Diabetes & Metabolism Journal

Volume 23(1); February 1999

The Genes of Hepatic Glucose Metabolism and Insulin Signaling.: Sei Hyun Baik; Korean Diabetes J. 1999;23(1):1-6. Published online January 1, 2001

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Original Articles

The Role of Oxidized Low Density Lipoprotein in Atherogenesis.: Hak Yeon Bae; Korean Diabetes J. 1999;23(1):7-11. Published online January 1, 2001

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Effect of Oxidized LDL on Neutrophil Adhesion and Transendothelial Migration.: Seok Man Son, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 1999;23(1):12-24. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It is well recognized that oxidized low density lipoproteins (ox-LDL) play a critical role in the pathogenesis of atherosclerosis. The activation of circulating leukocytes and their adhesion to the vascular endothelium in response to acute stimuli characterize the first step in initiation of an acute inflammatory response. Through the action of degranulation products, adherent leukocytes induce vascular hyperpermeability and contribute to vascular injury. So, we have investigated the neutrophil adhesion to vascular endothelium, a constant feature of early atherogenesis and transendothelial migration of neutrophil induced by ox-LDL. METHOD: In a series of experiments, human umbilical vascular endothelial cells (HUVECs) were incubated for 24 h after addition of native human LDL (100 ug/mL) and of ox-LDL (100 ug/mL) to the medium. The adherence of 51Cr-labeled neutrophils to endothelial monolayers was measured by neutrophil adhesion assay. For diapedesis experiments, HUVECs were grown to confluence on 8.0um pore cell culture inserts. 51Cr-labeled neutrophils were added to the apical surface of HUVEC monolayers and allowed to migrate into the lower chamber for 3 h under the same preparations of native and oxidized LDLs. Reaults: The secretion of IL-8 depended on the concentration of IL-1a and LPS used to stimulate endothelial monolayers in vitro. In addition, ox-LDL triggered secretion of IL-8 from cultured HUVECs compared to that of n-LDL (867.6 pg/mL vs. 273.1 pg/mL, p<0.01). Increased adherence of neutrophils to HUVECs vs observed with ox-LDL preparation compared to native LDL preparation (36.8+1.5% vs. 25.9+1.7%, p<0.05). Similarly, neutrophil migration across cultured endothelial monolayers was also significantly increased by ox-LDL (48.7+3.8% vs. 34.4+2.9%, p<0.05). CONCLUSION: These results show that ox-LD1. can induce increased neutrophil adhesion and migration through IL-8, a potent effector of neutophil functions, secreted by stimulated endothelial cells. So, we suggest that ox-LDL may affect many components of the atherogenic process, including the early step in the initiation of m acute inflammation of vascular endothelial cells.

Changes of Insulin-like Growth Factor- I, Insulin-like Growth Factor Binding Protein-3 and 24-hour Urinary Growth Hormone in PrepubertalChildren with Insulin Dependent Diabetes Mellitus.: Choong Ho Shin, Sei Won Yang; Korean Diabetes J. 1999;23(1):25-35. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The growth hormone - insulin-like growth factor-I(GH/IGF-I) axis and the insulin nutrition axis constitute two major anabolic hormone systems that interact at varous levels. It is well established that patients with type 1 diabetes mellitus have elevated GH levels and inappropriate low IGF-I for high GH levels. Such a deranged GH/IGF-I axis may complicate the somatic growth of children with diabetes. The purpose of this study assess the nature of deranged GH/IGF-I axis and the effect on somatic growth. METHODS: In the present study, serum levels of IGF-I and IGFBP-3 were measured in 31 prepubertal children with type 1 DM (age, 8.93.1yr) and were compared with those levels in children with normal short stature (control) (age, 8.4+/-2.5 yr). RESULTS: In diabetic patients, age-adjusted serum levels of IGF-I and IGFBP-3 were significantly lower than those in controls (p<0.05). The difference of serum levels of IGF-I and IGFBP-3 between diabetic patients and control increased with chronologic age. There was no difference in 24-h urinary GH (24-h uGH) excretion between diabetic patients and normal controls. Simple regression analysis reveled no correlation between height SDS (standard deviation score)and HbA, (average 7.4%), IGF-I, IGFBP-3, urinary growth hormone, and chronological age. But height SDS had a tendency to decrease with the duration of diabetes, but without statistical significance. In diabetic patients, the 24-h uGH expressed as ng/24 h was correlated with chronologic age, IGF-I, and IGFBP-3, but such correlation was not obsc:rved when the 24-h uGH was expressed as ng/g creatinine In the control group, the 24-h u(GH was expressed as ng/24 h, correlated with only IGFRP-3. CONCLUSION: The growth impairment during puberty (which may be dependent on the degree of blood glucose control), rather than during prepuberty is probably responsible for the reduced final adult height in diabetic patients. This might be partly due to a relatively good blood glucose ontrol during prepubertal period. More importantly, it is suggested that this reduced final adult height comes from a gradual decrease in IGF-I and IGFBP-3 levels for long period during diabetes, regardless of the 24-h urinary growth hormone excretion.

