Peripheral blood mitochondrial DNA content correlates with lipid oxidation rate during euglycemic clamps in healthy young men

doi:10.1016/S0168-8227(99)00086-8

Diabetes Research and Clinical Practice

Volume 46, Issue 2, November 1999, Pages 149-154

https://doi.org/10.1016/S0168-8227(99)00086-8 Get rights and content

Abstract

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.

Introduction

The mitochondrion is the chief site of intracellular respiration and energy metabolism. Qualitative changes in mitochondrial DNA (mtDNA), such as mutations and deletions, have been implicated in the pathogenesis of diabetes mellitus [1], [2], [3], [4]. This can, however, explain only a very small proportion of the patients with diabetes mellitus [5], [6].

In addition to the qualitative changes, mtDNA is subject to quantitative changes [7], [8]. It was recently found that mtDNA content of peripheral blood leukocytes is decreased in the patients with diabetes mellitus[9], the finding of which has been confirmed by another group [10]. It has been suggested that increased oxidative stress in diabetes may be responsible for both qualitative and quantitative changes in mtDNA [9], [10]. However, there is another possibility that decrease in mtDNA content may be involved in the pathogenesis of diabetes rather than a consequence of diabetes, because this decrease preceded the development of diabetes [9]. In fact, mtDNA content correlated with the clinical parameters of insulin resistance syndrome, including diastolic blood pressure and waist-to-hip ratio.

This prompted one to investigate whether there is a correlation between mtDNA content and the biochemical parameters of insulin resistance in non-diabetic subjects. MtDNA content of peripheral blood leukocytes was studied in Korean healthy young men, and this was correlated with various parameters of fuel metabolism at baseline and during euglycemic hyperinsulinemic clamps.

Section snippets

Subjects

Eleven male medical students were recruited for this study. Their mean age was 22.6 (range, 21–26) years and their mean body mass index (BMI) was 22.2 (range, 17.7–29.4) kg/m². No subjects had a history of major illness or showed any evidence of systemic disease. They were not taking any medication and there was no history of diabetes mellitus among first-degree relatives. Before their participation, the nature, purpose and possible risks of the study were explained, and all gave written

Correlation between mtDNA content and metabolic parameters at base line

There was no statistically significant correlation between mtDNA content and metabolic parameters such as BMI, WHR and blood pressure (Table 1). Neither basal fat oxidation rates nor carbohydrate oxidation rates were related with mtDNA content.

Correlation between mtDNA content and metabolic parameters during the clamps

As expected, there was a significant increase in cabohydrate oxidation rate (2.97±0.28 vs 1.58±0.26 mg/kg per min, P<0.001) and a significant decrease in fat oxidation rate (0.18±0.10 vs 0.70±0.12 mg/kg per min, P<0.001) during the euglycemic clamps when

Discussion

This study showed for the first time that in healthy young male subjects, the mtDNA content of peripheral blood leukocytes correlated positively with fat oxidation rate during the euglycemic clamps and the decrement of it from the basal state. Similarly, the increment in carbohydrate oxidation rate induced by euglycemic clamps correlated negatively with mtDNA content. Thus, it appears that the higher the mtDNA content, the more fat and the less carbohydrates are used as an energy source in a

Acknowledgements

This paper was supported by a grant from the Korean Ministry of Science and Technology Special Development Research Fund and a grant from Seoul National University Hospital (02-97-007). We are indebted to Dr Chang Hyun Yoon at the Department of Physiology and Biophysics, University of Southern California, for invaluable suggestions.

