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Volume 29(3); May 2005
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Review
Gene Therapy for Diabetes Mellitus.
Jeong Hyun Park
Korean Diabetes J. 2005;29(3):173-180.   Published online May 1, 2005
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No abstract available.
Original Articles
The Association of Interleukin-6 Gene Promoter Region Polymorphism G174C with Insulin Resistance and Metabolic Syndrome in Korean Women.
Eun Jung Rhee, Won Young Lee, Se Yeon Kim, Eun Sook Oh, Ki Hyun Baek, Ki Won Oh, Moo Il Kang, Sun Woo Kim
Korean Diabetes J. 2005;29(3):181-188.   Published online May 1, 2005
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BACKGROUND
Interleukin(IL)-6 is a cytokine that is produced from immune cells and adipose tissue. It is thought to be a factor to explain the link between insulin resistance and inflammation, and it is also thought to be involved in glucose metabolism and lipid metabolism. We observed the frequency of the G174C polymorphism in the IL-6 gene promoter region in Korean women and we investigated the association of fasting glucose, insulin resistance indices and metabolic syndrome. METHODS: Measurements of the blood pressure, body fat, fasting glucose, insulin, lipid profiles and anthropometric measurements were done for 268 Korean women(mean age 51.4yrs, range 37~73yrs). Homeostasis model assessement(HOMA) and the quantitative insulin sensitivity check index(QUICKI) were calculated and the presence of metabolic syndrome was assessed according to ATP III criteria. Genotyping was done with the PCRRFLP method on the blood samples of the participants. RESULTS: The allele frequencies were 0.965 for the G allele and 0.035 for the C allele, and they were in Hardy-Weinberg equilibrium(P=0.50). The fasting insulin level and HOMA were significantly higher and the QUICKI was significantly lower in the C allele carriers compared with non-carriers. Although the prevalence of metabolic syndrome was not significantly different according to the different genotypes, among the individual components, the prevalence of hypertriglyceridemia was significantly higher in the C allele carriers compared with the non-carriers. There were no differences in the prevalence of normoglycemia, fasting hyperglycemia and provisional diabetes according to the different genotypes. CONCLUSION: The G174C polymorphism in The IL-6 promoter region was not frequently observed in Korean women. The insulin resistance indices were higher in the C allele carriers compared with the non-carriers. Although the prevalence of metabolic syndrome was not associated with the polymorphism, the prevalence of hypertriglyceridemia was higher in The C allele carriers, suggesting that it is possibile for candidate gene of insulin resistance
The Relationship Between the C1818T Polymorphism in Exon 4 of the klotho Gene with Fasting Glucose and Insulin Levels in Korean Women.
Ki Won Oh, Eun Joo Yun, Eun Jung Rhee, Won Young Lee, Ki Hyun Baek, Kun Ho Yoon, Moo Il Kang, Seong Gyun Kim, Cheol Young Park, Sung Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Sung Woo Park
Korean Diabetes J. 2005;29(3):189-197.   Published online May 1, 2005
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BACKGROUND
