Diabetes & Metabolism Journal

Volume 31(4); July 2007

Review

Peroxisome Proliferator Activated Receptor-delta (PPAR-delta).: Kyung Mook Choi; Korean Diabetes J. 2007;31(4):297-301. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.297

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The development of novel treatments for the metabolic syndrome is imminent for decreasing the prevalence of type 2 diabetes and cardiovascular disease. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor super-family of ligand-induced transcription factors. Among them, PPAR-alpha and PPAR-gamma are therapeutic targets for dyslipidemia and insulin resistance. Recent studies have uncovered a dual benefit of PPAR-delta for both dyslipidemia and insulin resistance. Furthermore, PPAR-delta enhances fatty acid oxidation and energy uncoupling in adipose tissue and muscle. PPAR-delta activation seems to operate similarly to the caloric restriction and prolonged exercise. Combined effects of PPAR-delta make it a promising therapeutic target for the metabolic syndrome, and ongoing studies about PPAR-delta will improve our knowledge of the physiologic regulation of whole body energy metabolism.

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Novel Cinnamic Acid Derivatives as Potential PPARδ Agonists for Metabolic Syndrome: Design, Synthesis, Evaluation and Docking Studies
Ajay Chauhan, Ajmer S. Grewal, Deepti Pandita, Viney Lather
Current Drug Discovery Technologies.2020; 17(3): 338. CrossRef

Original Articles

gamma-glutamylcysteine Synthetase (gamma-GCS) mRNA Expression in INS-1 Cells and Patients with Type 2 Diabetes Mellitus.: Jae Hong Kim, Chan Hee Lee, Jun Sung Moon, Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee; Korean Diabetes J. 2007;31(4):302-309. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.302

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Abstract PDF: BACKGROUND
Hyperglycemia is a well-recognized pathogenic factor of long term complications in diabetes mellitus and hyperglycemia also generates reactive oxygen species (ROS) in beta cells when ROS accumulate in excess for prolonged periods of time, they cause chronic oxidative stress and adverse effects. Unfortunately, the islet contacts low capacity of endogenous antioxidant effects. But, gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for glutathione synthesis, is well represented in islets. METHODS: This study is to evaluate the changes in the activity of gamma-GCS, glutathione in beta-cells exposed to high glucose, in pancreatic tissue of OLETF (Otsuka Long Evans Tokushima Fatty) and LETO (Long-Evans Tokushima Otsuka) rats, in leukocytes from patients with Korean type 2 DM (T2DM) and to disclose the effects of high blood glucose on this impairment in patients with T2DM. We divided our patients into 3 groups by HbA1c (controls: n = 20, well controls diabetes: n=24, poorly controlled diabetes: n = 36). RESULTS: We observed that decreased glutathione level, gamma-GCS expression, glucose-stimulated (GSIS) and increased intracellular peroxide level in the INS-1 cells exposed to 30 mM glucose condition. Also decreased glutathione level at erythrocytes, gamma-GCS expression at leukocytes and increased oxidized LDL, MDA (malondialdehyde) level at plasma from patients with T2DM compared to controls (esp, poorly controlled patients). CONCLUSION: These results suggest that insufficient antioxidant defenses by the glutathione pathway may be one of the factors responsible for development of complications in T2DM.

AICAR Reversed the Glucolipotoxicity Induced beta-cell Dysfunction through Suppression of PPAR-gamma-coactivator-1 (PGC-1) Overexpression.: Hyuk Sang Kwon, Ji Won Kim, Heon Seok Park, Seung Hyun Ko, Bong Yun Cha, Ho Young Son, Kun Ho Yoon; Korean Diabetes J. 2007;31(4):310-318. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.310

