Diabetes Mellitus Patients.: Young Hee Rho, Nan Hee Kim, Dong Lim Kim, Dong Hyun Shin, Sin Gon Kim, Kyung Mook Choi, Woo Hyuk Song, Sei Hyun Baik, Woo Keun Seo, Min Kyu Park, Dong Seop Choi; Korean Diabetes J. 2002;26(3):208-219. Published online June 1, 2002

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Abstract PDF: BACKGROUND
Diabetic autonomic neuropathy is a relatively common diabetic complication, associated with high long-term mortality. Ewing's test is known as the 'gold standard' for evaluating and diagnosing this disease, yet is not widely used due to the inconvenient procedures of the test. 24-hour Holter EKG monitoring, and the analytical product, heart rate variability, is being introduced as a relatively simple and reliable procedure for the evaluation of diabetic autonomic neuropathy. We explored whether such heart rate variability products derived from Holter monitoring, correlated with the presence, absence, or severity of diabetes mellitus, and whether it correlated well with conventional autonomic tests. METHODS: We compared 59 type 2 diabetic patients with 71 normal subjects. All underwent 24-hr Holter EKG monitoring and basic autonomic evaluations, such as the head-up tilting, hand grip, and deep breathing-heart rate variability tests. Those who had diabetes also underwent evaluation for basic blood chemistry, and complication studies, for things such as: 24-hour urine albumin excretion, fundoscopy and nerve conduction. RESULTS: Variables for heart rate variability were expressed as SDDN, rMSSD, LF, HF, and LF/HF, where SDDN is the Standard Deviation of all RR intervals, rMSSD the square root of the mean of the sum of the squares of differences between adjacent RR intervals, LF the power in the Low Frequency range and HF the power in the High Frequency range, with LF/HF being the ratio between LF and HF. Heart rate variability was significantly lower in terms of rMSSD, LF, HF, but not in terms of the LF/HF ratio, for the diabetic patients compared to the normal subjects. These three variables also correlated with the conventional autonomic tests of systolic blood pressure changes during standing up (negatively), and heart rate variability during deep breathing (positively). SDDN, rMSSD, LF, and HF also correlated negatively with the duration of diabetes. SDDN, LF and HF were significantly lower among patients who had complications such as: retinopathy, nephropathy or peripheral neuropathy, than in those who did not. CONCLUSION: Heart rate variability was lower in type 2 diabetic patients than the control subjects, which correlated well with the duration of diabetes mellitus, diabetic chronic complications and the conventional autonomic nervous function tests, so could be an useful adjunct or even a replacement, for conventional autonomic nervous system testing procedures. More research is needed in this field.

Effect of Nerve Growth Factor on Cultured Mouse Dorsal Root Ganglion Cells in Hyperglycemic Condition.: Byoung Hyun Park, Chung Gu Cho, Geun Young Jang, Ki Hun Kim, Seung Taeck Park; Korean Diabetes J. 2001;25(4):286-296. Published online August 1, 2001

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Abstract PDF: BACKGROUND
Multiple etiology of diabetic neuropathy has been proposed, including altered polyol metabolism, superoxide radical formation, protein glycation, vascular insufficiency, blunted nitric oxide production and neurotrophic factor (NTF) deficiency. Nerve growth factor (NGF) is a member and family of neurotrophic factors. NGF is produced in tissues innervated by its responsive neurons. In the peripheral nervous system, NGF messenger RNA (mRNA) is produced in target fields of small pain and temperature-mediating dorsal root ganglia (DRG) sensory neurons and sympathetic neurons. NGF has been shown to promote their survival, differentiation, and maintenance. However, the mechanism of neuronal damage in diabetes and the effect of NGF on diabetic neuropathy are not clear. METHODS: In order to clarify the effect of NGF, the changes of cell viability were evaluated by MTT assay on mouse cultured dorsal root ganglion cells which were grown with media containing concentrations of high glucose for inducing hyperglycemic condition. Furthermore, the neuroprotective effect of nerve growth factor (NGF) against hyperglycemia-induced dorsal root ganglion cell changes were also examined. RESULTS: 1. Cell viability of cultured mouse dorsal root ganglion cells treated with hyperglycemic media made with 15, 25 mM glucose was markedly decreased in a dose-dependent manner when compared with control medium (normoglycemic medium) containing concentration of 5.5 mM glucose (p<0.05). 2. Cultured dorsal root ganglion cells exposed to hyperglycemic medium made with 25 mM glucose for 72 hours showed morphological changes such as dissociations, loss of neurites and decrease of cell viability (p<0.05). 3. Pretreatment of 150 ng/mL NGF for 2 hours significantly increased the cell viability of cultured dorsal root ganglion cells which exposed to hyperglycemic medium (25 mM glucose for 72 hours). CONCLUSION: Findings from this study suggested that hyperglycemic condition induces the decrease of cell viability and morphological changes (loss of neurites, dissociation) on cultured dorsal root ganglion cells of mouse. Furthermore, selective neurotrophic factors such as NGF are very effective in preventing dysfunction and morphological changes of DRG cells induced by hyperglycemic condition.

