Diabetes & Metabolism Journal

Volume 27(3); June 2003

Review

Epidemiological Characteristics of Diabetes Mellitus among Korean Population.: Byoung Doo Rhee; Korean Diabetes J. 2003;27(3):173-178. Published online June 1, 2003

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Abstract PDF: No abstract available.

Editorial

Relationship Between Diabetic Nephropathy and Plasminogen Activator Inhibitor-1.: Bong Soo Cha, Hae Jin Kim; Korean Diabetes J. 2003;27(3):179-185. Published online June 1, 2003

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Abstract PDF: No abstract available.

Original Articles

Plasminogen Activator Inhibitor-1 (PAI-1)/tissue Plasminogen Activator (t-PA) Levels and PAI-1 4G/5G Promoter Polymorphism in Type 2 Diabetes with Microalbuminuria.: Seong Hee Kwon, Young Joo Park, In Kyong Jeong, Jae Joon Koh, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2003;27(3):186-198. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Persistent microalbuminuria in diabetic patients is a risk factor of cardiovascular mortality. Increased plasma plasminogen activator inhibitor type-1 (PAI-1) levels have been observed in diabetic patients with overt nephropathy. However, there have been few studies on diabetic patients with microalbuminuria. The expression of PAI-1 may be influenced by the polymorphism of the PAI-1 genotype promoter. The aim of this study was to investigate the relationship between the plasma PAI-1/t-PA levels, polymorphism of the PAI-1 4G/5G promoter and microalbuminuria in type 2 diabetes. METHODS: The plasma PAI-1/t-PA levels and polymorphisms of the PAI-1 promoter were measured in type 2 diabetic patients without nephropathy (n=30), and with microalbuminuria (n=30) and overt proteinuria (n=20). The correlation between the amount of urinary albumin excretion and plasma PAI-1/t-PA levels were investigated using Pearson's correlation analyses. RESULTS: The plasma PAI-1/t-PA levels and polymorphisms of the PAI-1 promoter showed no significant difference between the three groups in relation to the urinary albumin excretion. There were no differences in the plasma PAI-1/t-PA levels between the genotypes of the polymorphism of the PAI-1 promoter. No association was found between the amount of urinary albumin excretion and the plasma PAI-1/t-PA levels and genotypes of the polymorphism of the PAI-1 promoter. CONCLUSION: These results show that there was no decrease in the fibrinolytic state in type 2 diabetics with microalbuminuria, compared to normoalbuminuria, which also suggest that polymorphisms of the PAI-1 4G/5G promoter do not affect the plasma PAI-1/t-PA levels in type 2 diabetic patients with microalbuminuria.

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.

The Effect of Nitric Oxide on Insulin Binding and Insulin Receptor Recycling in Bovine Aortic Endothelial Cells.: Hyuk Sang Kwon, Oak Kee Hong, Hee Soo Kim, Jung Min Lee, Sung Rae Kim, Sung Dae Moon, Sang Ah Jang, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):213-227. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The coexistence of insulin resistance and endothelial dysfunction is commonly observed in a variety of metabolic and cardiovascular disorders, including athero-sclerosis and type 2 diabetes mellitus. Because nitric oxide (NO), or nitric oxide synthase (NOS), has been suggested as a significant contributing factor in the development of endothelial dysfunction and insulin resistance, reactive NO or NOS were investigated to see if they contribute to the insulin internalization pathway. METHODS: The production of NO (Nitrite), the expression of eNOS (endothelial NOS), insulin binding and the insulin receptor internalization and recycling, following 48 hours of incubation with bradykinin (BK), acetylcholine (Ach), NG-monomethyl- L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) in Bovine aortic endothelial cells (BAECs), were examined. RESULTS: The results were as follows: 1. In relation to the time course, the production of eNOS was increased, but was decreased after 8 hours of incubation. The production of eNOS in the L-NMMA and L-NAME treated groups was significantly decreased compared with that of the controls (p<0.05). 2. The specific insulin bindings to the receptors of the endothelial cells were maximized within 20 mins, and then decreased. At 20 mins, the binding rate of the L-NMMA treated group was significantly decreased compared to that of the controls. At a concentration of 0.4ng/ml of unlabelled insulin, the specific insulin binding of the L-NMMA treated group was significantly decreased compared to that of the controls (p<0.05). 3. The internalization of 125I-insulin into the endothelial cells, as assessed by the acid washing dissociation method, occurred rapidly. The internalized radioactivity of 125I-insulin, at 20 mins, was significantly increased in the BK and Ach groups compared with the controls (p<0.05). 4. The recycling of the internalized insulin receptors showed no significant differences between the study groups, but the recycling was slightly delayed compared with controls in the Ach group. CONCLUSION: In conclusion, the NO generating substances, BK and Ach, and the inhibitory substance, L-NMMA, may influence the binding and internalization of insulin-insulin receptors. Our results suggest that NO might contribute to the transcytosis of insulin in BAECs

