Glycoproteins Having Lipid Mobilizing Properties an Therapeutic Uses Thereof

a technology of glycoproteins and lipids, applied in the field of medical formulations and supplements, can solve the problems of diabetes mellitus being a major cause of morbidity and mortality, no widely accepted treatment for cachexia, and current therapies that appear to not work, so as to improve insulin responsiveness, prevent weight loss, and improve body weight and insulin responsiveness

Inactive Publication Date: 2013-06-06
ASTON UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The present invention is based in part on the finding that Zinc-α2-glycoprotein has an effect on body weight and insulin responsiveness in adult obese hyperglycemic (ob/ob) mice and mature Wistar rats, and that anti-ZAG antibodies

Problems solved by technology

Although about 30 to 40% claim to be trying to lose weight or maintain lost weight, current therapies appear not to be working.
While cachexia may be mediated by certain cytokines, especially tumor necrosis factor-α, IL-1b, and IL-6, which are produced by tumor cells and host cells in the tissue mass, there is currently no widely accepted treatment for cachexia.
Diabetes mellitus is a major cause of morbidity and mortality.
Chronically elevated blood glucose leads to debilitating complications: nephropathy, often necessitating dialysis or renal transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty liver disease, sometimes progressing to cirrhosis; and vulnerabili

Method used

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  • Glycoproteins Having Lipid Mobilizing Properties an Therapeutic Uses Thereof
  • Glycoproteins Having Lipid Mobilizing Properties an Therapeutic Uses Thereof
  • Glycoproteins Having Lipid Mobilizing Properties an Therapeutic Uses Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Zinc-α2-glycoprotein Attenuates Hyperglycemia

[0240]To evaluate the ability of Zinc-α2-glycoprotein (ZAG) to attenuate obesity and hyperglycemia ob / ob mice were administered ZAG which induced a loss of body weight, and a rise in body temperature, suggesting an increased energy expenditure. Expression of uncoupling proteins-1 and -3 in brown adipose tissue were increased, while there was a decrease in serum levels of glucose, triglycerides and non-esterified fatty acids, despite an increase in glycerol, indicative of increased lipolysis. There was a decrease in plasma insulin and an improved response to intravenous glucose together with an increased glucose uptake into adipocytes and skeletal muscle. Expression of hormone-sensitive lipase in epididymal adipocytes was increased. There was an increase in skeletal muscle mass due to an increase in protein synthesis and decrease in degradation. This suggests that ZAG may be effective in the treatment of hyperglycemia.

[0241]Dulbeccos' Modi...

example 2

Interval Administration of Zinc-α2-glycoprotein

[0271]It was observed that long-term daily administration of ZAG in ob / ob mice results in a cessation of weight loss. As such, it was determined that a break of 3-4 days followed by re-infusion ZAG resulted in continued weight loss and amelioration of the symptoms associated with hyperglycemia.

[0272]While not wanting to be limited by theory, it may be that the subjects are receiving too much ZAG or that there is receptor desensitization as is seen with TNF. A pilot study was performed with 2 mice in each group to determine optimal scheduling of ZAG delivery. An 8-10g weight loss from a 90g mouse was observed in about 3 weeks.

[0273]Adipocytes were removed from mice after 5 days of ZAG and their responsiveness to isoprenaline (iso) was measured after culture in the absence of ZAG (FIG. 9). The responsiveness to iso is higher in ZAG treated mice and this continues for a further 4 days (which was when expression of ZAG and HSL were increase...

example 3

Zinc-α2-glycoprotein Attenuates Muscle Atrophy in ob / ob Mouse

[0274]This example demonstrates the mechanism by which ZAG attenuates muscle atrophy in the ob / ob mouse using a newly developed in vitro model (Russell et al, Exp. Cell Res. 315, 16-25, 2009). This utilizes murine myotubes subjected to high concentrations of glucose (10 or 25 mM). As shown in FIG. 18 high glucose stimulates an increase in protein degradation (FIG. 18A), and depresses protein synthesis (FIG. 18B), and both of these effects were completely attenuated by ZAG (25 μg / ml). It was therefore determined if the effect of ZAG was mediated through a β3-AR using the antagonist SR59230A. However the SR compound (i.e., SR59230A) can also act as a β-agonist, which it seemed to do in these experiments. Thus protein degradation induced by both 10 and 25 mM glucose was attenuated by both ZAG and the SR compound, and the combination was additive rather than antagonistic (FIG. 19). For protein synthesis (FIG. 20) the SR compou...

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Abstract

The invention provides formulations and methods for ameliorating symptoms associated with metabolic disorders, such as cachexia, hypoglycemia, obesity, diabetes, and the like by administering Zn-α2-glycoproteins or a functional fragment thereof, alone or in combination with additional agents, such as β adrenergin receptor agonists, β adrenergin receptor antagonists, and/or glycemic control agents.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates generally to medicinal formulations and supplements, and more particularly, to formulations and methods for altering the metabolism of a subject, as well as ameliorating disorders such as cachexia, obesity, diabetes and insulin resistance.[0003]2. Background Information[0004]The prevalence of obesity in adults, children and adolescents has increased rapidly over the past 30 years in the United States and globally and continues to rise. Obesity is classically defined based on the percentage of body fat or, more recently, the body mass index (BMI), also called Quetlet index (National Task Force on the Prevention and Treatment of Obesity, Arch. Intern. Med., 160: 898-904 (2000); Khaodhiar, L. et al., Clin. Cornerstone, 2: 17-31 (1999)). The BMI is defined as the ratio of weight (kg) divided by height (in meters) squared.[0005]Overweight and obesity are associated with increasing the risk of de...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K31/138A61K45/06
CPCA23L1/305C07K14/473A61K9/0043A61K9/0053A61K31/137A61K38/17A61K38/1709A61K38/26A61K38/28A61K47/48215A61K47/4823A61K9/0014A61K45/06A61K38/1741A61K31/138A61K2300/00A23L33/17A61K47/60A61K47/61A61P11/00A61P13/12A61P19/02A61P21/00A61P21/04A61P3/00A61P3/04A61P31/04A61P31/18A61P35/00A61P3/06A61P43/00A61P5/50A61P7/00A61P9/04A61P3/10
Inventor TISDALE, MICHAEL J.RUSSELL, STEVEN
Owner ASTON UNIV
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