Diabetes & Metabolism Journal

Response

Response: Predictive Clinical Parameters for the Therapeutic Efficacy of Sitagliptin in Korean Type 2 Diabetes Mellitus (Diabetes Metab J 2011;35:159-65): Soon Ae Kim, Woo Ho Shim, Eun Hae Lee, Young Mi Lee, Sun Hee Beom, Eun Sook Kim, Jeong Seon Yoo, Ji Sun Nam, Min Ho Cho, Jong Suk Park, Chul Woo Ahn, Kyung Rae Kim; Diabetes Metab J. 2011;35(3):300-301. Published online June 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.3.300

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Efficacy and Safety of Switching from Sitagliptin to Ipragliflozin in Obese Japanese Patients with Type 2 Diabetes Mellitus: A Single-Arm Multicenter Interventional Study
Kentaro Watanabe, Susumu Yamaguchi, Yoshinori Kosakai, Tetsuya Ioji, Hisamitsu Ishihara
Clinical Drug Investigation.2023; 43(12): 927. CrossRef

Original Articles

Predictive Clinical Parameters for the Therapeutic Efficacy of Sitagliptin in Korean Type 2 Diabetes Mellitus: Soon Ae Kim, Woo Ho Shim, Eun Hae Lee, Young Mi Lee, Sun Hee Beom, Eun Sook Kim, Jeong Seon Yoo, Ji Sun Nam, Min Ho Cho, Jong Suk Park, Chul Woo Ahn, Kyung Rae Kim; Diabetes Metab J. 2011;35(2):159-165. Published online April 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.2.159

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Background

Sitagliptin is a highly selective dipeptidyl peptide-4 (DPP-4) inhibitor that increases blood levels of active glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrophic polypeptide (GIP), resulting in increased insulin secretion. While studies conducted in other countries have indicated the efficacy and safety of using sitagliptin to treat type 2 diabetes mellitus (T2DM), its predictors of effects to sitagliptin are not well understood. Therefore, we evaluated the predictive clinical parameters for the therapeutic benefits of sitagliptin when added to an ongoing metformin or sulfonylurea therapy in Korean T2DM subjects.

Methods

We obtained data from 251 Korean T2DM subjects who had recently started taking sitagliptin as add-on therapy. Exclusion criteria included any insulin use. Changes in HbA1c (ΔHbA1c) and fasting plasma glucose (ΔFPG) were assessed by comparing baseline levels prior to sitagliptin administration to levels 12 and 24 weeks after treatment. Responders were defined as subjects who experienced decrease from baseline of >10% in ΔHbA1c or >20% in ΔFPG levels at 24 weeks.

Results

We classified 81% of the subjects (204 out of 251) as responders. The responder group had a lower mean body mass index (23.70±2.40 vs. 26.00±2.26, P≤0.01) and were younger (58.83±11.57 years vs. 62.87±12.09 years, P=0.03) than the non-responder group.

Conclusion

In Korean T2DM subjects, sitagliptin responders had lower body mass index and were younger compared to non-responders.

Citations

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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.

Activation of NF-kappaB and AP-1 in Peripheral Blood Mononuclear Cells Isolated from Patients with Diabetic Nephropathy.: Jisun Nam, Min Ho Cho, Jong Suk Park, Geun Taek Lee, Hai Jin Kim, Eun Seok Kang, Yu Mie Lee, Chul Woo Ahn, Bong Soo Cha, Eun Jig Lee, Sung Kil Lim, Kyung Rae Kim, Hun Joo Ha, Hyun Chul Lee; Korean Diabetes J. 2007;31(3):261-273. Published online May 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.3.261

