Diabetes & Metabolism Journal

Original Articles

Genetic Association of Mitochondrial DNA Polymorphisms with Type 2 Diabetes Mellitus.: Tae Su Han, Jee Hye Choi, Jina Park, Kwang Ho Lee, Ae Ja Park; Korean Diabetes J. 2009;33(5):382-391. Published online October 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.5.382

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Abstract PDF: BACKGROUND
Although many single nucleotide polymorphisms (SNPs) of mtDNA have been found to be associated with type 2 diabetes mellitus, the results of studies using different population samples and different methods are mixed. Therefore, we conducted a genetic association study of mtDNA SNPs and type 2 diabetes mellitus in a Korean sample and compared our results with those of studies conducted in other human populations. METHODS: A total of 298 blood samples from 147 type 2 diabetic patients and 151 normal controls were surveyed for SNPs via PCR directed sequencing. Sequencing analyses were performed using the SeqMan module of the DNASTAR program. The identified SNPs were compared to previously reported SNP lists on NCBI and V-mitoSNP. RESULTS: A total of 24 SNPs were identified in the MT-RNR2, MR-TL1 and MT-ND1 mtDNA genes in Korean type 2 diabetes mellitus patients and normal controls. The SNPs identified in the Korean sample were not closely associated with the type 2 diabetes mellitus phenotype, a significantly different result from those previously observed in European, Chinese and Japanese samples. Additionally, a haplotype and prevalence analysis could not detect any differences between the type 2 diabetes mellitus patients and normal controls. CONCLUSION: The 24 mtDNA SNPs were not associated with type 2 diabetes mellitus risk in our Korean sample. The results of the present study support the possibility that mtDNA SNPs have a differential effect on the risk of type 2 diabetes mellitus according to geographical origin.

Fetal Protein Deficiency Causes Long Term Changes in Mitochondrial DNA Content of Liver and Muscle in Female Sprague-Dawley Rats.: Suk Kyeong Kim, Min Seon Kim, Youn Young Kim, Do Joon Park, Kyong Soo Park, Ki Up Lee, Hong Kyu Lee; Korean Diabetes J. 2003;27(2):115-122. Published online April 1, 2003

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Abstract PDF: BACKGROUND
Epidemiological data suggest a strong association between low birth weight and the increased risk of metabolic syndrome, including type 2 diabetes, hypertension and cardiovascular disease, in adult life. However, the underlying mechanisms are largely unknown. In our previous study, the mitochondrial DNA (mtDNA) copy number in peripheral blood leukocytes was decreased in patients with type 2 diabetes and insulin resistance. To test the hypothesis that mitochondrial changes may serve as a link between fetal under nutrition and insulin resistance in later life, the effects of fetal protein malnutrition on the mitochondria of the liver and skeletal muscle, the main sites of insulin action in adulthood, were investigated. METHODS: Eight-week old female rats were divided into 2 groups and fed on either a control diet (casein 180 g/kg diet) (n=5) or a low protein diet (casein 80 g/kg diet) (n=7) for 15 days prior to mating. They were mated with 10 week-old male Sprague Dawley rats that had been fed on the control diet. The female offspring, born to the mothers fed the low protein diet, were randomly divided into 2 groups 4 weeks after birth, and weaned on either the low protein (low protein group, n=48) or control diet (resuscitated group, n=48). As a control group, the offspring born to the mothers fed the control diet were weaned on the control diet (n=48). The animals in each group were again randomly divided into 4 groups, and sacrificed at 5, 10, 15 and 20 weeks of age, respectively (n=12 per group). The body weight, liver and muscle mtDNA content were measured at weeks 5, 10, 15 and 20. RESULTS: The mtDNA contents of the liver and skeletal muscle were reduced in fetal malnourished adult rats, and were not restored to normal levels even when proper nutrition was supplied after weaning. CONCLUSION: Our findings indicate that under nutrition in early life causes long lasting changes in the mitochondria DNA content of the liver and muscles, which may contribute to the development of insulin resistance in later life.

