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Rbp4 in insulin sensitivity/resistance, diabetes, and obesity

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Rbp4 in insulin sensitivity/resistance, diabetes, and obesity


Methods for screening molecules that modulate the activity of Retinol Binding Protein 4 (RBP4) and their use in treatment of insulin resistance are described. Also described are methods of diagnosing insulin resistance and related conditions by detecting modulation of RBP4 activity.
Related Terms: G Protein Insulin Insulin Resistance Obesity Retinol Diabetes Modulate Modulation

Browse recent Beth Israel Deaconess Medical Center, Inc. patents - Boston, MA, US
USPTO Applicaton #: #20140044737 - Class: 4241721 (USPTO) -
Drug, Bio-affecting And Body Treating Compositions > Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material >Binds Eukaryotic Cell Or Component Thereof Or Substance Produced By Said Eukaryotic Cell (e.g., Honey, Etc.)

Inventors: Barbara B. Kahn, Qin Yang, Tim Graham, Odile Peroni

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The Patent Description & Claims data below is from USPTO Patent Application 20140044737, Rbp4 in insulin sensitivity/resistance, diabetes, and obesity.

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RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 13/477,790 filed May 22, 2012, which is a continuation of U.S. application Ser. No. 12/455,324, filed Jun. 1, 2009, now U.S. Pat. No. 8,231,862, which is a divisional of U.S. application Ser. No. 11/009,409, filed Dec. 10, 2004, now U.S. Pat. No. 7,553,631, which claims the benefit of U.S. Provisional Application No. 60/528,919, filed Dec. 11, 2003. The entire teachings of the above applications are incorporated herein by reference.

GOVERNMENT SUPPORT

The invention was supported, in whole or in part, by a grant RO1DK43051 from the National Institutes of Health. The Government has certain rights in the invention.

INCORPORATION BY REFERENCE OF MATERIAL IN ASCII TEXT FILE

This application incorporates by reference the Sequence Listing contained in the following ASCII text file being submitted concurrently herewith: a) File name: 14402039011SEQUENCELISTING.txt; created Oct. 24, 2013, 1 KB in size.

BACKGROUND OF THE INVENTION

Insulin resistance in the peripheral tissues such as muscle and fat is associated with increased secretion of insulin by pancreatic β-cells. The secreted insulin promotes glucose utilization and inhibits production of glucose by the liver. However, the pancreatic β-cells often cannot sustain the increased production of insulin resulting in the eventual decrease of insulin production and glucose intolerance.

Insulin resistance is characterized, for example, by increased glucose concentration in the blood, increased insulin concentration in the blood, decreased ability to metabolize glucose in response to insulin, or a combination of any of the above. Insulin resistance is thought to predict possible later development of diabetic disease, such as Type 2 Diabetes. However, even in the absence of diabetes, insulin resistance is a major risk factor for cardiovascular disease (Despres, et al., N. Engl. J. Med 334:952-957 (1996)). The loss of insulin production in insulin resistance and diabetes results in increased blood glucose or hyperglycemia. Hyperglycemia in turn can contribute to long term illness such as nephropathy, neuropathy, and retinopathy.

Insulin resistance is also associated with abnormalities in glucose and lipid metabolism, obesity, kidney disease, high blood pressure and increased risk for cardiovascular disease. The association of insulin resistance with these other abnormalities is referred to as “Insulin Resistance Syndrome” or “Metabolic Syndrome” or “Syndrome X”. In particular, Metabolic Syndrome has been characterized as the co-occurrence of obesity (especially central obesity), dyslipidemia (especially high levels of triglycerides and low levels of high density lipoprotein cholesterol), hyperglycemia and hypertension. People with Metabolic Syndrome are at increased risk for diabetes or cardiovascular disease relative to people without the syndrome (Meigs, J. B., BMJ: 327, 61-62, (2003)).

