WO2011146892A2

WO2011146892A2 - Methods and compositions for treating disorders associated with impaired insulin production or secretion

Info

Publication number: WO2011146892A2
Application number: PCT/US2011/037440
Authority: WO
Inventors: Jonathan Kil; Eric D. Lynch; Paul R. Robertson
Original assignee: Sound Pharmaceuticals, Inc.; Pacific Northwest Diabetes Research Institute
Priority date: 2010-05-21
Filing date: 2011-05-20
Publication date: 2011-11-24
Also published as: WO2011146892A9

Abstract

Compositions and methods for the treatment and prevention of disorders associated with impaired insulin production or secretion including hyperglycemia and obesity are provided herein. Compositions and methods for promoting the production of insulin are also provided. The methods described herein include administering a therapeutically effective amount of an insulin-promoting composition including at least one seleno-organic compound.

Description

METHODS AND COMPOSITIONS FOR TREATING DISORDERS ASSOCIATED WITH IMPAIRED INSULIN PRODUCTION OR SECRETION

Technical Field

[0001] This disclosure relates to methods and compositions for promoting insulin secretion and treating disorders associated with impaired insulin secretion. In certain embodiments, this disclosure relates to methods and compositions for the treatment of inadequate insulin production or secretion, including conditions associated with the development and progression of diabetes, such as, for example pancreatic islet beta-cell dysfunction, impaired glucose tolerance, hyperglycemia, insulin resistance, and obesity.

Background

[0002] Genetic and acquired abnormalities that affect insulin sensitivity and insulin secretion may lead to the development of pathologies including insulin resistance, decreased insulin production or secretion, hyperglycemia, obesity, and diabetes. Diabetes is a group of disorders characterized by persistent variable hyperglycemia due to inadequate production or secretion of insulin by the body and/or an inadequate response to insulin by the body. The prevalence of diabetes in the United States is estimated to be around 8% of the population, with approximately 10% of those cases being Type I diabetes mellitus (also known as "juvenile-onset" diabetes or "insulin-dependent" diabetes) and approximately 90% of those cases being Type II diabetes mellitus (also known as "adult-onset" diabetes or "non-insulin dependent" diabetes). Type II diabetes is characterized, in part, by insulin resistance, impaired insulin secretion and abnormalities in the function of pancreatic islet beta-cells ("islet cells"). For example, Type II diabetes is characterized by a decline in islet cell function, insulin resistance, impaired glucose tolerance, and hyperglycemia. Diabetes associated hyperglycemia, can lead to chronic complications, such as retinopathy, peripheral neuropathies, kidney failure, and various vascular complications including cardiac disease. In the context of Type II diabetes, islet cells fail to produce and secrete sufficient amounts of insulin, and inadequate insulin secretion in response to glucose results in increasingly higher circulating blood glucose levels, which, in turn, results in further damage to islet cells and other organs, obesity, and worsening of the diabetic condition. Brief Description of the Drawings

[0003] Figure 1 shows EGFP expression in ARE10c1 cells after ebselen treatment.

[0004] Figure 2 is a histogram showing insulin expression in ARE10c1 cells after ebselen treatment.

[0005] Figure 3 shows the results of an oral glucose tolerance test in ZDF rats treated with different dosages of ebselen.

[0006] Figure 4 shows the areas under the curve for glucose levels in ZDF rats treated with different dosages of ebselen.

[0007] Figure 5 is a graph showing the blood glucose levels for ZDF rats treated with 128 mg/kg/day of ebselen.

[0008] Figure 6 is a graph showing the effect of ebselen treatment on insulin secretion in ZDF rats from 6 to 12 weeks of age.

[0009] Figure 7 shows the glucose stimulated insulin secretion levels from isolated islets taken from ZDF rats treated with 128 mg/kg/day of ebselen.

[0010] Figure 8 shows the body weight measurements for ebselen-treated and untreated ZDF rats.