The Effects of High Glucose, Insulin and TGF-beta 1 on Proliferation and Differentiation of the Pancreatic Stellate Cells.: Oak Kee Hong, Hyuk Sang Kwon, Kyu Hyun Yeom, Marie Lee, Ji Hun Yang, Seung Hyeon Ko, Soon Jib Yoo, Hyun Sik Son, Kun Ho Yoon, Bong Yeon Cha, Kwang Woo Lee, Ho Yong Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):228-240. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Although chronic pancreatitis gives rise to fibrosis of pancreatic exocrine tissue, and type 2 diabetes is accompanied by pancreatic fibrosis, the mechanisms of fibrogenesis in the pancreas have been insufficiently studied. The activated Pancreatic stellate cells (PSC) have recently been identified in human and experimental fibrotic areas from chronic panceatitis tissues. As PSC are similar in their morphology and biochemistry to hepatic stellate cells, they are suspected to play the same role in pancreatic fibrogenesis as the hepatic stellate cells in liver fibrosis. The PSC were isolated from the rat pancreata, and mediators stimulating the proliferation and differentiation identified. METHODS: The pancreatic stellate shaped cells were isolated by a minor modification to the method described by Apte et al (ref), using a Nycodenz gradient. The isolated PSCs were confirmed by phase-contrast and by the immunofluorescence of vimentin, desmin and smooth muscle a-actin (a-SMA). The level of alpha-SMA was quantified by Western blot in the PSCs in the culture, over time, and the cell proliferation was measured by 3[H]-Thymidine incorporation. The effect of the proliferation and differentiation of the PSC were assessed in relation to D-glucose (500 mg/dL), Insulin (10 IU/mL) and TGF-beta (10 ng/mL) treatment of the culture medium. RESULTS: The stellate shaped cells from the rat pancreata grew readily in the culture. Unactivated PSCs, cultured for 3 days, had an angular appearance, contained lipid droplets, manifesting positive vitamin A autofliuorescence, and stained positively for vimentin and desmin, but negatively for alpha-SMA. Within 4~8 days of primary culturing, the PSCs were activated, the sizes and numbers of the fat droplets decreased, the cells flattened, developed long cytoplasmic extensions and expressed alpha-SMA. After 3 passages, almost 100% of the cells were positive for alpha-SMA expression, indicating a myofibroblast type of differentiation in vitro. The addition of high-glucose concentrations and insulin to the activated PSCs significantly stimulated cell proliferation (194.4+/-8.3, 175.0+/-31.0 vs. control), and when the combination of high- glucose and insulin was applied, the cell proliferation was increased to an even greater extent (247.0+/-21.8 vs. control). CONCLUSIONS: Pancreata stellate cells can be isolated, and cultured in vitro, from normal SD rats. High concentrations of glucose and insulin in culture medium activated the PSC proliferation.