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Abstract PDF: BACKGROUND
Glucolipotoxicity plays an important role in the progression of type 2 diabetes mellitus via inducing insulin secretory dysfunction. Expression of insulin gene in pancreatic beta cell might be regulated by AMP-activated protein kinase (AMPK), which is recognized as a key molecule of energy metabolism. We studied the effects of AMPK on glucolipotoxicity-induced beta-cell dysfunction by suppression of PPAR-gamma-coactivator-1 (PGC-1) in vitro and in vivo. Method: Glucolipotoxicity was induced by 33.3 mM glucose and 0.6 mM (palmitate and oleate) for 3 days in isolated rat islets. Messenger RNA (mRNA) expressions of beta-cell specific gene like insulin, BETA2/NeuroD and PGC-1 induced by glucolipotoxic condition and their changes with 5-aminoimidazole-4-carboxy-amide-1-D-ribofuranoside (AICAR) treatment were investigated using RT-PCR. We also examined glucose stimulated insulin secretion in same conditions. Furthermore, SD rats were submitted to a 90% partial pancreatectomy (Px) and randomized into two groups; Ad-GFP-infected Px rats (n = 3) and Ad-siPGC- 1-infected Px rats (n = 3). Then, the Px rats were infected with Ad-GFP or Ad-siPGC-1 (1 x 10(9) pfu) via celiac artery. After 12 days of viral infection, we measured body weight and performed the intraperitoneal glucose tolerance test (IP-GTT). RESULTS: Glucolipotoxicity resulted in blunting of glucose-stimulated insulin secretion, which was recovered by the AICAR treatment in vitro. Suppression in their expressions of insulin and BETA2/NeuroD gene by glucolipotoxic condition were improved with AICAR treatment. However, PGC-1alpha expression was gradually increased by glucolipotoxicity, and suppressed by AICAR treatment. Overexpression of PGC-1 using an adenoviral vector in freshly isolated rat islets suppressed insulin gene expression. We also confirmed the function of PGC-1 using an Ad-siPGC-1 in vivo. Direct infection of Ad-siPGC-1 in 90% pancreatectomized rats significantly improved glucose tolerance and increased body weight. CONCLUSION: AMPK could protect against glucolipotoxicity induced beta-cell dysfunction and the suppression of PGC-1 gene expression might involved in the insulin regulatory mechanism by AMPK.

The Effect of Rosiglitazone on Gluose Metabolism and Insulin Sensitivity in Non Obese Type 2 Diabetic Rat Models.: Mi Jin Kim, Eui Jong Chung, Byung Wook Ha, Ji Hoon Kim, Su Min Nam, Mi Young Lee, Jang Hyun Kho, Young Goo Shin, Choon Hee Chung; Korean Diabetes J. 2007;31(4):319-325. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.319

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Abstract PDF: BACKGROUND
In Korea, most of type 2 diabetic patients are non obese. We made non obese type 2 diabetic rat models, which were characterized by insulin resistance and insulin secretion defect. Our study aimed to investigate the effect of rosiglitazone on glucose metabolism and insulin sensitivity in non obese type 2 diabetic rat models. Furthermore, we may estimate the effect of rosiglitazone treatment in non obese type 2 diabetic patients in Korea. METHODS: 20 male newborn (12 hours old) Sprague-Dawley rats were made diabetes by streptozotocin (75 mg/kg, intraperitoneal injection). At 16 weeks old, diabetes were confirmed by intraperitoneal glucose tolerance test (IPGTT, 30% D/W, 2 kg/kg). After that, diabetic groups were divided into two groups. One group was fed on normal chow and rosiglitazone (3 mg/kg/day) and the other group was fed on normal chow for eight weeks. At the age of 24 weeks, we measured body weight (BW), plasma glucose, insulin, C-peptide levels. And we performed IPGTT and insulin tolerance test (ITT) in two groups. Thereafter, we determined the insulin content of pancreas and epididymal fat weight. RESULTS: Body weight was significantly higher in rosiglitazone group than control group. On IPGTT, plasma glucose, insulin and C-peptide levels were not significantly different between two groups. But, on insulin tolerance test, Kitt (%/min) values of rosiglitazone group were significantly higher than control group (2.7 vs. 1.8). The insulin content of pancreas and epididymal fat weight was not different between two groups. CONCLUSION: These results suggested that rosiglitazone improved insulin sensitivity in non obese type 2 diabetes rat models independent of glucose level.

