Diabetes & Metabolism Journal

Original Article

R1467H Variants of Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) are Associated with Type 2 Diabetes Mellitus in Koreans: Qing Song Jin, So Hun Kim, Shan-Ji Piao, Hyun Ae Lim, Seung Youn Lee, Seong Bin Hong, Yong Seong Kim, Hun-Jae Lee, Moonsuk Nam; Korean Diabetes J. 2010;34(6):368-373. Published online December 31, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.6.368

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Background

The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of Rho GTPases and is thought to influence insulin signaling. The R1467H variant of ARHGEF11 has been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) in Western populations.

Methods

We investigated the effects of the R1467H variant on susceptibility to T2DM as well as related traits in a Korean population. We genotyped the R1467H (rs945508) of ARHGEF11 in 689 unrelated T2DM patients and 249 non-diabetic individuals and compared the clinical and biochemical characteristics according to different alleles.

Results

The H allele was significantly more frequent in T2DM cases than in controls (P = 0.037, 17.1% and 13.1%; respectively). H homozygocity was associated with a higher risk of T2DM compared to those with R/R or R/H genotype (odds ratio, 5.24; 95% confidence interval, 1.06 to 25.83; P = 0.042). The fasting plasma glucose, HbA1c, fasting insulin, HOMA2-IR and HOMA2-%β levels did not differ significantly between different genotypes.

Conclusion

Our study replicated associations of the ARHGEF11 polymorphism with increased risk of T2DM in a Korean population and thus supports previous data implicating a potential role of ARHGEF11 in the etiology of T2DM. Further studies revealing the underlying mechanism for this association are needed.

Citations

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Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia
Jie Yan, Rina Su, Wanyi Zhang, Yumei Wei, Chen Wang, Li Lin, Hui Feng, Huixia Yang
The Journal of Maternal-Fetal & Neonatal Medicine.2021; 34(3): 422. CrossRef
Loss of Arhgef11 in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury
Ashley C. Johnson, Wenjie Wu, Esinam M. Attipoe, Jennifer M. Sasser, Erin B. Taylor, Kurt C. Showmaker, Patrick B. Kyle, Merry L. Lindsey, Michael R. Garrett
Hypertension.2020; 75(4): 1012. CrossRef
Transgenerational Obesity and Alteration of ARHGEF11 in the Rat Liver Induced by Intrauterine Hyperglycemia
Wanyi Zhang, Rina Su, Hui Feng, Li Lin, Chen Wang, Huixia Yang
Journal of Diabetes Research.2019; 2019: 1. CrossRef
ARHGEF11 affecting the placental insulin signaling pathway in fetal macrosomia of normal glucose tolerance pregnant women
Wanyi Zhang, Rina Su, Li Lin, Huixia Yang
Placenta.2018; 63: 7. CrossRef
Genetic variants and clinical relevance associated with gestational diabetes mellitus in Chinese women: a case-control study
Jie Yan, Rina Su, Deng Ao, Yan Wang, Haijun Wang, Huixia Yang
The Journal of Maternal-Fetal & Neonatal Medicine.2018; 31(16): 2115. CrossRef
Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis
Yutaka Mizuki, Manabu Takaki, Shinji Sakamoto, Sojiro Okamoto, Makiko Kishimoto, Yuko Okahisa, Masahiko Itoh, Norihito Yamada
International Journal of Molecular Sciences.2016; 18(1): 67. CrossRef
Allelic Variants in Arhgef11 via the Rho-Rock Pathway Are Linked to Epithelial–Mesenchymal Transition and Contributes to Kidney Injury in the Dahl Salt-Sensitive Rat
Zhen Jia, Ashley C. Johnson, Xuexiang Wang, Zibiao Guo, Albert W. Dreisbach, Jack R. Lewin, Patrick B. Kyle, Michael R. Garrett, Maria Pia Rastaldi
PLOS ONE.2015; 10(7): e0132553. CrossRef
The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes
Ying-Ju Chang, Scott Pownall, Thomas E Jensen, Samar Mouaaz, Warren Foltz, Lily Zhou, Nicole Liadis, Minna Woo, Zhenyue Hao, Previn Dutt, Philip J Bilan, Amira Klip, Tak Mak, Vuk Stambolic
eLife.2015;[Epub] CrossRef
Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population
Yutaka Mizuki, Manabu Takaki, Yuko Okahisa, Shinji Sakamoto, Masafumi Kodama, Hiroshi Ujike, Yosuke Uchitomi
Human Psychopharmacology: Clinical and Experimental.2014; 29(6): 552. CrossRef
Small G proteins and their regulators in cellular signalling
Roland Csépányi-Kömi, Magdolna Lévay, Erzsébet Ligeti
Molecular and Cellular Endocrinology.2012; 353(1-2): 10. 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