Relationship of Insulin-like Growth Factor(IGF)-1, IGF-2, IGF Binding Protein(IGFBP)-3, and Mitochondrial DNA Amount in the Umbilical Cord Blood to Birth Weight.: Yun Yong Lee, Do Joon Park, Chan Soo Shin, Kyong Soo Park, Hong Kyu Lee, Jong Kwan Jun, Boh Yun Yoon, Jih Yeun Song, Bong Sun Kang; Korean Diabetes J. 1999;23(1):36-45. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Reaven proposed a syndrome (syndrome X), consisting of glucose intolerance, hypertension, hyperinsulinemia, dyslipidemia, as a clinical entity. The fundamental metabolic defect of this syndrome was recognized as insulin resistance, but the pathophysiology of insulin resistance is not clarified as of yet. Recent evidence, suggests that non-insulin dependent diabetes mellitus (NIDDM) ancl lipid and cardiovascular abnormalities-syndrome X-are associated with intrauterine growth retar- dation (IUGR). Recently Shin reported that the amounts of mitochondrial DNA (mtDNA) in a given amount of genomic DNA were lower in NIDDM patients than in healthy controls, and the amount of mtDNA is negatively correlated with blood pressure ancl waist-hip ratio. Birth weight is known to be correlated with levels of insulin-like growth factors (IGFs). The purpose of this study was to identify the correlation of low birth weight with reduced mtDNA and syndrome X. We investigated the relationship of birth weight to IGFs and the amount of mtDNA METHODS: 72 singleton pregnancy babies and their mathers admitted in Seoul National University Hospital from March to May, 1997 were studied. After delivery, the cord blcxxl and maternal venous blood sampling was done. Using the imnnmoradiometric assay (IRMA) the IGF-l, IGF-2, IGFBP-3 was measured from cord and maternal plasma. Among them only 27 pairs samples were measured mtDNA amount with competitive PCR method in their buffy coat. Then statistical analysis was done within these paratneters. RESULTS: Birth weight is correlated significantly with cord plasma IGF-1 (r=0.32, p<0.01), IGFBP-3 (r=0.44, p<0.01), prepregnancy maternal body weight (r=0.45, p<0.01), maternal mtDNA amount (r=0.63, p<0.01). Cord blood mtDNA is correlated with maternal mtDNA amount (r=0.55, p<0,01). In multiple regression analysis, the maternal mtDNA was found to be the only independent factor related to birth weight (p<0.01). COMCLUSION: We have found the correlation between birth weight and maternal prepregnancy body weight and mtDNA amount. The clinical implications of this result remain yet to be deiermined.

