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Lipids That Increase Insulin Sensitivity And Methods Of Using The Same

Inactive Publication Date: 2015-05-14
BETH ISRAEL DEACONESS MEDICAL CENT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides methods for monitoring and treating metabolic disorders such as obesity, type 2 diabetes, and cardiovascular disease by measuring the levels of specific lipids in biological samples. These lipids, called fatty acyl fatty hydroxy acids (FAHFAs), are upregulated in mice with a specific genetic mutation and are associated with insulin resistance and dendritic cell activation. The invention also provides methods for using FAHFAs to decrease inflammation and increase insulin secretion and sensitivity in cells and mammals. The FAHFAs can be detected using various methods such as MS / MS or immunoassay.

Problems solved by technology

The prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan.
Complications from obesity and type-2 diabetes include vascular disease, which detracts from quality of life further and increases mortality.

Method used

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  • Lipids That Increase Insulin Sensitivity And Methods Of Using The Same
  • Lipids That Increase Insulin Sensitivity And Methods Of Using The Same
  • Lipids That Increase Insulin Sensitivity And Methods Of Using The Same

Examples

Experimental program
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Effect test

example 1

Identification of a Novel Class of Fatty Acid Conjugates by Metabolomics

[0149]As described herein, a novel class of lipid metabolites has been identified through the application of metabolomics to the analysis of adipose tissue from transgenic mice that overexpress the insulin-responsive glucose transporter, GLUT4, in adipose tissue but not in muscle [1-3]. Glucose disposal was enhanced in isolated adipocytes from transgenic mice versus wild-type controls. This led to altered gene expression, including genes involved in lipid metabolism, and whole-body insulin sensitivity was improved despite the fact that GLUT4 overexpression was localized to adipose tissue. Furthermore, adipose GLUT4 overexpression can reverse the insulin resistance and diabetes in mice lacking GLUT4 in muscle [3]. These data suggested that a circulating factor, perhaps a lipid, may exert anti-diabetic effects on peripheral tissues in these mice.

[0150]Given the elevated expression of genes involved in lipid metabo...

example 2

FAHFAs in White Adipose Tissue (WAT)

[0169]From a previous study, it was found that there is a strong correlation between adipose-ChREBP expression and insulin sensitivity in humans (FIG. 20). Because enhanced lipogenesis in WAT of mice with adipose-selective overexpression of Glut4 was found to be critical for the enhanced insulin sensitivity in this model [24-25], and because Glut4 is markedly down-regulated in WAT in obese and insulin resistant humans [1], the determinates of which lipids were being synthesized in response to increased adipose-Glut4 expression was carried out by an untargeted lipidomics analysis. Many classes of lipids were altered in WAT of adipose-Glut4 overexpressing mice but one class stood out as very highly upregulated (FIG. 3, cluster in upper right). Using Mass Spectrometry, it was determined that this is a novel class of lipids that has not been described before in mammalian tissues. Structural studies revealed that they were fatty acyl hydroxy fatty acid...

example 3

PAHSA Levels in Serum from Insulin-Resistant Human Subjects

[0172]Since the FAHFAs were first found to be elevated in diabetes-resistant mouse model (AG4OX mice), it was important to determine whether FAHFA levels correlated with insulin sensitivity in a well-defined cohort of human subjects. Samples of human serum were obtained from a cohort of twenty-four Swedish volunteers at the Lundberg Laboratory for Diabetes Research. Eight of these volunteers were lean and insulin-sensitive, eight were lean but insulin-resistant, and eight were obese and insulin-resistant (FIG. 25). Subjects with a body mass index (BMI), calculated as their total mass in kilograms divided by the square of their height in meters, below 25 kg / m2 were considered to be lean, and subjects with a BMI above 30 kg / m2 were considered to be obese. The volunteers had fasted for 12 hours, after which their blood serum was sampled. In order to divide the cohort into insulin-sensitive and insulin-resistant groups, subjects...

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Abstract

The invention provides, inter alia, fatty acyl hydroxy fatty acid (FAHFA; a novel class of estolide-related molecules) and diagnostic and treatment methods for a variety of disorders—including diabetes-related disorders, Metabolic Syndrome, polycyctic ovarian syndrome, cancer, and inflammatory disorders using them; as well as methods of screening for additional compounds that are useful in treating these disorders and / or that modulate FAHFA levels, FAHFA-mediated signaling, and FAHFA-mediated biological effects.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 642,176, filed on May 3, 2012 and U.S. Provisional Application No. 61 / 792,505, filed Mar. 15, 2013. The entire teachings of the above applications are incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with government support under P30DK57521, P30DK046200 and R37DK43051 from the National Institutes of Health. The government has certain rights in the invention.BACKGROUND[0003]The prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the Glut4-glucose transporter and alterations in adipose-Glut4 expression or function regulate systemic insulin sensitivity. Downregulation of adipose tissue-Glut4 occurs early in diabetes development. Complications from obesity and type-2 diabete...

Claims

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Application Information

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IPC IPC(8): C07C69/22G01N33/543C07D495/04
CPCC07C69/22G01N2500/04G01N33/54306C07D495/04G01N33/92C07C69/24C07C69/533C07C69/58
Inventor KAHN, BARBARA B.HERMAN, MARK A.SAGHATELIAN, ALANHOMAN, EDWIN
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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