A novel gene, termed klotho has been identified as a suppressor of several aging phenotypes, and a genetic defect of klotho in mice resulted in a syndrome resembling human aging, i.e., a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis, and pulmonary emphysema. Since klotho mice also showed an abnormal glucose metabolism, we investigated the relationship between the C1818T polymorphism in exon 4 of the klotho gene and fasting glucose and insulin resistance in Korean women to observe its contribution to glucose metabolism. METHODS: The weight, height, blood pressure, fasting blood glucose, insulin, and lipid profiles were measured in 241 women(mean age, 51.2+/-7.0yr) by using the standard methods. Homeostasis model assessment(HOMA)-insulin resistance(IR), the quantitative insulin sensitivity check index(QUICKI) and HOMAbeta-cell were calculated. The genotyping of the C1818T polymorphism in exon 4 of the klotho gene was performed by allelic discrimination with using a 5' nuclease polymerase chain reaction assay. RESULTS: The allele frequencies were 0.805 for the C allele and 0.195 for the T allele, and they were in Hardy-Weinberg equilibrium(P=0.290). The mean fasting blood glucose(P= 0.005) and HOMA IR(P=0.035) were significantly higher in the T allele carriers compared with the non-carriers. After adjustment was made for age, fasting blood glucose was persistently significant(P=0.015), but the HOMA-IR became marginally significant(P=0.063). In the premenopausal women, the T allele carriers showed a higher mean fasting blood glucose(P=0.038), insulin(P=0.024), HOMA-IR(P=0.010), total cholesterol(P=0.039), and triglyceride levels(P=0.031) than in the non-carriers. After adjustment was made for age, the fasting blood glucose, insulin, HOMA-IR and triglyceride were persistently significant(P= 0.043, P=0.026, P=0.011, P=0.040). Also, the QUICKI, total cholesterol and low-density ilpo-protein cholesterol became marginally significant(P=0.073, P=0.061, P=0.098). For the postmenopausal women, the T allele carriers showed a tendency for higher mean fasting blood glucose levels(P=0.065) and lower HOMA beta-cell levels(P=0.085) than in the noncarriers. These differences became non-significant after adjustment was made for age. CONCLUSION: We observed that the C1818T polymorphism in exon 4 of the klotho gene was partly associated with glucose metabolism in Korean women. Also, these data suggest that the C1818T polymorphism is related with some cardiovascular risk factors in Korean women. The mechanism linking this gene with glucose metabolism warrants further study
Taurine-Mediated Restoration of Glucose Sensitivity of Pancreatic Beta Cells in OLETF Rats.
So Yeon Kim, Keun Gyu Park, In Kyu Lee, Seong Il Nam, Dae Kyu Song
Korean Diabetes J. 2005;29(3):198-205.   Published online May 1, 2005
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BACKGROUND
An OLETF(Otsuka Long-Evans Tokushima Fatty) rat is a model of type 2 diabetes that is characterized by obesity-induced insulin resistance. Taurine has been known to be beneficial for type 2 diabetes. This study evaluated the potential taurine effect on the insulin response to high glucose in the islets of OLETF rats. METHODS: One percent of taurine was put in the drinking water for the taurine group of OLETF rats at the time of their being 20 to 39 weeks of age. At 40 weeks, the pancreatic islets and beta cells were obtained to measure the glucose-stimulated insulin secretion(GSIS) and the ATP-sensitive K+(KATP) channel current. RESULTS: Taurine supplementation had no effect on the weight change of the rats when this was measured weekly from 20 to 39 weeks(mean+/-SE: 702+/-19g in the control group vs. 688+/-18g in the taurine group at the 39th week). However, the GSIS was significantly potentiated in the taurine-treated rats(8.9+/-1.3% vs. 13.2+/-3.2% of the total secreted at 15 mM glucose for 1h). The glucose-induced KATP channel inhibition in the beta cells was also greater in the taurine group. CONCLUSION: Taurine supplementation is a beneficial tool for the restoration of GSIS in the pancreatic islet of the OLETF rats. Maintenance of blood taurine level may be important in treating type 2 diabetic patients, who are subject to a low blood level of taurine
Analysis of the Relative Importance of Insulin Resistance and Insulin Secretion Defect by Homeostasis Model Assessment in Korean Type 2 Diabetic Patients.