Detailed Description

[0011] Compositions and methods for treatment and prevention of disorders associated with impaired insulin production and secretion are disclosed herein. More particularly, compositions and methods for promoting insulin production and secretion and treating disorders associated with hyperglycemia, pancreatic islet beta-cell dysfunction, impaired glucose tolerance, obesity, and insulin resistance are disclosed herein. Furthermore, compositions and methods for treating the development and progression of Type II diabetes are disclosed. The methods described herein include administering a therapeutically effective amount of a composition for promoting insulin secretion. As described herein, compositions for promoting insulin secretion suitable for use in methods according to the present description may include at least one seleno-organic compound. In one embodiment, a composition for promoting insulin secretion includes at least one seleno-organic composition that is a glutathione peroxidase mimetic. In specific embodiments, the seleno-organic compound may be selected from one or more of ebselen (2-phenyl- 1 ,2-benzisoseleazol-3 (2H)-one), di-ebselen, 6A,6B-diseleninic acid-6A',6B'- selenium bridged β-cyclodextrin (6-diSeCD), and 2,2'-diseleno-bis- -cyclodextrin (2- diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0012] The present inventors have found that seleno-organic compounds, such as ebselen, can be insulin-promoting compounds and can promote the expression and secretion of insulin, improve glucose tolerance, inhibit the development of hyperglycemia, and inhibit weight gain associated with onset and progression of Type II diabetes. In particular, the insulin-promoting compositions described herein, have been found to promote production of insulin in islet cells, inhibit development of hyperglycemia associated with development of Type II diabetes, improve glucose tolerance, and return or maintain blood glucose levels to within a normal range. In certain embodiments, insulin-promoting compositions as described herein are capable of returning blood glucose levels to within a normal range in a subject, even after the subject has developed hyperglycemia.

[0013] As used herein, "inhibit," "inhibiting," and "inhibition" mean to prevent, decrease, inactivate, or reverse an activity, response, condition, disease, or other biological parameter. "Inhibit," "inhibiting," and "inhibition" can include, but is not limited to the complete ablation of the activity, response, condition, or disease. "Inhibit," "inhibiting," and "inhibition" can also include, for example, a slowing or reduction of an activity, response, condition, disease, or other biological parameter as compared to a native level, with the term "native level" referring to a level evident in the absence of an inhibiting agent. "Inhibit," "inhibiting," and "inhibition" can also include, for example, reversal of an activity, response, condition, disease, or other biological parameter as compared to a native level, with the term "native level" referring to a level evident in the absence of an inhibiting agent. In this context, a reduction can be any measurable reduction. In particular embodiments, a reduction can be, for example, a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between the specifically recited percentages, as compared to a native level.

[0014] As used herein, "promote," "promotion," and "promoting" refer to preservation, restoration, or increase in an activity, response, condition, or other biological parameter. "Promote," "promotion," and "promoting" can include, but are not limited to, the initiation of an activity, response, condition, or biological parameter. Alternatively, "promote," "promotion," and "promoting" can include preservation of an activity, response, condition, or other biological parameter in light of a condition that would otherwise degrade, reduce or eliminate the relevant activity, response, condition, or other biological parameter. "Promote," "promotion," and "promoting" can also include, for example, an increase in the activity, response, condition, or biological parameter as compared to a native or control level. In particular embodiments, the increase in an activity, response, condition, or other biological parameter can be an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more, including any amount of increase in between the specifically recited percentages, as compared to native or control levels, with the term "native level" referring to a level evident in the absence of a promoting agent.

[0015] A "subject" refers to an animal in which an insulin-promoting composition as described herein will have a therapeutic effect. In one embodiment, the subject is a human being.

[0016] A "therapeutically effective amount" is the amount of compound which achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease of disorder.

[0017] An insulin-promoting composition as described herein includes at least one seleno-organic compound. In one embodiment, an insulin-promoting composition as disclosed herein may include a seleno-organic compound that is a glutathione peroxidase mimetic. In particular embodiments, the seleno-organic compound may be selected from one or more of ebselen, di-ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD), and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. The insulin-promoting compositions described herein may provide sufficient amounts of a seleno-organic compound to facilitate delivery of therapeutically effective amounts of the insulin-promoting composition. In one embodiment, an insulin-promoting composition may comprise a formulation wherein the one or more seleno-organic compounds included in the composition account for between about 5 wt% about 95 wt% of the composition. In one such embodiment, for example, the seleno-organic compound included in the insulin-promoting composition may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the composition may include a formulation comprising approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 wt% ebselen.