Effects of Peroxisome Proliferator-activated Receptor-gamma(PPARgamma) on the Pancreatic beta Cell Proliferation.: Jung Hyun Noh, Tae Young Yang, In Kyung Jeong, Jae Hun Chung, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee; Korean Diabetes J. 2003;27(3):241-252. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The effects and mechanisms of PPARgamma ligands on the cell proliferation in pancreatic beta cells were examined. METHODS: PPARgamma 1 cDNA was overexpressed in INS-1 cells using an adenoviral vector. The cell proliferations were measured by the MTT assay method, following the treatments with troglitazone (TGZ), rosiglitazone (RGZ), 15d-prostaglandin J2 (15d-PGJ2) or retinoic acid (RA), at increasing doses, in INS-1 and PPARgamma overexpressed INS-1 cells. The apoptosis, telomere length and cell cycles were determined after the PPARgamma ligand treatment. RESULTS: The long-term incubation, with PPARgamma ligands over 24 hr, inhibited the INS-1 cell proliferation rate. Apoptosis was not observed with the PPARgamma ligand treatment. G1 cell cycle arrest was observed with the troglitazone treatment. The telomere length remained unchanged following the TGZ treatment. The basal cell proliferation rate was unaffected by the overexpression of PPARgamma . After 48 h of TGZ treatment, the proliferation of the INS-1 cells was inhibited, in a dose- dependent manner, both with and without the overexpression. Moreover, the degree of inhibition was exaggerated in the PPARgamma overexpressed cells compared to beta gal overexpressed cells. CONCLUSION: PPARgamma ligands have direct inhibitory effects on the proliferation of INS-1 cells. Although the basal cell proliferation rate was not affected by PPARgamma overexpression, the PPARgamma overexpression and PPARgamma ligands have a synergistic inhibitory effect on the cell proliferation rate in pancreatic beta cells. G1 cell cycle arrest may be involved in the reduction of cell proliferation due to PPARgamma ligands.

Effect of Glucose Concentrations on the Cell Proliferation and Expression of L-type Calcium Channel mRNA in Cultured Rat Aortic Vascular Smooth Muscle Cells.: Young Jung Cho, Hyung Joon Yoo, Hong Woo Nam, Ji Young Suh, In Kyung Jeong, Sung Hee Ihm, Hyeon Kyu Kim, Cheol Young Park, Jae Myung Yoo, Doo Man Kim, Moon Gi Choi, Sung Woo Park; Korean Diabetes J. 2003;27(3):253-259. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation is one of the major pathogenic mechanisms for atherosclerosis. It is known that L-type calcium channels play a role in VSMC proliferation in diabetic rats. However, there have been no studies that show an association between the L-type calcium channels and the VSMC proliferation due to various glucose concentrations in the culture media. Therefore, the association between the voltage-dependent L-type calcium channels of the VSMCs, and the growth of vascular smooth muscle cells, was examined. METHODS: Rat aortic VSMCs were isolated from the aorta of Sprague-Dawley and OLETF rats, using an enzymic method. The VSMCs were cultured in various concentrations of glucose (5.5, 11.0, 16.6, 25, 30 and 40 mM). The VSMCs (1x10(4) cells in 24-well plates) were incubated in the presence of Bay K 8644 (10(-6)M), both with and without verapamil (10(-6)M), for 48 hours. The proliferation was then assessed by the MTT (methylthiazole tetrazolium) assay, and the expression of L-type calcium channel mRNA by RT-PCR. RESULTS: The vascular smooth muscle cell proliferation was significantly increased, in a dose-dependent manner, with glucose concentrations below 25 mM in both in a dose-dependent manner, with glucose concentrations below 25 mM in both kinds of rat. However, the increase in the VSMC proliferation of the OLETF rat was significantly higher than in the Sprague-Dawley rat. After the Bay K 8644 treatment, with the same glucose concentration, the VSMC proliferation and the expression of L-type calcium channel mRNA were significantly increased in both kinds of rat. After treatment with verapamil, the increased VSMC proliferation and expression of L-type calcium channel mRNA, due to the Bay K 8644, were suppressed to control levels in both kinds of rat. CONCLUSION: The results suggest that below certain concentrations of glucose, 25 mM, the L-type calcium channels may play a role in the VSMC proliferation of OLETF and Sprague-Dawley rats. The growth of the VSMCs in OLETF rats, due to various glucose concentrations (< 25 mM), was significantly higher than in the Sprague-Dawley rats.

