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Aims: We previously showed that circulating mitochondrial DNA (MtDNA) levels are altered in diabetic nephropathy. The aim of the current study was to determine if circulating MtDNA levels are altered in patients with diabetic retinopathy., Methods: Patients with diabetes (n=220) were studied in a clinical setting using a cross-sectional study design as the following groups: DR-0 (no retinopathy, n=53), DR-m (mild non-proliferative diabetic retinopathy NPDR, n=98) and DR-s (severe proliferative diabetic retinopathy, n=69). MtDNA content in peripheral blood DNA was measured as the mitochondrial to nuclear genome ratio using real time qPCR. Circulating cytokines were measured using the luminex assay and MtDNA damage was assessed using PCR. Differences were considered significant at P<0.05., Results: Circulating MtDNA values were higher in DR-m compared to DR-0 (P=0.02) and decreased in DR-s compared to DR-m (P=0.001). These changes remained significant after adjusting for associated parameters. In parallel there were increased levels of circulating cytokines IL-4 (P=0.005) and TNF-α (P=0.02) in the DR-s group and increased MtDNA damage in DR-m patients compared to DR-0 (P=0.03)., Conclusions: Our data show that circulating MtDNA levels are independently associated with diabetic retinopathy, showing an increase in DR-m and decrease in DR-s with a parallel increase in MtDNA damage and inflammation. Hyperglycemia-induced changes in MtDNA in early diabetes may contribute to inflammation and progression of diabetic retinopathy. Longitudinal studies should be carried out to determine a potential causality of MtDNA in diabetic retinopathy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We report that mitochondrial DNA (MtDNA) copy numbers are increased in peripheral blood of patients with diabetic nephropathy (DN). Using qPCR for quantitation, we found a 2-4-fold significant increase (p<0.05) in the mean MtDNA values in DN patients vs. healthy controls and diabetics without nephropathy. Increased MtDNA in DN could contribute to increased oxidative stress.

Objective: The aim of this study was to examine the potential influence of insulin resistance (IR), hyperglycemia and oxidative stress on leucocytes mitochondrial DNA (mtDNA) content., Research Design and Method: One hundred twenty-five T2DM, 101 IFG and 70 normal subjects were enrolled in this study. The quantity of relative mtDNA content was measured by a real-time PCR and corrected by simultaneous measurement of the nuclear DNA. Parameters of lipid peroxidation, thiobarbituric acid reactive substance (TBARS), and total free thiols as antioxidative status were measured from serum samples. IR was assessed by homeostasis model assessment in the non-diabetic groups. Relationships among different variables were analyzed by general linear model correlation., Results: In all subjects, after correcting for age, sex and BMI, there were progressive increases of leucocyte mtDNA copy number, TBARS, and total reduced thiols with progressive dysregulation of glucose metabolism (normal vs. IFG vs. T2DM). Furthermore, correlation between mtDNA content and glucose dysregulation persisted after sequential correction for age, sex, BMI and TBARS. The independent predictor of mtDNA content by regression analysis was hyperglycemia. In non-diabetic group, influence of family history of diabetes on mtDNA content turned to non-significant after correcting for fasting plasma glucose (FPG). Correlation study revealed that mtDNA content was correlated with FPG (P<0.001), but not IR., Conclusion: Our results indicate that hyperglycemia, not IR, is associated with an increase of leucocyte mtDNA copy number in cases of glucose dysregulation.

Abnormalities in mitochondrial DNA(mtDNA) have been implicated in the pathogenesis of diabetes mellitus. We recently reported that decreased mtDNA content precedes the development of diabetes mellitus and is associated with parameters of insulin resistance. In this study, we examined whether there is any relation between mtDNA content and insulin secretion. We compared the mtDNA content of peripheral blood leukocytes with the parameters of insulin secretion measured by hyperglycemic clamp in a group of healthy young men. There were statistically significant correlations between mtDNA content in peripheral blood and fasting plasma insulin (r=-0.43, P<0.05) and C-peptide levels (r=-0.44, P<0.05). MtDNA content also correlated negatively with acute insulin response(r=-0.48, P<0.05), late insulin response (r=-0.50, P<0.05) during hyperglycemic clamp and insulin secretion after glucagon stimulation (r=-0.60, P<0.01). mtDNA content in peripheral blood correlated negatively with homeostasis model (HOMA) insulin resistance (r=-0.45, P<0.05) although it did not correlate with the insulin insensitivity index (M/I) during hyperglycemic clamp. In summary, the mtDNA content of peripheral blood correlated negatively with indices of insulin resistance and insulin secretion in healthy young men. The compensatory response of pancreas beta cells to insulin resistance might contribute in part to increased insulin secretion in these subjects.