Transcriptional Regulation of Insulin and CXCL10 Gene by Peroxisome Proliferator Activated Receptor gamma Coactivator-1alpha.: Won Gu Jang, In Kyu Lee, Eun Jung Kim, Seong Yeol Ryu, Bo Wan Kim, Jung Guk Kim; Korean Diabetes J. 2007;31(4):326-335. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.326

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Abstract PDF: BACKGROUND
Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which act as a coactivator of nuclear receptors and several other transcription factors. This study was performed to evaluate the expressional regulation of insulin and inflammatory response genes by PGC-1alpha. METHODS: Transient transfection assays were performed to measure the promoter activity of the insulin and CXCL10 gene. The insulin gene expression levels in INS-1 cells were determined by Northern blot analysis. Differentially expressed genes by PGC-1alpha overexpression in HASMCs were confirmed using DNA microarray, real-time PCR and Northen blot analysis. RESULTS: Insulin promoter activity and mRNA levels were suppressed by GR and Ad-PGC-1alpha. Northern blot analysis of the INS-1 cells revealed that infection with Ad-PGC-1alpha markedly reduced the amount of insulin mRNA and treatment of Dex enhanced this effect in an additive manner. The PGC-1alpha-specific siRNA decreased insulin expression that was induced by Dex in the GR-expressing INS-1 cells was nearly restored by this siRNA treatment. We found that when vascular smooth muscle cells (VSMCs) overexpressed PGC-1alpha, immune or inflammatory response genes were highly expressed. For example, promoter activity and mRNA level of CXCL10 gene were increased by PGC-1alpha. CONCLUSION: PGC-1alpha overexpression inhibited insulin promoter activity in INS-1 cells and enhanced expressions of inflammatory response genes (CXCL10, CXCL11, TNFLSF10) in VSMCs.

Randomized Controlled Trial

Short-term Therapeutic Efficacy of Different Oral Hypoglycemic Agents Combined with Once Daily Insulin Glargine in Type 2 Diabetic Subjects with Failure of Sulfonylurea and Metformin Combination.: Seong Il Hong, Hyeong Jin Kim, Jong Myon Bae, Sun Ok Song, Kyung Suk Park, Byung Soo Jeon, Seun Duk Hwang, Jin Yi Choi, Jeong Hun Kim, Hyuk Jin Kwon, Ja Sung Choi, Myoung Lyeol Woo, Ji Hoon Cho, Young Jun Won; Korean Diabetes J. 2007;31(4):336-342. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.336

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Abstract PDF: Backgroud: Although the extended duration of action of insulin glargine supports a convenient once daily injection, the combination with other short acting insulins or oral hypoglycemic agents is required to control postprandial hyperglycemia in type 2 diabetes. The present study was designed to compare the short-term therapeutic efficacy of oral hypoglycemic agents with once daily insulin glargine, switching from a multiple daily injection regimen. METHODS: After control with the intensive regimen (daily lispro insulin and glargine) during 5~7 days, 80 in-patients with type 2 diabetes were randomized and treated with four oral hypoglycemic agents (glimepiride 4 mg qd, metformin 500 mg bid, nateglinide 90 mg tid, or acarbose 100 mg tid) plus once daily insulin glargine during 5 days. Blood glucose concentration was recorded by seven daily estimations (before each meal, 2 hours after each meal, and bedtime). Blood glucose concentrations and area under the curves (AUCs) of blood glucose were compared among four groups. RESULTS: The area under the curve of blood glucose of metformin, glimepiride, nateglinide, and acarbose groups were 165.5 +/- 46.0, 178.5 +/- 36.5, 209.9 +/- 55.1, and 224.9 +/- 55.8 mmol/L/hr respectively. Blood glucose concentrations and area under the curves of blood glucose of glimepiride and metformin groups were significantly lower than those of acarbose group. Also, those of metformin group were significantly lower than those of nateglinide group. Conclusions: Metformin or glimepiride are more effective oral hypoglycemic agent than nateglinide or acarbose in the combination with insulin glargine in type 2 diabetic subjects with failure of sulfonylurea and metformin combination.