Decreased expression of the insulin responsive glucose transporter, GLUT4, is seen in adipocytes in nearly all insulin resistant states in humans and rodents (Shepherd, P. R. and Cohn, B. B., N Engl. J. Med. 341:248-257 (1999)). However, the mechanism by which decreased expression of GLUT4 contributes to systemic insulin resistance has not been clear because adipose tissue contributes very little to total body glucose disposal.

Due to the association of insulin resistance with later development of diabetes and cardiovascular disease, and the prevalence of insulin resistance worldwide, the need exists for additional metabolic or endocrine targets for the development of treatments that alleviate or mitigate diseases associated with insulin resistance. A need also exists for additional detection/diagnostic methods of insulin resistance, Metabolic Syndrome and Type II diabetes to allow for the earliest possible intervention through life-style changes and/or medication.

SUMMARY

OF THE INVENTION

The present invention provides important new targets and screening methods for the detection and/or identification of molecules or agents that can be used for the development of treatments that alleviate or mitigate symptoms and diseases associated with insulin resistance, Metabolic Syndrome, and Type 2 diabetes. As shown herein for the first time, elevation of serum of Retinol Binding Protein 4 (RBP4) causes insulin resistance and impaired glucose tolerance, whereas lowering of serum RBP4 improves insulin action and glucose tolerance. The results in several mouse models of insulin resistance are confirmed by human data. Furthermore, treatment of ob/ob mice with a retinamide that disrupts the interaction between RBP4 and transthyretin thereby leading to a lowering of plasma RPB4 levels, and a reduction in long-term morbidity. It appears that RBP4 may be a mechanistic link by which down regulation of GLUT4 expression in adipocytes causes systemic insulin resistance.

As described herein, RBP4 can be used as an early marker for insulin resistance and related conditions such as Metabolic Syndrome, because an increased level of RBP4 is correlated with insulin resistance in humans and mice, even in the absence of, or before the occurrence of, conditions related to insulin resistance such as diabetes and/or obesity. In addition, RBP4 is a novel target to develop treatments that reduce insulin resistance. Furthermore, reduction of RBP4 activity in individuals with insulin resistance is a novel therapy for treatment of insulin resistance and related conditions.

The present invention relates to methods for identifying compounds that modulate RBP4 activity. The methods comprise contacting RBP4 with a test compound and comparing the level of RBP4 activity in the presence of the test compound to the level of RBP4 activity in the absence of the test compound to determine modulation of RBP4 activity, wherein an alteration of RBP4 activity is indicative of a compound that modulates RBP4 activity.

The present invention also relates to methods of identifying compounds that reduce circulating levels of RBP4 in a mammal. Such methods include in vitro and in vivo methods. In one embodiment, the method comprises the steps of administering a test compound to the mammal, obtaining a sample (such as a urine sample or blood sample) from the mammal, and comparing the level of RBP4 in the sample after administration of the test compound to the level of RBP4 in a control sample prior to administration of the test compound, wherein an increase in RBP4 in the urine sample or decrease in the blood sample after administration of the test compound as compared to the control sample is indicative of a compound that reduces in circulating levels of RBP4.

The present invention also relates to methods of reducing insulin resistance in a mammal. The method comprises administering to a mammal a compound that reduces the activity of RBP4.

The present invention also relates to methods of diagnosing insulin resistance or a related condition in a mammal. The methods comprise measuring RBP4 activity in a biological sample obtained from the mammal, wherein an increase in RBP4 activity is indicative of insulin resistance or related condition.

Using RBP4 as a marker for insulin resistance or related conditions is advantageous because it does not require fasting or any special preparation by the patient, RBP4 is a stable compound under routine collection conditions, and RBP4 can be detected in a blood drop from a skin prick, or in urine.

