Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-06-12
2001-06-05
Marschel, Ardin H. (Department: 1631)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007100
Reexamination Certificate
active
06242200
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of identification of the sulfonylurea receptor in human adipocytes and other adipocyte-selective calcium channels and calcium mobilization antagonists and use of these factors for treatment of obesity, diabetes, and insulin-resistance related syndromes.
BACKGROUND OF THE INVENTION
Mice with dominant mutations at the agouti locus, including lethal yellow (A
y
) and viable yellow (A
vy
) are characterized by obesity, insulin resistance, and yellow coat color. The mouse agouti gene normally regulates differential pigment production in hair-bulb melanocytes. Each melanocyte in the hair bulb switches between the production of eumelanin (black) and phaeomelanin (yellow), producing the wild-type mouse coat color of a black hair with a subapical band of yellow. Agouti mutations disrupt this switching process and form a dominance hierarchy in which the dominant alleles produce a yellow coat and the recessive alleles produce a black coat.
Although agouti is normally expressed in neonatal skin, dominant agouti mutations are characterized by ectopic overexpression of agouti throughout life. This is due to mutations in the promoter/regulatory region rather than in protein-coding domain. Transgenic mice designed to express the agouti coding portion in a ubiquitous manner also develop a syndrome of obesity, hyperinsulinemia, hyperglycemia and yellow coat color, similar to A
vy
mutation, demonstrating that ectopic overexpression of the agouti gene is directly responsible for pleiotropic effects associated with dominant agouti mutations. However, the mechanism linking this pigmentation gene to obesity has not yet been identified.
There is needed methods for the identification of compositions and compounds for the treatment and control of insulin resistance-related disorders.
SUMMARY OF THE INVENTION
The invention provides methods for identifying compounds and compositions useful in the regulation of weight, the treatment of obesity, diabetes and other insulin resistance-related disorders hypertension, cardiovascular disease and the like. The methods comprise the use of adipocytes and predipocytes in assays and screens for compounds or compositions of interest. The present invention recognizes the presence of the sulfonylurea receptor in adipocytes and its utility in identifying compounds and in treating obesity and other insulin resistance-related disorders.
In addition to assaying for agonists and antagonists of the sulfonylurea receptor, the methods of the invention also provide for identifying novel calcium channels or other calcium regulatory channels that are selectively expressed in human adipocytes as compared to human preadipocytes and for screening adipocytes for compounds that selectively antagonize calcium. These compounds may be used in the treatment of obesity and diabetes and other insulin resistance-related disorders.
Once identified, the compounds of the invention can be used in pharmaceutical compositions for the treatment of insulin resistance-related disorders and to regulate lipogenesis and lipolysis.
REFERENCES:
Byyny et al. “Cytosolic Calcium and Insulin Resistance in Elderly Patients With Essential Hypertension”,American Journal of Hypertension 5(7):459-464. (Jul. 1992).
Zemel “Insulin Resistance, Obesity and Hypertension: An Overview”,J. Nutr. 125(6S):1715S-1717S. (Apr. 1994).
Zemel “Insulin Resistance vs. Hyperinsulinemia in Hypertension: Insulin Regulation of Ca2+Transport and Ca2+-Regulation of Insulin Sensitivity”,J. Nutr. 125(6S):1738S-1743S. (Apr. 1994).
Kim et al. “Agouti Regulation of Intracellular Calcium: Role of Melanocortin Receptors”,Am J Physiol 272(3 Pt 1):E379-84. (Mar. 1997).
Zemel et al. “Agouti Regulation of Intracellular Calcium: Role in the Insulin Resistance of Viable Yellow Mice”,Proc. Natl. Acad. Sci. USA 92:4733-4737. (May 1995).
Jones et al. (1996) “Upregulation of Adipocyte Metabolism by Agouti Protein: Possible Paracrine Actions in Yellow Mouse Obesity”,Am. J. Physiol. 270:E192-E196.
Xue et al. (Oct. 1998) “The Agouti Gene Product Inhibits Lipolysis in Human Adipocytes Via a Ca2+-Dependent Mechanism”,FASEB J. 12:1391-1396.
Abel et al. “Impaired Recovery of Vascular Smooth Muscle Intracellular calcium Following Agonist Stimulation in Insulin Resistant (Zucker Obese) Rats”,American Journal of Hypertension 6(6 Pt 1):500-504. (Jun. 1993).
Zemel et al. (1992) “Hypertension in Insulin-Resistant Zucker Obese Rats is Independent of Sympathetic Neural Support”,American Journal of Physiology 262(3 Pt 1):E368-E371.
Aguilar-Bryan et al. (1995) “Cloning of the &bgr; Cell High-Affinity Sulfonylurea Receptor: A Regulator of Insulin Secretion”,Science 268:423-426.