Case Reports

A Case of Insulinoma Associated with Type 2 Diabetes Mellitus.: Sung Soo Yoo, Wan Sub Shim, Chul Hyun Kim, Ki Cheol Ha, Seung Min Lye, Eun Joo Kim, So Hun Kim, Seong Bin Hong, Moonsuk Nam, Yong Seong Kim; Korean Diabetes J. 2007;31(6):517-519. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.517

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Abstract PDF: An insulinoma is an endocrine tumor of the pancreas derived from the beta cells with abnormal insulin secretion. An insulinoma is rare, the incidence being estimated at only four per one million person-years. The association of diabetes mellitus and insulinoma is extraordinarily rare, but we should not overlook an insulinoma as a possible cause of hypoglycemia in patients with diabetes mellitus. A 70-year-old diabetic man who had been treated with oral hypoglycemic agents for type 2 diabetes suffered from night sweating for 10 days. Even after he stopped taking his oral hypoglycemic agents, the night sweating continued. The patient was admitted to evaluate the cause of the recurrent hypoglycemic events. After a 72-hour fasting test and selective arterial calcium stimulation test with venous sampling, he was diagnosed with insulinoma accompanied by type 2 diabetes mellitus. In the course of the study, the patient was also incidentally diagnosed with lung cancer.

A Case of Fulminant Type 1 Diabetes Associated with Pregnancy.: Hyung Kwon Yu, Moonsuk Nam, Wan Sub Shim, Hyun Jung Chung, Eun Joo Kim, Seong Bin Hong, Yong Seong Kim; Korean Diabetes J. 2007;31(2):180-183. Published online March 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.2.180

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Abstract PDF

Type 1 diabetes is characterized by insulin deficiency due to destruction of pancreatic beta-cells. A novel subtype of type 1B which is rapidly developed without any evidence of autoimmunity has been recently proposed as fulminant type I diabetes. In female patients of child-bearing age, the onset of fulminant type 1 diabetes occurred frequently during pregnancy or after delivery in Japan, however, there was no report about fulminant type 1 diabetes associated with pregnancy in Korea. We report a case of fulminant type 1 diabetes associated with pregnancy. A 28-year-old woman suffering from excessive thirst with vomiting and general weakness after four days from normal spontaneous vaginal delivery presented to our hospital. Laboratory examination revealed a high blood glucose level and evidence of diabetic ketoacidosis, butHbA1c level was normal. These findings suggested a very recent onset of diabetes mellitus. Serum C-peptide level was very low level. Antibodies to glutamic acid decarboxylase (GAD) was weakly positive. After fluid and insulin based management, patient successfully recovered without any serious complication.

Citations

Citations to this article as recorded by

Fulminant Type 1 Diabetes Developing during Pregnancy in Patient with Gestational Diabetes Mellitus
Jong Ha Baek, Kyong Young Kim, Soo-Kyoung Kim, Jung Hwa Jung, Jong Ryeol Hahm, Jaehoon Jung
The Korean Journal of Medicine.2017; 92(2): 186. CrossRef
Fulminant Type 1 Diabetes with Robust Recovery in Insulin Secretion in a Pregnant Woman as an Initial Manifestation of Third-Trimester Intrauterine Fetal Death
Mi-Hae Seo, Hyosang Han, Ji Yun Jeong, Jun-Yong Chang, Sun Young Jung
Soonchunhyang Medical Science.2017; 23(2): 118. CrossRef
A Case of Fulminant Type 1 Diabetes during Pregnancy
Tae-Seon Oh, Heesoo Jung, Hye Rim Kang, Tae Kyun Kim, Min Jeong Kwon, Soon Hee Lee, Jeong Hyun Park
The Journal of Korean Diabetes.2016; 17(2): 134. CrossRef
A Case of Fulminant Type 1 Diabetes Mellitus Complicated with Ischemic Ileitis
Se-Won Oh, Ju-Ri Park, Yun-Jeong Lee, Hee-Yeong Kim, Ji-A Seo, Nan-Hee Kim, Kyung-Mook Choi, Sei-Hyun Baik, Dong-Seop Choi, Sin-Gon Kim
Journal of Korean Endocrine Society.2009; 24(2): 116. CrossRef