Both qualitative and quantitative changes in mitochondrial DNA (mtDNA) have been implicated in the pathogenesis of diabetes mellitus. It was previously found that decreased mtDNA content preceded the development of diabetes and mtDNA content correlated with the clinical parameters of insulin resistance syndrome, including diastolic blood pressure and waist-hip ratio. These results prompted one to look whether there are correlations between mtDNA content and the biochemical parameters of insulin resistance in non-diabetic subjects. MtDNA content of peripheral blood leukocytes was measured in Korean healthy young men, and this was correlated with various parameters of fuel metabolism at baseline and during euglycemic hyperinsulinemic clamps with indirect calorimetry. MtDNA content in peripheral blood leukocytes did not correlate with insulin sensitivity index or other metabolic variables such as body mass index (BMI), waist-to-hip ratio (WHR) and blood pressure. However, mtDNA content showed a positive significant correlation with fat oxidation rate during euglycemic clamps (r = 0.61, P < 0.05). Changes in fat oxidation rate and carbohydrate oxidation rate during the clamps were significantly correlated with mtDNA content (r = 0.65, P < 0.05, r = -0.65, P < 0.05, respectively). These results suggest that mtDNA content in peripheral blood may not correlate with insulin resistance per se but with some aspect of insulin resistance in healthy young men.

Although mitochondrial DNA (mtDNA) abnormalities are known to cause insulin deficiency, insulin resistance and diabetes mellitus, it's quantitative aspect was not addressed well. In this review, mitochondrial genome hypothesis of thrifty phenomenon is proposed, based on the data and review of literatures. From a population based epidemiologic study, it was found that mtDNA quantity was decreased in the peripheral blood of diabetic subjects, and also in those subjects who will convert to diabetes mellitus within 2 years. In this population, low mtDNA subjects were found to have higher blood pressure and high waist hip ratio. These findings suggested mtDNA status might be quantitatively linked to the insulin resistance syndrome. As quantitative relationships between peripheral blood mtDNA levels and insulin requirement, and energy utilization pattern (fat and carbohydrate oxidation during hyperinsulinemic clamp studies) were observed in a group of male students; and maternal mtDNA content (peripheral blood) correlated with birth weight and peripheral blood mtDNA content of the offspring in another study, possibility of thrifty phenotype phenomena might be due to the low mitochondrial status arose. As thrifty phenotype phenomenon shows the quantitatively continuous relationship between involved parameters and characteristics of 'imprinting', a possible mechanism is suggested.

Qualitative changes in mitochondrial DNA (mtDNA), such as mutations and deletions, have been implicated in the pathogenesis of diabetes mellitus. In addition to the qualitative changes, mtDNA is subject to quantitative changes, and is vulnerable to oxidative stress, resulting in both qualitative and quantitative changes. This study was performed to investigate whether quantitative changes in mtDNA occur in non-insulin-dependent diabetes mellitus (NIDDM) patients and also in pre-diabetic subjects. MtDNA content from peripheral blood was measured by slot-blot analysis in 55 NIDDM patients and 29 age- and sex-matched control subjects. We have also analysed the mtDNA copies by quantitative polymerase chain reaction (PCR) method in 23 pre-diabetic subjects who converted to diabetic in 2 years and 22 age- and sex-matched control subjects who remained non-diabetic. Mean mtDNA quantity measured by slot blot method was 35% lower in patients with NIDDM than in control subjects (12.3+/-8.1 vs. 19.1+/-8.2 AU/microg DNA; P < 0.05). MtDNA quantities did not correlate with age, body mass index, duration of diabetes or HbA1c levels. We have also found that the mtDNA copies in subjects who converted to diabetes in 2 years were lower than in controls even before the development of diabetes (102.8+/-41.5 vs. 137.8+/-67.7 copies/pg template DNA P < 0.05). Inverse correlations were noted between mtDNA content and baseline waist hip circumference ratio (WHR) (r = -0.31, P < 0.05), and fasting glucose level (r = - 0.35, P < 0.05), diastolic blood pressure (r = -0.36, P < 0.05), and WHR (r = -0.40, P < 0.01) after development of diabetes. In conclusion, we demonstrate that the content of mtDNA decreases in peripheral blood of patients with NIDDM and the lower mtDNA levels precede the development of diabetes.