Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Reexamination Certificate
2001-08-07
2003-11-25
Leary, Louise N. (Department: 1654)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
C435S014000, C435S007400, C435S004000
Reexamination Certificate
active
06653094
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to diabetes mellitus, and in particular to compositions and methods for the diagnosis, prognosis and treatment of type 2 diabetes.
BACKGROUND OF THE INVENTION
Type 2 diabetes mellitus, or “late onset” diabetes, is a common, degenerative disease affecting 5 to 10 percent of the population in developed countries. The propensity for developing type 2 diabetes mellitus (“type 2 DM”) is reportedly maternally inherited, suggesting a mitochondrial genetic involvement. (Alcolado, J. C. and Alcolado, R.,
Br. Med. J.
302:1178-1180 (1991); Reny, S. L.,
International J. Epidem.
23:886-890 (1994)). Diabetes is a heterogeneous disorder with a strong genetic component; monozygotic twins are highly concordant and there is a high incidence of the disease among first degree relatives of affected individuals.
Current pharmacological therapies for type 2 DM include injected insulin, and oral agents that are designed to lower blood glucose levels. Currently available oral agents include (i) the sulfonylureas, which act by enhancing the sensitivity of the pancreatic beta cell to glucose, thereby increasing insulin secretion in response to a given glucose load; (ii) the biguanides, which improve glucose disposal rates and inhibit hepatic glucose output; (iii) the thiazolidinediones, which improve peripheral insulin sensitivity through interaction with nuclear peroxisome proliferator-activated receptors (PPAR, see, e.g., Spiegelman, 1998
Diabetes
47:507-514; Schoonjans et al., 1997
Curr. Opin. Lipidol.
8:159-166; Staels et al., 1997
Biochimie
79:95-99), (iv) repaglinide, which enhances insulin secretion through interaction with ATP-dependent potassium channels; and (v) acarbose, which decreases intestinal absorption of carbohydrates.
At the cellular level, the degenerative phenotype that may be characteristic of late onset diabetes mellitus includes indicators of altered mitochondrial respiratory function, for example impaired insulin secretion, decreased ATP synthesis and increased levels of reactive oxygen species. Studies have shown that type 2 DM may be preceded by or associated with certain related disorders. For example, it is estimated that forty million individuals in the U.S. suffer from impaired glucose tolerance (IGT). Following a glucose load, ciruculating glucose concentrations in IGT patients rise to higher levels, and return to baseline levels more slowly, than in unaffected individuals. A small percentage of IGT individuals (5-10%) progress to non-insulin dependent diabetes (NIDDM) each year. This form of diabetes mellitus, type 2 DM, is associated with decreased release of insulin by pancreatic beta cells and a decreased end-organ response to insulin. Other symptoms of diabetes mellitus and conditions that precede or are associated with diabetes mellitus include obesity, vascular pathologies, peripheral and sensory neuropathies and blindness.
It is clear that none of the current pharmacological therapies corrects the underlying biochemical defect in type 2 DM. Neither do any of these currently available treatments improve all of the physiological abnormalities in type 2 DM such as impaired insulin secretion, insulin resistance and/or excessive hepatic glucose output. In addition, treatment failures are common with these agents, such that multi-drug therapy is frequently necessary.
Due to the strong genetic component of diabetes mellitus, the nuclear genome has been the main focus of the search for causative genetic mutations. However, despite intense effort, nuclear genes that segregate with diabetes mellitus are rare and include, for example, mutations in the insulin gene, the insulin receptor gene and the glucokinase gene. By comparison, although a number of altered mitochondrial genes that segregate with diabetes mellitus have been reported (see generally e.g., PCT/US95/04063), relationships amongst mitochondrial and extramitochondrial factors that contribute to cellular respiratory and/or metabolic activities as they pertain to diabetes remain poorly understood.
Clearly there is a need for improved diagnostic methods for early detection of a risk for developing type 2 DM, and for better therapeutics that are targeted to correct biochemical and/or metabolic defects responsible for this disease, regardless of whether such a defect underlying altered mitochondrial function may have mitochondrial or extramitochondrial origins. The present invention provides compositions and methods related to indicators of altered mitochondrial function that are useful for determining the risk and degree of progression of type 2 DM and for treating this disease, and offers other related advantages.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method for identifying a risk for Type 2 diabetes in a human subject, comprising comparing the level of at least one indicator of altered mitochondrial function in a biological sample from the subject with a control sample; and therefrom identifying the risk for Type 2 diabetes.
It is another aspect of the invention to provide a method for determining a degree of disease progression in a human subject having Type 2 diabetes, comprising: comparing the level of at least one indicator of altered mitochondrial function in each of first and second biological samples, the first and second biological samples being obtained from the subject at a first time point and a second time point, respectively; and therefrom determining the degree of progression of Type 2 diabetes. In yet another aspect the invention provides a method of identifying an agent suitable for treating a human subject suspected of being at risk for having type 2 diabetes, comprising: comparing the level of at least one indicator of altered mitochondrial function in one or more biological samples obtained from the subject in the presence and absence of a candidate agent; and therefrom determining the suitability of the candidate agent for treating type 2 diabetes. In still another aspect of the invention, there is provided a method of determining the suitability of an agent for treating a subject suspected of being at risk for having type 2 diabetes, comprising: comparing the level of at least one indicator of altered mitochondrial function in a biological sample obtained from the subject before and after administering to the subject a candidate agent; and therefrom determining the suitability of the candidate agent for treating type 2 diabetes.
Turning to another aspect, the invention provides a method of determining the suitability of an agent for treating a human subject suspected of being at risk for having type 2 diabetes, comprising comparing the level of at least one indicator of altered mitochondrial function in at least one biological sample obtained from a plurality of subjects before and after administering to each of the subjects a candidate agent; and therefrom determining the suitability of the candidate agent for treating type 2 diabetes.
It is another aspect of the present invention to provide a method of stratifying human subjects according to type 2 diabetes subtypes, comprising: comparing the level of at least one indicator of altered mitochondrial function in at least one biological sample obtained from each of a plurality of subjects; and therefrom stratifying the subjects according to type 2 diabetes subtype. In yet another aspect the invention provides a method of stratifying human subjects according to type 2 diabetes subtypes, comprising: comparing the level of at least one indicator of altered mitochondrial function in a biological sample obtained from each of a plurality of subjects before and after administering to each of the subjects a candidate agent; and therefrom stratifying the subjects according to type 2 diabetes subtype.
According to certain embodiments within any of the above aspects of the invention, the indicator of altered mitochondrial function is a mitochondrial electron transport chain enzyme. In certain embodiments the step of comparing comprises measuring electron t
Anderson Christen M.
Davis Robert E.
Leary Louise N.
MitoKor, Inc.
Seed IP Law Group
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