Original Articles

The Correlation between Central Obesity and Glucose, Lipid Metabolism and Macrovascular Complication in Elderly Type 2 Diabetes.: Eui Dal Jung, Jihyun Lee, Ho Sang Shon; Korean Diabetes J. 2007;31(4):343-350. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.343

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Abstract PDF

BACKGROUND
Obesity is related to abnormal lipid metabolism and macrovascular complication and accumulated fat on the abdomen in elderly diabetic patients. The aim of this study was to compare elderly diabetic patients' body fat composition with middle-aged patients and evaluate the role of central obesity on glucose and lipid metabolism and macrovascular complications in elderly type 2 diabetic patients. METHODS: We defined elderly patients who are over 65 years old and who waist circumference is over than 90 cm in men and 85 cm in women and waist-hip ratio (WHR) was over than 0.90 in men and 0.85 in women defined central obesity. % body fat were measured a bioimpedence analysis using DSM (Direct Segmental Measurement by 8-point electrode) method (Inbody 3.0, Biospace, Seoul, Korea) in two hundred two type 2 diabetes. Laboratory parameters such as fasting blood glucose, HbA1c, and lipid profile were included in this study and also investigated the macrovascular complication. RESULTS: 1) The ninety-five elderly diabetic patients, compared with middle-aged diabetic patients, were similar BMI and % of body fat but significantly increased waist circumference (P < 0.05) and WHR (P < 0.001). 2) In pearson's correlations, waist circumference was correlated with BMI (r = 0.927, P < 0.001), WHR (r = 0.851, P < 0.001), % body fat (r = 0.519, P < 0.001), total cholesterol (r = 0.255, P < 0.05), triglyceride (r = 0.365, P < 0.001), and LDL-cholesterol (r = 0.271, P < 0.05) in elderly diabetic patients. And WHR was also correlated with BMI (r = 0.744, P < 0.001), waist circumference (r = 0.851, P < 0.001), % body fat (r = 0.425, P < 0.001), total cholesterol (r = 0.372, P < 0.001), triglyceride (r = 0.408, P < 0.001), and LDL-cholesterol (r = 0.386, P < 0.001). 3) The obese elderly diabetic patients had increased triglyceride, total cholesterol and LDL-cholesterol but not related with macrovascular complication compared with lean elderly patients. CONCLUSION: In elderly type 2 diabetic patients are more central obesity although the same weight compared with middle-aged patients. Waist circumference and WHR were highly correlated with body fat composition and lipid profile in elderly diabetes. In obese elderly patients have abnormal lipid profile but not more macrovascular complication.

Citations

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Potential Benefits of Acupuncture and Herbs for Obesity-Related Chronic Inflammation by Adipokines
Ji-Youn Kim, Seon-Eun Baek, Rehna Paula Ginting, Min-Woo Lee, Jeong-Eun Yoo
Evidence-Based Complementary and Alternative Medicine.2020; 2020: 1. CrossRef
A Nationwide Survey about the Current Status of Glycemic Control and Complications in Diabetic Patients in 2006 - The Committee of the Korean Diabetes Association on the Epidemiology of Diabetes Mellitus -
Soo Lim, Dae Jung Kim, In-Kyung Jeong, Hyun Shik Son, Choon Hee Chung, Gwanpyo Koh, Dae Ho Lee, Kyu Chang Won, Jeong Hyun Park, Tae Sun Park, Jihyun Ahn, Jaetaek Kim, Keun-Gyu Park, Seung Hyun Ko, Yu-Bae Ahn, Inkyu Lee
Korean Diabetes Journal.2009; 33(1): 48. CrossRef

