Diabetes & Metabolism Journal

Original Articles

Drug/Regimen
Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial: Jie-Eun Lee, Seung Hee Yu, Sung Rae Kim, Kyu Jeung Ahn, Kee-Ho Song, In-Kyu Lee, Ho-Sang Shon, In Joo Kim, Soo Lim, Doo-Man Kim, Choon Hee Chung, Won-Young Lee, Soon Hee Lee, Dong Joon Kim, Sung-Rae Cho, Chang Hee Jung, Hyun Jeong Jeon, Seung-Hwan Lee, Keun-Young Park, Sang Youl Rhee, Sin Gon Kim, Seok O Park, Dae Jung Kim, Byung Joon Kim, Sang Ah Lee, Yong-Hyun Kim, Kyung-Soo Kim, Ji A Seo, Il Seong Nam-Goong, Chang Won Lee, Duk Kyu Kim, Sang Wook Kim, Chung Gu Cho, Jung Han Kim, Yeo-Joo Kim, Jae-Myung Yoo, Kyung Wan Min, Moon-Kyu Lee; Diabetes Metab J. 2024;48(4):730-739. Published online May 20, 2024; DOI: https://doi.org/10.4093/dmj.2023.0077

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Abstract PDF Supplementary Material PubReader ePub: Background
It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia.
Methods
This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment.
Results
After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. −0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (−55.20% vs. −7.69%, P<0.001) without previously unknown adverse drug events.
Conclusion
The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin’s preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Drug/Regimen
Safety and Effectiveness of Empagliflozin in Korean Patients with Type 2 Diabetes Mellitus: Results from a Nationwide Post-Marketing Surveillance: Jun Sung Moon, Nam Hoon Kim, Jin Oh Na, Jae Hyoung Cho, In-Kyung Jeong, Soon Hee Lee, Ji-Oh Mok, Nan Hee Kim, Dong Jin Chung, Jinhong Cho, Dong Woo Lee, Sun Woo Lee, Kyu Chang Won; Diabetes Metab J. 2023;47(1):82-91. Published online June 20, 2022; DOI: https://doi.org/10.4093/dmj.2021.0356

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Background
To evaluate the safety and effectiveness of empagliflozin in routine clinical settings, we collected and assessed the clinical profiles of Korean patients with type 2 diabetes mellitus.
Methods
This was a post-marketing surveillance study of empagliflozin 10 and 25 mg. Information on adverse events and adverse drug reactions (ADRs) was collected as safety data sets. Available effectiveness outcomes, including glycosylated hemoglobin (HbA1c) level, fasting plasma glucose, body weight, and blood pressure, were assessed.
Results
The incidence rate of ADRs was 5.14% in the safety dataset (n=3,231). Pollakiuria, pruritis genital, and weight loss were the most common ADRs. ADRs of special interest accounted for only 1.18%, and there were no serious events that led to mortality or hospitalization. In the effectiveness data set (n=2,567), empagliflozin significantly reduced the mean HbA1c level and body weight during the study period by –0.68%±1.39% and –1.91±3.37 kg (both P<0.0001), respectively. In addition, shorter disease duration, absence of dyslipidemia, and higher baseline HbA1c levels were identified as the clinical features characteristic of a “responder” to empagliflozin therapy.
Conclusion
Empagliflozin is a safe and potent glucose-lowering drug in routine use among Korean patients with type 2 diabetes mellitus. It is expected to have better glycemic efficacy in Korean patients with poorly controlled type 2 diabetes mellitus.

Citations

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Evaluation of Efficacy and Safety of Empagliflozin in Bangladeshi Patients with Type 2 Diabetes Mellitus (EFFISAEM Study)
Mohammad Saifuddin, Ajit Kumar Paul, Sultana Marufa Shefin, Md. Jahangir Alam, Shahjada Selim, Sunjida Islam, Tanjina Hossain, Sadiqa Tuqan, Nusrat Sultana, Marufa Mustari, Ramen Chandra Basak, Kazi Ali Aftab, Indrajit Prasad, Mohammad Rafiq Uddin, Shoma
Indian Journal of Endocrinology and Metabolism.2024;[Epub] CrossRef
Blood pressure reduction with empagliflozin in Japanese patients with type 2 diabetes and cardiovascular diseases: a post-hoc sub-analysis of the placebo-controlled randomized EMBLEM trial
Atsushi Tanaka, Michio Shimabukuro, Hiroki Teragawa, Hisako Yoshida, Yosuke Okada, Toshinari Takamura, Isao Taguchi, Shigeru Toyoda, Hirofumi Tomiyama, Shinichiro Ueda, Yukihito Higashi, Koichi Node, Junya Ako, Hirohisa Amano, Itaru Hisauchi, Yumi Ikehara
Hypertension Research.2024; 47(9): 2295. CrossRef
Comparison of the Pharmacokinetics, Safety, and Tolerability of Two Empagliflozin Formulations in Healthy Korean Subjects
Xu Jiang, Sungyeun Bae, Deok Yong Yoon, Shin Jung Park, Jaeseong Oh, Joo-Youn Cho, Kyung-Sang Yu
Drug Design, Development and Therapy.2023; Volume 17: 2137. CrossRef
Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials
Chun Xing Li, Li Yan Liu, Chen Xiao Zhang, Xu Hua Geng, Si Meng Gu, Yu Qiao Wang, Hua Liu, Qing Xie, Shuo Liang
Frontiers in Endocrinology.2023;[Epub] CrossRef