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Abstract PDF: BACKGROUND
We evaluated the role of oxidative stress in diabetic nephropathy by measuring intracellular reactive oxygen species (ROS) and redox-sensitive transcription factors in isolated peripheral mononuclear cells (PBMC). METHODS: From 66 diabetic patients with or without diabetic nephropathy (Group III and II, respectively) and 49 normal control subjects (Group I), spontaneous and stimulated ROS levels, activities of nuclear factor-kappa B (NF-kappaB), activator protein-1 (AP-1), and specificity protein1 (Sp1) in PBMC, urinary and PBMC TGF-beta1 (transforming growth factor-beta1), and 24-hour urinary albumin excretion (UAE) were measured. RESULTS: Spontaneous ROS was significantly higher in group III and II than group I (60.7 +/- 3.3 vs. 60.0 +/- 3.0 vs. 41.1 +/- 2.4%, respectively), and stimulated ROS were significantly higher in Group III compared to Group II (Increment of H2O2-induced ROS production: 21.8 +/- 2.2 vs. 11.1 +/- 2.0%, respectively; increment of PMA-induced ROS production 23.5 +/- 4.5 vs. 21.6 +/- 2.2%, respectively). The activities of NF-kappaB and AP-1, but not of Sp1, were significantly higher in Group III than in Group II (2.53 vs. 2.0 vs. 1.43-fold, respectively). Both PBMC- and urinary TGF-beta1 levels were higher in Group III than Group II (3.23 +/- 0.39 vs. 1.99 +/- 0.68 ng/mg in PBMCs, 16.88 +/- 6.84 vs. 5.61 +/- 1.57 ng/mL in urine, both respectively), and they were significantly correlated with activities of NF-kappaB and AP-1 and 24-hour UAE. CONCLUSIONS: Increased intracellular ROS generation in PBMCs of diabetic patients is involved in the pathogenesis of diabetic nephropathy through activation of NF-kappaB and AP-1, but not Sp1, and increased expression of TGF-beta1.

Relationship of LDL Particle Size to IMT and Insulin Resistance in Non-Diabetic Adult.: Jina Park, Chul Sik Kim, Jong Suk Park, Dol Mi Kim, Min Ho Cho, Jee Hyun Kong, Hai Jin Kim, Jeong Ho Kim, Chul Woo Ahn, Kyung Rae Kim, Bong Soo Cha, Sung Kil Lim, Hyun Chul Lee; Korean Diabetes J. 2005;29(4):333-343. Published online July 1, 2005

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Abstract PDF: BACKGROUND
The aims of this study were to investigate the predictor of the low density lipoprotein(LDL) particle size and the relationship of the LDL particle size to the levels of insulin resistance and the carotid intima-media thickness (IMT) in healthy Koreans. METHODS: The subjects were 47 and 89 clinically healthy males and females, aged between 32 and 70years, without medications that could potentially alter glucose and lipid metabolisms. The mean LDL particle size was determined by polyacrylamide tube gel electrophoresis(Lipoprint(r) LDL, Quantimetrix), the insulin resistance using a short insulin tolerance test kit, and the subclinical atherosclerosis from the carotid intima-media thickness. RESULTS: The LDL particle size was found to be significantly correlated with insulin resistance using a simple Pearson's correlation(r=0.233, P<0.01), but the independent predictors of the LDL particle size, as determined by a multiple stepwise regression analysis, were serum triglyceride(TG), high density lipoprotein(HDL) cholesterol level and age(beta=-0.403, P=< 0.001; beta=0.309, P=0.003; beta=-0.219, P=0.016, respectively). Significant relationships were found between an increasing IMT and the traditional risk factors of atherosclerosis: age, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure(r=0.490, P<0.001; r=-0.251, P<0.01; r=0.211, P<0.05; r=0.298, P<0.01; r=0.263, P<0.01, respectively). However, no significant correlation was found between an increasing IMT and the LDL particle size (r=-0.172, P=0.075). CONCLUSION: The best predictors for the LDL particle size were the serum TG level, HDL cholesterol level and age. Insulin resistance was not found to be an independent predictor of the LDL particle size. Small dense LDL was not found to be a predictor of the IMT in healthy Koreans.