In addition, using RBP4 as a marker for insulin resistance or related conditions may be useful in many at risk populations including obese and non-obese relatives of individuals with Type 2 diabetes patients with other criteria for the metabolic syndrome such as hypertension and in or hyperlipidemia and polycystic ovarian syndrome. RBP4 levels may also be useful to distinguish between Type 1 and Type 2 diabetes in newly diagnosed patients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of the aP2-Cre transgene construct.

FIG. 2 shows representative northern blots demonstrating that CRE expression is limited to brown and white adipose tissue (BAT and WAT, respectively) in two independent lines of transgenic mice.

FIG. 3 shows representative immunoblots of GLUT4 in perigonadal (PG) and subcutaneous (SQ), WAT and BAT, gastrocnemius skeletal muscle and heart of wildtype (WT) and GLUT 4 adipose knockout mice (AG4KO) from both aP2-Cre transgenic lines.

FIG. 4A is a growth curve in grams versus age (weeks) showing that AG4KO mice (dark circles) have normal growth compared to WT mice (light circles).

FIG. 4B is a bar graph showing the gonadal fat pad weight in mg/mouse in control (left bar) and AG4KO mice (right bar).

FIG. 4C is a bar graph comparing adipocyte size in μg lipid/cell in control (left bar) in AG4KO mice (right bar).

FIG. 5A is an immunoblot showing GLUT4 content from WT, Lox/Lox, and AG4KO mice.

FIG. 5B is a bar graph showing basal and insulin-stimulated glucose uptake in isolated muscle of AG4KO mice (N=5) in WT mice (N=5).

FIG. 6A shows a dose response curve for insulin-stimulated glucose uptake in isolated adipocytes from AG4KO mice (closed circles) and control mice (open circles).

FIG. 6B shows clearance of blood glucose (glucose tolerance test, GTT) (1 mg/kg) after injection of 1 mg glucose per kg body weight (i.p.) in AG4KO mice (filled circles) and WT controls (open circles).

FIG. 7A shows insulin-stimulated whole body glucose uptake in control (left bar) and AG4KO mice (right bar).

FIG. 7B shows hepatic glucose production in the presence or absence of insulin in control (left bars) and AG4KO mice (right bars).

FIG. 8A shows insulin-stimulated 2-deoxyglucose transport in vivo in white adipose tissue (WAT) from control (left bar) and AG4KO mice (right bar).

FIG. 8B shows insulin-stimulated 2-deoxyglucose transport in vivo in brown adipose tissue (BAT) from control (left bar) and AG4KO mice (right bar).

FIG. 8C shows insulin-stimulated 2-deoxyglucose transport in vivo in muscle from control (left bar) and AG4KO mice (right bar).

FIG. 9 shows immunoblots of insulin-stimulated phosphorylation of the insulin receptor (top panel) or Insulin Receptor Substitute-1 (IRS1) (bottom panel) from control (left column set) and AG4KO mice (right column set).

FIG. 10 shows insulin-stimulated 2-deoxyglucose uptake in 3T3-L1 adipocytes in the presence increasing concentrations of either serum from control mice (left group) or serum from AG4KO mice (right group).

FIG. 11 shows a schematic of the microarray analysis of white adipose tissue (WAT) RNA.

FIG. 12 shows RBP4 mRNA level determined by rt-PCR derived from WAT from wild type mice (open squares) and from AG4KO mice (closed squares); the lines indicate the average value for each group.

FIG. 13 shows RBP4 mRNA expression level in G4AKO (mice (left middle bar) Cre mice (left bar), control mice (right middle bar) and GLUT4 over expressing mice (right bar).

FIG. 14 shows RBP4 mRNA expression level in the liver of control (left bar) and AG4KO mice (right bar).



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stats Patent Info
Application #
US 20140044737 A1
Publish Date
02/13/2014
Document #
File Date
09/02/2014
USPTO Class
Other USPTO Classes
International Class
/
Drawings
0


G Protein
Insulin
Insulin Resistance
Obesity
Retinol
Diabetes
Modulate
Modulation


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