Drug/Regimen
Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study: Jeong Mi Kim, Sang Soo Kim, Jong Ho Kim, Mi Kyung Kim, Tae Nyun Kim, Soon Hee Lee, Chang Won Lee, Ja Young Park, Eun Sook Kim, Kwang Jae Lee, Young Sik Choi, Duk Kyu Kim, In Joo Kim; Diabetes Metab J. 2020;44(1):67-77. Published online July 11, 2019; DOI: https://doi.org/10.4093/dmj.2018.0274

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Background

There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM.

Methods

This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement.

Results

Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: −0.81%, P<0.001; glimepiride: −1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001).

Conclusion

Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.

Citations

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Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial
Ji-Yeon Park, Joonyub Lee, Yoon-Hee Choi, Kyung Wan Min, Kyung Ah Han, Kyu Jeung Ahn, Soo Lim, Young-Hyun Kim, Chul Woo Ahn, Kyung Mook Choi, Kun-Ho Yoon
Diabetes & Metabolism Journal.2024; 48(5): 915. CrossRef
Efficacy and Safety of Pioglitazone Add-on in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Dapagliflozin: A Multicenter, Randomized, Double-blind, and Placebo-controlled Study
Yun Kyung Cho, Kyung-Soo Kim, Byung-Wan Lee, Jun Hwa Hong, Jae Myung Yu, Soo Lim, Ye An Kim, Chang Beom Lee, Sang Soo Kim, Soo Heon Kwak, Woo Je Lee
Clinical Therapeutics.2024; 46(9): 662. CrossRef
Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial
Ji Hye Heo, Kyung Ah Han, Jun Hwa Hong, Hyun-Ae Seo, Eun-Gyoung Hong, Jae Myung Yu, Hye Seung Jung, Bong-Soo Cha
Diabetes & Metabolism Journal.2024; 48(5): 937. CrossRef
Cost-effectiveness and budget impact analysis of fixed combination of alogliptin and pioglitazone in the treatment of type 2 diabetes mellitus
Yu.V. Strunina, N.A. Petunina
Medical Technologies. Assessment and Choice.2023; (3): 70. CrossRef
Pioglitazone-Enhanced Brown Fat Whitening Contributes to Weight Gain in Diet-Induced Obese Mice
Piaojian Yu, Wei Wang, Wanrong Guo, Lidan Cheng, Zhiping Wan, Yanglei Cheng, Yunfeng Shen, Fen Xu
Experimental and Clinical Endocrinology & Diabetes.2023; 131(11): 595. CrossRef
Compliance with Cardiovascular Prevention Guidelines in Type 2 Diabetes Individuals in a Middle-Income Region: A Cross-Sectional Analysis
Joaquim Barreto, Beatriz Luchiari, Vaneza L. W. Wolf, Isabella Bonilha, Ticiane G. Bovi, Barbara S. Assato, Ikaro Breder, Sheila T. Kimura-Medorima, Daniel B. Munhoz, Thiago Quinaglia, Otavio R. Coelho-Filho, Luiz Sergio F. Carvalho, Wilson Nadruz, Andrei
Diagnostics.2022; 12(4): 814. CrossRef
Effects of Glimepiride Combined with Recombinant Human Insulin Injection on Serum IGF-1, VEGF and TRACP-5b Oxidative Stress Levels in Patients with Type 2 Diabetes Mellitus
Xue Chen, Sheng Kang, Zeqing Bao, Ciara Hughes
Evidence-Based Complementary and Alternative Medicine.2022; 2022: 1. CrossRef
Glycaemic control with add‐on thiazolidinedione or a sodium‐glucose co‐transporter‐2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24‐week, randomized controlled trial
Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef
Development and validation of a sensitive LC-MS/MS method for pioglitazone: application towards pharmacokinetic and tissue distribution study in rats
Kusuma Kumari G., Praveen Thaggikuppe Krishnamurthy, Ravi Kiran Ammu V. V. V., Kurawattimath Vishwanath, S. T. Narenderan, B. Babu, Nagappan Krishnaveni
RSC Advances.2021; 11(19): 11437. CrossRef
Compliance with Cardiovascular Prevention Guidelines in Individuals with Type 2 Diabetes in a Middle-Income Region: Cross-Sectional Analysis
Joaquim Barreto, Beatriz Luchiari, Vaneza Lira W. Wolf, Isabella Bonilha, Ticiane G. Bovi, Barbara S. Assato, Ikaro Breder, Sheila T. Kimura-Medorima, Daniel B. Munhoz, Thiago Quinaglia, Otavio R. Coelho-Filho, Luiz Sérgio Fernandes de Carvalho, Wilson Na
SSRN Electronic Journal .2021;[Epub] CrossRef

