Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
2001-09-13
2004-02-10
Nguyen, Dave T. (Department: 1635)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C800S008000, C800S021000
Reexamination Certificate
active
06689938
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a non-human animal model for obesity and uses of such an animal for studying and developing methods for identifying compounds for use in the regulation of insulin resistance in obesity and type II diabetes, as well as a method of treating insulin resistance in obesity and type II diabetes by administration of such compounds.
BACKGROUND OF THE INVENTION
Diabetes, and conditions related thereto, are major health concerns throughout the world, and, particularly in the United States, contribute to morbidity and mortality. Non-insulin dependent diabetes mellitus (NIDDM), also known as type II diabetes, is the major form of diabetes in developed countries. While a large number of environmental and genetic factors contribute to the risk of NIDDM in the United States, prolonged obesity is by far the largest risk factor. The molecular basis of this association, however, is not fully understood. As a consequence, efficient means of therapeutical intervention are lacking.
Before the development of diabetes, many obese patients develop a peripheral resistance to the actions of insulin. The molecular basis of insulin-resistance in obesity has been the subject of intensive study, by nonetheless remains elusive. Insights into components and mechanisms of the link between obesity and insulin resistance have been gained from mouse models of obesity which display obesity-induced insulin resistance. The molecular basis of the various mouse obesity models covers a range of mechanisms; nonetheless these all develop diabetes, either before or after the onset of obesity.
Obesity in humans and rodents is commonly associated with insulin resistance, (i.e., smaller than expected responses to a given dose of insulin) (LeRoith et al., Diabetes Mellitus: a Fundamental and Clinical Text. (Lippincott-Raven, Philadelphia, 1996); DeFronzo et al.,
Diabetes Care
15:318-68 (1992); Rifkin et al., Diabetes Mellitus, (Elsevier, N.Y., 1990)). The mechanisms linking obesity and insulin resistance are not known. Studies on the potential mechanistic basis of obesity-induced insulin resistance have revealed numerous potential sites, making a single basic mechanism for explaining insulin insensitivity unlikely (Rifkin et al., Diabetes Mellitus, (Elsevier, N.Y., 1990)). Both insulin secretion and action can be impaired. Accordingly, sites at the anatomical, cellular, and molecular level are the &bgr;-cells of the pancreas, and membrane carriers and enzymes regulating metabolic pathways in liver, fat, and muscle. An example for impaired insulin secretion can be found in a rodent model of obesity with non-insulin-dependent diabetes mellitus, the Zucker diabetic fatty (fa/fa) rat, where overaccumulation of triglycerides in the pancreatic islets leads to gradual depletion of &bgr; cells (Lee et al.,
Proc Natl Acad Sci USA
91:10878-82 (1994); Shimabukuro et al.,
Proc Natl Acad Sci USA
95:2498-502 (1998)). Insulin action can be impaired in a number of ways, involving insulin sensitive carriers or pathways, or the insulin receptor directly. Earlier studies indicated that quantitative regulation of the insulin sensitive glucose transporters (Glut-4) may contribute to insulin resistance; however, this factor alone is probably inadequate to explain the extent of insulin resistance. For instance, mutant mice lacking Glut-4 develop only mild hyperinsulinemia (Katz et al.,
Nature
377:151-5 (1995)). More recently studies have focused on defects at the level of the insulin receptors themselves and at post-receptor events in type 2 diabetes, specifically the intrinsic catalytic activity of the insulin receptor and downstream signaling events. A reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in both animals and humans with type 2 diabetes (Le Marchand-Brustel et al.,
J Recept Signal Transduct Res
