Diabetes & Metabolism Journal

Volume 23(6); December 1999

Original Articles

Role of Nitric Oxide on the Insulin Secretion of Rat Pancreas.: Moon Suk Nam, Sung Ki Kim, Seong Bin Hong, Yeo Joo Kim, Mi Rim Kim, Yong Seong Kim, Young Duk Song, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1999;23(6):748-756. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetes mellitus could occur when insulin secretion of pancreas is inadequate in response to blood glucose. The mechanisms on failure of pancreatic beta cell are still not known. Several recent experiments have reported that nitric oxide (NO) may be considered as a modulator of insulin secretion and impairment associated with the beta cell. The present study was purposed to investigate the role of nitric oxide on the secretion of insulin of rat pancreas in vivo and in vitro. METHODS: The plasma insulin and glucose were measured after intravenous injection of nitric oxide synthase (NOS) inhibitor (NG-nitro-L-arginine methyl. ester, L-NAME) in male rat. Insulin release was determmed during stimulation of NOS inhibitor and nitric oxide donor (hydroxylamine) in the isolated pancreatic islets. RESULT: 1. The insulin secretory response with L-arginine stimulation after injection of NOS inhibitor (L-NAME) in rat was increased resulting in mild hypoglycemia which recovered promptly. This showed that NO were related with L-arginine induced insulin secretion. 2. After isolation of pancreatic islet, 11,0 mM glucose induced insulin release was increased in culture media and L-arginine (1.0 mM) induced insulin release was also increased compared with control (6.72+/-0.66 vs. 3.48+/-0.42 prnol/islet/hour, p<0.05). 3. L-arginine induced insulin release was increased with L-NAME in the isolated rat pancreatic islets (12.5+/-1.38 vs, 7.23+/-0.93 ng/islet/ hour, p<0.05). 4. Glucose induced insulin release was progressively inhibited by NO donor hydroxylamine in the isolated rat pancreas islet (6.72+/-0.75 vs. 2.46+/-0.60 pmol/islet/hour p<0.05). CONCLUSION: These results strongly suggest that nitric oxide is a negative modulator of insulin release in normal rats induced by the nutrient secretagogues L-arginine and glucose in vivo and in vitro. Further investigation on the mechanism of nitric oxide in insulin secretory pathway will be necessary.

Effects of Insulin and Vitamin E on the Apoptosis of Pancreatic Islet Cells in Multiple Low dose Streptozotocin Induced Diabetic (LDSD) Mice.: Yong Hyun Kim, Jeong Hun Oh, Nan Hee Kim, Kyung Muk Choi, Sang Jin Kim, Sei Hyun Baik, Eung Seok Lee, Min Chul Lee, Dong Seop Choi; Korean Diabetes J. 1999;23(6):757-767. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Type 1 diabetes mellitus results from irreversible loss of beta cells in pancreatic islet. It is generally known that abnormal MHC expression and interaction of variable cytokines play a role in beta cell death, but the precise mechanism of beta cell death is unknown. Apoptosis is a physiological form of cell death and can play an important role in beta cell death in experimental diabetic animal models. Thus, in insulin and vitamin E treated LDSD mice and streptozotocin treated control mice. We attempted to comparing the levels of blood glucose (BG), the degree of insulitis, and number of apoptotic cells. Our study goal was to understand inhibition of apoptosis which thought to play an important mechanism in reducing the degree of hyperglycemia and insulitis. METHODS: In 3 LDSD mice groups (group 1: control group with streptozotocin only, group 2: streptozotocin plus insulin, group 3: streptozotocin plus vitamin E), the effects of insulin and vitamin E on the blood glucose levels and the degree of insulitis were evaluated. The number of apoptotic cells of pancreatic islet was compared using double staining immunohistochemical method. RESULT: The levels of BG, degree of insulitis and the rate of apoptosis of pancreatic islet cells were decreased in insulin and vitamin E treated groups when compared to the control group. There was no difference in number of apoptotic cells between insulin and vitamin E treated group, but levels of BG and degree of insulitis were higher in vitamin E treated group than insulin treated group as time elapsed. CONCLUSION: Insulin and vitamin E can decrease the elevation of BG and the degree of insulitis via inhibition of apoptosis in LDSD mice.