Prevalence of Diabetes Mellitus(Fasting Plasma Glucose by the ADA Criteria) and Impaired Fasting Glucose according to Anthropometric Characteristics and Dietary Habits: 1998 National Health and Nutrition Survey.: Chul Sik Kim, Eun Kyong Jeong, Jina Park, Min Ho Cho, Ji Sun Nam, Hai Jin Kim, Jee Hyun Kong, Jong Suk Park, Joo Young Nam, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Chung Mo Nam; Korean Diabetes J. 2005;29(2):151-166. Published online March 1, 2005

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Abstract PDF: BACKGROUND
The study is based on the National Health and Nutrition Examination Survey in Korea(1998). With these data, we want to predict the prevalence of diabetes mellitus(DM) and impaired fasting glucose(IFG), By investigating anthropometric characteristics and dietary intake habits, we also wanted to analyze any significant correlation between those factors and the prevalences of DM and IFG. METHODS: The study group was comprised of 8,166 people, a representative group of Koreans, who had undergone a health check-up and food intake survey among the total 39,331 members of 12,189 families who were surveyed. RESULTS: The final results are as the follows. 1) The peak prevalence of DM was 15.92% among women in their sixties and 18.21% among men in their fifties, and that of IFG was found to be 16.27% of women in their seventies and 14.09% of men in their sixties. 2) When analyzing the eating habits and the prevalences of DM and IFG, we found that women with more glucose intake had a lesser risk of DM, but this was of no statistical significance. 3) In men, age, total cholesterol, triglyceride(TG), and hypertension(HTN) were revealed as meaningful factors and in women, age, TG, and HTN were revealed as meaningful factors. As to the IFG, in females, age and TG were meaningful factors, and in males, age, TG, the waist/hip ratio (WHR), and body mass index (BMI) were meaningful factors. CONCLUSION: Although this study could not demonstrate meaningful correlation between diet habits and DM, the prevalence of IFG and the recent increase in the prevalence of DM in Koreans, owing to alterations in their diet habits, demands further organized group study for a better understanding of their relationship

Case Report

A Case of Severe Prolonged Hypoglycemia Caused by Combined Ramipril and Amiloride Treatment in a Nondiabetic Woman.: Min Ho Cho, Dol Mi Kim, Chul Sik Kim, Joug Suk Park, Joo Young Nam, Jin Hyuck Chang, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):554-557. Published online December 1, 2004

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Abstract PDF: The relationship between angiotensin converting enzyme inhibition and hypoglycemia remains controversial. An 82-year-old, nondiabetic woman who had taken ramipril 5 mg with amiloride 5 mg for two months was admitted to the hospital because of her altered mentality. Her plasma glucose was 1.5 mmol/L and she regained her consciousness after normalization of the plasma glucose. The recurrent attacks of hypoglycemia ended when she stopped taking ramipril. Her hypoglycemia was thought to result from the combined deficiency of catecholamines and cortisol that was induced by a deficiency of angiotensin II. The glucagoninsensitivity was thought to result from a chronic elevation of bradykinin due to the ACE inhibitor, and the relative hyperinsulinemia was though to be cased by the amiloride.

Original Articles

Apolipoprotein E Genetic Polymorphism and Diabetic Microangiopathy in Type 2 Diabetic Patients.: Jong Suk Park, Joo Young Nam, Chul Sik Kim, Dol Mi Kim, Min Ho Cho, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):511-520. Published online December 1, 2004

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Abstract PDF: BACKGROUND
The pathophysiological causes for the development and progression of diabetic microangiopathy are not well known, but the apo E genetic polymorphism has been proposed to be involved in the disease's development and progression. The aim of this study was to investigate the association between the apo E genetic polymorphism and diabetic microangiopathy in Korean type 2 diabetic patients. METHODS: One hundred eighteen patients with type 2 diabetes who had a duration of diabetes longer than 8 years were divided into the three apo E groups (the E2, E3 and E4 groups). The plasma levels of lipids were measured. The frequency of diabetic nephropathy, retinopathy and neuropathy were compared among the three apo E genotype groups. RESULTS: The frequency of overt nephropathy was significantly greater for the apo E2 patients with diabetes (46.7%) than for the apo E3 (16.7%) or apo E4 patients (10.5%). Logistical regression analysis showed that the odds ratio of the apo E2 and apo E4 genotypes for the presence of overt nephropathy were 4.779 (P < 0.01) and 0.643 (P = 0.583), respectively. Plasma TG levels were significantly greater for the apo E2 patients. This study did not find any association between diabetic retinopathy, neuropathy and apo E polymorphism. CONCLUSION: Apo E2 is a positive risk factor for diabetic nephropathy in Korean type 2 diabetic patients. TG may have an important role in diabetic nephropathy.