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Very interestingly, we also found that the mtDNA copy number was correlated with both insulin resistance and insulin secretory function [6], which suggested that the decreased mtDNA copy number might be responsible for the two major defects in type 2 diabetes: insulin resistance in the peripheral tissue and impaired insulin secretion from pancreatic β cells. Furthermore, in a study of young volunteers [7,8], we found that mtDNA copy number of peripheral blood cells was positively correlated with fat oxidation rate, insulin sensitivity, and insulin secretion. In addition, decreased mtDNA copy number was associated with increased plasma homocystein level, which is known to be a non-traditional risk factor of cardiovascular disease [9].
Mitochondria are the intracellular organelles responsible for the generation of ATP by the process of oxidative phosphorylation (OXPHOS) and have their own DNA containing genes for 13 subunits of OXPHOS and 2 rRNAs and 22 tRNAs for their protein synthesis machinery. Since mitochondrial DNA (mtDNA) has limited coding capacity, nuclear genes make a major contribution to mitochondrial architecture, metabolic systems and biogenesis. Nowadays, there is a growing body of evidence that the mitochondrial dysfunction plays a crucial role in the pathogenesis of type 2 diabetes. In this review, we showed that mtDNA copy number in peripheral blood cells is associated with various pathophysiological characteristics of type 2 diabetes such as insulin resistance and insulin secretory defect. In addition, peripheral blood mtDNA copy number is a risk factor for the development of type 2 diabetes. Common polymorphisms in mtDNA and nuclear genes regulating mitochondrial function might be associated with type 2 diabetes. Elucidation of genetic factors regulating mitochondrial function would be of help to understand how mitochondrial dysfunction is linked to the pathogenesis of type 2 diabetes.
Peripheral blood mitochondrial DNA content is inversely correlated with insulin secretion during hyperglycemic clamp studies in healthy young men
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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.
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A hypothesis that mitochondrial genome itself is the thrifty genome has been advanced, as both its mutation, or quality, and amount in the peripheral blood, or quantity, are found to have close relationship to diabetes mellitus, or more specifically insulin resistance. Mere presence of relationship, however, does not establish cause-effect relation. Usually a genetic ‘cause’ is established, when a knockout of putative gene produces disease phenotype. However, absence of mitochondrial genome is incompatible with life. Here the argument advanced by Bradford Hill was applied to the proof of a hypothesis, as most of the data are from epidemiological observations; it is biologically plausible that both mtDNA quality and quantity are related to insulin resistance. The relationship had enough strength of association, dose-response relation, and consistency of relationship. Temporally association, decrease of mtDNA content preceding onset of diabetes, was also observed. Good hypothesis generates many predictions, which could be verified experimentally and which is biologically plausible.
Correlation of plasma homocysteine and mitochondrial DNA content in peripheral blood in healthy women
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Hyperhomocysteinemia is an independent risk factor of cardiovascular disease and associated with insulin resistance, although their causal relationship remains unclear. A previous report has shown that high concentration of homocysteine damages mitochondrial gene expression, function and structure. As we found recently, the mitochondrial DNA (mtDNA) contents are inversely correlated with insulin resistance parameters. Thus there is possibility that plasma total homocysteine (tHcy) level is somewhat correlated with mtDNA content. Sixty healthy women (mean age 40.3±20.9 yr, range 18–78 yr) were recruited to investigate the correlation of plasma tHcy level and mtDNA content in peripheral blood. A significant negative correlation was found between plasma tHcy levels and mtDNA content (r=−0.507, P<0.01). Plasma tHcy and mtDNA content have an independent effect on each other and on insulin resistance (HOMA-insulin resistance (IR) score) respectively in multiple regression model. Plasma tHcy showed positive correlations with age (r=0.407), W/H ratio (r=0.370), total cholesterol (r=0.338), LDL-cholesterol (r=0.317) and insulin resistance (HOMA-IR score) (r=0.261); and a negative correlation with folate (r=−0.273). MtDNA content showed negative correlations with age (r=−0.407), BMI (r=−0.440), W/H ratio (r=−0.659), SBP (r=−0.350), total cholesterol (r=−0.340), triglyceride (r=−0.376), LDL-cholesterol (r=−0.349), fasting plasma insulin (r=−0.483), and insulin resistance (HOMA-IR score) (r=−0.423); and a positive correlation with folate (r=0.299). In this study, there was a significant inverse correlation between plasma tHcy level and mtDNA content. Further study will be warranted to elucidate the mechanism by which two factors are associated.
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It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive.
In this study, we assessed the heritability of mtDNA content in buccal cells and analyzed the association of mtDNA content in blood with prevalent and incident T2D.
mtDNA content from cells from buccal and blood samples was assessed using a real-time PCR-based assay. Heritability of mtDNA content was estimated in 391 twins from the Netherlands Twin Register. The association with prevalent T2D was tested in a case control study from The Netherlands (n = 329). Incident T2D was analyzed using prospective samples from Finland (n = 444) and The Netherlands (n = 238).
We measured the heritability of mtDNA content and the association of mtDNA content in blood with prevalent and incident T2D.
A heritability of mtDNA content of 35% (19-48%) was estimated in the twin families. We did not observe evidence of an association between mtDNA content and prevalent or incident T2D and related traits. Furthermore, we observed a decline in mtDNA content with increasing age that was male specific (P = 0.001).
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Peripheral blood mitochondrial DNA content correlates with lipid oxidation rate during euglycemic clamps in healthy young men

Abstract

Introduction

Section snippets

Subjects

Correlation between mtDNA content and metabolic parameters at base line

Correlation between mtDNA content and metabolic parameters during the clamps

Discussion

Acknowledgements

Lancet

Biochim. Biophys. Acta

Diabetes Res. Clin. Pract.

Lancet

Maternally transmitted diabetes and deafness associated with 10.4 kb deletion

Nat. Genet.

Mutation in mitochondrial tRNA(Leu, UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness

Nat. Genet.

A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA

N. Engl. J. Med.

Maternally inherited diabetes and deafness: a new diabetes subtype

Diabetologia

Mutation in mitochondrial tRNA^{(Leu, UUR)} gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness