Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-08-01
2001-05-15
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200
Reexamination Certificate
active
06232078
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for predicting the development of type 2 diabetes before the manifestation of the symptoms in a subject by measuring the mitochondrial DNA(“mtDNA”) content in peripheral blood.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.
The diagnostic criteria for diabetes mellitus recommended by American Diabetes Association are 1) symptoms of diabetes plus casual plasma glucose concentration of 200 mg/dl or higher, 2) fasting plasma glucose concentration of 126 mg/dl or higher, and 3) 2-hour plasma glucose level of 200 mg/dl or higher during the oral glucose tolerance test using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. When any one of the above criteria is met, it must be confirmed, on a subsequent day, by any one of the three methods given above for warranting the diagnosis of diabetes (Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,
Diabetes Care, Vol.
23,
Supplement
1, S4-S19(January 2000)).
Type 2 diabetes, i.e., non-insulin dependent diabetes, is characterized by insulin resistance and relative insulin deficiency (Olefsky, J. M. et al.,
Am. J. Physiol.,
243, E15-E30(1982)). Insulin resistance precedes overt type 2 diabetes mellitus in most cases. Detection of insulin resistance before the development of diabetes mellitus may lead to prevention of diabetes. Moreover, insulin resistance is commonly observed in syndrome X (insulin resistance syndrome) which is a loose disease category including diabetes mellitus, hypertension, hyperlipidemia and obesity. Testing for insulin resistance and preclinical diabetes includes insulin clamp technique and modified intravenous glucose tolerance test (DeFronzo et al.,
Am. J Physiol.,
237, E214-223(1979)). However, these testing methods are complicated and time-consuming and, moreover, the insulin clamp technique is not suitable for applying to many people simultaneously. Accordingly, there has existed a need to develop a more convenient method for preclinically diagnosing diabetes mellitus.
As reviewed by Gerbitz et al., the mitochondrial DNA (mtDNA) has been identified as the gene that is directly related to the pathogenesis of diabetes (Gerbitz, K. D. et al.,
Biochim. Biophys. Acta,
1271, 253-260(1995)). Furthermore, Ames et al. have reported that the aging mechanism involves an increase in the number of impaired mitochondria (Ames, B. N. M. et al.,
Proc. Natl. Acad. Sci. U.S.A.,
90, 7915-7922(1993)), which suggests the possibility that the cause of insulin resistance syndrome may be found in mitochondria since the aging process is accompanied by increased appearance of clinical symptoms of the insulin resistance syndrome.
Hitherto, most pathological studies on mtDNA focused on its biochemical nature, such as mutation or deletion thereof (Shoffner, J. M. and Wallace, D. C., “Oxidative phosphorylation diseases” in
The Metabolic and Molecular Bases of Inherited Disease
, Vol. 1, pp 1535-1610. Scrier C. R., Beaudet A. L., Sly W. S., Valle D., ded., McGraw Hill, International Edition), while only a limited number of studies have dealt with the quantitative aspect of mtDNA. Shin reported that the amount of mtDNA in peripheral blood of a diabetic patient is lower than normal (Shin, C. S.,
J. Kor. Diabetes Asso.,
18, 344-350(1994)), and Antonetti et al. reported that the muscular mtDNA content is low in a diabetic patient (Antonetti, D. A. et al.,
J. Clin. Invest.,
95, 1383-1388(1995)). However, these studies, which measured the mtDNA of diabetes patents by Southern blot analysis having inherently poor reproducibility, have failed to fulfill the need to develop a convenient and reliable method which may be used as an index in diagnosing diabetes prior to the onset of the disease.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a method for predicting the development of type 2 diabetes before the manifestation of the symptoms in a subject.
In accordance with the present invention, there is provided a method for predicting the development of type 2 diabetes in a subject, which comprises measuring the mitochondrial DNA (mtDNA) content in peripheral blood of the subject, comparing the measured mtDNA content with that of a normal control, and predicting the increased risk of development of diabetes when the subject's mtDNA content is lower than that of the normal control.
REFERENCES:
Antonetti et al., J. Clin. Invest. vol. 95, pp 1383-1388, 1995.*
Shin, C.S., J. Kor Diabetes Assoc. vol. 18, pp 344-350,1995.
Lee Hong-Kyu
Park Kyong-Soo
Shin Chan-Soo
Anderson Kill & Olick PC
Jones W. Gary
Lee Hong-Kyu
Souaya Jehanne
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