[0018] In particular embodiments, the insulin-promoting compositions described herein may be provided as a pharmaceutical composition, wherein the one or more seleno-organic compounds are combined within one or more of a pharmaceutically acceptable carrier, excipient, diluent, or other compounds that facilitate administration of the insulin-promoting compositions to a subject. Pharmaceutically acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Maack Publishing Co. (A.R. Gennaro (Ed.) 1985). Administration of insulin-promoting compositions described herein is accomplished by any effective route, e.g., orally or parenterally. Methods of parenteral delivery include, for example, intra-arterial, subcutaneous, intramedullary, intravenous, intramuscular, intrasternal, intracavernous, intrathecal, intrameatal, intraurethral injection or infusion techniques, as well as intranasal, sublingual, buccal, rectal, and vaginal administration.

[0019] Insulin-promoting compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art, in dosages suitable for oral administration. Such carriers enable the insulin-promoting compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a subject. Insulin-promoting compositions for oral administration can be obtained, for example, through combination of one or more seleno-organic compounds with a solid excipient through, for instance, known granulation processes for providing compositions suitable for tableting or for inclusion in a capsule. In other embodiments, insulin- promoting compositions for oral administration as described herein can be obtained, through combination of one or more seleno-organic compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Examples of excipients suitable for formulating insulin-promoting compositions for oral administration include carbohydrate or protein fillers. Such excipients include, but are not limited to: sugars, including lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0020] Where pharmaceutical formulations of the insulin-promoting compositions described herein are formulated using dragee cores, such cores may be provided with suitable coatings, such as concentrated sugar solutions, which may also contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0021] In further embodiments, insulin-promoting compositions suited for oral administration can be formulated, for example, as push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain one or more seleno-organic compounds mixed with, for example, filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the one or more seleno-organic compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. In certain embodiments, an insulin-promoting composition as described herein can be formulated, for example, as a 100-1200 mg capsules. For example, an insulin-promoting composition as described herein can be formulated as a 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000,1 100, and 1200 mg capsule.

[0022] Where the insulin-promoting compositions are provided as pharmaceutical compositions or dosage forms for oral administration, such compositions may optionally include one or more pharmaceutically acceptable sweetening agents, preservatives, dyestuffs, flavorings, or any combination thereof. When the composition is in the form of a solid, unit dosage form, such as a tablet, the compositions may include a core formulation covered in one or more of a protective, functional or cosmetic coating, as is well known in the art. Moreover, in particular embodiments, dyestuffs or pigments may be added to a dosage form for oral administration or a coating included in or provided over such dosage form for purposes of product identification or to characterize the quantity of active compound (i.e., dosage).

[0023] In specific embodiments, insulin-promoting compositions for parenteral administration include aqueous solutions of one or more one or more seleno-organic compounds, such as, for example, a glutathione peroxidase mimetic. For injection, the insulin-promoting compositions described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, where an insulin-promoting composition is formulated as a suspension, the composition may also contain suitable stabilizers or agents, which increase the solubility of one or more seleno- organic compounds to allow for the preparation of highly concentrated formulations.

[0024] Where an insulin-promoting composition as described herein is prepared for topical or nasal administration, penetrants appropriate to the particular barrier to be permeated may be incorporated in the composition in order to achieve a desired flux of one or more seleno-organic compounds. Such penetrants are generally known in the art.

[0025] Insulin-promoting compositions according to the present description may be manufactured according to techniques known in the art (e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes). In particular embodiments, the insulin-promoting compositions described herein may also be modified to provide appropriate release characteristics, e.g., sustained release or targeted release, by conventional means (e.g., through the use of a functional coating and/or known matrices or materials providing sustained or targeted release of active agents). After the insulin-promoting compositions described herein have been prepared, they can be placed in an appropriate container and labeled for use.

[0026] The methods provided herein include methods for treating disorders associated with impaired insulin secretion, hyperglycemia, pancreatic islet beta-cell dysfunction, impaired glucose tolerance, and insulin resistance. In particular embodiments, the methods described herein include treating conditions associated with the development and progression of Type II diabetes. For example, in some embodiments, the methods described herein include methods for promoting insulin secretion. In one such embodiment, the method includes promoting insulin secretion from islet cells exhibiting impaired insulin secretion. In other embodiments, methods for inhibiting development of hyperglycemia are provided. In certain such embodiments, the methods described herein include methods for returning blood glucose levels in a subject suffering from hyperglycemia to within a normal range. In still other embodiments, methods for promoting glucose tolerance are described. In each of the embodiments of the methods described herein, a therapeutically effective amount of an insulin-promoting composition as described herein is administered.