Original Articles

Development of Two Parallel Diabetes Knowledge Tests.: Wan Sub Shim, Seong Bin Hong, Yeon Sil Choi, Yun Jin Choi, Sook Hee Ahn, Kee Young Min, Eun Joo Kim, Ie Byung Park, Moonsuk Nam, Yong Seong Kim; Korean Diabetes J. 2006;30(6):476-486. Published online November 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.6.476

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Abstract PDF

BACKGROUND
Knowledge evaluation about diabetes mellitus is necessary to self-manage diabetes effectively. We developed two parallel diabetes knowledge tests to meet a need for reliable knowledge assessment in diabetic patients. MATERIALS AND METHODS: The 75-items (59 items for general knowledge test, 16 items for insulin use subscale) were administered to 102 diabetic patients who visited Inha University Hospital. The items which had the appropriate difficulty (0.25~0.80) and good discrimination index (above 0.25) were selected. However, the items which are thought to be an important item for education were also selected even though they did not meet the criteria of reliability and discrimination index. Two parallel diabetes knowledge tests were developed after matching the selected appropriate items for similar contents. RESULTS: 102 patients fulfilled the tests and their mean age was 54.1 +/- 11.5 years. Mean percentage of correct questionnaires was 60.9 +/- 12.5% for general test and 45.9 +/- 19.5% for insulin use subscale. There were significant differences of scores between patients with high and low education level, between patients with high income per household and low income level per household, between patients with the history of diabetes education and without history of diabetes education, and between the old (> or = 50 yrs) and the young (< 50 yrs) age group. However, there was no significant difference of scores according to diabetes duration and complication or not. The selected two tests had a similar score. And their Cronbach alpha was appropriate (> 0.70) in both tests. CONCLUSIONS: We developed two parallel diabetes knowledge tests. These tests can be used as an important means in evaluating the diabetes knowledge and effect of education in diabetic patients.

Citations

Citations to this article as recorded by

Health literacy and diabetes self‐care activities: The mediating effect of knowledge and patient activation
Su Hyun Kim
International Journal of Nursing Practice.2021;[Epub] CrossRef
Factors influencing psychological insulin resistance in type 2 diabetes patients
Ji Hyeon Yu, Hye Young Kim, Sung Reul Kim, Eun Ko, Heung Yong Jin
International Journal of Nursing Practice.2019;[Epub] CrossRef
A new comprehensive diabetes health literacy scale: Development and psychometric evaluation
Eun-Hyun Lee, Young Whee Lee, Kwan-Woo Lee, Moonsuk Nam, So Hun Kim
International Journal of Nursing Studies.2018; 88: 1. CrossRef
Effect of a Simulated Education-based Hypoglycemia Scenario Using a High-fidelity Simulator on Acquisition and Retention of Diabetes Knowledge and Academic Self-efficacy in Nursing Students
Jiyoung Kim, Narae Heo
Journal of Korean Academic Society of Nursing Education.2017; 23(3): 319. CrossRef
Clinical Evaluation of OneTouch Diabetes Management Software System in Patients with Type 2 Diabetes Mellitus
Jung Min Kim, Hey Jean Lee, Keum Ok Kim, Jong Chul Won, Kyung Soo Ko, Byung Doo Rhee
Diabetes & Metabolism Journal.2016; 40(2): 129. CrossRef
Relationship Between Duration of Type 2 Diabetes and Self-Reported Participation in Diabetes Education in Korea
Jongnam Hwang, Jeffrey A. Johnson
Asia Pacific Journal of Public Health.2015; 27(2): NP311. CrossRef
Factors Influencing Diabetes Educational Needs in Patients with Diabetes Mellitus
Seon-Yeong Park, Pok-Ja Oh
Journal of the Korea Academia-Industrial cooperation Society.2014; 15(7): 4301. CrossRef
The Effect of the Experience of Diabetes Education on Knowledge, Self-Care Behavior and Glycosylated Hemoglobin in Type 2 Diabetic Patients
Seung Hei Moon, Young Whee Lee, Ok-Kyung Ham, Soo-Hyun Kim
The Journal of Korean Academic Society of Nursing Education.2014; 20(1): 81. CrossRef
Factors Affecting Highly Educated Elders' Diabetic Health Leader Attitude
Kiwol Sung, Jiran Nam, Mijin Yu
Journal of Korean Academy of Community Health Nursing.2014; 25(2): 119. CrossRef
Nutrition Knowledge, Dietary Attitude, and Dietary Behavior among Children and Adolescents with Type 1 Diabetes
Na-Yeon Noh, So-Young Nam, Hee-Suk Kang, Ji-Eun Lee, Soo-Kyung Lee
Korean Journal of Community Nutrition.2013; 18(2): 101. CrossRef
Effect of Diabetes Education Program on Glycemic Control and Self Management for Patients with Type 2 Diabetes Mellitus
Ji Hyun Kim, Sang Ah Chang
Korean Diabetes Journal.2009; 33(6): 518. CrossRef