Wan Sub Shim, Soo Kyung Kim, Hae Jin Kim, Jae Hoon Moon, Eun Seok Kang, Yu Mie Rhee, Chul Woo Ahn, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Bong Soo Cha
Korean Diabetes J. 2005;29(3):206-214.   Published online May 1, 2005
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AbstractAbstract PDF
BACKGROUND
Type 2 diabetes is characterized by defects in both insulin secretion and insulin sensitivity. However, the relative importance of insulin secretion and insulin resistance in Korean type 2 diabetic patients has not been well characterized in any study that has included a large number of subjects. Therefore, this study aimed to evaluate the relative importance of insulin sensitivity and the function of the beta cell in Korean type 2 diabetic patients. METHODS: We applied the HOMA model to 1,162 type 2 diabetic patients (654 males and, 508 females) who did not use insulin and we assessed HOMAIR and HOMAbetacell & its relation to the other parameters. RESULTS: The HOMAIR of Korean type 2 diabetic patients was 2.29(range: 0.31~37.17) and the HOMAbetacell of Korean type 2 diabetic patients was 32.17(range: 1.04~1310.79). The HOMAIR of Korean type 2 diabetic male patients was 2.15(range: 0.31~16.6) and that of Korean type 2 diabetic female patients was 2.47(range: 0.36~37.17). The HOMAbetacell of Korean type 2 diabetic male patients was 30.1(range: 1.04~462.34) and that of Korean type 2 diabetic female patients was 35.42(range: 2.60~1310.79). The HOMAIR and HOMAbetacell were significantly higher in females than males. There was no significant correlation between HOMAIR and age, and the duration of diabetes, but there was significant correlation between HOMAIR and BMI, fasting glucose, HbA1c and the fasting insulin. There was no significant correlation between age and HOMAbetacell. However, there was significant correlation between HOMAbetacell and BMI, the duration of diabetes, the fasting glucose, HbA1c and the fasting insulin. The longer the duration of diabetes, the more the HOMAbetacell was decreased but there was no change of HOMAIR with respect to the duration of diabetes. As expected, the subjects with a lower HOMAIR and a higher HOMAbetacell had the best glycemic control. Those with a higher HOMAIR and lower HOMAbetacell had the worst glycemic control although they had taken larger amount of oral hypoglycemic agents. Interestingly, the patients with a lower HOMAIR and higher HOMAbetacell had better glycemic control than those patients with a higher HOMAIR and lower HOMAbetacell. CONCLUSION: Both insulin secretion and insulin resistance are important in glycemic control but it seems that insulin secretion is a more important factor in glycemic control than insulin resistance in the Korean type 2 diabetic patients
Prolonged QT Interval and the BMI, Systolic BP and HDL-Cholesterol in Type 2 Diabetic Patients.
Chunggu Cho, Hye Jung No, Hyo Jeong Oh, Bong Joon Yang, Ha Young Kim, Byoung Hyun Park
Korean Diabetes J. 2005;29(3):215-222.   Published online May 1, 2005
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AbstractAbstract PDF
BACKGROUND
A prolonged QT interval is considered as an indicator of an increased risk of coronary heart disease, malignant ventricular arrhythmias and/or sudden death. QT interval prolongation has been reported to be a common finding in patients with obesity and diabetic autonomic neuropathy and it is well known that both leptin and insulin stimulate sympathetic activity. The waist to hip ratio and the plasma insulin levels were recently reported to be correlated with the QT intervals and the sympathovagal balance. The aim of the present study was to evaluate the association of the features of metabolic syndrome and the QT interval in type 2 diabetic patients. METHODS: We studied 114 type 2 diabetes(45 males and 69 females). The QT intervals were measured by a software program and then the QTc was calculated. The fasting glucose, total cholesterol, triglyceride and high-density lipoprotein(HDL)-cholesterol, HbAIC and Cpeptide were measured. All the patients received clinical tests for cardiovascular autonomic dysfunction by the Ewing's method. RESULTS: A significant difference was found in the mean QT interval between the patients with an autonomic score>=1 and the patients who were without cardiac autonomic neuropathy(autonomic score=0). On Pearson's simple regression analysis, the QT interval showed positive correlations with the BMI, fasting C-peptide, systolic blood pressure(sBP), and age. The QT interval also showed negative correlation with the HDL-cholesterol. The associations of the QTc with triglyceride, fasting glucose, and the autonomic score did not reach statistical significance. On the multiple regression analysis, the QT interval was independently correlated with BMI, systolic BP and HDL-cholesterol but not with the other variables that we tested(c-peptide, autonomic score, diastolic blood pressure, glycated hemoglobin, triglyceride and cholesterol). CONCLUSION: Our results suggest that a variety of features of metabolic syndrome are associated with QT interval prolongation in the type 2 diabetic patients
Comparison of the Relationship of Leptin to Metabolic Parameters Between Premenopausal Normal Weight and Obese Women.
