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Associations between hyperglycaemia and somatic transversion mutations in mitochondrial DNA of people with diabetes
1The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto-city, Nagano-prefecture, Japan. jkamiyan@hsp.md.shinshu-u.ac.jp
Aims/Hypothesis:
Considering that increased oxidative stress induced by hyperglycaemia plays a possible role in the pathogenesis of diabetic complications and that mitochondrial DNA (mDNA) is thought to be more vulnerable than nuclear DNA, we investigated what somatic mutations actually occur in the mDNA of diabetic patients. We also studied the relations between those mutations and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) which is known to increase considerably in people with diabetes.
Methods:
We identified somatic mutations by subcloning and sequencing two segments of mDNA [control region (nt 15996-16401) and the segment encompassing t-RNA(Leu(UUR))(nt 3149-3404)] in the peripheral blood cells of six diabetic women and control subjects matched for age and sex. This was done in 20 colonies each. In each case we also assayed urinary 8-OHdG.
Results:
No difference in the aggregate somatic mutational burden of mDNA was found between patients and control subjects. However, the incidence of somatic transversion mutations in mDNA was significantly higher in diabetic patients than in control subjects (13.93+/-4.57 x 10(-5) vs 1.27+/-1.27 x 10(-5) mutations per base pair; p=0.031, according to Mann-Whitney U-test). There was no significant difference in transition mutations. A correlation was found between the transversion mutational burden and HbA(1)c values, but not between it and 8-OHdG content in the urine.
Conclusions/Interpretation:
We showed that somatic transversion point mutations of mDNA increase in diabetic patients. Such transversion mutations can become a new biomarker for mDNA damage associated with hyperglycaemia and possibly caused by oxidative stress but not reflected by urinary 8-OHdG.
Insights
Diabetic patients show increased somatic transversion mutations in mitochondrial DNA (mDNA). These mutations, linked to hyperglycemia, may serve as a novel biomarker for mDNA damage, independent of urinary 8-hydroxy-2'-deoxyguanosine levels.
Area of Science:
- Genetics and Molecular Biology
- Endocrinology and Metabolism
- Biochemistry
Background:
- Hyperglycemia in diabetes mellitus contributes to oxidative stress, a known factor in diabetic complications.
- Mitochondrial DNA (mDNA) is considered more susceptible to oxidative damage than nuclear DNA.
- Urinary 8-hydroxy-2 -deoxyguanosine (8-OHdG) is an established marker for oxidative stress in diabetes.
Purpose of the Study:
- To investigate the occurrence of somatic mutations in the mitochondrial DNA (mDNA) of diabetic patients.
- To explore the relationship between mDNA mutations and urinary 8-OHdG levels in individuals with diabetes.
Main Methods:
- Somatic mutations in specific mDNA segments (control region and tRNA-Leu(UUR)) were identified via subcloning and sequencing in peripheral blood cells.
- Peripheral blood cells from six diabetic women and matched control subjects were analyzed.
- Urinary 8-OHdG levels were measured in all participants.
Main Results:
- No significant difference in the overall burden of somatic mDNA mutations was observed between diabetic patients and controls.
- Diabetic patients exhibited a significantly higher incidence of somatic transversion mutations in mDNA compared to controls (p=0.031).
- A correlation was found between the burden of transversion mutations and HbA1c levels, but not with urinary 8-OHdG.
Conclusions:
- Somatic transversion point mutations in mDNA are elevated in diabetic patients.
- These transversion mutations represent a potential new biomarker for mDNA damage associated with hyperglycemia and oxidative stress.
- Urinary 8-OHdG levels do not appear to reflect this specific type of mDNA damage in diabetes.
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