The percent change of body weight in patients with type 2 diabetes using rosiglitazone for 1 year.: Seong Bin Hong, Hwi Ra Park, Eun A Kim, Kyung wook Lee, Moonsuk Nam, Yong Seong Kim; Korean Diabetes J. 2006;30(1):47-53. Published online January 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.1.47

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Abstract PDF: BACKGROUND
Rosiglitazone(RSG) is known as a potent agonist for the PPARgamma. It improves glycemic control by improving insulin sensitivity in peripheral tissues. And it is associated with body weight gain. The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor(PPAR)gamma2 has recently been shown to be associated with insulin sensitivity. This study was performed to evaluate the body weight change during the long term rosiglitazone treatment and the role of PPARgamma2 polymorphism, Pro12Ala as an indicator to predict the clinical response of RSG in type 2 diabetes patients. METHOD: The study subjects were 214 type 2 diabetic patients(117 male, 97 female) who were received a daily 1 year course of 4 mg RSG combined with sulfonylurea or metformin. The Pro12Ala polymorphism of the PPARgamma2 was determined by the restriction fragment length polymorphism(RFLP) method. Body weight, height, waist circumference, fasting glucose, insulin, c-peptide and lipid profile were measured. RESULTS: After RSG treatment, body weight change was 2.4 +/- 3.8%, 4.5 +/- 9.8% of baseline body weight at 12, 24 weeks respectively. Body weight gains were increased to 5.6 +/- 10.1% at the end of 1 year. The HbA1C, serum insulin level and HOMA index were decreased following the rosiglitazone therapy. The allele frequency of the Ala12Pro polymorphism of the PPARgamma2 was 0.016. The number of Ala12Pro variant of the PPARgamma2 was too low to predict clinical response of RSG. Body weight gain was correlated with basal fasting plasma glucose, post-prandial 2 hour glucose and HbA1c level(p<0.05). There was no correlation between baseline body weight and change. CONCLUSION: This results showed that Pro12Ala polymorphism was not acceptable for the predictor of RSG induced weight gain and clinical response. However, body weight gain was increased in who had high glucose level, and correlated positively with glucose decrease. 1st 3 month weight gain was best predictor of weight change during 1 year.

Case Report

Two Cases of Diabetic Ketoacidosis Associated with Atypical Antipsychotics.: Seung Hee Lee, Kum Ho Yi, Eun A Kim, Seong Bin Hong, Moon Suk Nam, Yong Seong Kim; Korean Diabetes J. 2005;29(6):566-570. Published online November 1, 2005

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Abstract PDF: Atypical antipsychotics have been widely used for the management of patients with schizophrenia and other psychotic disorders. However, they may be associated with a greater risk of metabolic abnormalities than others, including weight gain, hyperlipidemia, and new-onset type 2 diabetes mellitus or diabetic ketoacidosis (DKA). We report two cases of reversible DKA and new-onset DM that developed in patients treated with atypical antipsychotics. A 42-year-old male patient with schizophrenia who was on olanzapine admitted to the hospital because of DKA. He had been taking olanzapine for 5 months. Five months before the admission, his fasting serum glucose levels were 109 m/dL. Another 34-year-old male with no previous history of diabetes mellitus was admitted to the hospital and subsequently diagnosed with DKA. The patient had been taking risperidone. Clinicians should monitor blood glucose concentrations periodically in patients taking atypical antipsychotics.