19:217-28 (1999)). Importantly, this occurs in all of the major insulin-sensitive tissues, namely the muscle, fat and liver. Disruption of IRS-2 in mice impairs both peripheral insulin signaling and pancreatic &bgr;-cell function (Withers et al.,
Nature
391:900-4 (1998)). Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin (Kerouz et al.,
J Clin Invest
100:3164-72 (1997)). The regulation of gene expression by insulin in the liver is impaired for the genes for glucokinase and phosphoenolpyruvate carboxykinase (PEPCK) (Friedman et al.,
J Biol Chem
272:31475-81 (1997)). A modulator of insulin action is tumor necrosis factor (TNF)-&agr;, which blocks insulin through its ability to inhibit insulin receptor tyrosine kinase activity (Feinstein et al.,
J Biol Chem
268:26055-8 (1993)). Mice lacking TNF-&agr; function are protected from obesity-induced insulin resistance (Uysal et al.,
Nature
389:610-4 (1997)). Another modulator of insulin sensitivity is protein tyrosine phosphatase-1B (PTP-1B) which acts as a negative regulator of insulin signaling (Cicirelli et al.,
Proc Natl Acad Sci USA
87:5514-8 (1990)). Mice deficient in PTP-1B are interestingly more sensitive to insulin but resistant to obesity (Elchebly et al.,
Science
283:1544-8 (1999)). Most recent studies have focused on the peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;), a member of the nuclear-hormone-receptor family (Auwerx,
Diabetologia
42:1033-49 (1999)). Mutations in humans of PPAR&ggr; suggest that this molecule is required for normal insulin sensitivity in humans (Barroso et al.,
Nature
402:880-3 (1999)). It is not clear at the moment whether insulin resistance in human obesity might result from impaired PPAR&ggr; signaling. What is now clear is that decreased signaling capacity of the insulin receptor can be an important component of obesity-induced insulin resistance.
At the intracellular, metabolic enzyme, level, insulin-resistance in obesity seems to consist of increased activities of key enzymes of pathways known to be stimulated by insulin (i.e. glycolysis, lipogenesis), but also of increased activities of key enzymes of pathways normally depressed by insulin (Belfiore et al.,
Int J Obes
3:301-23 (1979)). This failure of insulin to depress enzymes of catabolic pathways manifests itself in enhanced basal lipolysis in adipose tissue, increased amino acid release from muscle, and elevation in the activity of key gluconeogenic enzymes in the liver.
As mentioned above, there are a number of mouse models with genetic obesity-diabetes syndromes (Herberg, et al.,
Metabolism
26:59-99 (1977)). They characteristically have hyperglycemia, hyperinsulinemia, and obesity, albeit to different degrees, with different times of onset, and for different reasons. In the yellow obese mouse (A
y
/a) a dominant mutation of the agouti locus causes the ectopic, ubiquitous expression of the agouti protein, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus (Michaud et al.,
Proc Natl Acad Sci U S A
91:2562-6 (1994)). Obese (ob/ob) (Zhang et al.,
Nature
372:425-32 (1994)), diabetes (db/db) (Tartaglia et al.,
Cell
83:1263-71 (1995)), fat (cpe/cpe) (Naggert et al.,
Nat Genet
10:135-42 (1995)) and tubby (tub/tub) (Kleyn et al.,
Cell
85:281-90 (1996); Noben-Trauth et al.,
Nature
380:534-8 (1996)) are mutations in single recessive genes, specifically in the genes for leptin, the leptin receptor, carboxypeptidase E, and a member of a new family of genes encoding tubby-like proteins, respectively. Obese mice have a diabetes-like syndrome of hyperglycemia, glucose intolerance, and elevated plasma insulin. The diabetes syndrome develops after the onset of obesity, and is probably the result of it. In diabetes mice elevation of plasma insulin at 2 weeks of age precedes the onset of obesity at 3-4 weeks; blood glucose levels are elevated at 4-8 weeks. Fat mice have hyperinsulinemia consistent throughout life in association with hypertrophy and hyperplasia of the islets of Langerhans; hyperglycemia is transient. I
Brennan Miles B.
Hochgeschwender Ute
Angell Jon Eric
Nguyen Dave T.
Oklajoma Medical Research Foundation
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