Effects of Antioxidants on Ethidium Bromide-induced Inhibition of Insulin Secretion in Rat Pancreatic Islets.: Chul Hee Kim, Chan Hee Kim, Hyeong Kyu Park, Kyo Il Suh, Ki Up Lee; Korean Diabetes J. 2002;26(3):179-187. Published online June 1, 2002

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Abstract PDF: BACKGROUND
It was recently shown that mitochondrial function in pancreatic beta-cells is essential in nutrient-stimulated insulin secretion. The inhibition of mitochondrial DNA (mtDNA) transcription by ethidium bromide (EtBr) has been reported to suppress glucose-induced insulin secretion in beta-cell lines. This study was undertaken to examine the effects of EtBr on insulin secretion in isolated normal rat pancreatic islets, and to see whether antioxidants could protect the beta-cell function against the EtBr-induced impairment. METHODS: Pancreatic islets of normal Sprague-Dawley rats were isolated by intraductal injection of collagenase followed by Ficoll-gradient centrifugation. Isolated islets were treated with 0.2 +/- 2.0 microgram/mL of EtBr for 2 to 6 days, and the glucose-stimulated insulin secretion measured. The effects of the antioxidant, vitamin E and alpha-lipoic acid, on the EtBr-induced inhibition of insulin secretion were also examined. RESULTS: EtBr inhibited the basal and glucose-stimulated insulin secretion in normal rat pancreatic islets in a dose- and time-dependent manner. Vitamin E and alpha-lipoic acid prevented the EtBr-induced inhibition of insulin secretion. CONCLUSION: Our results show that antioxidant can protect normal rat pancreatic islets from the EtBr-induced inhibition of insulin secretion. This suggests that oxidative stress is involved in the pathogenesis of the insulin secretory defect associated with mitochondrial dysfunction.

Devrease of Mitochondrial DNA Content in Non-Insulin Dependent Diabetic Rats.: Ji Hyun Song, Sun Hee Yim, Bok Ghee Han, Hong Kyu Lee, Young Mi Kim, Kyong Soo Park, S Suzuki; Korean Diabetes J. 2000;24(2):202-215. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Although genetic disorder in diabetes mellitus (DM) is not well understood, it has been suggested that the maternally inherited mitochondrial DNA which does not follow the Mendel's laws is a genetic factor for DM. It was reported that the mitochondrial DNA contents in DM patients were decreased compared to the normal control. Similar decrease in mitochondrial DNA content before DM development was tested in animal models. METHOD: The mitochondrial DNA (mtDNA) content in various tissues obtained from two types of non-insulin dependent diabetic rats, Goto-Kakizaki (GK) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats at different ages were quantified. We also determined the quantity of hepatic COX subunit lll(COX III) mRNA, and the enzyme activities of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) in mitochondria isolated from liver and skeletal muscle were measured. RESULTS: At 6 weeks, mtDNA content of GK rat liver was 20% decreased compared to the Wistar control, The mtDNA content of Wistar rat liver was decreased to aging from 6 weeks to 24 weeks while mtDNA in GK rat liver remains relatively constant. In case of skeletal muscle, however, mtDNA contents in GK rats were 50% decreased compared to the control at 12 and 24 week old, Similarly, OLETF and LETO control rats showed the age-dependent decrease of mtDNA content in liver and pancreas. Especially the mtDNA contents in OLETF rat tissues were reduced at the younger age than the LETO control content. That is, at 6 weeks old mtDNA contents in OLETF rat pancreas and liver were only 50% of the control. The level of mitochondrial coded hepatic CDX subunit III mRNA tends to decrease with age. Despite the decrease of mtDNA content, hepatic COX lll mRNA level and COX activities and SDH activities were not altered significantly, implying that the change of mtDNA contents did not damage the mitochondrial gene transcription and mitochondrial function dramatically. CONCLUSIONS: This results suggest that mtDNA contents in pancreas and liver decrease age-dependently but it occurs at younger age in NIDDM. The decrease of mtDNA content at young age may be a cause of NIODM.

Prevalence of Islet Cell Autoantibodies and Mitochondrial DNA Mutation among Typical and Atypical Type 1 Diabetic Patients in Korea.: Hong kyu Lee, Kee Up Lee, Sung Kwan Hong, Byuong Doo Rhee, Dong Seop Choi, Hyoung Woo Lee, Sang Wook Kim, Hee Jin Kim, Nan Hee Kim, Kyong Soo Park, Woo Je Lee, Kyung Soo Ko; Korean Diabetes J. 1999;23(4):541-551. Published online January 1, 2001