Hee Kyoung Kim, Keun Gyu Park, Mi Kyung Kim, Young Yun Jang, Sang Yoon Kim, Eui Dal Jung, Hye Soo Kim, Ju Ho Do, In Kyu Lee
Korean Diabetes J. 2005;29(3):223-230.   Published online May 1, 2005
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AbstractAbstract PDF
BACKGROUND
Leptin is mainly secreted from adipose tissue, and it is a crucial factor for metabolic syndrome that is characterized by obesity, insulin resistance, hypertension and dyslipidemia. We measured the serum leptin concentrations and compared them with the body fat distribution and metabolic risk factors in premenopausal normal weight and obese women. METHODS: 231 premenopausal obese women participated in this study. The subjects were grouped based on their body mass index(BMI). The number of normal weight group women(BMI<25kg/m2) and the number of obese group women(BMI> or = 25kg/m2) were 90 and 141, respectively. We measured the plasma leptin concentration and such metabolic risk factors as fasting glucose, insulin, triglyceride(TG), systolic blood pressure(SBP) and diastolic blood pressure(DBP). The subcutaneous adipose tissue area(SAT) and the visceral adipose tissue area(VAT) were determined by computed tomography. The BMI, waist to hip ratio(WHR) and homeostasis model assessment(HOMA-IR) were calculated. RESULTS: In the obese group, the leptin levels were positively correlated with the BMI and SAT as well as with such metabolic risk factors as fasting serum glucose, insulin, HOMA-IR, TG, SBP and DBP. Although leptin levels were positively correlated with BMI and SAT in the normal weight group, they were not correlated with the metabolic risk factors. CONCLUSION: The present study showed that the leptin levels in the normal weight group were not associated with the metabolic risk factors. Therefore, the degree of obesity must be considered before leptin can be used as a predictor for metabolic syndrome including diabetes and coronary heart disease
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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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
Eighteen-Year Trends in Korean Diabetic Patients(1981 through 1998).
Hyejin Lee, Kyung Ah Han, Kyung Wan Min, Eung Jin Kim
Korean Diabetes J. 2005;29(3):239-246.   Published online May 1, 2005
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BACKGROUND
This study was conducted to determine trends in the age, gender, body mass index(BMI), and fasting blood glucose of the diagnosed Korean diabetic patients. METHODS: The medical records were obtained on 32,867 Korean diabetic patients who were treated at the Eulji Diabetes Center from 1981 to 1998. We investigated the age, gender, height, weight, BMI and fasting blood glucose. Regression analysis was used to analyze the time trends. RESULTS: BMI(from 23.2kg/m2 to 24.1kg/m2, P<0.001) and weight(from 59.6kg to 61.9kg, P<0.001) were gradually increased over the 18 years. and these factors were still significant after correction for age. The age of onset(from 45year to 51year, P<0.001) was also increased over the 18 years. The fasting blood glucose level was decreased from 10.2 mmol/L to 7.2mmol/L P<0.001). The portion of male patients was significantly decreased over the 18 years(from 52.1% to 47.4%). CONCLUSION: Over the 18years, the weight and BMI at the time of diagnosis were increased. And the onset age of diabetes was increased, according to an aging society. As it was easy to gain access the medical service, the fasting blood glucose level was decreased, and the prevalence of female patients was increased over 18 years in Korea
Evaluation of the Indicator Test(NeurocheckTM) in the Diagnosis of Peripheral Neuropathy among Type 2 Diabetic Patients.