Others
Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor: Na Han, You Jeong Kim, Su Min Park, Seung Man Kim, Ji Suk Lee, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Mi-kyung Kim, Byoung Doo Rhee, Jeong Hyun Park; Diabetes Metab J. 2016;40(5):396-405. Published online September 1, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.396

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Background

Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion.

Methods

PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions.

Results

Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells.

Conclusion

Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.

Citations

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Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway
Yinli Shi, Pei Sheng, Ming Guo, Kai Chen, Yun Zhao, Xu Wang, Mianhua Wu, Bo Li
Current Computer-Aided Drug Design.2024; 20(6): 911. CrossRef
Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors
Gyuri Kim, Myungeun Yoo, Min Hee Hong, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Hye Ryun Kim, Yong-ho Lee, Byoung Chul Cho
Cancer Chemotherapy and Pharmacology.2019; 84(2): 405. CrossRef

Current Status of Prescription in Type 2 Diabetic Patients from General Hospitals in Busan: Ji Hye Suk, Chang Won Lee, Sung Pyo Son, Min Cheol Kim, Jun Hyeob Ahn, Kwang Jae Lee, Ja Young Park, Sun Hye Shin, Min Jeong Kwon, Sang Soo Kim, Bo Hyun Kim, Soon Hee Lee, Jeong Hyun Park, In Joo Kim; Diabetes Metab J. 2014;38(3):230-239. Published online June 17, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.3.230

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Background

Data regarding the prescription status of individuals with diabetes are limited. This study was an analysis of participants from the relationship between cardiovascular disease and brachial-ankle pulse wave velocity in patients with type 2 diabetes (REBOUND) Study, which was a prospective multicenter cohort study recruited from eight general hospitals in Busan, Korea. We performed this study to investigate the current status of prescription in Korean type 2 diabetic patients.

Methods

Type 2 diabetic patients aged 30 years or more were recruited and data were collected for demographics, medical history, medications, blood pressure, and laboratory tests.

Results

Three thousands and fifty-eight type 2 diabetic patients were recruited. Mean age, duration of diabetes, and HbA1c were 59 years, 7.6 years, and 7.2%, respectively. Prevalence of hypertension was 66%. Overall, 7.3% of patients were treated with diet and exercise only, 68.2% with oral hypoglycemic agents (OHAs) only, 5.3% with insulin only, and 19.2% with both insulin and OHA. The percentage of patients using antihypertensive, antidyslipidemic, antiplatelet agents was similar as about 60%. The prevalence of statins and aspirin users was 52% and 32%, respectively.

Conclusion

In our study, two thirds of type 2 diabetic patients were treated with OHA only, and one fifth with insulin plus OHA, and 5% with insulin only. More than half of the patients were using each of antihypertensive, antidyslipidemic, or antiplatelet agents. About a half of the patients were treated with statins and one third were treated with aspirin.