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Abstract PDF: BACKGROUND
American Diabetes Association (ADA) proposed new criteria for the classification of diabetic patients, which were mainly based on the presence of autoimmune markers. But it is questionable if we can apply the new ADA criteria to Korean type 1 diabetic patients directly. In this study, we measured several autoantibodies to islet cell in Korean subjects with typical and atypical clinical manifestations of type 1 diabetes mellitus. And mutation of mitochondrial DNA was analyzed in the same patients. METHODS: We measured fasting serum C-peptide in 1870 diabetic patients attending the diabetes clinic of Asan Medical Center. Among the 117 patients with fasting serum C-peptide less than 0.6 ng/mL, glucagon-stimulated C-peptide was measured, and 57 Patients showed the level less than 1 ng/mL and they were diagnosed as type 1 diabetic patients. They were subgrouped into typical (n=26, needed insulin injection within 1 year after diagnosis) and atypical (n=30, did not need insulin for more than l year after diagnosis) type 1 diabetic patients. ICA was measured by indirect immunofluorescence method. Anti-GAD antibody was measured by radioimmunoassay. Anti-ICA512 antibody was measured by western blotting. Mitochondrial DNA 3243 mutation was detected using restriction enzyme Apa-I digestion of the amplified genomic DNA from the subjects. RESULTS: 1) Median age of onset was 40 years for atypical type 1 diabetes patients, while it was 27.5 years for typical type 1 diabetes patients. Average duration of insulin requirement was 0.18 years for typical group and 5.73 years for atypical group. In this series, only typical type 1 diabetic patients experienced diabetic ketoacidosis. 2) Only 50 % of typical type 1 diabetic patients and 47 % of atypical type 1 diabetic patients had at least one autoantibody among ICA, anti-GAD antibody and anti-ICA512 antibody. 3) Mitochondrial DNA 3243 point mutation was detected in 3 patients with atypical type 1 diabetes (10 %), but it was not found in patients with typical type 1 diabetes. CONCLUSION: These results suggest that the prevalence of autoantibodies in Korean type 1 diabetic patients was lower than that reported in Caucasians irrespective of clinical features. Therefore, it may not be easy to apply this new diabetes classification of ADA to Korean type 1 diabetic patients. In addition, mitochondrial DNA mutation may be responsible for some of the Korean atypical type 1 diabetic patients.

The Prevalence of the Mitochondrial DNA 16189 Variant in Korean Adults and Its Association with Insulin Resistance.: Seong Yeun Kim, Hang Kyu Lee, Do Joon Park, Bo Yeon Cho, Suk Kyeong Kim, Geon Sang Park, Jae Hyun Kim, Kyong Soo Park, Bong Sun Kang; Korean Diabetes J. 1999;23(3):299-306. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Mutations in mitochondrial DNA (mtDNA) are of potential importance in the pathogenesis of diabetes mellitus. MtDNA 3243 mutation (G->A) is famous and associated with insulin secretory defect, but it is found in only 0.52% of type 2 diabetes mellitus and it can explain only a small proportion of the patients with diabetes mellitus. Recently Poulton et al. showed that the 16189 variant (T C transition) in mtDNA was associated with insulin resistance in Caucasians. They showed that the prevalence of the 16189 variant in the American was 11% and the people with the 16189 variant had higher fasting insulin and HOMA insulin resistance than the people without the 16l89 variant. In this study, we investigated the prevalence of the 161S9 variant in Korean adults and its association with insulin resistance. METHODS: We utilized the stored blood samples from community-based diabetes survey conducted in Yonchon County, Korea in 1993. We randomly selected 160 samples. We extracted the DNA from peripheral blood samples and examined the 16189 variant by PCR and restrictive enzyme digestion. We measured BMI, waist-hip ratio, blood pressure, fasting glucose, postprandial 2 hour glucose, fasting insulin, total cholesterol, triglyceride and HDL- cholesterol. HOMA insulin resistance and beta-cell function were calculated from fasting glucose and fasting insulin. RESULTS: The prevalence of the 16189 variant in Korean adults was 28.8% (46/160), higher than in the American, but the same as in the Japanese. The subjects with the 16189 variant had higher fasting glucose and BMI than the subjects without the 16189 variant, but fasting insulin, HOMA insulin resistance, beta-cell function, cholesterol and blood pressure were not different between the two groups. CONCLUSION: The prevalence of the 16189 variant in the Korean is higher than in the Caucasian but the same as in the Japanese. Our results support that a frequent mitochondrial variant may contribute to the phenotype related to insulin resistance. However, further detailed studies must be made in a large number of patients.

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.

