Diabetes & Metabolism Journal

Volume 25(6); December 2001

Reviews

Differentiation of Pancreatic Islets.: Ki Ho Song; Korean Diabetes J. 2001;25(6):399-405. Published online December 1, 2001

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Abstract PDF: No abstract available.

Evaluation of Vascular Endothelial Function.: In Kyu Lee; Korean Diabetes J. 2001;25(6):406-423. Published online December 1, 2001

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Abstract PDF: No abstract available.

Editorial

The Prevalence of the Islet-specific Autoantibodies in Korean Patients with Type 1 Diabetes Mellitus.: Yong Soo Park; Korean Diabetes J. 2001;25(6):424-429. Published online December 1, 2001

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Abstract PDF: No abstract available.

Original Articles

The Prevalence of Islet Cell Cytoplasmic Antibody in Korean Type 1 Diabetes: Possible Replacement with Combined Measurement of Anti-GAD, Anti-ICA512, and Anti-phogrin Antibodies.: Kyoung Ah Kim, Dong Jun Kim, Jae Hoon Chung, Yong Ki Min, Moon Kyu Lee, Kwang Won Kim, Dong Kyu Jin, Kyung Soo Ko, Sang Jin Kim, Myung Shik Lee; Korean Diabetes J. 2001;25(6):430-445. Published online December 1, 2001

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Abstract PDF: BACKGROUND
Type 1 diabetes includes all forms of autoimmune-mediated and idiopathic beta-cell destruction leading to an absolute insulin deficiency. Evidence of an autoimmune pathogenesis was assessed by studying cytoplasmic islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), antibodies reacting with an islet tyrosine phosphatase-related molecule referred to as ICA512 (ICA512A), or its homologue phogrin (phogrin-A). In comparison with ICA, the best validation to assess the risk of type 1 diabetes, shows that a combination of antibodies to GADA with ICA512A has the power to detect a majority of ICA and 97~100% of subjects who progressed to overt diabetes. These findings suggest the possibility of replacing the laborious ICA test in the screening programs to identify subjects at risk of progressing to type 1 diabetes or forclassifying the stage of diabetes at the time of diagnosis. Up to now, it is unclear whether these results are applicable to the slowly progressive type 1 diabetes that appears to be more prevalent in Asian than in western countries. The prevalence of combined autoantibody testing (1 of GADA, ICA512A, or phogrin-A) was investigated in the patients with type 1 diabetes (typical and slowly progressive) and type 2 diabetes, and compared with that of ICA which is a more laborious and insensitive test. METHODS: The ICA assay was performed using immunoenzymatic staining of frozen human (blood group O) pancreatic sections with serial dilutions of serum samples with peroxidase-labeled protein A. For the GADA determination, commercially available GADA radioimmunoassay kits utilizing the 125I-labeled recombinant GAD65 (RSR , United Kingdom) as an antigen was used. Either ICA512A or phogrin-A were detected by a radioligand-binding assay after in vitro transcription and translation using the clone ICA512bdc or phogrin cDNA. Serum was obtainedfrom 76 patients with type 1 diabetes (mean age 22.8+/-14.0 years), 22 patients with slowly progressive type 1 diabetes (mean age 37.9+/-13.9 years) and 39 patients with type 2 diabetes (mean age 45.3+/-12.3 years). Typical and slowly progressive type 1 diabetes patients had the disease for between 4.0+/-4.6 and 10.1+/-9.5 years, respectively at the earliest serum sampling. RESULTS: 1) In typical type 1 diabetes, 30% of patients tested positive for ICA and 57% for the combined autoantibody test (1 of GADA, ICA512A, or phogrin-A). In the slowly progressive type 1 diabetes group, 18% of patients tested positive for ICA and 50% for the combined autoantibody test. In type 2 diabetes, 7.7% and 5.1% tested positive, respectively. 2) Ninety-six percent of ICA-positive patients expressed one or more of the 3 auto-antibody specificities in typical type 1 diabetes. Among the 53 ICA-negative patients with typical type 1 diabetes, 40% had one or more of these auto-antibodies. In the slowly progressive type 1 diabetes, 100% of the ICA-positive and 39% of the ICA- negative patients expressed one or more of the 3 autoantibody specificities. 3) Of the 23 patients with ICA-positive typical type 1 diabetes patients, 87% had a positive result for GADA, 48% for ICA512A, 44% for phogrin-A, and 96% for GADA or ICA512A. Of the 4 patients with ICA-positive slowly progressive type 1 diabetes, three had a positive result for GADA, and 1 for ICA512A. 4) When the prevalence of combined autoantibody testing was analyzed according to the duration of diabetes, the prevalence in patients tested within 4 years after the diagnosis and more than 4 years after the diagnosis was 61% and 52%, respectively in typical type 1 diabetes. Furthermore, that for the ICA was 37% and 21%, respectively. In the slowly progressive type 1 diabetes, the prevalence of combined auto-antibody testing was 88% and 25%, respectively (p<0.05), while that of ICA was 25% and 13%, respectively. 5) In typical type 1 diabetes, ICA were detected more frequently in patients younger than 15 years of age (48%) than in older patients (23%) (p<0.05), while the prevalence of combined auto-antibody testing -was not different according to the onset age (65% vs 53%). CONCLUSION: Combined autoantibody testing for GADA and ICA512A is more sensitive that ICA in type 1 diabetes. Therefore, it could replace the laborious ICA measurement and may be useful for discriminating the etiology of adult onset atypical diabetes.