Citations

Citations to this article as recorded by

A double‐blind, Randomized controlled trial on glucose‐lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase‐4 inhibitor therapy: REFIND study
Soree Ryang, Sang Soo Kim, Ji Cheol Bae, Ji Min Han, Su Kyoung Kwon, Young Il Kim, Il Seong Nam‐Goong, Eun Sook Kim, Mi‐kyung Kim, Chang Won Lee, Soyeon Yoo, Gwanpyo Koh, Min Jeong Kwon, Jeong Hyun Park, In Joo Kim
Diabetes, Obesity and Metabolism.2022; 24(9): 1800. CrossRef
Arterial stiffness is an independent predictor for risk of mortality in patients with type 2 diabetes mellitus: the REBOUND study
Jeong Mi Kim, Sang Soo Kim, In Joo Kim, Jong Ho Kim, Bo Hyun Kim, Mi Kyung Kim, Soon Hee Lee, Chang Won Lee, Min Chul Kim, Jun Hyeob Ahn, Jinmi Kim
Cardiovascular Diabetology.2020;[Epub] CrossRef
Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study
Jeong Mi Kim, Sang Soo Kim, Jong Ho Kim, Mi Kyung Kim, Tae Nyun Kim, Soon Hee Lee, Chang Won Lee, Ja Young Park, Eun Sook Kim, Kwang Jae Lee, Young Sik Choi, Duk Kyu Kim, In Joo Kim
Diabetes & Metabolism Journal.2020; 44(1): 67. CrossRef
Efficacy and safety of sitagliptin/metformin fixed‐dose combination compared with glimepiride in patients with type 2 diabetes: A multicenter randomized double‐blind study
Sang Soo Kim, In Joo Kim, Kwang Jae Lee, Jeong Hyun Park, Young Il Kim, Young Sil Lee, Sung Chang Chung, Sang Jin Lee
Journal of Diabetes.2017; 9(4): 412. CrossRef
Arterial Stiffness Is More Associated with Albuminuria than Decreased Glomerular Filtration Rate in Patients with Type 2 Diabetes Mellitus: The REBOUND Study
Jong Ho Kim, Sang Soo Kim, In Joo Kim, Bo Hyun Kim, Ja Young Park, Chang Won Lee, Ji Hye Suk, Sun Hae Shin, Sung Pyo Son, Min Chul Kim, Jun Hyeob Ahn, Kwang Jae Lee, Min Jung Kwon, Soon Hee Lee, Jeong Hyun Park
Journal of Diabetes Research.2017; 2017: 1. CrossRef
Insulin therapy for adult patients with type 2 diabetes mellitus: a position statement of the Korean Diabetes Association, 2017
Byung-Wan Lee, Jin Hwa Kim, Seung-Hyun Ko, Kyu Yeon Hur, Nan-Hee Kim, Sang Youl Rhee, Hyun Jin Kim, Min Kyong Moon, Seok-O Park, Kyung Mook Choi
The Korean Journal of Internal Medicine.2017; 32(6): 967. CrossRef
Insulin Therapy for Adult Patients with Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association, 2017
Byung-Wan Lee, Jin Hwa Kim, Seung-Hyun Ko, Kyu-Yeon Hur, Nan-Hee Kim, Sang Youl Rhee, Hyun Jin Kim, Min Kyong Moon, Seok-O Park, Kyung Mook Choi
Diabetes & Metabolism Journal.2017; 41(5): 367. CrossRef
Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment
Yeoree Yang, Jeong-Ah Shin, Hae Kyung Yang, Seung-Hwan Lee, Seung-Hyun Ko, Yu-Bae Ahn, Kun-Ho Yoon, Jae-Hyoung Cho
Diabetes & Metabolism Journal.2016; 40(6): 454. CrossRef
Comparison of Vildagliptin and Pioglitazone in Korean Patients with Type 2 Diabetes Inadequately Controlled with Metformin
Jong Ho Kim, Sang Soo Kim, Hong Sun Baek, In Kyu Lee, Dong Jin Chung, Ho Sang Sohn, Hak Yeon Bae, Mi Kyung Kim, Jeong Hyun Park, Young Sik Choi, Young Il Kim, Jong Ryeal Hahm, Chang Won Lee, Sung Rae Jo, Mi Kyung Park, Kwang Jae Lee, In Joo Kim
Diabetes & Metabolism Journal.2016; 40(3): 230. CrossRef

The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition: Min Jeong Kwon, Hye Suk Chung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Mi Kyung Kim, Jeong Hyun Park; Diabetes Metab J. 2011;35(5):480-488. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.480

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Background

β-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.

Methods

Apoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.

Results

Addition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.

Conclusion

GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load.

Citations

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The antagonistic atorvastatin-glibenclamide interactions suppressed the atorvastatin-induced Bax/cytochrome c/p53 mRNA expressions and increased Rho A mRNA expression in B16f10 melanoma cell culture
Maryam Malek, Nasim Dana, Ahmad Ghasemi, Maedeh Ghasemi
Gene Reports.2021; 23: 101156. CrossRef
Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism
Marcus Lundberg, Anton Stenwall, Angie Tegehall, Olle Korsgren, Oskar Skog
Islets.2018; 10(2): 69. CrossRef
Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases
Tae Jung, Kyung Choi
International Journal of Molecular Sciences.2016; 17(2): 192. CrossRef
The TRPA1 channel and oral hypoglycemic agents
Carlos Manlio Diaz-Garcia
Channels.2013; 7(6): 420. CrossRef
Dimethyl sulfoxide reduces hepatocellular lipid accumulation through autophagy induction
Young Mi Song, Sun-Ok Song, Yong-Keun Jung, Eun-Seok Kang, Bong Soo Cha, Hyun Chul Lee, Byung-Wan Lee
Autophagy.2012; 8(7): 1085. CrossRef
The Duration of Sulfonylurea Treatment Is Associated withβ-Cell Dysfunction in Patients with Type 2 Diabetes Mellitus
Mi-Seon Shin, Jee Hee Yu, Chang Hee Jung, Jenie Yoonoo Hwang, Woo Je Lee, Min-Seon Kim, Joong-Yeol Park
Diabetes Technology & Therapeutics.2012; 14(11): 1033. CrossRef

The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells: Mi Kyung Kim, Hye Sook Jung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Min Jeong Kwon, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2010;34(1):47-54. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.47

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Background

Blood glucose level continuously fluctuates within a certain range in the human body. In diabetes patients, the extent of such fluctuation is large, despite the strict control of blood glucose. Blood glucose fluctuation has been shown to mediate more adverse effects on vascular endothelial cells and diabetes complications than chronic hyperglycemia, which has been explained as due to oxidative stress. As few previous studies have reported the effects of chronic and intermittent hyperglycemia on the apoptosis and function of pancreatic beta cells, this study reported herein was performed to investigate such effects on these cells.