Differential Effects of Palmitate and Docosahexaenoic acid on ATP-sensitive K+ Channel Activity of Pancreatic beta-cells.: Yong Woon Kim, Kyeung Oh Doh, Dae Kyu Song, Jae Hoon Bae, Won Kyun Park, Kyu Jang Won, Hyoung Woo Lee, Suck Kang Lee; Korean Diabetes J. 1999;23(6):768-776. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Elevated levels of free fatty acids markedly enhance insulin secretion. However, dietary polyunsaturated fatty supplementation decrease insulin secretion. The effects of different type of fatty acids on cultured pancreatic beta cell remain controversy. Therefore, the specific goal of this study was to confirm the effect of palmitate and docosahexaenoic acid (DHA) on pancreatic beta-cells. We measured ATP-sensitive K+ (KATP) channel activity by patch clamp technique. METHOD: Pancreatic beta-cells were isolated from male Sprague-Dawley rats and cultured on the cover glass in the culture media. KATP channel activity of pancreatic beta-cells were measured by the cell-attached mode of the patch clamp technique. We treated 30 micrometer of palmitate and DHA dissolved with 3% albumin solution. RESULT: 30 micrometer of palmitate inhibited KATP channel activity. Moreover, after additions of 5 and 10 mM glucose, additional and dose dependent inhibitory effects were revealed. However, 30 micrometer of DHA did not have these additional inhibitory effect treated with 5 and lOmM glucose. CONCLUSION: Palmitate as a saturated fatty acid inhibited activity of KATP channel and increased inhibitory effect of glucose on this channel activity, however, DHA as a polyunsaturated fatty acid attenuated inhibitory effect of glucose on this channel activity.

Changes of TBARS and GGTase in Ischemia / Reflowed Kidney of Alloxan-diabetic Rat.: Jong Hoon Chung, Hak Yeon Bae, Jong Hee Cha, Jae Yoon Park, Pyoung Sim Park, Kwang Sam Koh, Byoung Rai Lee; Korean Diabetes J. 1999;23(6):777-784. Published online January 1, 2001

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Abstract PDF: BACKGROUND
To investigate the influence of diabetes mellitus (DM) on ischemia/reflow injury, the contents of thiobarbituric acid reactive substance (TBARS: marker of peroxidative cell injury), and the activity of gamma-glutamyltransferase (GGTase: marker of brush border membrane injury) were measured in ischemia/reflowed kidney of diabetic rats. METHODS: Rats were divided into the 3 groups; control (C), diabetes for 2 weeks (DM2) and diabetes for 4 weeks (DM4), and DM was induced by alloxan (80 mg/kg ip). Left kidney was subjected to 30 min of ischemia and 15 min of blood reflow, and the right kidney was used as a control kidney. The activities of antioxidant enzymes and GGTase, and the contents of TBARS were determined in kidney homogenate. RESULT: Catalase activity in ischemia/reflowed kidney was decreased 20% (p<0.05) in C, 34% (p<0.01) in DM2 and 23% (p<0.01) in DM4, while the change of SOD and GSHPx activities were not observed in kidney of diabetic rats cornpared with group C. TBARS contents, when ischemia/reflow, increased by 23% in C, 19% (p<0.01) in DM2, 16% in DM4, while the activity of GGTase decreased by 40% i#n C, 54% in DM2, and 55% (p<0.01) in kidney of DM4. CONCLUSION: The TBARS contents in ischemia/ reflow kidney of diabetic group showed no change, while GGTase activity was decreased significantly when compared with control group. This study may suggested that in ischemia/reflow kidney, the peroxidative membrane lipid injury was not increased, but the brush border membrane injury was increased by DM.