Original Articles

Resurvey of Alternative Medicine in Korean Type 2 Diabetes Mellitus after 10Years.: Kyung Wook Lee, Seong Bin Hong, Kee Young Min, Seung Yong Lee, Moonsuk Nam, Yong Seong Kim, Chul Woo Ahn, Bong Soo Cha, Kyung Rae Kim, Hyun Chul Lee, Kwan Woo Lee, Tae Sun Park; Korean Diabetes J. 2005;29(3):231-238. Published online May 1, 2005

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Abstract PDF: BACKGROUND
Despite tremendous advances in modern medicine, the interest in alternative medicine, including those medicines used for the treatment of diabetes has intensified throughout the industrialized world. We conducted a clinical resurvey of the dlternative medicines used for diabetic treatment, and we compared the results with those from the previous survey. METHODS: From July through October 2004, a total of 1,233 type 2 diabetics attending diabetes clinics in five university hospitals were interviewed and asked 14 questions that were identical to those questions asked 10 years ago during the earlied study. RESULTS: On the average, the respondents, having an average age of 58.9+/-11.4years, suffered diabetes for 8.7+/-7.3years with 7.7+/-1.4% HbA1c. The percentage of patients who experienced using alternative medicine for diabetic treatment plummeted from 73.9% to 33.2% over the last 10 years. Herbal medicine maintained its high popularity with increase an being seen in supplementary food use. The average per-capita spending on alternative medicine changed from 520,000 Korea Won on five types of medicine in 1994 to 730,000 on two types of medicine in 2004. Regarding the information sources, the family and relatives topped the list again(70.3%). Information sources such as mass media almost doubled to 20.2%, and the internet accounted for 1.2% in 2004. The majority of the users said again in 2004 that the medicine was `inefficacious'(63.5%) but those who answered positively inched up by 3.1% from 14.5% in 1994. To the question if they would try a new alternative medicine, the majority answered negatively in 2004(43% of the experienced group, 52.3% of the inexperienced group), and this was unlike the results in 1994 when the positive responses prevailed(78.6% and 72.7% respectively). CONCLUSION: Alternative medicine use among the type 2 diabetic patients has declined in the last 10 years. The patients overall attitude toward alternative medicine has turned negative, and this is primarily attributable the to continuous, proper education by mass media and social groups

Genetic Polymorphism of Glucagon-Like Peptide 1 Receptor in Korean Type 2 Diabetes Mellitus.: Kyung Wook Lee, Meihua Jiang, Shanji Piao, Eun A Kim, Seong Bin Hong, Moon Suk Nam, Yong Seong Kim, Kyong Soo Park, Hyun Chul Lee; Korean Diabetes J. 2005;29(1):30-38. Published online January 1, 2005

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Abstract PDF: BACKGROUND
Glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal L-cells, which stimulates insulin secretion from cells. The biological action of GLP-1 is mediated by the glucagon-like peptide-1 receptor (GLP-1R), which is 463 amino acids in size, with 7 transmembrane domains. Because GLP-1 plays an important modulatory role in regulating glucose-stimulated insulin, the GLP-1R could be a candidate gene contributing to impaired -cell function and the development of this genetically heterogeneous disorder. Recently, four GLP-1R SNPs were identified in Caucasian diabetic individuals, and for the SNP at the Leu- 260Phe (A/C) position, statistically significant differences were detected in the distribution of genotypes between type 2 diabetic and nondiabetic subjects. We replicated the genetic association between the SNP at the leu260Phe (A/C) position in the GLP-1R gene and Korean type 2 diabetes mellitus. METHODS: The Leu260Phe polymorphism in the GLP-1R gene was determined using a PCR- RFLP method (the genotypes were determined according to the results of polymerase chain reaction products after digestion and the digestive enzyme was BbsI) in 419 Korean type 2 diabetic patients and 345 nondiabetic subjects. RESULTS: In contrast to the Caucasian report, there was no significant difference in the frequencies of alleles, and genotypes between Korean type 2 diabetic and nondiabetic subjects. When analyzed according to gender, BMI and age of onset, the genotype distribution of type 2 diabetic subjects was not significantly different from nondiabetic subjects. CONCLUSION: The Leu260Phe polymorphism in the GLP-1R gene was not associated with type 2 diabetes mellitus, and we were unable to replicate the genetic association between this polymorphism and Korean type 2 diabetes mellitus

High Carbohydrate Diet Effects on the Development of Diabetes Mellitus and Modification of Pancreatic Islets in OLETF Rats.: Sung Ki Kim, Seong Bin Hong, Hwi Ra Park, Eun A Kim, Kyung Wook Lee, Moon Suk Nam, Yong Seong Kim; Korean Diabetes J. 2004;28(3):187-198. Published online June 1, 2004