Effect of Decreased Plasma Free Fatty Acids by an Antilipolytic Agent on Plasma Glucose Level and Liver Glycogen Content in Streptozotocin - induced Diabetic Rat.: Yun Ey Chung, Sang Wook Kim, Jin Yub Kim, Eun Sook Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1999;23(1):46-54. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Increased availability of plasma free fatty acid (FFA) leads to an inhibition of glucose utilization in peripheral tissue and to an increase of gluconeogenesis in the liver. A previous study has shown that a decrease in plasma FFA profoundly inhitbits hepatic gluconeogenesis, but total hepatic glucose production is maintained due to a com pensatory increase in glycogenolysis. It has been suggested that this hepatic autoregulatory mechanism is defective in the diabetic state, but there has been no firm evidence to confirm this. This study was performed to see the effect of decreasing plasma FFA on plasma glucose and hepatic glucose metabolism in diabetic rats, METHODS: Eight nondiabetic and 8 streptozotocin-induced diabetic rats were used. Blood sampling for plasma glucose and free fatty acid and liver biopsy for measurement of glycogen content were done after intravenous phenobarbital ancsthesia. Acipimox (50 mg/kg in saline) was administered via gastric tube. Plasma glucose and FFA were measured at 30, 60 and 120 min. Liver biopsy was repeated at 120 min. RESULTS: Baseline plasma glucose and FFA were higher in diabetic rats than in nondiabetic rats (18.8 +1.4 mmol/L vs. 6.9+0.8 mmol/L, 720+/-36 umol/L vs. 420+40 umol/L p<0.001 respectively). Hepatic glycogen content was higer in nondiabetic rats (31.8 +1.6mg/g liver vs. 26.02.Dmg/g liver, p<0.01). After acipimox administration, plasma glucose decreased profoundly in diabetic rats (18.8+1.4 mmol/L to 9.2+1.2 mmol/L, p<0.001) but not in nondiabetic rats. Glycogen content was significantly reduced in both groups (p<0.001). However, the difference in the contents was much smaller in the diabetic group compared with the nondiabetic group (6.5+2.1 mg/g liver vs. 19.2+ l.9 mg/g liver, p<0.001). CONCLUSION: 1t is suggested that the intrahepatic autoregulatory mechanism, which maintains hepatic glucose production constant in nondiabetic rats, is defective in diabetic rats.

Plasma Concentrations of Plasminogen Activator Inhibitor-1(PAI-1) and Lipoprotein(a) in Non-Insulin-Dependent Diabetes Mellitus with Peripheral Vascular Disease.: Sung Jin Nam, Sung Rae Cho, Choo Sung Kim, Sang Gyun Woo, Hee Jin Choi, Sang Ki Kim, Jae Hong Park, In Kyu Lee, Seong Bum Han, Seung Yup Han, Chung Chul Kim; Korean Diabetes J. 1999;23(1):55-61. Published online January 1, 2001

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Abstract PDF: OBJECTIVES
The plasminogen activator inhibitor-1 (PAI-I) and lipoprotein(a) are considered as important fibrinolysis inhibitors. We evaluated PAI-1 and Lp(a) concentrations in Korean non-insulin- dependent diabetes mellitus (NIDDM) patients with or without peripheral vascular disorder. METHODS: By using National Diabetes Data Group (NDDG) criteria as a diabetes mellitus diagnostic criteria, a total of 127 Korean NIDDM patients were seleeted. The ankle brachial index was measured by segrnental volume plethysmography to diagnose peripheral vascular disease. We also examined clinical and biochemical parameters in NIDDM patients. RESULTS: The duration of diabetes, systolic and diastolic pressures was significantly higher in diabetic patients with peripheral vascular disease (Group 2) than in diabetic patients without peripheal vascular disease (Group 1). The 24 hour urine microalbumin and PAI-1 levels in Group 2 were also significantly higher and the HDL-cholesterol level was lower than in Group 1. There were significant correlations between the plasma level of PAI-1 and BMI (r=0.466, p=0,007) or C-peptide level(r=0.517, p=0.012). Multivariate logistic regression analysis showed that Lp(a) and PAI-1 are independent risk factors for peripheral vascular disease. CONCLUSION: In the light of these results, it seems reasonable to suggest that high levels of PAI-1 and Lp(a) in NlDDM patients may play a role in the pathogenesis of peripheral vascular disease.

Pathogenetic Heterogeneity of Type 2 Diabetes Mellitus in Korea.: Seok Won Park, Yong Seok Yun, Young Duk Song, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1999;23(1):62-69. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance and insulin sec- retory dysfunction are considered as pathogenetic meehanisms leading to type 2 diabetes mellitus. In Korea, clinical features of type 2 diabetes are quite different from those of western countries. There are many non-obese patients and some even experienced considerable weight 1oss around the onset of diabetes mellitus. We investigated the insulin secretory function and in vivo insulin sensitivity in Korean patients with type 2 diabetes. METHODS: 38 patients with type 2 diabetes mellitus (age; 47.3+/-9.1 yrs) and 30 control subjects (age; 25.72.7 yrs) were included in this study. Type 2 diabetic subjects were further divided into obese (BMI >25, n=13) and non-obese (BMI<25, n=25) groups. Insulin secretory responses to the 75g aal gluxse loading and euglycemic hyperinsulinemic clamp test were performed on all subjects. RESULTS: Type 2 diabetic subjects had significantly lower serum insulin levels at 30 min of OGTT, regardless of their obesity, compared to the control subjects. Mean glucose disposal rates (M-values) were decreased by 36% in non-obese type 2 diabetic subjects and 58% in obese type 2 diahetic subjects compared to the control subjects. But, about half (12/25) of non-obese type 2 diabetic subjects and 30% (4/13) of obese type 2 diabetic subjects had normal insulin sensitivity, defined by 95% confidence interval of control subjects. Insulin sensitivity index (M-value) was correlated with BMI, WHR, fasting insulin, and HDL-cholesterol concentrations in type 2 diabetic subjects. CONCLUSION: In Korean type 2 diabetic subjects, impairment of early-phase insulin secretion may be an universal finding, but insulin resistance is observed in about 60% of subjects. This result suggest that there is pathogenetic heterogeneity of type 2 diabetes rnellitus in Korea.