Tae Seo Sohn, Hyun Shik Son, Jae Myung Yu, Bong Soo Cha, Kyung Wan Min, Sei Hyun Baik
Korean Diabetes J. 2005;29(3):247-253.   Published online May 1, 2005
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AbstractAbstract PDF
BACKGROUND
Eighty-five percent of the lower-limb amputations that are done for patients with diabetes are preceded by foot ulceration, and this suggests that prevention and the appropriate management of foot lesions are of paramount importance. Ulceration is caused by several factors acting together, but they are particularly caused by neuropathy. Various aspects of the neurovascular function can be evaluated with specialized tests, but these tests have generally not been well standardized and they have limited clinical utility. A new indicator test(NeurocheckTM) that utilizes the water-induced color change of a cobaltII compound from blue to pink has been introduced. The aim of the present study was to evaluate this new indicator test in the diagnosis of peripheral neuropathy among type 2 diabetic patients. METHOD: This study included 124 diabetic patients(45 men and 79 women) who were recruited from 5 diabetic centers in Korea. The presence of diabetic neuropathy was diagnosed by nerve conduction study. The degree of the patient's symptom was checked as the total symptom score(TSS). Autonomic sudomotor neuropathy was assessed by means of the new indicator test(NeurocheckTM). The degree of color change in 10 minutes was assessed as a complete color change, an incomplete color change or no color change. RESULTS: Of the 124 diabetics patients we investigated, 109 patients were proven to have peripheral neuropathy by nerve conduction study. Autonomic sudomotor neuropathy by NeurocheckTM was diagnosed in 94 patients with peripheral neuropathy(86.2%) and in 6 patients(40%) without peripheral neuropathy. The overall measure of agreement between NeurocheckTM and the electrodiagnostic test was 0.3673(0.1547, 0.58). The sensitivity and specificity of NeurocheckTM was higher in women(91.2% and 63.6%, respectively) than in men(78.0% and 50.0%, respectively). The measure of agreement in women was 0.5093(0.2396, 0.9601) and in the men it was 0.1567(-0.1423, 0.4588). CONCLUSION: The new indicator test has a high sensitivity for the diagnosis of peripheral neuropathy among diabetic patients, especially in women. It is likely that the new indicator test is useful clinically as a screening and diagnostic tool for diabetic neuropathy. Since the specificity of the test is somewhat low, the patients with a high total symptom score and who are without sudomotor neuropathy may need further diagnostic evaluation on neuropathy
Self-Management and Health-Related Quality of Life in Adolescent and Adulthood Diabetic Patients.
Bong Suk Park, Gi Nam Jin, Youn Chung Choi, Ji Hee Chung, Kyoung Hoe Kim, Mi Young Lee, Jang Hyun Koh, Choon Hee Chung
Korean Diabetes J. 2005;29(3):254-261.   Published online May 1, 2005
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AbstractAbstract PDF
BACKGROUND
The purposes of this study are to analyze the factors that influence selfmanagement and health-related QOL, and to provide useful informations to improve the QOL in adolescent and adult diabetic patients. METHODS: For this study, we interviewed 126 adolescent and adult diabetic patients who visited the Yonsei University Wonju Christian Hospital from March 4th, 2004 to April 5th, 2004. RESULTS: We examined the relationship between the socio-demographic characteristics and the health-related quality of life(QOL). There were statistically significant relationships between the QOL-and employment, years of education, income level and marriage status, but not between the health-related QOL and age and gender. Furthermore, there were no statistically significant relationships between the health-related QOL and smoking or drinking, nor between type 1 and 2 diabetic patients. The health-related QOL was significantly higher for an increased diabetes duration and for a greater number of symptoms, but the QOL was significantly lower in the presence of complications and hospital admission. The health-related QOL was lower when the preprandial blood glucose levels and HbA1c concentrations were higher, but it was higher when the hemoglobin and hematocrit levels were higher. Regarding the treatment methods, the health-related QOL was significantly lower for those patients who took insulin injection. The QOL was higher when the general self-management and diet therapy were well-controlled. Meanwhile, those subjects who had obtained medical informations from doctors, the media(including the internet and TV) and nurses in that order, they selected diet therapy as the hardest factor in the management of their diabetes. CONCLUSION: Adolescent and adult diabetic patients need continuous education and assistance to improve their health-related QOL and to keep from developing complications
Case Reports
A Case of Concurrent Emphysematous Pyelonephritis and Emphysematous Cholecystitis in a Patient with Diabetes Mellitus.