In vivo Corneal Confocal Microscopy and Nerve Growth Factor in Diabetic Microvascular Complications.: Ji Sun Nam, Young Jae Cho, Tae Woong Noh, Chul Sik Kim, Jong Suk Park, Min ho Cho, Hai Jin Kim, Ji Eun Yoon, Han Young Jung, Eun Seok Kang, Yu Mie Rhee, Hyung Keun Lee, Chul Woo Ahn, Bong Soo Cha, Eun Jig Lee, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2007;31(4):351-361. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.351

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Abstract PDF: BACKGROUND
In vivo corneal confocal microscopy (IVCCM) is being recognized as a non-invasive, early diagnostic tool for diabetic neuropathy, for it provides a clear image of corneal subbasal nerve plexus in detail. Nerve growth factors (NGF) are believed to regulate peripheral and central nervous system, neuronal differentiation, and regeneration of damaged nerves, and their role in diabetic neuropathy is being emphasized these days. Moreover, NGFs and receptors are also expressed in retina and renal mesangial cells, suggesting their possible role in the common pathogenesis of diabetic microvascular complications. We plan to examine corneal structures of diabetic patients and compare IVCCM with conventional tools and analyze their serum and tear NGF levels. METHODS: IVCCM, nerve conduction velocity (NCV), and serum, urine, and tear samplings were done to 42 diabetic patients. From IVCCM, we measured corneal nerve density, branch, and tortuosity, total corneal/epithelial thickness, and the number of endothelial/keratocyte cells, and we checked patients' biochemical profiles and serum and tear NGF levels. RESULTS: Patients with more severe neuropathy had less corneal endothelial cells (3105 +/- 218 vs. 2537 +/- 142 vs. 2350 +/- 73/mm3 vs. 1914 +/- 465/mm3, P = 0.02), higher serum NGF (36 +/- 15 vs. 60 +/- 57.66 vs. 80 +/- 57.63 vs. 109 +/- 60.81 pg/mL, P = 0.39) and tear NGF levels (135.00 +/- 11.94 vs. 304.29 +/- 242.44 vs. 538.50 +/- 251.92 vs. 719.50 +/- 92.63 pg/mL, P = 0.01). There was a positive correlation between neuropathy and corneal nerve tortuosity (r2 = 0.479, P = 0.044) and negative correlation between neuropathy and endothelial cell count (r2 = -0.709, P = 0.002). Interestingly, similar changes were seen in other microvascular complications as well. CONCLUSION: Our results provide a possibility of using novel tools, IVCCM and NGF, as common diagnostic tools for diabetic microvascular complications, but it should be followed by a large population study.

Current Status of Diabetes Management in Korea Using National Health Insurance Database.: Seok Won Park, Dae Jung Kim, Kyung Wan Min, Sei Hyun Baik, Kyung Mook Choi, Ie Byung Park, Jeong Hyun Park, Hyun Shik Son, Chul Woo Ahn, Jee Young Oh, Juneyoung Lee, Choon Hee Chung, Jaiyong Kim, Hwayoung Kim; Korean Diabetes J. 2007;31(4):362-367. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.362