Prevalence of Insulin Resistance Syndrome in Subjects Living in Jungup District , Korea.: Sang Wook Kim, Jin Yub Kim, Eun Sook Kim, Young Il Kim, Moo Song Lee, Hyeong Ho Kim, Joong Yeoul Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1999;23(1):70-78. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The clustering of hypertension, impaired glucose tolerance, low HDL cholesteml and high triglyceride is known as insulin resistance syndrome (IRS). We studied the prevalence of insulin resistance syndrome among subjects living in Jungup district, Korea. METHODS: Among a total of 151,000 subjects over 40 years of years living in Jungup district, a sample of 1,791 was selected using a random cluster sampling method. Oral glucose tolerance test revealed 1,018 subjects with normal or impaired glucose tolerance. The IRS was defined as the coexistence of two or more components of triad; hypertension, impaired glucose tolerance and dyslipidemia (triglycerides >= 200mg/dL and HDL <45 mg/dL for woman, HDL < 35 mg/dL for men). RESULTS: Twenty-one percent of men and 45% of women were obese and 50.8% and 61.9% were hypertensive. Eleven percent of men and 16 percent of women were found to have dyslipidemia. The prevalence of impaired glucose tolerance was 10.2% for men and 15.7% for women. The prevalence of IRS in the Jungup population was 12.8% for men and 19.6% for women. The prevalence of IRS increased according to the plasma level of insulin. There was a positive correlation between the number of components of IRS and the level of fasting plasma insulin. CONCLUSION: We conclude that the prevalence of IRS is high in Korean subjects. The close correlation between the IRS components and fasting insulin level suggests that cardiovascular risk is associated with insulin resistance.

Microalbuminuria in Diabetic and Non-diabetic Subjects: A population Based Study.: Young Il Kim, Yun Ey Chung, Jin Yup Kim, Sang Wook Kim, Eun Sook Kim, Moo Song Lee, Joong Yeoul Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1999;23(1):79-86. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Microalbuminuria is associated with increased cardiovascular mortality in type 2 diabetic patients and non-diabetic subjects. This study was undertaken to determine the prevalence ot microalbuminuria among diabetic and non-diabetic subjects in Korea and to determine the factors associated with microalbuminuria. METHOD: A sample of 1,791 subjects aged > 40 years living in Jungup district were selected from the 28,380 inhabitants using a random cluster sampling method. Among these subjects, 1,006 of them (56.1%) underwent the 75 g oral glucose tolerance test that was also part of the timed overnight urine collection. 46 subjects were excluded because they had signs of urinary tract infection (n=41) or overt proteinuria (n=5). Microalbuminuria was defined as urinary albumin excretion rate (UAER) between 20 and 200 pg/min. RESULTS: Subjects with microalbuminuria had a higher weight and body mass index (BMI), abdominal circumference, systolic and diastolic blood pressure (BP), fasting and 2hr plasma glucose, fasting semm insulin and proinsulin concentrations than subjects without microalbuminuria. The prevalence of micro- albuminuria increased as the glucose tolerance worsened[6.0% in normal glucose tolerance, 11.8% in impaired glucose tolerance (IGT) and 21.8% in diabetes, respectively; x trend=25.9, p<0.(0001]. Mean UAER of subjects with hypertension was greater than that of subjects without hypertension (7.8+0.9ug/min vs. 9.6+0.7ug/min, p<0.001). Univariate analysis revealed that the UAER was significantly (p<0.05) correlated with weight and BMI, abdominal circumference, systolic and diastolic BP, fasting and 2hr plasma glucose, fasting serum insulin and proinsulin after sex-adjustment. Multiple regression analysis revealed that weight or BMI, diastolic BP, 2hr plasma glucose and fasting serum insulin were independently associated with UAER in non-diabetic subjects. CONCLUSION: The present study demonstrates that the prevalence of microalburninuria is higher in patients with glucose intolerance. The association of the UAER with BMI, diastolic BP, 2hr plasma glucose and fasting serum insulin suggest that microalbuminuria is a feature of the insulin resistance syndrome.