Methods

For chronic hyperglycemia, INS-1 cells were cultured for 5 days with changes of RPMI 1640 medium containing 33 mM glucose every 12 hours. For intermittent hyperglycemia, the medium containing 11 mM glucose was exchanged with the medium containing 33 mM glucose every 12 hours. Apoptosis was assessed by TUNEL assay Hoechst staining and cleaved caspase 3. Insulin secretory capacity was assessed, and the expression of Mn-SOD and Bcl-2 was measured by Western blotting.

Results

In comparison to the control group, INS-1 cells exposed to chronic hyperglycemia and intermittent hyperglycemia showed an increase in apoptosis. The apoptosis of INS-1 cells exposed to intermittent hyperglycemia increased significantly more than the apoptosis of INS-1 cells exposed to chronic hyperglycemia. In comparison to the control group, the insulin secretory capacity in the two hyperglycemic states was decreased, and more with intermittent hyperglycemia than with chronic hyperglycemia. The expression of Mn-SOD and Bcl-2 increased more with chronic hyperglycemia than with intermittent hyperglycemia.

Conclusion

Intermittent hyperglycemia induced a higher degree of apoptosis and decreased the insulin secretory capacity more in pancreatic beta cells than chronic hyperglycemia. This activity may be mediated by the anti-oxidative enzyme Mn-SOD and the anti-apoptotic signal Bcl-2.

Citations

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Sixu Xin, Xin Zhao, Jiaxiang Ding, Xiaomei Zhang
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Plant polyphenols mechanisms of action on insulin resistance and against the loss of pancreatic beta cells
Camelia Papuc, Gheorghe V. Goran, Corina N. Predescu, Liliana Tudoreanu, Georgeta Ștefan
Critical Reviews in Food Science and Nutrition.2022; 62(2): 325. CrossRef
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Age‐specific associations of glycated haemoglobin variability with cardiovascular disease and mortality in patients with type 2 diabetes mellitus: A 10‐ year cohort study
Eric Yuk Fai Wan, Esther Yee Tak Yu, Weng Yee Chin, Florence Ting Yan Ng, Shu Ming Cheryl Chia, Ian Chi Kei Wong, Esther Wai Yin Chan, Cindy Lo Kuen Lam
Diabetes, Obesity and Metabolism.2020; 22(8): 1316. CrossRef
Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications
Zhen-Ye Zhang, Ling-Feng Miao, Ling-Ling Qian, Ning Wang, Miao-Miao Qi, Yu-Min Zhang, Shi-Peng Dang, Ying Wu, Ru-Xing Wang
Frontiers in Endocrinology.2019;[Epub] CrossRef
Resolution on the results of the first working meeting of the scientific advisory board «Actual problems of glycemic variability as a new criterion of glycemic control and safety of diabetes therapy»
Mikhail B. Antsiferov, Gagik R. Galstyan, Alexey V. Zilov, Alexander Y. Mayorov, Tatyana N. Markova, Nikolay A. Demidov, Olga M. Koteshkova, Dmitry N. Laptev, Alisa V. Vitebskaya
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Intermittent High Glucose Enhances the Proliferation of Rat Aortic Vascular Smooth Muscle Cells More Than Constant High Glucose via the Mitogen-Activated Protein Kinase Pathway
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Cloning of Novel Epidermal Growth Factor (EGF) Plasmid for Gene Therapy on Diabetic Foot Ulcer.: Hye Sook Chung, Chang Shin Yoon, Min Jeong Kwon, Mi Kyung Kim, Soon Hee Lee, Kyung Soo Ko, Byung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2008;32(2):131-140. Published online April 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.2.131

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BACKGROUND
Epidermal Growth Factor (EGF) is one of the important growth factors involved in the epithelialization during cutaneous wound healing. Peptide EGF has been used for the treatment of diabetic foot ulcer. But the inferiority of cost-effectiveness and the inconvenience of daily application might have restricted its wide clinical usage. EGF gene therapy could dramatically improve the efficacy and inconvenience through long-term expression and bypassing the EGF degradation by hostile non-specific proteinases expressed in the wound bed. METHODS: EGF DNAs were amplified via PCR. For the more effective secretion from the transfected cell, we inserted furin cleavage site into EGF plasmids. The efficacy of novel plasmid pbeta-EGF was verified by transfection into the various animal cell lines, and the biologic potency of expressed EGF was confirmed via phosphorylation of PI3K and GSK3beta by Western blotting. RESULTS: We tested various kinds of human EGFs. One of the human EGF isoforms, EGF(828) including a membrane-anchoring domain was successfully released as the mature EGF protein in the cell culture media. Also EGF plasmid including furin cleavage site showed more than 2-fold increased EGF expression compared with the sequence without furin cleavage site. CONCLUSION: In conclusion, these findings suggest that mature EGF could be released easily out of cells by modifying EGF DNA sequence. Our novel EGF plasmid DNA could markedly increase the efficiency of non-viral gene therapy for diabetic foot ulcer.