Chronic Diabetic Complications in the Insulin- Treated Animal Model of Type 2 Diabetes Mellitus.: Jee Won Park, Sung Kyu Lee, Hyo Jung Kim, Hae Lim Noh, Chang Young Hah, Su Jin Lee, Yoon Sok Chung, Kwan Woo Lee, Hyun Man Kim, Eun Ju Paek; Korean Diabetes J. 2001;25(3):200-210. Published online June 1, 2001

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Abstract PDF: BACKGROUND
Non-Insulin Dependent Diabetes Mellitus (NIDDM) is a characterized by insulin resistance and impairment of beta cell function. OLETF male rat usually developed NIDDM and obesity at 20 weeks old spontaneously. It is a metabolically characterized by insulin resistance in onset of early disease. However, body weight and insulin secretory function was gradually reduced during the diabetes developed. These characteristics of disease is similar to Korean type 2 diabetic patients. NIDDM patients in Korea are thought to be different from traditional NIDDM in western countries. They are non obese type and also has reduced insulin secretory function compared to western countries. These patients are not easily managed on diet and/or oral hypoglycemic agent. Reduced C-peptide and insulin concentrations in these patients are similar to patients with IDDM. In these patients, insulin therapy is effective to control glucose level. Therefore, we investigated the effect of insulin and oral hypoglycemic therapy to glucose control and severity of chronic complications in OLETF male rats of 6weeks (42 weeks old) and 14 weeks (50 weeks old) treated groups. MATERIAL AND METHODS: The OLETF male rats which are 36 weeks old is diagnosed to NIDDM. A total of 20 rats were stratified into the three groups: control group (n=3), OHA's group; rats treated by OHA's (n=3) and insulin group; rats treated with insulin (n=4). We evaluated anthropometry, fasting glucose and 75 gram OGATT, nerve conduction studies, sclerotic degree of kidney and thickness of carotid arteries at 42 and 50 weeks old. RESULTS: In the 42 weeks old groups (6 weeks treated group), there was a significant difference in weight gain in group 3 but no differences were observed in kidney tissue pathology and thickness of carotid arteries. In the 50 weeks old groups (14 weeks treated group), there were also no changes in the kidneys and arteries, but weight gain and peak amplitude in NCV was significantly higher in insulin - treated group. CONCLUSIONS: OLETF male rats as NIDDM animal mocel, with late stage diabetic complications show weight loss and decreased insulin secretory capacity. Insulin treated group shows improved blood glucose control. Also it showed improved severity of diabetic neuropathy.

The Effect of Ginkgo Biloba Extract on Diabetic Peripheral Neuropathy - A 12 week, randomized, placebo-controlled, double-blind trial -.: Kyung Mook Choi, Dong Rim Kim, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi; Korean Diabetes J. 2000;24(3):375-384. Published online January 1, 2001

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Abstract PDF: BACKGROUND
In the pathogenesis of diabetic neuropathy, metabolic derangement and ischemic damage have been considered as the major possible mechanisms. Ginkgo biloba extract was known to improve microcirculation by its vasodilator and antiplatelet effects, and used for peripheral and cerebral circulatory disorder. It also acts as free radical scavenger and inhibits oxidative damage. Thus, in this study we evaluate the effects of Ginkgo biloba extract on symptoms and nerve conduction study in patients with diabetic peripheral neuropathy. METHODS: In this study, over 3 months period, we recruited a total of 33 type 2 diabetic patients with peripheral neuropathy. Nineteen patients were randomly assigned to receive placebo, and fourteen patients to receive Ginkgo biloba extract (40 mg tid) for a duration of 12 weeks. We measured fasting blood glucose, postprandial 2 hour blood glucose levels, glycosylated hemoglobin and the lipid profiles. Clinical evaluation included neuropathy symptom score and nerve conduction study, and it was performed before and after the treatment. RESULTS: During the treatment, fasting blood glucose, postprandial 2 hour blood glucose, glycosylated hemoglobin and the lipid profiles were not significantly changed. Furthermore, no significant changes of neuropathy symptom score were observed during the treatment period. However, in Ginkgo biloba extract treatment group, motor nerve conduction velocities of median and ulnar nerve were improved significantly when compared to the placebo group. CONCLUSION: With the 12 weeks Ginkgo biloba extract treatment, we observed some improvement of nerve conduction velocity without any serious side effect.