Plasma Adiponectin Concentration and Insulin Resistance in Type 2 Diabetes.: Mi Jin Kim, Yoen Lee, Byon Jun Lee, Jai Ho Yoen, Sang Youl Shin, Young Goo Shin, Choon Hee Chung; Korean Diabetes J. 2003;27(3):260-271. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Insulin resistance, which implies impairment of insulin signaling in target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor- , plas- minogen activator inhibitor-1, leptin, resistin, angiotensinogen and adiponectin. Adiponectin has been estimated to be a protective adipocytokine against atherosclerosis and to have an anti-inflammatory effect. In this study, the relationship between the fasting plasma adiponectin concentration and the adiposity, body composition, insulin sensitivity (ITT, HOMA(IR), QUICK), lipid profile, fasting insulin concentration were examined in type 2 diabetes. The difference in the adiponectin concentrations of diabetic and non-diabetic subjects were also examined, with adjustment for sex, age and body mass index. METHODS: One hundred ans two type 2 diabetes and 50 controls were the subjects of this study. After a 12-h overnight fast, all subjects underwent a 75g oral glucose tolerance test. Baseline blood samples were drawn to determine the fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride and the LDL- and HDL- cholesterol levels. The body composition was estimated by a bioelectric impedance analyzer (Inbody 2.0(r)) and the insulin sensitivity by an insulin tolerance test (ITT), HOMA(IR) and QUICKI method. RESULTS: In the diabetic group, the fasting adiponectin concentrations were higher in the women than the men. The fasting adiponectin concentrations were negatively correlated with the BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMA(IR) (r=-0.233). In addition, they were positively correlated with the systolic blood pressure (r=0.321) and HDL-cholesterol (r=0.291). From a multiple logistic regression analysis the systolic blood pressure and HDL-cholesterol were found to be independent variables that influenced the adiponectin concentration. The adiponectin concentrations were significantly lowered in the diabetic than the non-diabetic group, with the exception of the obese male subjects. CONCLUSION: The plasma adiponectin concentrations were closely related to the insulin resistance parameters in type 2 diabetic patients.

Effects of Rosiglitazone on Body Fat Mass and Distribution in Type 2 Diabetic Patients.: Hong Kyu Kim, Hyo Joong Yoon, Seung Min You, Ki Young Lee, Hye Young Park, Moon Ho Kang; Korean Diabetes J. 2003;27(3):272-279. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Rosiglitazone, an insulin-sensitizing drug of the thiazolidinediones class, has a high affinity for the ligands of the peroxisome proliferator activated receptor-gamma(PPAR-gamma), is highly expressed in adipose tissue, and plays an important role in the differentiation of adipocyte. The influence of rosiglitazone was investigated on the total fat mass and regional adiposity in type 2 diabetic patients. METHODS: Rosiglitazone (4 mg/day) was administered for 6 months to type 2 diabetic patients (n=20) whose glycemic control was unacceptable with the use of other treatments. Measurements of the total, trunk and leg region body fats (by dual energy X-ray absorptiometry) and abdominal fat distributions (by computed tomography) were compared before and after treatment. RESULTS: Nine patients received rosiglitazone monotherapy and 11 a combined therapy of sulfonylurea and/or metformin. The HbA1C, serum insulin level and homeostasis model assessment insulin resistance index were decreased following the rosiglitazone therapy, but the body weight and BMI were increased. As for the body fat changes, the total (19,382+/-4,786 vs. 22,940+/- 7,300 g, p<0.01), trunk (11,399+/- 2,678 vs. 13,960+/-4,698 g, p<0.01) and leg (4,734+/-1,319 vs. 6,203+/-2,231g, p<0.05) region fat masses were significantly increased. The percentage increase in the total, trunk and leg region fat masses were 20+/-25, 25+/-35 and 58+/-130%, respectively. As for abdominal fat distribution after the treatment, the visceral fat area (225+/-84 vs. 187+/-87 cm2, p<0.05) was significantly decreased, while the subcutaneous fat area tended to increase (178+/-83 vs. 201+/-80 cm2, NS), although these were not statistically significant. The visceral/subcutaneous fat ratio (V/S ratio) was significantly decreased (1.45+/- 0.64 vs. 0.95+/-0.25, p<0.05). CONCLUSION: Although the total body fat mass was increased following the rosiglitazone therapy, a shift in the body fat distribution, from the visceral to the subcutaneous region, was observed, which may be associated with an improvement in insulin resistance. However, a long-term assessment of the consequences of an increasing total fat mass and change in the body fat distribution will be required.