The Degree of Atherosclerosis and the Metabolic Characteristics according to the Abdominal Obesity in Type 2 Diabetic Patients.: Chul Sik Kim, Jong Suk Park, Joo Young Nam, Jina Park, Min Ho Cho, Ji Sun Nam, Dol Mi Kim, Soo Jee Yoon, Jae Hyun Nam, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(5):377-391. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Many of the maturity-onset type 2 diabetic patients with hypertension and dyslipidemia in Korea are not associated with obesity. However, these patients are at risk for developing macrovascular complications such as atherosclerosis due to hyperinsulinemia, insulin resistance and abdominal obesity. The aims of this study were to compare the clinical and biochemical differences between the type 2 diabetic patients that are with and without abdominal obesity, and we also wished to investigate the degree of insulin resistance and atherosclerosis in these patients. METHODS: Among 530 type 2 diabetes mellitus (DM) patients, the percentages of under-weight (UW), normal-weight (NW), over-weight (OW) and obese (OB) (BMI <20, 20-25, 25-29.9 and > or =30, respectively) subjects were 8.9%, 62.1%, 25.1% and 3.9%, respectively. To evaluate the severity of their atherosclerosis, the coronary artery calcification (CAC) score was measured by electron beam computed tomography, and the intima-media thickness (IMT) of the common carotid artery and the ankle-brachial pressure index (ABPI) were also measured. The Insulin sensitivity index (ISI) was measured by the plasma glucose disappearance rate (kitt: %/min). RESULTS: 1. There were no differences in age, duration of DM and the HbA1c levels according to BMI for both the men and women, but the waist-hip ratio (WHR) and systolic blood pressure (SBP) were significantly different among each group. Serum triglyceride (TG), HDL-cholesterol (HDL-C), free fatty acid (FFA), fibrinogen, and fasting c-peptide levels, {excluding total cholesterol (TC)}, were also significantly different. The ISI, which is a marker for insulin resistance, as well correlated with the patients' BMI. Subjects having an with ISI above 2.5%/min were considered as having insulin resistance, and 28%, 60%, 68% and 75% of patients in the UW, NW, OW and OB groups, respectively, demonstrated insulin resistance. The visceral fat area/subcutaneous fat area ratio and visceral fat area/thigh muscle area ratio also increased with BMI. 2. The median values of the WHR were 0.95 for the men and 0.91 for the women. There were no significant differences for age, BMI, duration of DM and HbA1c between patients with and without abdominal obesity, but the SBP, TG, HDL-C, FFA, fibrinogen and ISI were significantly different between those two groups. 3. For the OW group as well as the NW group, the carotid IMT, ABPI and CAC scores were significantly different between the patients with and without abdominal obesity. However, there were no differences between the NW group and the OW group. CONCLUSION: In conclusion, those patients with abdominal obesity, regardless of their BMIs, have a higher prevalence for atherosclerosis, dyslipidemia, and hypertension, compared to those patients without abdominal obesity. Therefore, it is important to screen for atherosclerosis and to manage it accordingly, for the patients with insulin resistance or abdominal obesity in order to decrease their risk of developing atherosclerotic events.

Role of Activation of NF- B and AP-1 by Oxidative Stress in Atherosclerosis in Diabetic Patients.: Chul Sik Kim, Geun Taek Lee, Jina Park, Min Ho Cho, Joo Young Nam, Jong Suk Park, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(4):255-264. Published online August 1, 2004