[0027] The amount of insulin-promoting composition actually administered in a given method will be dependent upon the individual to which treatment is to be applied, the nature of the condition to be treated, and the amount of seleno-organic compound material included in the composition. The amount of insulin-promoting composition administered may be an optimized amount, such that a desired therapeutic effect is achieved without an unacceptable level of side-effects. With the benefit of the teachings provided herein, determination of a therapeutically effective dose is well within the capability of those skilled in the art. Of course, the skilled person will realize that divided and partial doses are also within the scope of the methods described herein.

[0028] Moreover, for the insulin-promoting compositions described herein, in some embodiments, a therapeutically effective dose may be estimated initially by either using cell culture assays or an appropriate animal model (e.g., an animal model involving primates, rats, guinea pigs, dogs, or other laboratory animals). Even further, one or more animal models may be used to inform the concentration of seleno-organic compound material to be included in the insulin-promoting compositions described herein, and one or more animal models may be used to determine a desired route of administration. Such information can then be used to determine useful doses and routes for administration in a desired subject.

[0029] Therapeutic efficacy and possible toxicity of insulin-promoting compositions described herein can be determined by standard pharmaceutical procedures, in cell cultures or experimental animals (e.g., ED₅₀, the dose therapeutically effective in 50% of the population; and LD₅o, the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio ED₅₀ /LD₅₀. Insulin-promoting compositions which exhibit large therapeutic indices may be selected for administration to subjects. Data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in an intended subject or class of subjects (e.g., humans). In particular embodiments, the amount of an insulin-promoting composition administered to a subject provides a dose of the one or more seleno-organic compounds that results in a circulating concentration that lies within a range of circulating concentrations that include the ED₅₀, while exhibiting little or no toxicity. The dosage of a given seleno-organic compound may vary within this range, depending, for example, upon the dosage form employed, sensitivity of the subject, and the route of administration selected.

[0030] In specific embodiments of the methods described herein, an insulin- promoting composition as described herein is administered to a subject in need thereof in an amount sufficient to deliver a dose of one or more seleno-organic compounds selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of one of or more seleno-organic compounds selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0031] In another embodiment, the methods described herein may include administering an insulin-promoting composition to a subject in need thereof in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration of the seleno-organic compound ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ. In certain embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of at least one seleno-organic compound sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. [0032] In each of the embodiments of the methods described herein, the seleno- organic compound included in the insulin-promoting composition administered to a subject may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In alternative embodiments of the methods described herein, the insulin-promoting compositions administered to a subject may include at least one glutathione peroxidase mimetic selected from di-ebselen, 6A,6B-diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- - cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0033] Methods for treating disorders associated with impaired insulin production in a subject are provided. In one embodiment, the method includes administering a therapeutically effective amount of an insulin-promoting composition to the subject. In the methods for treating disorders associated with impaired insulin production described herein, the seleno-organic compound included in the insulin-promoting composition administered to the subject may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In one embodiment, where ebselen is selected as the seleno-organic compound, the insulin-promoting composition may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0034] In one embodiment of a method for treating disorders associated with impaired insulin production, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of the one or more seleno-organic compounds that achieves a blood plasma concentration of the seleno-organic compound selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid-6A',6B'-selenium bridged β- cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno-organic compound included in the insulin- promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6- diSeCD); and 2,2'-diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0035] Methods for promoting insulin secretion are also provided. The methods for promoting secretion of insulin in islet cells described herein include administering a therapeutically effective amount of an insulin-promoting composition such that production of insulin in islet cells is increased. In certain embodiments of such a method, insulin production in islet cells is increased by about 25-500%. In particular embodiments of the methods for promoting production of insulin in islet cells as described herein, the seleno-organic compound included in the insulin-promoting composition administered may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In particular embodiments where ebselen is selected as the seleno-organic compound, ebselen may be included in the insulin-promoting composition in a concentration as described herein. In specific embodiments where ebselen is selected as the seleno-organic compound, the insulin-promoting composition may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other embodiments where ebselen is selected as the seleno-organic compound, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day. [0036] In one embodiment of a method for promoting insulin secretion, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin- promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid- 6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- - cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0037] In further embodiments, methods for treating hyperglycemia are provided. The methods for treating hyperglycemia described herein include administering a therapeutically effective amount of an insulin-promoting composition such that development or progression of hyperglycemia is inhibited. In certain embodiments of methods for treating hyperglycemia described herein, the seleno-organic compound included in the insulin-promoting composition administered may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In particular embodiments where ebselen is selected as the seleno-organic compound, ebselen may be included in the insulin-promoting composition in a concentration as described herein. In specific embodiments, where ebselen is selected as the seleno-organic compound, the insulin-promoting composition may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0038] In one embodiment of a method for treating hyperglycemia, the insulin- promoting composition is administered to the subject in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin- promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid- 6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- - cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0039] In specific embodiments of the methods of treating hyperglycemia described herein, the insulin-promoting composition is administered to the subject at a dose and frequency that results in maintaining blood glucose levels in the subject at levels within 10% of normal physiological levels. In certain such embodiments, the seleno-organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject according to a dosage described herein. In one such embodiment, where ebselen is included as the seleno-organic compound included in an insulin-promoting composition administered in a method for maintaining blood glucose levels in the subject at levels within 10% of normal physiological levels, the insulin-promoting composition may be administered in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. Alternatively, where ebselen is included as the seleno-organic compound included in an insulin-promoting composition administered in a method for maintaining blood glucose levels in the subject at levels within 10% of normal physiological levels, the insulin-promoting composition may be administered in an amount sufficient to achieve a blood plasma concentration of ebselen selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ.