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Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer
Min J. Kwon, Songhie An, Sunghyun Choi, Kihoon Nam, Hye S. Jung, Chang S. Yoon, Jung H. Ko, Hye J. Jun, Tae K. Kim, Soo J. Jung, Jeong H. Park, Yan Lee, Jong‐Sang Park
The Journal of Gene Medicine.2012; 14(4): 272. CrossRef

Cytoprotective Effect by Antioxidant Activity of Quercetin in INS-1 Cell Line.: Min Jeong Kwon, Hye Sook Jung, Mi Kyung Kim, Seong Hoon Kang, Gwang Wook Seo, Jae Kwang Song, Tae Yeon Yoon, Min Kyeong Jeon, Tae Hwan Ha, Chang Shin Yoon, Mi Kyung Kim, Woo Je Lee, Jeong Hyun Noh, Soo Kyung Kwon, Dong Joon Kim, Kyung Soo Koh, Byung Doo Rhee, Kyung Ho Lim, Soon Hee Lee, Jeong Hyun Park; Korean Diabetes J. 2007;31(5):383-390. Published online September 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.5.383

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Abstract PDF

BACKGROUND
Oxidative stress is induced under diabetic conditions and causes various forms of tissue damages in the patients with diabetes. Recently, pancreatic beta cells are regarded as a putative target of oxidative stress-induced tissue damage, and this seems to explain in part the progressive deterioration of beta cell function in type 2 diabetes. The aim of this study was to examine the potential of Quercetin (QE) to protect INS-1 cells from the H2O2-induced oxidative stress and the effects of QE on the glucose-stimulated insulin secretion in INS-1 cells. METHODS: To study the cell viability, cells were incubated with H2O2 and/or QE at the various concentrations. To confirm the protective effect by QE in response to H2O2, the levels of antioxidant enzymes were assessed by RT-PCR and Western blot, and glutathione peroxidase activities were quantified by spectrophotometrical method. Glucose-stimulated insulin secretion (GSIS) was measured by ELISA. RESULTS: Cell incubations were performed with 80 microM of H2O2 for 5 hours to induce 40 - 50% of cell death. QE gradually showed protective effect (IC50 = 50 microM) in dose-dependent manner. Superoxide dismutase (SOD) mRNA level in H2O2 + QE group was increased as compared to H2O2 group, but catalase did not changed. And the QE recruited glutathione peroxidase activity against H2O2-induced oxidative injuries in INS-1 cells. CONCLUSION: In conclusion, these findings suggest that QE might have protective effect on beta cells by ameliorating oxidative stress and preserving insulin secretory function.

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Anti-diabetic effects of Allium tuberosum rottler extracts and lactic acid bacteria fermented extracts in type 2 diabetic mice model
Bae Jin Kim, Seung Kyeung Jo, Yoo Seok Jeong, Hee Kyoung Jung
Korean Journal of Food Preservation.2015; 22(1): 134. CrossRef
Protective Effects of Sasa Borealis Leaves Extract on High Glucose-Induced Oxidative Stress in Human Umbilical Vein Endothelial Cells
Ji-Young Hwang, Ji-Sook Han
Journal of the Korean Society of Food Science and Nutrition.2010; 39(12): 1753. CrossRef

Serum Adiponectin, TNF-alpha, IL-6 and Insulin Resistance in Women with Polycystic Ovary Syndrome.: Young A Kim, Jung Hyun Noh, Dong Jun Kim, Tae Hyun Um, Chong Rae Cho, Na young Jang, Soo Kyung Kwon, Soon Hee Lee, Jeong Hyun Park, Kyung Soo Ko, Byoung Doo Rhee, Kyung Ho Lim; Korean Diabetes J. 2006;30(2):104-111. Published online March 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.2.104