Effect of Nerve Growth Factor on Cultured Rat Schwann Cells in Hyperglycemic Condition.: Geun Young Hyung, Kyoung Hee Kim, Seung Hoon Baek, Geun Young Jang, Chung Gu Cho; Korean Diabetes J. 2000;24(1):10-18. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Nerve growth factor (NGF) is produced in tissues innervafed by its responsive neurons. In the peripheral nervous system, NGF messenger RNA (mRNA) is produced in target fields of small pain and temperature-mediating dorsal root ganglia (DRG) sensory neurons and sympathetic neurons. NGF receptors are expressed in these neurons, and NGF has been shown to promote their survival, differentiation, as well as maintenance. However, the mechanism of neuronal damage in diabetes and the effect of NGF on diabetic neuropathy are unclear. METHODS: in order to clarify the effect of hyperglycemia, the hyperglycemia-induced cytotoxic effects were evaluated by MTT assay on cultured rat Schwann cells, Schwann cells were grown with media containing concentrations of high glucose for inducing hyperglycemic condition. The neuroprotective effect of nerve growth factor (NGF) against hyperglycemia-induced Schwann cell changes were also examined. RESULT: 1. MMT50 value was at concentration of 25mM glucose after 72 hours, 2. Cell viability of cultured rat Schwann cells treated with hyperglycemic media made with 25~35mM glucose was markedly decreased in a dose-dependent manner when compared with control medium (normoglycemic medium) containing concentration of 5.5 mM glucose, While cell number did not show a dose- dependent decrease. 3. Cultured Schwann cells exposed to hyperglycemic medium made with 25mM glucose for 72 hours did nof show any morphological change as well as decrease of cell number. 4. Pretreatment of 10 ng/mL NGF for 2 hours increased remarkably the cell viability of cultured Schwann cells exposed to hyperglycemic medium(25mM glucose for 72 hours). CONCLUSIONS: The results from this study suggested that hyperglycemic condition induces the decrease of cell viability on cultured Schwann cells of rat. But it did not show the decrease of cell number and rnorphological change. The selective neurotrophic factors such as NGF are very effective in preventing dysfunction of cells induced by hyperglycemic condition.

Analgesic Effects of DA-5018, a New Capsaicin Derivative, in Hyperalgesia of Experimental Diabetic Neuropathy.: Eun Ju Bae, Soon How Kim, Moon Ho Son, Hee Kee Kim, Myeong Soo Shin, Hyun Ji Kim, Won Bae Kim; Korean Diabetes J. 1997;21(1):91-101. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Painful peripheral neuropathy is one of the most common complications of diabetes and not responsive to conventional analgesics. Capsaicin cream has been used to treat the pain associated with diabetic neuropathy, rheumatoid arthritis, osteoarthritis and postherpetic neuralgia. But its common side effect, burning sensation, limits the use of it. DA-5018 is a newly synthesized capsaicin derivative which shows more potent systemic and topical analgesia than capsaicin in various animal models of acute and chronic pain, but has little skin irritaion. This study was designed to evaluate the effect of DA-5018 administered systemically or topically on hyperalgesia in streptozotocin-induced diabetic and galactosaemic rats. METHODS: One group of SD rats was treated with streptozotocin(60mg/kg, I.v.) and the pain thresholds were determined weekly by Randall-Selitto paw pressure test. And the other group of SD rats was maintained on 50%-galactose diet until 4~5 weeks and the pain thresholds were determined as well, Drugs were administered subcutaneously once a day for 7 days or topically to the paw for 5 hours a day for 10 days at a time when the hyperalgesia was already present. The increase of pain thresholds by drug was regarded as an indication of analgesia. RESULTS: Streptozotocin-diabetic rats displayed a reduction of pain threshold. Similarly, galactosefeeding resulted in significant reduction of pain threshold. It is concluded that hyperalgesia is a constant feature of sensory dysfunction in experimental models of diabetic and nutritional neuropathy. DA-5018(0.2, 0.5mg/kg, s.c.) produced significant antinociception with efficacy similar to that of capsaicin(10mg/kg, s.c.) in streptozotocin-induced hyperalgesia and furthermore, no tolerance developed for 7 days. And this analgesic effect was superior to desipramine(10mg/kg, s.c.). But ketoprofen(10mg/kg, s.c.) produced no analgesia. Topically, 0.3% DA-5018 cream was as effective as Zostrix-HP(capsaicin 0.075%) both in streptozotocin-diabetic and galactosefed rats while Kenofen gel(ketoprofen 3%) was ineffective to reduce pain. CONCLUSION: These results demonstrate the potent analgesic efficacy of DA-5018 in diabetic pain models and suggest that topical DA-5018 cream may relieves pain caused by diabetic neuropathy offering an alternative for patients not responsive to other treatments or unable to tolerate capsaicin.

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