The Effect of alpha-Lipoic Acid on Vascular Smooth Muscle Cell Proliferation, Migration, Neointimal Formation and PAI-1 Expression.: Dong Woo Shin, Dong Wook Lee, Sang Jun Lee, Hye Soon Kim, Hyo Gyoung Kang, Jong Deok Ahn, In Kyu Lee; Korean Diabetes J. 2001;25(6):446-459. Published online December 1, 2001

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Abstract PDF: BACKGROUND
Exposure to large amounts of glucose causes a characteristic dysfunction and morphologic changes of the endothelium by an increased production of reactive oxygen species (ROS) in diabetes. The plasminogen activator inhibitor-1 (PAI-1), which modulates fibrinolysis and cell migration, may influence proteolysis and neointimal formation in vascular smooth muscle cells (VSMC). Antioxidants have been proposed to inhibit multiple proatherogenic events. This study investigated the effect of (alpha)-Lipoic acid on PAI-1 expression and VSMC proliferation and migration both in vivo and in vitro. METHODS: In the in vitro study, cultured rat aortic smooth muscle cells (RASMC) were incubated in a medium containing high glucose (22 mM) and 100 nM angiotensin II for 4 hour. After (alpha)-Lipoic acidtreatment, a -migration and growth assay of the RASMC, and a gel mobility shift assay and reporter gene analysis for nuclear factor- B (NF-kappa B) and northern blot analysis for PAI-1 were performed. In the in vivo study, the effect of (alpha)-Lipoic acid on neointimal hyperplasia in a rat carotid balloon injury model was evaluated. RESULTS: RASMC migration was inhibited significantly by (alpha)-Lipoic acid (p<0.01), but their proliferation was not inhibited. The NF-kappa B DNA binding activity and NF-kappa B promoter activity was inhibited by (alpha)-Lipoic acid significantly (p<0.01). (alpha)-Lipoic acid inhibited PAI-1 mRNA expression by high glucose and angiotensin II in dose dependent manner (p<0.05). In the rat carotid artery balloon injury model, neointimal formation was reduced by (alpha)-Lipoic acid treatment in a dose dependent manner significantly (p<0.01). CONCLUSION: (alpha)-Lipoic acid suppresses migration, but not proliferation in RASMC. (alpha)-Lipoic acid also reduce neointima formation in a rat carotid balloon injured model. This effect might be related to the blocking of NF-kappa B which increase the expression of the genes associated with atherosclerosis including TNF-alpha, IL-1, IL-6, endothelin-1, MCP-1, VCAM-1, ICAM-1, E-selectin, tissue factor.