[0040] In further embodiments of the methods of treating hyperglycemia described herein, the insulin-promoting composition is administered to the subject at a dose and frequency that results in a blood glucose level in the subject ranging from about 100 mg/dl to about 200 mg/dl. In certain such embodiments, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject according to the dosage described herein. In one such embodiment, where ebselen is included as the seleno-organic compound included in an insulin-promoting composition administered in a method for providing a blood glucose level in the subject ranging from about 100 mg/dl to about 200 mg/dl, the insulin-promoting composition may be administered in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. Alternatively, where ebselen is included as the seleno-organic compound included in an insulin- promoting composition administered in a method for providing a blood glucose level in the subject ranging from about 100 mg/dl to about 200 mg/dl, the insulin- promoting composition may be administered in an amount sufficient to achieve a blood plasma concentration of ebselen selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ.

[0041] Methods for promoting glucose tolerance in a subject are also provided. As used herein, the term "glucose tolerance" refers to a subject's ability to clear glucose from the blood and maintain a normal blood glucose level. In one embodiment, a subject's glucose tolerance is determined by an oral glucose tolerance test (OGTT), which assesses the subject's ability to metabolize glucose. For example, in an OGTT, a subject first fasts at least 8 hours but not more than 16 hours. A fasting blood glucose level is then taken, following which the subject receives an orally delivered glucose challenge, which comprises 75 grams of glucose. After receiving the glucose challenge, the blood glucose levels of the subject are tested every 30 to 60 minutes for up to 3 hours after receiving the challenge dose. In a subject with normal glucose tolerance, the blood glucose levels will rise and then fall quickly. In a subject with impaired glucose tolerance, glucose levels rise higher than normal and fail to come back down as fast. More particularly, in a normal subject, fasting blood glucose levels range from about 60 -100 mg/dL, and the blood glucose levels after a 75-gram oral glucose tolerance test are as follows: at 1 hour post administration, blood glucose levels are less than about 200 mg/dL; and at 2 hours post administration, blood glucose levels are less than about 140 mg/dL. After administration of the glucose challenge, a subject exhibiting blood glucose levels of between about 140-200 mg/dL is considered to have impaired glucose tolerance, and blood glucose levels greater than about 200 mg/dL after administration of the glucose challenge is a sign of diabetes.

[0042] The methods for promoting glucose tolerance described herein include administering a therapeutically effective amount of an insulin-promoting composition to a subject exhibiting impaired glucose tolerance. In one embodiment, the insulin- promoting composition is administered to the subject at a dose and frequency that improves the glucose tolerance in the subject such that, upon administration of a glucose challenge as described herein, the subject's blood glucose levels are less than about 200 mg/dL at 1 hour post administration and less than about 140 mg/dL at 2 hours post administration. In another embodiment, the insulin-promoting composition is administered to the subject at a dose and frequency that improves the glucose tolerance in the subject such that, upon administration of a glucose challenge as described herein, the subject's blood glucose levels do not exceed about 200 mg/dL.