Proliferative Ability of Aortic Smooth Muscle Cells and Lipid Peroxidation of Red Blood Cell Membrane in Diabetic Rats.: Sae Young Park, Hyung Joon Yoo, Kyun Soo Kim, Hyun Kyu Kim, Doo Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Sung Woo Park; Korean Diabetes J. 1999;23(6):785-792. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetes mellitus is a known risk factor for atherosclerosis, and lipid peroxidation, expression of oxidative stress, is also known to related to diabetes mellitus. The purpose of this study was to investigate the proliferative behaviour of cultured vascular smooth muscle cells (VSMCs) and the alteration of lipid peroxidation in relation to the pathogenesis of diabetic atherosclerosis. METHODS: Seven streptozotocin-induced insulin dependent diabetic Sprague Dawley rats and 7 normal rats were studied. Using enzyme method, aortic VSMCs was cultured in diabetic rats. and proliferation was compared between normal and diabetic rat. The membrane lipid peroxidaton of erythrocytes was determined by measurement of malonyl- dialdehyde(MDA), an end-product of fatty acid peroxidation with thiobarbituric acid (TBA) reaction. MDA-TBA colored complex concentration was calculated with the extinction coefficient of MDA-TBA complex at 532nm = 1.56X105cm-lM-1. RESULT: 1. The proliferative ability of cultured VSMCs was much higher in diabetic rats than in nondiabetic ones (p<0.05). 2. Compared with normal control rats, MDA concentration of diabetic rats was significantly increased (p<0.05). CONCLUSION: We concluded that proliferation of cultured VSMCs is due to oxidative stress in diabetes mellitus as a result of the increased proliferative ability of cultured VSMCs combined with increased lipid pemxidation in diabetic rats.

Mutations in Hepatocyte Nuclear Factor-la in Early-Onset Type 2 Diabetes Mellitus in Korea.: Kyoung Ah Kim, Myung Shik Lee, Kyu Jeung Ahn, Jae Hoon Chung, Yong Ki Min, Moon Kyu Lee, Ki Up Lee, Ghi Su Kim, Kyoung Ho Suk, Dae Yeun Hwang, Kwang Won Kim; Korean Diabetes J. 1999;23(6):793-802. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Type 2 diabetes mellitus is a heterogeneous disorder caused by the unfavorable combination of genetic and environmental factors. Maturity-onset diabetes of the young (MODY) is a rare form of familial type 2 diabetes mellitus characterized by an early onset, and it is appearance in at least three consecutive generations, consistent with an autosomal dominant mode of inheritance. It accounts for 1~3% of type 2 diabetes mellitus cases. As of today, five different MODY genes have been identified. In 1996, Yamagata et al. reported that MODY3 and MODY 1 were caused by mutations in hepatocyte nuclear factor (HNF) la and 4a, respectively. Furthermore, there have been reports that HNF-la gene mutation could be a cause of early-onset type 2 diabetes mellitus with familial history, although these patients do not fulfill the clinical criteria of MODY. Therefore, the purpose of this study was to examine the mutation of HNF-la gene in early-onset type 2 diabetes mellitus in Korean subjects. METHODS: Sixteen cases of early-onset type 2 diabetes mellitus with familial history were included in the study. Five of these subjects were MODY patients according to our revised criteria. DNA was isolated from peripheral blood. The 10 exons and flanking introns of the HNF-1 a gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced using an AmpliTaq FS Dye Terminator Cycle Sequencing Kit (Perkin-Elmer Applied Biosystems). RESULT: Mutation in the HNF-la gene was identified in 1 of the 16 patients. It was a hitherto unreported novel missense mutation, R263L. This mutation co-segregated with type 2 diabetes mellitus or impaired glucose tolerance in his family and was not found in family members with normal glucose tolerance. CONCLUSION: Findings from this study suggests that MODY3 caused by mutation of HNF-la gene is also present in early onset type 2 diabetic of Korean subjects. This is the first time that HNF-la mutation causing MODY was identified in Korea.

Association Between Uncoupling Protein-1 and 3-adrenergic Receptor Gene Polymorphisms and Energy Metabolism in normal Korean Adults.: Jae Han Kim, Seog Ki Yun, Chul Hee Kim, Dong Won Byun, Young Sun Kim, Kyo Il Suh, Myung Hi Yoo; Korean Diabetes J. 1999;23(6):803-813. Published online January 1, 2001

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The beta3-adrenergic receptor (beta3-AR) and uncoupling protein 1 (UCP-1), expressed mainly in brown adipose tissue, are involved in the regulation of thermogenesis and lipolysis. Recent studies have shown that polymorphisms of the 3-AR (Trp64Arg) and UCP-1 (-3826, A to G) genes are associated with low basal metabolic rate (BMR) and obesity. METHODS: We investigated the effects of the beta3- AR and UCP-1 gene polymorphisms on body fat and energy metabolism in 65 normal Korean men aged from 21 to 36 years. The Trp64Arg mutation of the beta3-AR gene and A to G polymorphism (-3826) of UCP-1 gene were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. RESULT: In normal Koreans, Arg64 allele frequency of the beta3-AR was 0.15 and the allele frequency of the A to G substitution of the UCP-1 gene was 0.48. No significant difference was found in BMR, body fat and abdominal fat amount in relation to beta3-AR or UCP-1 genotypes. However, when the polymorphisms of the two genes were combined, the subjects with the polymorphisms of both UCP-1 and g-AR genes were found to have higher body mass index, higher total fat and abdominal fat amount, lower BMR, and lower fat oxidation rate when compared with the subjects without these polymorphisms. CONCLUSION: These results suggest that the polymorphisms of either beta3-AR or UCP-1 gene alone did not significantly affect BMR, fat oxidation and body fat amounts, but both UCP-1 and beta3-AR genes polymorphisms have synergistic effects on decreased basal metabolic rate, fat oxidation rate, and increased body fat in normal Korean adults.

Risk Factors of Peripheral Vascular Disease (PVD) and Nutritional Factors in Diabetic Patients over 60 Years Old Complicated with PVD Diagnosed by Ankle-Brachial Index ( ABI ).: Yoo Sun Chung, Hyung Joon Yoo, Sung O Seo, Hyun Kyu Kim, Doo Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Sung Woo Park; Korean Diabetes J. 1999;23(6):814-821. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The subjects with diabetes mellitus are at high risk for peripheral vascular disease (PVD). The ABI (Ankle-Brachial Index) was done for diagnosis of PVD in diabetes. Numerous studies have been conducted to determine the risk factors for diabetes PVD. Most of the risk factors have been found are largely affected by the age and patients nutritional status to some extent. Especially in older diabetes, risk factors cannot be evaluated by numerical values only, for most patients are in background of poor nutritional support. Therefore, in this study, our aim was to evaluate on the influences of the nutritional status as the risk factors for PVD in older patients, ie., 60 years and older. METHODS: We selected 59 patients who are above 60 years old and took neither anti-hypertensive drug nor lipid lowering agents. All subjects ABI was measured by IMEXLAB 9000 and the study group was stratified according to the ABI values: the normal (ABI >10), PVD group (ABI <0.9). The ABI (Ankle-Brachial Index) was measured by The data were analyzed using one-way analysis of variance. If statistically significant effect was found, post hoc analysis (e.g., Newman-Keuls' test) was performed to evaluate the difference between the groups. The values are expressed as the mean+/-standard error (SE). RESULT: There was significant difference in smoking (ABI < 0.9; 0.54+/-0.16 packs/day, ABI > 1.0; 0.35+/-0.08 packs/day), the serum level triglyceride(ABI < 0.9; 1.960.19 mmol/L, ABI > 1.0; 1.56 + 0.21 mmol/L), HDL-cholesterol(ABI < 0.9; 0.88+/-0.11 mmol/L, ABI > 1.0; 1.10+/-0.08 mmol/1) when compared between the normal and ABI decreased subjects(P < 0.05). However, we found no significant differences in systolic blood pressure, total cholesterol and LDL-C between the two groups. Serum level of the nutritional factors such as albumin, transferrin, total lympocyte count, folate, zinc were lower than the normal values in both groups. However, these levels were not statistically significant when two groups compared. CONCLUSION: The relationship between the known PVD risk factors and PVD in older diabetes was weak. Therefore, based on the findings from this study, we suggest that when investigators interpretate the risk factors of PVD in elderly patients one must consider nutritional effects along the other factors.