Randomized Controlled Trial

Establishment of Blood Glucose Monitoring System using Internet.: Hee Soo Kim, Jae Hyoung Cho, Hyuk Sang Kwon, Jin Hee Lee, Bok Re Song, Jung A Oh, Kun Ho Yoon, Ho Young Son; Korean Diabetes J. 2003;27(3):280-287. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The internet has been used world wide as a communication tool. To improve the quality of glucose control, the effectiveness of an Internet-based Blood Glucose Monitoring System (IBGMS), on changes in HbA1c levels, was investigated. RESEARCH DESIGN AND METHODS: A randomized clinical trial, involving 110 patients who had visited outpatient's clinic at the Kangnam St. Mary's Hospital diabetes center for 3 months, was conducted. The study subjects were treated with IBGMS for 12 weeks, with a control group receiving the usual outpatient management for the same period. HbA1C and other laboratory tests were performed at the baseline and at the end of the study. RESULTS: There were no significant differences found between the two groups at the baseline measurements, with respect to age, sex, diabetes duration, body mass index, blood pressure, HbA1C and other laboratory data. In the follow up tests, the study group showed a significant reduction in the HbA1C level, by 7.1% (0.54% absolute, p=0.001), while the control group showed an increased HbA1C level (p=0.054). Moreover, there was an 11.1% reduction (0.92% absolute, p<0.001) in the HbA1C level in the patients with HbA1C levels > or =7.0% at baseline in the study group, but those with HbA1C levels <7.0% maintained good HbA1c levels, 6.32%, by the end of the study. CONCLUSIONS: This new IBGMS resulted in a significant reduction in the HbA1C levels during the study period. We propose this IBGMS as a new method for glycemic control.

Original Article

Normative Data of Intima-medial Thickness in Korean Adults and the Estimation of the Relative Risk of Macrovascular Diseases Using this Data in Type 2 Diabetic Subjects.: H J Kim, Y J Won, D J Kim, C W Ahn, B S Cha, S K Lim, K R Kim, H C Lee, K B Huh; Korean Diabetes J. 2003;27(3):288-298. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The reference values of the carotid mean intima-medial thickness (IMT), in subjects without diabetes or macrovascular diseases, were estimated, which were used to establish the relative risks of macrovascular diseases in type 2 diabetic subjects. METHODS: High resolution B-mode ultrasonography was performed in 1229 nondiabetic subjects, without ischemic heart disease, cerebral infarction or peripheral vascular disease, and in 830 type 2 diabetic subjects. The nondiabetic subjects were participating in medical checkups at the Health Promotion Center. The height, weight, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, high density lipoprotein-cholesterol and fasting insulin level were measured in all subjects. RESULTS: The nondiabetic subjects, without ischemic heart disease, cerebral infarction or peripheral arterial obstructive diseases, were classified by age (31~40, 41~50, 51~60, 61~70 and >70 years) and sex. There were significant differences between the diabetic and nondiabetic subjects in relation to the age groups, but no significant difference was found between the sexes. Independent risk factors associated with the carotid mean IMT in the nondiabetic subjects were age, systolic blood pressure and body mass index, and those in the diabetic subjects were age, duration of diabetes and a low density lipoprotein-cholesterol level. The relative risks of ischemic heart disease, cerebral infarction and peripheral vascular disease, due to the presence of an increased IMT, were 2.34 (CI; 1.32~4.14), 2.95 (CI; 1.57~5.54) and 3.64 (CI; 1.79~7.40) in the diabetic subjects. CONCLUSION: It was concluded that the reference values of the IMT, as classified by age, in the subjects without diabetes or macrovascular diseases, favorably reflected the risks of macrovascular diseases in the type 2 diabetic subjects

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