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Abstract PDF

BACKGROUND
To determine plasma adipokines such as adiponectin, IL-6 and TNF-alpha concentrations in women with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adipocytokines to the hormonal and metabolic parameters, including measures of insulin resistance (IR). METHODS: Forty-four selected women were classified as follows: 13 obese (body mass index [BMI] > or = 25 kg/m(2)) with PCOS; 15 non-obese (BMI < 25 kg/m(2)) with PCOS; 8 obese without PCOS, and 8 non-obese without PCOS. Blood samples were collected from all women with or without PCOS after an overnight fast. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone, 17-alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), insulin, glucose, adiponectin, TNF-alpha and IL-6 were measured. Measures of IR included HOMA-IR and QUICKI. RESULTS: In non-obese group, fasting insulin levels and HOMA-IR in PCOS were significantly higher compared to control. However, Adiponectin, TNF-alpha and IL-6 concentrations were found not to be different in obese women with PCOS as compared with obese women without PCOS and in non-obese women with PCOS as compared with non-obese women without PCOS. Adiponectin concentrations correlated inversely with BMI, waist circumference (WC), total fat mass, serum insulin, and HOMA-IR in PCOS group. However, multiple regression analysis showed that BMI was the only independent determinant of adiponectin concentration. CONCLUSION: Our results suggest that insulin sensitivity per se probably does not play any role in the control of adipokines levels such as adiponectin, TNF-alpha and IL-6 in PCOS women

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Adiponectin in Women with Polycystic Ovary Syndrome
Hyun-Young Shin, Duk-Chul Lee, Ji-Won Lee
Korean Journal of Family Medicine.2011; 32(4): 243. CrossRef

Effect of Heat Shock on the Vascular Reactivity and Expression of Heat Shock Protein in an Animal Model of Type 2 Diabetes Mellitus (OLETF rat).: Soon Hee Lee, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2003;27(3):199-212. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Heat shock proteins (HSPs) are highly expressed in cardiovascular tissues, with heat shock possibly modulating the vascular reactivity to vasoactive agents. An abnormal vascular reactivity has been shown in diabetes, and may be closely associated to diabetic vascular complications. The aim of this study was to investigate the effects of heat shock on the vascular reactivity and the expression of HSP70 in the isolated aortae of OLETF rats, a commonly used animal model for type 2 diabetes mellitus, and LETO rats, as age matched controls. METHODS: In 4 ring segments of the thoracic aorta isolated from each rat, the endothelium was denuded in 2 (EC-) and reserved in the other 2 (EC+). To induce heat shock, the aortic rings were exposed to 42 degrees C for 45 minutes. The vascular reactivity responses to various vasoactive agents were measured by organ chamber studies, and by changes in the HSP expression, using Western blotting of the aortic rings in the OLETF rats and controls. RESULTS: The contractile responses to KCl became apparent 4 hours after the end of the heat shock induction. After heat shock, the phenylnephrine-induced contractile responses were similarly increased in the OLETF rats and the controls, but the increase was more significant in the EC(-) than the EC(+) rings, in both the OLETF rats and the controls. The relaxative responses to either acetylcholine (ACh) in the EC(+) aortic rings, or to sodium nitroprusside in the EC(-) rings, were not significantly affected by the heat shock treatment in either the OLETF rats or the controls, although the maximal relaxative response to ACh before the induction of the heat shock was lower in the aortic rings of the OLETF rats than in the controls. The HSP70 levels before the heat shock were higher in the aortic rings of the OLETF rats than in the controls, whereas those after heat shock were higher than those before in both the OLETF rats and the controls. The increase in the expression of HSP70 following the heat shock was higher in rings of the controls than in those of the OLETF rats. The HSP70 levels following the heat shock were increased to a greater extent in the EC(+) than the EC(-) rings of both the OLETF rats and the controls. CONCLUSION: These results suggest that the vascular reactivity to heat shock was decreased to a greater extent in the aortae of OLETF rats than in those of the controls, and that HSP70 seems to play an important role in the vascular response to heat shock through interaction of the endothelium and the smooth muscle.

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.

Effect and Mechanism of Vascular Endothelial Growth Factor on Endothelial Nitric Oxide Synthase Expression in Aortic Endothelial Cells.: Soon Hee Lee, Jung Guk Kim, Joong Yeol Park, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2002;26(5):396-404. Published online October 1, 2002

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Abstract PDF: BACKGROUND
Vascular endothelial growth factor (VEGF), a soluble angiogenic factor produced by many tumor and normal cells, is a potent angiogenic and vascular permeability factor. VEGF plays a key role in both pathological and physiological angiogenesis. There are many recent findings regarding the role of VEGF in diabetic microvascular and macrovascular diseases. Many approaches with VEGF-related therapies begin to treat and prevent these complications and have been used for the treatment of microvascular complications such as diabetic retinopathy, whereas VEGF agonists have been used to treat macrovascular complications such as myocardial infarction and peripheral limb ischemia. Nitric oxide (NO) is known to mediate many physiological and pathological functions, including modulation of vascular tone, permeability, and capillary growth. Recent reports indicate that NO may play an intimate role in VEGF signaling. Therefore, we hypothesized that the expression of eNOS may be regulated by VEGF. The objectives of the present study were to determine whether VEGF up-regulates the expression of endothelial NO synthase (eNOS) in endothelial cells and to elucidate the mechanism that mediate this response. METHODS: Endothelial cells were isolated from bovine aortae. The expression of eNOS was assessed by Northern blotting analysis. To evaluate the mechanism of VEGF-induced eNOS expression, endothelial cells were conditioned with VEGF and pretreated with phorbol-12-myristate acetate (PMA), a protein kinase C (PKC) activator, or GF109203X (GFX), a PKC inhibitor. The changes of eNOS gene expression. RESULTS: VEGF significantly increased the expression of eNOS mRNA in bovine aortic endothelial cells (BAEC) in time and dose dependent manners. PMA increased the expression of eNOS mRNA, as well as the VEGF-induced expression of eNOS mRNA in endothelial cells, while inhibition of the PKC activity, with the GFX blocked the upregulation of the VEGF-induced eNOS mRNA. CONCLUSION: The results suggest that VEGF upregulates eNOS gene expression in aortic endothelial cells, by a PKC dependent pathway and, eNOS may be important in the development of VEGF-induced angiopathy.