Relationship of Insulin-like Growth Factor(IGF)-1, IGF-2, IGF Binding Protein(IGFBP)-3, and Mitochondrial DNA Amount in the Umbilical Cord Blood to Birth Weight.: Yun Yong Lee, Do Joon Park, Chan Soo Shin, Kyong Soo Park, Hong Kyu Lee, Jong Kwan Jun, Boh Yun Yoon, Jih Yeun Song, Bong Sun Kang; Korean Diabetes J. 1999;23(1):36-45. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Reaven proposed a syndrome (syndrome X), consisting of glucose intolerance, hypertension, hyperinsulinemia, dyslipidemia, as a clinical entity. The fundamental metabolic defect of this syndrome was recognized as insulin resistance, but the pathophysiology of insulin resistance is not clarified as of yet. Recent evidence, suggests that non-insulin dependent diabetes mellitus (NIDDM) ancl lipid and cardiovascular abnormalities-syndrome X-are associated with intrauterine growth retar- dation (IUGR). Recently Shin reported that the amounts of mitochondrial DNA (mtDNA) in a given amount of genomic DNA were lower in NIDDM patients than in healthy controls, and the amount of mtDNA is negatively correlated with blood pressure ancl waist-hip ratio. Birth weight is known to be correlated with levels of insulin-like growth factors (IGFs). The purpose of this study was to identify the correlation of low birth weight with reduced mtDNA and syndrome X. We investigated the relationship of birth weight to IGFs and the amount of mtDNA METHODS: 72 singleton pregnancy babies and their mathers admitted in Seoul National University Hospital from March to May, 1997 were studied. After delivery, the cord blcxxl and maternal venous blood sampling was done. Using the imnnmoradiometric assay (IRMA) the IGF-l, IGF-2, IGFBP-3 was measured from cord and maternal plasma. Among them only 27 pairs samples were measured mtDNA amount with competitive PCR method in their buffy coat. Then statistical analysis was done within these paratneters. RESULTS: Birth weight is correlated significantly with cord plasma IGF-1 (r=0.32, p<0.01), IGFBP-3 (r=0.44, p<0.01), prepregnancy maternal body weight (r=0.45, p<0.01), maternal mtDNA amount (r=0.63, p<0.01). Cord blood mtDNA is correlated with maternal mtDNA amount (r=0.55, p<0,01). In multiple regression analysis, the maternal mtDNA was found to be the only independent factor related to birth weight (p<0.01). COMCLUSION: We have found the correlation between birth weight and maternal prepregnancy body weight and mtDNA amount. The clinical implications of this result remain yet to be deiermined.

Decreased Mitochondrial DNA Content in Peripheral Blood Leukocyte procedes the Development of Type 2 Diabetes Mellitus.: Jae Joon Koh, Jong Ho Ahn, Soon Ja Kwon, Ji Hyun Song, Chan Soo Shin, Do Joon Park, Kyong Soo Park, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 1998;22(1):56-64. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Mitochondrial mutations and deletions, have been implicated in the pathogenesis of diabetes mellitus. This can explain only a very small proportion of the patients with diabetes mellitus. Mitochondrial DNA(mtDNA) is vulnerable to oxidative stress, resulting in both qualitative and quantitative changes. We reported that the amount of mtBNA decreased in the peripheral blood leukocyte of patients with NIDDM. In this study, we examined that decreased mtDNA content preceded the development of NIDDM{Non-insulin dependent diabetes mellitus) and correlated with various insulin resistance parameters.In this study, we demonstrated that the amount of mtDNA decreased in peripheral blood leukocyte of patients with NIDDM. Furthermore, we found that lower mtDNA levels preceded the development of diabetes mellitus. METHODS: We utilized the stored blood samples from two community-based survey conducted in Yonchon County, Korea in 1993 and 1995. We selected 23 newly diagnosed diabetic patients and 22 age- and sex-matched control subjects. The buffy coats of peripheral blood samples were used for the competitive PCR and the products pairs were separated by gel EP. The content of mtDNA was calculated with the densitometry. RESULTS: There were no difference in the initial anthropometric parameters, blood pressure and lipid profiles between subjects who became diabetic converters and non converters. The mean quantity of mtDNA was lower in the converters, with 102.8+ 41.5 copies/pg template DNA compared to 137.8+ 67.7 copies/pg template DNA of the controls(p 0.05). The significant inverse correlations were noted between mtDNA content and WHR(r=0.31, p<0.05) in the first, and fasting glucose level(r=-0.35, p<0.05), diastolic blood pressures(r=-0.36, p<0.05), and WHR(r=-0.40, p<0.01) in the second survey. The correlations with the serum levels of total and high density cholesterol, triglyceride, insulin and proinsulin were not statistically significant. CONCLUSION: Although a relationship between diabetes and mitochondrial dysfunction has been suspected. This study showed that decreased mtDNA content in peripheral blood proceded the development of NIDDM. This is the first study to demonstrate that quantitative changes in mtDNA precede the development of NIDDM.

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