Se Hyung Lee, Ji Hoon Kim, Jong Young Lee, Tae Hyuck Choi, Gil Hyun Gang, Myoung Sook Shim, Jin Yub Kim
Korean Diabetes J. 2005;29(3):262-266.   Published online May 1, 2005
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AbstractAbstract PDF
Several unusual infections such as malignant otitis externa, rhinocerebral mucormycosis, emphysematous pyelonephritis and emphysematous cholecystitis exclusively occur in diabetic patients. Each of these diseases is a rare, but potentially life-threatening infection. Therefore, prompt diagnosis and early medical and operative intervention will be necessary for these diseases. We report herein a very rare case in which emphysematous pyelonephritis and emphysematous cholecystitis were simultaneously diagnosed. A 45-year-old man, who was previously diagnosed with secondary diabetes mellitus due to chronic alcoholic pancreatitis ten years earlier, presented with fever and right upper quadrant abdominal pain for 3 days. Abdominal computed tomography showed an air-fluid level in the lumen of the gall bladder and there was gas collection within the right renal parenchyma. Broad-spectrum antibiotics therapy was initiated and cholecystectomy and right nephrectomy were performed. Escherichia coli bacteria were isolated from the culture of the blood, urine and sputum. The patient recovered and was discharged in a healthy state
A Case of Diabetic Ketoacidosis in a GAD Antibody-positive Diabetes Patients who Recently Experienced Hyperglycemic Hyperosmolar State.
Jang Won Son, Seok Hong Lee, Jung Ahn Lee, Jaetaek Kim, Yeon Sahng Oh, Soon Hyun Shinn
Korean Diabetes J. 2005;29(3):267-270.   Published online May 1, 2005
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AbstractAbstract PDF
The term latent autoimmune diabetes in adults(LADA) was introduced to define adult diabetic patients who initially do not require insulin, but they have the immune markers of type 1 diabetes and in a number of cases, these patients progress to insulin dependency. LADA patients have several features of classic type 1 diabetes in addition to islet cell antibody positivity, including high rates of HLA-DR3 and DR4. We describe here a case of a patient with a diagnosis of LADA who, having been diagnosed with type 2 diabetes, was affected with diabetic ketoacidosis. In April 2000, a 65-year-old man was admitted to Chung-Ang University Hospital due to his decreased cognitive ability. The patient was diagnosed with type 2 diabetes 30-years ago and he was diagnosed 6-month ago as being in a hyperglycemic hyperosmolar state. He was positive for antibodies against GAD(anti-GAD, 31U/mL). His weight was 70kg, height 167cm, BMI 25 kg/m2 and the blood pressure was 86/52mmHg. No abnormalities on the physical examination were found. His acid-base balance was pH 6.937, serum bicarbonate 2.2mmol/L and the anion gap 38; he also had a strong positive reaction for ketones in his urine and serum. During half a year, the fasting C-peptide level decreased from 0.65nmol/L to 0.13nmol/L, which means the rapid progression of beta-cell destruction. Intensive treatment of LADA with insulin may improve this type of patients' quality of life, and so potentially save the beta-cell function and perhaps lessening the risk of a hyperglycemic crisis

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