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Abstract PDF

BACKGROUND
The prevalence of diabetes is steadily increasing in Korea. The increase in number of people with diabetes would ultimately result in premature death, poor quality of life, and increasing economic burden. However, in our country, researches regarding on the quality of diabetes management are lacking. This study was conducted in 2005 using National Health Insurance Database to know the current status of diabetes management in Korea. METHODS: We have randomly selected 3,902 subjects out of 2,503,754 subjects who had claims with diagnosis of diabetes between January 2003 to December 2003 by using two staged cluster sampling method. Field survey with review of medical records and telephone survey was conducted with standardized record forms developed by Korean Diabetes Association; Task Force Team For Basic Statistical Study of Korean Diabetes Mellitus. RESULTS: The age of diabetic subjects was 58.1 +/- 12.6 years and the duration of diabetes was 6.2 +/- 5.5 years. Hypertension was present in 54% of diabetic subjects. Among those with hypertension, 59% were controlled with blood pressure below 140/90 mmHg, but only 19% were controlled with blood pressure below 130/80 mmHg. Hyperlipidemia was present in 29% of diabetic subjects. Only 38% of those with hyperlipidemia were controlled with LDL-cholesterol below 100 mg/dL. For glycemic control, only 40% of diabetic subjects achieved the goal of HbA1c less than 7%, which was suggested by ADA. CONCLUSION: We found that only 20~40% of diabetic subjects in Korea achieved the management goal for glucose, blood pressure, and lipids. It seems urgent to develop a quality management program for diabetes subjects in Korea.

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Case Reports

A Case of Diabetic Ketoacidosis in Gestational Diabetes Mellitus.: Myung Hwan Kim, Eui Dal Jung, Seung Pyo Hong, Gyu Hwan Bae, Sun Young Ahn, Eon Ju Jeon, Seong Yeon Hong, Ji Hyun Lee, Ho Sang Son; Korean Diabetes J. 2007;31(4):368-371. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.368

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Abstract PDF: Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variant severity with onset or first recognition during present pregnancy. Recently the prevalence of GDM in Korean has reported as 1.7~4.0%. Diabetic ketoacidosis is a serious metabolic complication of diabetes with high mortality if undetected. Its occurrence is very rare in gestational diabetes patients, but is harmful to fetal and maternal health. A 26 years-old pregnant woman was admitted at 37 weeks gestation because of progressive generalized weakness, anorexia and weight loss. Initial physical examination reveals that she had been dehydrated, and blood pressure 130/80 mmHg, pulse rate 100/min, respiratory rate 20/min, and body temperature was 36.9 degrees C. Serum glucose was 545 mg/dL, pH 7.282, HCO3- 10.5 mmol/L, urine ketone 3+, urine glucose 2+ when initial laboratory work was done. She was treated with intravenous fluid and insulin under the impression of diabetic ketoacidosis. Her delivery was performed after 24 hours from admission because of suggestive fetal distress. After recovery, she is being treated with insulin at outpatient department. We experienced a appropriately treated case of diabetic ketoacidosis in pregnant woman with GDM, and report it with a literature review.

Two Cases of Autoantibody Negative Fulminant Type 1 Diabetes Mellitus.: Hwa Young Cho, Young Min Cho, Myoung Hee Park, Mi Yeon Kang, Ki Hwan Kim, Yun Hyi Ku, Eun Kyung Lee, Do Joon Park, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim, Bo Youn Cho, Hong Kyu Lee; Korean Diabetes J. 2007;31(4):372-376. Published online July 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.4.372

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Abstract PDF: Autoantibody negative fulminant type 1 diabetes mellitus is a novel subtype of type 1 diabetes, which is characterized by a remarkably abrupt onset, metabolic derangement such as diabetic ketoacidosis at diagnosis, low HbA1c level at onset and a negative islet-related autoantibodies. The prevalence of fulminant type 1 diabetes has large difference between Japan and other countries. The precise reason for this regional variation remains to be clarified. One of the possible explanations is genetic background such as genotype of class II HLA molecule. In addition, environment factors including viral infection are suggested as possible pathogenesis of the disease. Only a few cases with fulminant type 1 diabetes have been reported outside Japan, and most of these cases with definite diagnosis have been reported in Korea. We report here on two Korean patients that met the criteria for diagnosis of fulminant type 1 diabetes in accordance with their HLA genotypes.

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