The Effects of Uncoupling Protein 3 Overexpression on Glucose Metabolism in OLETF Rats in Vivo and Cultured Skeletal Muscle Cells in Vitro.: Jeong Hee Han, Hye Seon Park, Jung Min Koh, Ha Young Kim, Ho Kyung Kang, In Kyu Lee, Joong Yeol Park, Sung Kwan Hong, Jae Dam Lee, Ki Up Lee; Korean Diabetes J. 2001;25(6):460-468. Published online December 1, 2001

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Abstract PDF: BACKGROUND
UCP3 is a mitochondrial membrane protein expressed selectively in the skeletal muscle and brown adipose tissue. Since the skeletal muscle is the main organ determining insulin sensitivity in the body, it was hypothesized that UCP3 overexpression in skeletal muscle cells would improve glucose metabolism. METHODS: An adenovirus-UCP3 was produced by a recombinant DNA method. OLETF rats were divided into 2 groups. Four rats were injected with the adenovirus- UCP3 (UCP3 group) and others were injected with the adenovirus (control group) in the skeletal muscle. The UCP3 group was provided with the same quantity of food as that consumed by the control group on the previous day. Insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp method. In a separate experiment, glucose transport and glycogen synthesis we evaluated in C2C12 cells transfected with ether an adenovirus or the adenovirus-UCP3. RESULTS: The insulin sensitivity improved significantly and the body weight decreased in the UCP3 group. The glucose transport and glycogen synthesis were higher in the UCP3-C2C12 skeletal muscle cells at the basal state. After insulin treatment, glucose transport and glycogen synthesis were also higher in the UCP3-C2C12 cells but the increments were reduced after treatment with wortmannin, a PI3K inhibitor. CONCLUSION: Insulin sensitivity was higher in the UCP3-overexpressed OLETF rats in the in vivo study. UCP3 transfection also increased glucose transport and glycogen synthesis in the cultured skeletal muscle cells by a PI3K dependent mechanism.

The Effect of Long-term Treatment of Ramipril on Glucose Tolerance and Pancreatic Islets in Type 2 Diabetes Animal Model (OLETF Rats).: Seung Hyun Ko, Kun Ho Yoon, Myung Mi Kim, Yu Bae Ahn, Ki Ho Song, Soon Jib Yoo, Hyun Shik Son, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(6):469-482. Published online December 1, 2001

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Abstract PDF: BACKGROUND
In a Heart Outcomes Prevention Evaluation HOPE study, ramipril, a long- acting angiotensin-converting enzyme (ACE) inhibitor, significantly reduced the death rates the number of myocardial infarctions, strokes, heart failure as well as the risk of complications related to diabetes and of diabetes itself. However, it is known that ACE inhibitors improve glucose tolerance or insulin sensitivity or reduce the incidence of diabetes. METHODS: 24 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 400~450 g were used in this study. 4 groups of rats were examined in parallel for 40 weeks. The OLETF rats were randomized for treatment with an aqueous solution of ramipril ( 5mg/Kg) daily [OL (RMP), n=10)] and with saline [OL(CON), n=10)]. The LETO rats were also randomized in the same was as the OLETF rats (LT (RMP), n=10, LT (CON), n=10). The blood glucose level, body weight, systolic and diastolic blood pressure was assessed every month. At 3 and 6 months, the 24hrs urinary protein concentration was measured, and as insulin tolerance test and oral glucose tolerance test were conducted in all experimental groups. After 6 months, the body weight was matched for 2 months in each corresponding group. Subsequently, a 15% sucrose loading was done for 2 months. After the glucose tolerance test, the pancreas was excised and immunohistochemical staining was conducted for insulin to quantify the beta cell mass by a point-counting method. In addition, the islet morphology was evaluated in the pancreas. RESULTS: Ramipril treatment for a period of 6 months improved the 2hr blood glucose level, the area under the glucose curve in the oral glucose tolerance test, insulin sensitivity in addition to lowering significantly systolic and diastolic blood pressure and 24hrs urinary protein level significantly in OLETF rats. Of note, a lower weight gain was observed in both the ramipril-treated animals at 6 months. After weight matching, the AUCg and 2hr blood glucose level values were similar between the corresponding groups, but a 15% sucrose loading worsened the AUCg value. Histologically, the islets were less disorganized and the extent of fibrosis was lower in the ramipril- treated OLETF rats in the trichrome stain. CONCLUSION: Long-term treatment of ramipril, a long acting angiotensin-converting enzyme inhibitor may be useful for suppressing weight gain and proteinuria in addition to having aprotective effect on the islet to harmful stimuli such as hyperglycemia.

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