Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus
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, and is vulnerable to oxidative stress, resulting in both qualitative and quantitative changes 7, 8. In view of the importance of mitochondria in oxidative glucose metabolism and increased oxidative stress in diabetes mellitus, we postulated that there might be quantitative as well as qualitative mtDNA changes in diabetes mellitus. It has, in fact, been shown that induction of diabetes by streptozotocin in rats results in oxidant-mediated repression of mitochondrial transcription [9], and the quantity of mtDNA decreases in the islets of diabetes prone GK rat [10]. In human, mtDNA content was found to decrease in skeletal muscle of diabetic patients, while its transcription increased [11]. In this study, we demonstrate that the amount of mtDNA decreases in peripheral blood of patients with non-insulin-dependent diabetes mellitus (NIDDM). Furthermore, we found that lower mtDNA levels precede the development of diabetes mellitus and correlate with some parameters of insulin resistance.
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Subjects
Peripheral blood samples were collected from 55 NIDDM patients (50±11 years, M:F 29:26, body mass index 23.8±3.5 kg/m2) attending the diabetes clinic of Seoul National University Hospital, Seoul, Korea and 29 age- and sex-matched control subjects (50±7 years, M:F 14:15, body mass index 24.3±3.6 kg/m2).
We also selected 23 newly diagnosed diabetic patients and 22 age- and sex-matched control subjects from 1197 subjects who participated in both the first (1993) and the second (1995)
MtDNA quantity in NIDDM
Mean mtDNA quantity measured by Southern blot hybridisation analysis was 35% lower in patients with NIDDM than in control subjects (12.3±8.1 AU/μg DNA versus 19.1±8.2 AU/μg DNA; P<0.05) (Fig. 2). MtDNA quantities did not correlate with age, body mass index, duration of diabetes or HbA1c levels.
MtDNA quantity in subjects who developed diabetes mellitus
The characteristics and mtDNA quantity of subjects who developed diabetes mellitus within 2 years are shown in Table 2.
There were no differences in initial anthropometric parameters, blood pressure and
Discussion
This study showed that the mtDNA content of peripheral blood was lower in the patients with NIDDM. Moreover, this decrease was also observed in pre-diabetic subjects who developed diabetes mellitus in 2 years.
Although the qualitative changes of mtDNA such as mutations and deletions were reported to be associated with diabetes mellitus 1, 2, 3, 4, there was little information about the quantitative changes of mtDNA in diabetes mellitus. In this study, we demonstrated that mtDNA content in
Acknowledgements
This study was supported by grants from the Korean National Science Foundation Special Development Research Fund (KOSEF 93-0800-08-01-3) and Seoul National University Hospital (03-92-060). We are indebted to Yongsoo Park, M.D., Byungkook Yang, M.D., Youngsoo Shin, M.D., Yongik Kim, M.D., Jungja Lee, R.N. and all other people involved in the Yonchon District Health Project and surveys, who helped make this study possible.
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