The Difference of Intrarenal Hemodynamics in Type 2 Diabetic Nephropathy.: Ji Hyun Lee, Ye Dal Jung, Ho Sang Shon, Ki Sung Ahn, Duck Soo Chung; Korean Diabetes J. 1999;23(6):822-830. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetic nephropathy is a major microvascular complication in diabetic patients. No single etiologic factor has been identified to explain the development of diabetic nephropathy. Genetic factors, poor glycemic control, increased intra-glomerular pressure, systemic hypertension, and altered intrarenal hemodynamics may be contributed to the pathogenesis of diabetic nephropathy. Intrarenal duplex Doppler sonography can provide physiologic information reflecting the status of renal vascular resistance. Recently, there were some reports that obstructive renal disease and renal allograft rejection patients has altered intrarenal hemodynamics. So we investigate intrarenal hemo- dynamic abnormalities in diabetic patients with nephropathy and analyze the factors associated with increased intrarenal resistance METHODS: The patients were divided into the three groups. According to the levels of 24-hour urinary albumin excretion(UAE), group 1 (UAE<30mg/day, normoalbuminuria), group 2 (30 mg/day

Relation of Angiotensin Converting Enzyme (ACE) Gene Polymorphism to Insulin Sensitivity and Carotid Atherosclerosis in Female Nondiabetic Offspring of NIDDM Patients.: Jee Young Oh, Yeon Ah Sung, Nan Ho Kyung, Yeon Jin Jang; Korean Diabetes J. 1999;23(6):831-842. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Angiotensin converting enzyme (ACE) gene polymorphism has been known to related to atherosclerotic heart disease such as acute myocardial infarction or left ventricular hypertrophy, diabetic nephropathy or retinopathy, as well as, insulin sensitivity. However, an exact relationship between ACE gene polymorphism and aforementioned diseases have not been fully established. It has been suggested that NIDDM and atherosclerosis may have common pathogenesis since some of NIDDM patients already have atherosclerotic changes at the time of the initial diagnosis. Futhermore, offspring of NIDDM patients are considered as a high risk group for both NIDDM and atherosclerosis, and these two disorders are known to be affected by some common genetic factors. Therefore, in the present study, we planned to investigate, by analyzing female offspring of NIDDM patients (offspring), the relationship of ACE gene polymorphism to insulin resistance and atherosclerosis. METHODS: Fifty-three female offspring of patients with NIDDM were participated in this study, and twenty age-BMI matched normal glucose tolerant subjects without a family history of diabetes were selected as the controls. Based on 75-g oral glucose tolerance test, subjects were divided into normal glucose tolerance (n=42) or impaired glucose tolerance (n=ll). We assessed the patterns of body fat distribution by anthropometric measurement, bioelectric impedence analysis and computed tomogram; insulin sensitivity by minimal model analysis using insulin modified frequently sampled intravenous glucose tolerance test; carotid intima-medial thickness by ultrasonography. We investigated the alleles of the ACE gene by PCR. RESULT: 1. ACE genotypes in offspring were distributed as follows; 39.6% for II, 32.0% for ID, 28.4% for DD 55.7% for I al#lele, 44.3% for D allele. This distribution was not significantly different from those in controls (35.0% for II, 55.0% for ID, 10.0% for DD, 62.5% for I allele, and 37.5% for D allele). 2. There was no significant difference in body mass index (BMI), systolic and diastolic blood pressure, and serum lipid concentrations among three genotypes. However, in the subjects with ID genotype, VSR was significantly increased compared to the subjects with DD genotype (p<0.05). In the subjects with ID genotype, percent body fat, visceral fat area, CIMT were increased, and SI and SG were decreased in comparison to II and DD subjects, although the differences between the two groups did not reached the statistical significance. 3. When the subjects were divided into quartiles of CIMT, the frequency of ID genotype of ACE showed the tendency of increment from the lowest to the highest quartile of CIMT. 4. Multiple regression analysis showed that ACE genotypes was significantly associated with visceral obesity, carotid intima-medial thickening and insulin sensitivity. CONCLUSION: ACE genotypes was not significantly associated with visceral obesity, carotid intima- medial thickening and insulin sensitivity. However, to explore the true associations of ACE gene polymorphism with insulin resistance and ather-osclerosis, we further suggest and recommend prospective studies.