Alemzadeh et al. (1993) “Modification of Insulin Resistance by Diazoxide in Obese Zucker Rats”,Endocrinology 133(2):705-712.
Alemzadeh et al. (1996) “Antiobesity Effect of Diazoxide in Obese Zucker Rats”,Metabolism 45(4):334-341.
Alemzadeh et al. (Jun. 1998) “Beneficial Effect of Diazoxide in OBESe Hyperinsulinemic Adults”,J. Clin. Endocr. Met. 83(6):1911-1915.
Moustaid et al. (1996) “Insulin Increases Lipogenic Enzyme Activity in Human Adipocytes in Primary Culture”,J. Nutr. 126:865-870.
Jones et al. (1997) “Angiotensin II Increases Lipogenesis in 3T3-L1 and Human Adipose Cells”,Endocrinology 138(4):1512-1519.
Draznin et al. (1987) “Insulin and Glyburide Increase Cytosolic Free-Ca2+Concentration in Isolated Rat Adipocytes”,Diabetes 36:174-178.
Michaud et al. “Obesity and the Adipocyte”,Journal of Endocrinology 155(2):207-209 (Nov. 1997).
Ambrozy et al. “Effects of Dietary Calcium on Blood Pressure, Vascular Reactivity and Vascular Smooth Muscle Calcium Efflux Rate in Zucker Rats”,American Journal of Hypertension 4(7 Pt 1):592-596. (Jul. 1997).
Mynatt et al. “Combined Effects of Insulin Treatment and Adipose Tissue-Specific Agouti Expression on the Development of Obesity”,Proc. Natl. Acad. Sci. USA 94(3):919-922. (Apr. 1997).
Sowers et al. “Insulin Resistance, Carbohydrate Metabolism, and Hypertension”,American Journal of Hypertension 4(7 Pt 2):466S-472S. (Jul. 1991).
Zemel et al. “Insulin Attenuation of Vasoconstrictor Responses to Phenylephrine in Zucker Lean and Obese Rats”,American Journal of Hypertension 4(6):537-539. (Jun. 1991).
Kim et al. “The Effects of Calcium Channel Blockade on Agouti-Induced Obesity”,The FASEB Journal 10(14):1646-1652. (Dec. 1996).
Thomas et al. “Mutations in the Sulfonylurea Receptor Gene in Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy”,Science 268:426-429. (Apr. 1995).
Jacobs et al. “Sulfonylurea Potentiates Insulin-Induced Recruitment of Glucose Transport Carrier in Rat Adipocytes”,J. Biol. Chem. 260(5):2593-2596. (Mar. 1985).
Martz et al. “Sulfonylurea Binding to Adipocyte Membranes and Potentiation of Insulin-Stimulated Hexose Transport”,J. Biol. Chem. 264(23):13672-13678. (Aug. 1989).
Muller et al. (1996) “Characterization of the Molecular Mode of Action of the Sulfonylurea, Glimepiride, at Adipocytes”,Horm. Metab. Res. 28:469-487.
Muller et al. (1994) “Stimulation of Glucose Utilization in 3T3 Adipocytes and Rat Diaphragm In Vitro By the Sulphonylureas, Glimepiride and Glibenclamide, is Correlated with Modulations of the cAMP Regulatory Cascade”,Biochem. Pharmacol. 48(5):985-996.
Inagaki et al. “Reconstitution of IKATP: An Inward Rectifier Subunit Plus the Sulfonylurea Receptor”,Science 270:1166-1170. (Nov. 1995).
Draznin et al. “Possible Role of Cytosolic Free Calcium Concentrations in Mediating Insulin Resistance of Obesity and Hyperinsulinemia”,The Journal of Clinical Investigation 82(6):1848-1852. (Dec. 1988).
Lehmann et al. “An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor &ggr; (PPAR&ggr;)”,J. Biol. Chem. 270(22):12953-12956. (Feb. 1996).
Draznin et al. “The Existence of an Optimal Range of Cytosolic Free Calcium for Insulin-Stimulated Glucose Transport in Rat Adipocytes”,The Journal of Biological Chemistry 262(30):14385-14388. (Oct. 1987).
Sturgess et al. (Aug. 31, 1985) “The Sulphonylurea Receptor May
Moustaid-Mousse Naima
Wilkison William O.
Zemel Michael B.
King & Spalding
Knowles, Esq. Sherry M.
Marschel Ardin H.
Moran Marjorie A.
Zen Bio, Inc.
LandOfFree
Screening for SUR1 antagonists using adipocytes does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Screening for SUR1 antagonists using adipocytes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Screening for SUR1 antagonists using adipocytes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2530282