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Abstract PDF: BACKGROUND
The aim of this study was to evaluate the possible role of NF- B activation and AP-1 by oxidative stress in atherosclerosis in diabetic patients by measuring the carotid intima-media thickness, intracellular ROS generation and activation of transcription factors, including nuclear factor-kappa B (NF- B) and activator protein-1 (AP-1). METHODS: Sixty-six patients (28 males, 38 females; age 56.1 13.4 years; duration of diabetes 115.7 83.4 months) with type 2 diabetes mellitus (DM) were selected for this study. The DM patients included in this study were divided into those with a normal carotid intima-media thickness (Group II) and those with an increased intima-media thickness (Group III). 57 healthy controls matched for age and sex with the DM patients (Group I) were randomly selected. Dichlorodifluorescein (DCF)-sensitive intracellular ROS was measured by fluorescent spectrometry. The activities of NF- B and AP-1 in PBMCs were measured by an electrophoretic mobility shift assay. RESULTS: No differences were evident between the groups in terms of gender, age, BMI, blood pressure, total cholesterol, triglyceride, LDL-cholesterol and HDL-cholesterol. Spontaneous and H2O2 (or phorbol-12-myristate-13-acetate, PMA) stimulated ROS were significantly higher in the PBMCs from the DM patients with an increased intima-media thickness (Group III) than in those without (Group II), and were also higher in the control group (Group I). Moreover, the activities of NF- B and AP-1 were significantly higher in Group III than in Groups I or II. CONCLUSION: The present study demonstrates that intracellular ROS generation, and NF- B and AP-1 activation in PBMCs strongly correlates with the carotid artery IMT. These clinical results suggest that increased oxidative stress in PBMCs may play a role in the pathogenesis of atherosclerosis in DM patients .

Frequency of Anti-GAD Antibody in Non-obese, Adult-onset Type 2 Diabetes in Korea and Clinical and Biological Characteristics According to Anti-GAD Antibody.: Chul Sik Kim, Jina Park, Min Ho Cho, Jong Suk Park, Joo Young Nam, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(2):66-74. Published online April 1, 2004

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Abstract PDF: BACKGROUND
Some of the characteristic features of diabetes mellitus in Korea are that 70-80% of patients are non-obese or adult-onset type, and type 1 diabetes is very rare. Occasionally, autoantibodies to glutamic acid decarboxylase(GAD) are found in typical, type 2 diabetes mellitus patients(T2DM). The role of the autoantibody to GAD in T2DM is unknown. The aim of this study was to determine the clinical and biochemical characteristics between GAD-positive and GAD-negative non-obese, adult-onset diabetics in Korea. METHODS: A cohort of 428 type 2 diabetes patients was included. The measured autoantibodies to GAD were measured, and the C-peptide and HbA1c levels, anthropometric data(weight, height, body mass index and waist circumference), blood pressure and lipid profiles compared between the two groups. RESULTS: Compared to the antibody-negative group(n=374; 87.4%), patients with the anti-GAD antibody(n=54; 12.6%) had significantly lower C-peptide levels and were significantly younger. The anti GAD-positive group had a lower BMI, more frequently needed insulin supplements, and a lower prevalence of hypertension. There were no significant differences in gender and family history of diabetes between the two groups. CONCLUSION: The presence of the autoantibody to GAD allowed the group with more deteriorated beta-cell function and more frequent need for insulin supplements, but a lower prevalence of obesity and hypertension to be determined.

A Case of Insulin Dependent Diabetes Mellitus with MELAS Syndrome Associated with a Mutation of Mitochondrial DNA.: Min Ho Choi, Hyun Mi Rhim, Ki Won Oh, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Hyun Chul Lee, Kap Bum Huh; Korean Diabetes J. 1999;23(2):207-214. Published online January 1, 2001

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Abstract PDF: Mitochondrial mutations are associated with a wide range of disorders (Kearns-Sayre and chronic progressive external ophthalmoplegia syndromes, Myoclonic epilepsy and ragged-red fibre disease, Mitoehondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, Leighs disease ancl cerebellar ataxia plus pigmentary retinopathy syndromes), which is inherited maternally. A-to-G mutation at nuclcotide position 3243 was originally identified in MEI.AS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and accounted for about 80% of the MELAS cases, Recently, this mutation was reported in maternally inherited NIDDM patients. It was also repoded that approximatedly 1% of diabetic patients have this mutation. We performed the molecular genetic analysis of mtDNA in one female insulin dependent diabetic patient with MELAS syndrome and her family members, and also confirmed the A-to-G mutation at nucleotide 3243 of the mtRNA Leu(UUR) gene in their family members.

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