Randomized Controlled Trial

Efficacy and Safety of Glimepiride: A Novel Sulfonylurea Drug compared with Gliclazide in the Treatment of Type 2 Diabetes Mellitus: an Open , Randomized Comparative Multi - Center Clinical Study.: Sung Kwan Hong, Ki Up Lee, Yeon Sang Oh, Ho Young Son, Kwang Won Kim, Hyun Chul Lee, Kyung Rae Kim, Dong Seop Choi, Ie Byung Park, Young Seol Kim, Kwan Woo Lee, Hong Kyu Lee, Soon Hyun Shin; Korean Diabetes J. 1999;23(1):87-97. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Glimepiride (HOE490, Amaryl (R)) is a new, third generation sulfonylurea, which binds to a different protein of the sulfonylurea receptor than other sulfonylureas. Although there have been many studies proving the efficacy of glimepiride on Caucasian diabetic patients, only a few studies are available on Asian diabetic patients. We performed an open, randomized, comparative multicenter clinical trial to assess the efficacy and safety of glimepiride in Korean type 2 diabetic patients. METHOD: We recruited 262 type 2 cliabetic patients at 12 different university hospitals whose blood glucose was not controlled effectively with diet alone. Patients were randomized to 1~2mg glimepiride or 40~80mg gliclazide depending on the fasting blood glucose level. Doses were increased stepwise, up to 8mg for glimepiride (once-daily) and 320mg for gliclazide (>80 mg as dividedose) respectively, until metabolic control (fasting blood glucose < 7.9 mmol/L) or maximum dose was achieved. The quality of rnetabolic control was assessed by fasting blood glucose and HbA 1c as primary variables. Insulin, C-peptide and weight were monitored as secondary variables. Safety was assessed by obtaining patient history and laboratory values of relevant variables. RESULTS: Of the 262 patients randomized to treatment, 160(61%) patients completed the 18-week study. The rate of successful blood glucose control (3.9

Original Article

Clinical Characteristics of Diabetic Patients Controlled by Diet and Exercise.: Kil Sang Wang, Sung Bae Lee, Hyun Suk Lee, Jae Suk Jeon, Kyung Wan Min, Kyung Ah Han, Eung Jin Kim; Korean Diabetes J. 1999;23(1):98-107. Published online January 1, 2001

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Abstract PDF: BACKGROUND
In order to rnaintain blood glucose in ao acceptable range, some patients with type 2 diabetes mellitus may be able to their level manage with diet and exercise alone, but others require oral agents or insulin. To assess which factors gave important influences on therapeutic methocls, we investigated clinical characteristics and life-style in the type 2 diabetic patients who could be managed with diet and exercise alone. METHODS: We recruited patients with type 2 diabetes mellitus from Eulji Medical College Diabetes Center, who had dieted and exercised for over 3 years (99; group 1) and compared them with patients who were managed with oral agents (130; group 2) or insulin (47; group 3). We conducted the retrospective evaluation of age, sex, duration of DM, initial and recent BM1 (body mass index), serial HbA 1c, skipped period ratio of hospital follow-up, self monitoring of blood glucose (SMBG) or urine sugar, diet and exercise and educational chance for diabetes with dependency of folk remedies. RESULTS: The duration of the DM was significantly shorter in group 1 than in group 2 or 3 (p<0,05). Initial BMI and HbA. were not different among these three groups, but HMI reduction was more decreased in group 1 (p<0.05). The mean HbA, during follow-up was lower in group 1 (p<0.05). The skipped period ratio of hospital follow-up was lower in group 1 (p<0.05). SMBG was less frequent, the meal-time was more regular, extra-snacks were less frequent and folk remedies were rarely tried in group 1. CONCLUSION: This study suggests that the duration of DM, BMI reduction and mean HbA 1c, were associated with the therapeutic method in patients with type 2 diabetes mellitus. We would like to a]so emphasize the importance of SMBG, meal-time regularity, extra-snacks and folk remedies in the education of patients with type 2 diabetes mellitus.

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