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Abstract PDF: BACKGROUND
Diet has long been believed to be an important risk factor for type 2 diabetes. The composition of carbohydrates in the diet was higher in the past, where as now it is considerably reduced in the diet of Korean peoples, which is probably associated with the risk of developing type 2 diabetes. The aim of the present study was to investigate the long-term effect of high carbohydrate/low protein diets on the glucose and lipid metabolism and the pancreatic islet in OLETF(Otsuka Long-Evans Tokushima Fatty) rats, the animal model of type 2 diabetes. METHODS: Seven week old male OLETF rat were fed a high carbohydrate/low protein diet(carbohydrate 71.0%, fat 14.5%, protein 14.5%) as the experimental group, with an ordinary chow diet(carbohydrate 63.5%, fat 14.5%, protein 22%) fed to the controls. The plasma insulin, lipid profiles, free fatty acid and oral glucose tolerance were analyzed at 16 and 32 weeks. After the glucose tolerance test, the pancreas was excised, and immunohistochemical staining was conducted for the islet morphology and insulin mRNA to quantify the insulin secretory capacity. RESULTS: The basal glucose levels tended to be higher in the control group, but with no significant statistical difference. There were no differences in the serum insulin, total cholesterol, triglyceride, HDL-cholesterol and plasma free fatty acid levels between the two groups. The pancreatic islets of the control group showed multilobulation, with fibrotic changes; where as those of the experimental group were maintained normal profiles. A higher expression of insulin mRNA was observed in the experimental than in the control group. CONCLUSION: A high carbohydrate diet induced lower body weight increases, and protected against beta cell injury and decreased the development of abnormal glucose tolerance in OLETF rats. This may explain the growing incidence of diabetes with respect to the change in carbohydrate composition in the diet of Korean peoples. However, whether the protective effect of a high carbohydrate diet, against the development of diabetes in OLETF rats, can be attributed to small weight increases or if the change in food composition itself, or both needs to be determined.

Effect of Leptin on Alteration of beta-cell Mass in Rat Pancreas.: Seong Bin Hong, Yu Mi Han, Young Ju Park, Yun Joo Oe, Sung Ki Kim, Yoe Joo Kim, Moon Suk Nam, Yong Seong Kim, In Sun Park; Korean Diabetes J. 2002;26(4):253-264. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Diabetes mellitus can occur when insulin secretion and action are inadequate in relation to blood glucose level. Several experiments recently reported that leptin and pancreatic beta-cells have functional axis to interact each other. The present study was aimed to investigate the role of leptin on regulation of beta-cell mass during neonatal period when they show a dynamic growth. METHOD: Leptin was injected intraperitoneally to rat neonates for 7 days from the second day after birth. Using the pancreas of the rat pups, immunohistochemical stain, in-situ hybridization and northern blot for insulin were done for analysis of beta-cell mass as well as for insulin synthesis and secretion. In addition, PCNA (proliferating cell nuclear antigen) was examined to assess the effect of leptin on islet cell proliferation. RESULT: 1) The weight gain and blood glucose levels showed no significant difference between leptin injected groups (0.1 mg/kg, 0.5 mg/kg) and control one. 2) The weights of pancreas were not different between both group. 3) Pancreatic islets of rat who received leptin 0.5 mg/kg were reduced in area and number than those of normal pups. They also showed the decreased beta-cell number per islet compared with control as well as leptin 0.1 mg/kg injected groups (59+/-49 vs 47+/-31 vs 31+/-21 per islet, p<0.05). 4) The beta-cell mass of rat who received leptin 0.5 mg/kg decreased but there was no significant difference. 5) The mRNA expressions of insulin were not different among control, leptin 0.1 mg/kg and leptin 0.5 mg/kg group. 6) The expression of PCNA as a proliferation marker showed no difference between control and leptin injected group. CONCLUSION: These results reflected that leptin negatively regulated neonatal islet cell growth occurring in normal rat pups, and resulted to relative decrease of beta-cell number compared to the untreated control. We, therefore, suggest that leptin may play the important role in beta-cell mass during neonatal period.