Clustering of Risk Variables in Insulin Resistance Syndrome in Jungup District, Korea.: Sang Wook Kim, Myung Hoe Huh, Young Il Kim, Jin Yub Kim, Eun Sook Kim, Moo Song Lee, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1999;23(6):843-856. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance syndrome (IRS), a clustering of hypertension, impaired glucose tolerance, low HDL cholesterol and high triglyceride, is prevalent in Korea. We studied the correlational structure of IRS using factor analysis to evaluate whether a single process underlies in the clustering of these risk factors. METHODS: Factor analysis was performed using data from 1,018 non-diabetic subjects (388 men and 630 women) who participated in the Jungup epidemiological study. RESULTS: Factor analysis reduced 9 correlated risk factors to 4 independent factors, each reflecting a different aspect of IRS: hypertension factor (increased systolic and diastolic blood pressure), glucose intolerance factor (increased fasting and postload glucose), obesity factor (increased body mass index, waist circumference, and increased insulin), and dyslipidemia factor (increased trigly- cerides and decreased HDL cholesterol). Increased insulin was also loaded into dyslipidemia factor in men and glucose intolerance factor in women. These factors explained about 70% of the total variance in the data. Three factors such as the glucose intolerance factor, the dyslipidemia factor and the obesity factor, were linked through mutual association with hyperinsulinemia, while hypertension factor was not associated with hyperin- sulinemia. Age-adjusted mean BP by BMI tertile and fasting insulin level tertile for men and women increased progressively with increase in BMI in men and women. There was no significant elevation of mean BP according to increase in fasting insulin level. In contrast to premenopausal women in whom hyperinsulinemia show mutual association with the glucose intolerance factor, the dyslipidemia factor, and the obesity factor, hyperinsulinemia was only loaded into obesity factor in postmenopausal women. CONCLUSION: These results suggested that more than one process underlies the clustering of IRS. In sulin resistance alone did not seem to be the single underlying mechanism of IRS. Especially, hypertension was not correlated with hyperin- sulinemia.

Case Report

A Case of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Associated with Amitriptyline in a Patient with Diabetic Neuropathy.: Young Sil Lee, Seok Dong Yoo, Young Hyun Lee; Korean Diabetes J. 1999;23(6):857-862. Published online January 1, 2001

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Abstract PDF: Amitriptyline is an effective drug for diabetic neuropathy, but rarely cause syndrome of inappropriate antidiuretic hormone (SIADH) secondary to amitriptyline administration. We experienced a case of SIADH associated with amitriptyline in a patient with diabetic neuropathy. A 64-year-old diabetic women was admitted to the hospital because of severe general weakness and obtunded mentality. Medical history shows that she was treated with amitriptyline for peripheral painful diabetic neuropathy in the past 5 years. Her conditions were including severe hyponatremia, decreased serum osmolality, and elevated urine sodium concentrations, which is consistent with SIADH. With discontinuation of amitriptyline, fluid restriction and hypertonic saline administration, serum sodium level was normalized and general conditions improved. We experienced SIADH that was associated with amitriptyline treatment for diabetic neuropathy, thus the current report is to bring an awareness of hyponatremia in our medical community.

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