Chemistry: analytical and immunological testing – Nuclear magnetic resonance – electron spin resonance or other...
Reexamination Certificate
2000-04-19
2003-02-11
Soderquist, Arlen (Department: 1743)
Chemistry: analytical and immunological testing
Nuclear magnetic resonance, electron spin resonance or other...
C436S071000, C436S095000
Reexamination Certificate
active
06518069
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and computer program products for determining whether subjects are at risk for developing Type 2 diabetes and other insulin resistance disorders.
BACKGROUND OF THE INVENTION
Type 2 diabetes, sometimes referred to as adult-onset or non-insulin dependent diabetes mellitus (NIDDM), affects approximately 15 million people in the United States alone. Additionally, approximately 21 million Americans have impaired glucose tolerance or “borderline diabetes” (characterized by high blood sugar levels not high enough to be considered diabetic). Both Type 2 diabetes and borderline diabetes are related to insulin resistance, a condition where the body fails to respond normally to insulin. Insulin resistance is associated with other health problems, including high blood pressure and heart disease. If unchecked, insulin resistance may actually develop into Type 2 diabetes. Type 2 diabetes is associated with a two- to fourfold excess risk of coronary heart disease, and diabetic patients are at an increased risk for morbidity and mortality associated with cardiovascular disease.
Type 2 diabetes has been traditionally diagnosed by the detection of elevated levels of glucose (sugar) in the blood (hyperglycemia). While hyperglycemia is a strong indicator of diabetes, it is a very late stage development in the chain of events that lead from insulin resistance to full-blown diabetes. Accordingly, it would be desirable to have a way of identifying whether or not a subject is at risk for developing Type 2 diabetes (i.e., is predisposed to the condition) prior to the development of the classic symptoms, such as hyperglycemia. Earlier detection of indicators of the disease (e.g., detection of an increase in glucose levels prior to the levels reaching an elevation high enough to be considered hyperglycemia) may lead to more effective treatment of the disease, if not actual prevention of the onset of the disease.
The diagnosis of cardiovascular disorders such as coronary heart disease (CHD) is routinely accomplished by the measurement and analysis of blood cholesterol levels of subjects suspected of having such disorders. In such analyses, total serum cholesterol (TC) is measured, as well as plasma triglyceride levels (TG). Additionally, levels of the major lipoprotein constituents or classes of cholesterol are often measured. These major lipoprotein constituents include low density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL). The major lipoprotein constituents may be further subdivided into subclasses based on further refinement of particle densities. Krauss et al,
J. Lipid Research
23, 97-104 (1982); Atger et al.,
Clinical Chemistry
37, 1149-1152 (1991). A subclass of lipoprotein particles comprises particles which have common physical properties, such as density. Subclasses distinguished upon density may be considered as a subclass of the class of lipoprotein which contains particles of the subclasses' density.
U.S. Pat. No. 4,933,844 to Otvos describes the use of proton nuclear magnetic resonance (
1
H NMR) spectroscopy to analyze blood plasma and determine the concentration of the major lipoprotein constituents in a blood plasma sample. U.S. Pat. No. 5,343,389 to Otvos describes the use of
1
H NMR spectroscopy to analyze blood plasma or blood serum for concentrations of lipoprotein subclasses. The methods described in these patents rely on the fact that
1
H NMR spectra of human blood plasma contain two prominent peaks centered at approximately 1.2 and 0.8 ppm (relative to a chemical shift standard). These peaks arise from methylene (CH
2
) and methyl (CH
3
) protons, respectively, of plasma lipids. Each of these peaks is heterogeneous in nature, consisting of overlapping resonances from protons of the several chemically distinct classes of lipids present in plasma: triglycerides; cholesterol; cholesterol esters; and phospholipids. These lipids are packaged together into the three major classes of lipoprotein particles described above, which differ in density and in the proportions of lipids which they contain. The heterogeneity of these plasma signals is reflected by their complex lineshapes, which vary from person to person owing to variations of the plasma concentrations of the different lipoprotein particles, each of which has its own characteristically different NMR spectral properties. Additionally, lipoprotein subclasses of the major lipoprotein classes or constituents exhibit NMR-measurable properties that are distinct from other subclasses. The NMR properties of one subclass may be distinct in a number of ways, such as chemical shift or lineshape variations, which make the subclass distinguishable from other subclasses.
OBJECTS AND SUMMARY OF THE INVENTION
In view of the foregoing, it is an object of the present invention to provide a more reliable method for determining if a subject is at risk for developing Type 2 diabetes.
It is another object of the present invention to provide a more accurate and/or reliable method for determining if a subject is at risk for developing insulin resistance syndrome.
It is another object of the present invention to provide an improved method for determining if a subject is suffering from insulin resistance syndrome.
It is still another object of the present invention to provide an improved method for evaluating the efficacy of treatment of a subject suffering from Type 2 diabetes.
It is additionally another object of the invention to provide a method of determining the glucose concentration in a blood plasma or blood serum sample (“blood glucose levels”), and further to be able to determine blood glucose levels at sub-hyperglycemic levels.
In order to minimize the necessity of performing numerous, expensive and duplicative tests for determining risk for Type 2 diabetes and disorders of insulin resistance, it is still another object of the invention to provide a method of determining the glucose concentration in a blood plasma or blood serum sample concurrently with determining other lipid-based risk factors for Type 2 diabetes or disorders of insulin resistance.
It is an additional object of the present invention to provide an economical way of screening a subject's blood plasma sample to determine the subject's risk of developing Type 2 diabetes.
It is yet another object of the present invention to provide a computer program product for determining whether a subject is at risk for developing Type 2 diabetes.
These and other objects of the present invention are provided by a method for identifying a patient with an increased risk of developing Type 2 diabetes by analyzing the patient's NMR lipoprotein constituent measurements. Additionally, the risk of the patient developing Type 2 diabetes may further be determined by analyzing the patient's blood glucose levels with NMR spectral analysis. The ability to analyze a patient's blood glucose levels by NMR analysis provides several advantages in that it allows for a blood glucose measurement to be taken concurrently with a patient's lipoprotein constituent measurements, thus avoiding the need for multiple testing events for determining risk for Type 2 diabetes. Additionally, the sensitivity of the NMR-based blood glucose test performed in conjunction with an NMR-based blood lipoprotein test provides an earlier detection of risk for developing Type 2 diabetes. A moderately elevated blood glucose level in the absence of other indicators of risk for developing the disease may not be sufficient to alert a health care provider or a patient that an increased risk of developing the disorder is present. However, a moderately elevated blood glucose level, as detected by the NMR-based methods of the present invention, in conjunction with the presence of other risk factors identified by the NMR-based blood lipoprotein analysis of the present invention, enables a practitioner to determine the risk of developing disorder prior to the onset of the full-blown disease.
In par
Bennett Dennis W.
Otvos James D.
LipoScience, Inc.
Myers Bigel & Sibley & Sajovec
Soderquist Arlen
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