Serum Proinsulin, Proinsulin/Total Insulin Ratio and Insulin Resistance in Elderly-onset Type 2 Diabetes.: Yoon Ju Oh, Young Ju Park, Young Wan Kim, Sung Ki Kim, Seong Bin Hong, Yoe Joo Kim, Mi Rim Kim, Moon Suk Nam, Yong Seong Kim; Korean Diabetes J. 2001;25(2):113-124. Published online April 1, 2001

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Abstract PDF: BACKGROUND
It is well known that the concentration of serum proinsulin and the ratio of proinsulin/total insulin (P/I) are elevated in type 2 diabetes. Proinsulin is produced by the ribosome in pancreatic beta cells, undergoes maturation in Golgi body and exists in the form of secretory granules. Immature granules possess disproportionately large amount of proinsulin. When there is increased demand of insulin caused by diabetes, higher level of proinsulin is secreted from immature granules of dysfunctioning beta cells. Thus, the elevated concentration of proinsulin and the increased ratio of P/I are considered to be the markers of pancreatic dysfunction and predictors for the future development of diabetes. The elderly-onset type 2 diabetes is also thought to develop due to both dysfunction of insulin secretion by impaired beta cell with aging and increased insulin resistance in peripheral tissue due to less muscle mass and more fat. However, it is still controversial as to which mechanism is predominant in the development of type 2 diabetes. METHODS: We measured the levels of fasting blood glucose, serum proinsulin and specific human insulin by using radioimmunoassay kit, and calculated the P/I ratio and insulin sensitivity index in normal adults (40or=60, n=35) and also in the newly-diagnosed elderly type 2 diabetes (age>or=60, n=24). RESULTS: The concentration of serum proinsulin and the ratio of P/I in normal adults over age 40 were 7.70+/-6.08 pmol/L and 0.13+/-0.10, respectively. The concentration of proinsulin in the normal adult, normal elderly and elderly diabetes group were 6.50+/-3.71, 11.17+/-8.30 and 16.75+/-11.68 pmol/L. The differences among three groups were statistically significant (p= 0.0001). The P/I ratios for each of the three groups were 0.11+/-0.05, 0.17+/-0.12 and 0.16+/-0.08 (p=0.0004). P/I ratios in the elderly control and elderly diabetes were higher than that of the normal adult group. Insulin sensitivity index (ISI, 10,000/(basal glucose X basal insulin)) of elderly diabetes (1.19+/-0.89) was lower when compared with the indices of other groups (40or=60 control; 2.27+/-1.11, p=0.0001). CONCLUSION: Although the age-related reduction of pancreatic insulin secretory function attributes to the pathogenesis of old-age onset type 2 diabetes, it appears that the decreased insulin sensitivity may serve as more important factor in the development of the disease.

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.

Clinical Application of Electrogastrography in Type 2 Diabetic Gastroparesis.: Seong Bin Hong, Moon Suk Nam, Yoon Juo Oh, Sung Ki Kim, Yoe Joo Kim, Pum Soo Kim, Mi Rim Kim, Yong Seong Kim, Young Soo Kim; Korean Diabetes J. 1999;23(5):695-701. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Electrogastrography (EGG) enables the cutaneous measurement of gastric electric activity. Abnormal gastric slow wave frequencies have been observed in diabetic gastroparesis. The aim of this study was to know the clinical application of EGG, and to determine the relationship between gastric myoelectrical activity and gastric emptying time (GET) in patients with type 2 diabetes mellitus. METHODS: This study included 26 type 2 diabetic patients (11 men, 15 women, mean age 53+/-10 years, disease duration 10.5+/-6.5 years). They were given solid and liquid diet with 1 mCi (99m)Tc DTPA for measuring GET (Tl/2). They were divided into normal GET group (Tl(2 < 60 minutes) and delayed GET group (Tl/2 > 60 minutes). Gastric myoelec-trical activity was recorded by cutaneous EGG. EGG was recorded for 30 minutes in fasting state and 30 minutes in post-prandial state with same test meal. Several EGG variables including percentages of dominant frequency in the normal range (2 cycle per minute, cpm), bradygastria (0.5~2 cpm), tachygastria (4~9cpm), postprandial to preprandial power ratio, and dominant frequency instability coefficient (DFIC) were calculated by fast Fourier transformation. Result: Autonomic nerve function test showed no difference between normal GET group and delayed GET group. EGG values in delayed group did not differ from data in normal group. There were no correlation between b1ood glucose level and GET. In fasting, normal slow wave (r=-0.50, p<0,05) and bradygastria (r=0.50, p<0.05) were correlated with fasting blood glucose. And in postprandial state, normal slow wave (r=0.47, p<0.05) and bradygastria (r=0.84, p<0.05) were correlated significantly with fasting blood glucose. EGG parameters did not correlated with GET CONCLUSION : EGG may be influenced by blood glucose level, but seems to be less valuable for assessment of gastroparesis in Korean type 2 diabetes mellitus, according to our investigation.