Effect of Transforming Growth Factor-Induced Gene Product, beta ig-h3 on Proliferation, Migration, and Adhesion of Aortic Smooth Muscle Cells Cultured in High Glucose.: Sung Woo Ha, Gui Hwa Jung, He Jin Yeo, Jong Sup Bae, Soon Hee Lee, Jung Guk Kim, Rang Woon Park, In San Kim, Bo Wan Kim; Korean Diabetes J. 2002;26(4):286-295. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Diabetes mellitus is associated with a substantial increase in the prevalence of atherosclerotic disease. There are many factors which are involved in development of these processes. Transforming growth factor (TGF-beta) is known to be an important factor in the pathogenesis of diabetic vascular complications. TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that beta ig-h3 is induced by TGF-beta, we hypothesized that beta ig-h3 may also play a role in the development of diabetic angiopathy. Then, we examined the effects of beta ig-h3 on biologic function of vascular smooth muscle cells (VSMCs) and potential roles of beta ig-h3 in the pathognesis of diabetic angiopathy. METHODS: VSMCs were isolated from rat thoracic aorta. We conditioned cells with different concentration of TGF-beta or glucose. We measured TGF-beta and beta ig-h3 protein in cell supernatant by ELISA. We also examined whether TGF-beta involves in high glucose-induced beta ig-h3 expression. Finally, we did proliferation, migration, and adhesion assay to investigate biologic function of beta ig-h3 in VSMCs. RESULTS: Our results demonstrated that TGF-beta induced beta ig-h3 expression in VSMCs in dose dependent manners. High glucose induced TGF expression as well as beta ig-h3 protein. Finally, beta ig-h3 was found to support the proliferation, migration, and adhesion of rat VSMCs. CONCLUSION: These results suggest that high glucose-and TGF-beta-induced beta ig-h3 may play an important role in diabetic angiopathy by regulating proliferation, migration, and adhesion of VSMCs.

Effect of Heat Shock on the Vascular Reactivity in Diabetic Rat Aorta.: Seong Mo Koo, Soon Hee Lee, Jung Hun Han, Gi Young Jeong, In Kyum Kim, Jung Guk Kim, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2001;25(5):343-353. Published online October 1, 2001

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Abstract PDF: BACKGROUND
Heat shock has been known to change cellular response to noxious stimuli by inducing heat shock proteins (HSP). HSP are expressed in many tissues, and increased expression of some HSP enhances the survival of cells exposed to oxidative stress. Recently, Some HSP are known to associate with vascular reactivity. Under diabetic conditions, there is abnormal vascular reactivity to relaxing or contracting factors. Abnormal vascular response to some stimuli is an important role in the development of diabetic complications. However, the effects of heat shock on the vascular reactivity in diabetic condition is unclear. Therefore, we investigated effects of heat shock on the vascular reactivity in isolated aorta of streptozotocin-induced diabetic rats. METHODS: After mounced in organ bath, aortic ring preparations were exposed to 42 for 45 minutes followed by being subjected to contraction and relaxation in 4 hours. Tissues were frozen for measurement of HSP 70 and phosphorylation of myosin light chain after functional study. RESULTS: Heat shock not only increased expression of HSP70 in rat aorta but also augmented contraction to KCl and phenylephrine in the aorta of control and diabetic rats (p<0.05). Relaxation responses to acetylcholine (ACh) were not changed in the aorta of control rats with and without heat shock for 45 minutes. However, heat shock for 45 minutes decreased relaxative responses to ACh in the aorta of diabetic rats compared to those in the aorta of control rats. CONCLUSION: This result suggests that heat shock increases vascular contractility in the aorta of diabetic and control rats through the induction of HSP70 while heat shock seems to decrease relaxative response in the aorta of diabetic ratscompared to control rats (p<0.05). Whether heat shock impaired relaxative response in the aorta of diabetic rats deserves additional studies.

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