Insulin Secretory Dysfunction in the Patients with Untreated Hyperthyroidism.: Moon Suk Nam, Seung Yong Shin, Young Wan Kim, Seong Bin Hong, Yeo Joo Kim, Mi Rim Kim, Won Sick Choe, Yong Seong Kim; Korean Diabetes J. 1998;22(3):320-327. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Abnormal glucose metabolism with impaired glucose tolerance has been documented in patients with thyrotoxicosis, but the pathogenesis is not fully understood. Therefore, the aim of the present study was to study the secretory dysfunction of pancreatic 9-cell and to confirm hyperinsulinemia and hyperproinsulinemia during oral glucose tolerance test(OGTT) in patients with thyrotoxicosis. METHODS: After an overnight fast, 75 g OGTT was performed in 10 patients with hyperthyroidism and in 10 healthy control subjects matched for age, sex and hody mass index. Plasma insulin(immuno-reactive insulin, IRI), C-peptide, proinsulin levels were measured by radioimmunoassay. RESULTS: Fasting plasma glucose, insulin and C-peptide levels were similar in the two groups, but plasma proinsulin level was increased in patients with hyperthyroidism(p<0.05). A twofold rise of plasma proinsulin and the proinsulin/insulin ratio was also found in patients with hyperthyroidism during OGTT. The molar ratio of C-peptide and insulin(IRI) was similar in the two groups. CONCLUSION: Hyperinsulinemia and hyperproinsulinemia were found in patients with hyperthyroidism compared with controls. Disproportionally increased proinsulin level suggested a pancreatic secretory dysfunction in the patients with hyperthyroidism.

Serum Proinsulin Responses during Oral Glucose Tolerance Test in patients with Non-insulin Dependent Diabetes Mellitus.: Moon Suk Nam, Seong Bin Hong, Yeo Joo Kim, Mi Rim Kim, Yong Seong Kim, In Young Hyun, In Ho Kwak; Korean Diabetes J. 1997;21(4):356-364. Published online January 1, 2001

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Abstract PDF: BACKGROUND
When insulin is secreted from the pancreas, a small amount of proinsulin is also secreted at the same time. Pancreatic beta cell may release immature granules richer in proinsulin contents as well as mature granules in the over-stirnulated state. The significance of hyperproinsulinemia was recently reevaluated in the pathogenesis of non-insulin dependent diabetes mellitus(NIDDM). We studied proinsulin response at fasting and oral glucose tolerance test(OGTT) in NIDDM with a simple and sensitive human proinsulin radioimmunoassay system. METHODS: 22 new onset non-obese NIDDM patients and 11 matched healthy controls were selected for the study. The NIDDM group was divided into 3 groups(group 1; 7.8, group 2; 7.8~11, group 3; 11.0 mmol/L) according to the fasting plasma glucose level. After an overnight fast, a 75 g OGTT was performed and samples were analyzed with proinsulin and specific human insulin radioimmunoassay kits. RESULTS: The basal serum proinsulin level was reported as 9.29+/-4.19 pmol/L in normal control and as 18.09+/-9.32 pmol/L(p=0.04, compared with control) in diabetic group. The values in NIDDM group 1 and 2(18.07+/-9.D2; p=0.04, 21.60+/-6.98; p=0.03) were higher than in control. The molar ratia of the basal proinsulin to total insulin were also increased in NIDDM group 1 and 2(0.24, 0.28) than in control subjmts(0.13, p=0.03). The basal proinsulin and proineulin/total insulin ratio were highest in the group 2(p 0,05, than group 3). During oral glucose loading, the proinsulin response increased more slowly than total insulin response. The proinsulin and proinsulin/ total insulin ratio during oral glucose loading were higher in NIDDM group 1 and group 2 than cantrols. CONCLUSION: The basal proinsulin level in diabetic group was higher than in normal control. The proinsulin responses during oral glucose loading were higher in diabetic group 1 and 2 than controls. The proinlulin response increased more slowly than total insulin response during oral glucose loading. So we conclude that the proinsulin secretion frorn pancreatic beta cell is impaired in diabetic group. The mechanism about the metabolic pathway of the proinsulin secretion should be studied more.

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