[0043] In the methods for promoting glucose tolerance as described herein, the seleno-organic compound included in the insulin-promoting composition administered to the subject may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In particular embodiments where ebselen is selected as the seleno-organic compound, ebselen may be included in the insulin-promoting composition in a concentration as described herein. In specific embodiments where ebselen is selected as the seleno-organic compound, the insulin-promoting composition and may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0044] In one embodiment of a method for promoting glucose tolerance, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin- promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid- 6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- - cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0045] Methods for treating Type II diabetes in a subject are provided. In one embodiment, the method includes administering a therapeutically effective amount of an insulin-promoting composition to the subject. In the methods for treating Type II diabetes described herein, the seleno-organic compound included in the insulin- promoting composition administered to the subject may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In one embodiment, where ebselen is selected as the seleno-organic compound, the insulin-promoting composition may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0046] In one embodiment of a method for treating Type II diabetes, the insulin- promoting composition is administered to the subject in an amount sufficient to deliver a dose of the one or more seleno-organic compounds that achieves a blood plasma concentration of the seleno-organic compound selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin- promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid- 6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- - cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno- organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0047] Methods for inhibiting weight gain associated with hyperglycemia and diabetes are also described herein. The methods for inhibiting weight gain associated with hyperglycemia and diabetes described herein include administering a therapeutically effective amount of an insulin-promoting composition to a subject with hyperglycemia or diabetes. In one embodiment, the insulin-promoting composition is administered to the subject at a dose and frequency that reduces the weight gain in a subject normally associated with hyperglycemia and diabetes.

[0048] In the methods for inhibiting weight gain associated with hyperglycemia and diabetes as described herein, the seleno-organic compound included in the insulin-promoting composition administered to the subject may be ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In particular embodiments where ebselen is selected as the seleno-organic compound, ebselen may be included in the insulin-promoting composition in a concentration as described herein. In specific embodiments where ebselen is selected as the seleno- organic compound, the insulin-promoting composition and may be administered to the subject in a manner that provides a dose of ebselen selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day. In other such embodiments, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of ebselen selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg per day.

[0049] In one embodiment of a method for inhibiting weight gain associated with hyperglycemia and diabetes, the insulin-promoting composition is administered to the subject in an amount sufficient to deliver a dose of one or more seleno-organic compounds that achieves a blood plasma concentration selected from concentrations ranging from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ of the seleno-organic compound. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid-6A',6B'-selenium bridged β- cyclodextrin (6-diSeCD); and 2,2'-diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another such embodiment, the seleno-organic compound included in the insulin- promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In another embodiment, the seleno-organic compound included in the insulin-promoting composition is at least one of ebselen, di-ebselen, 6A,6B-diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6- diSeCD); and 2,2'-diseleno-bis- -cyclodextrin (2-diSeCD), including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the insulin-promoting composition is administered to the subject in an amount sufficient to achieve a blood plasma concentration of the seleno-organic compound selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 μΜ. In one such embodiment, the seleno-organic compound included in the insulin-promoting composition is ebselen, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

[0050] In certain embodiments of the methods described herein, the insulin- promoting composition administered to the subject may include one or more known anti-hyperglycemic agents in addition to the one or more seleno-organic compounds. In such embodiments, for example, the insulin-promoting composition may include one or more seleno-organic compounds in combination with one or more anti- hyperglycemic agents selected from, for example, insulin, sulfonylurea, a thiazolidinedione (TZI)), metformin, glucagon-like peptide 1 (GLP-1 ) and/or a dipeptidyl peptidase-4 (DPPIV) inhibitor. In alternative embodiments, the methods described herein may include administering an insulin-promoting composition including one or more seleno-organic compounds, as described herein, in combination with second composition including a known anti-hyperglycemic agent. Again suitable anti-hyperglycemic agents for use in such an embodiment may be selected from, for example, those described above. Where the methods described herein include administration of an insulin-promoting composition in combination with a second composition including a known anti-hyperglycemic agent, the two compositions may be administered substantially simultaneously or sequentially. The known anti-hyperglycemic agent may be administered in dosages currently employed in the art. [0051] All publications referred to in this specification, are incorporated herein by reference, in their entirety.

Examples

Example 1— Insulin Expression in Rat Cells after Ebselen Treatment

[0052] Insulin gene expression was measured in vitro in the rat cell line ARE10c1 . The ARE10c1 cell line were derived from clones of NuTu-19 rat ovarian cancer cell line with a stably integrated Green Fluorescent Protein (GFP) expression vector regulated by a thymidine kinase promoter under the control of 4 antioxidant response elements (AREs). This cell line was evaluated by quantitative RT-PCR using a TaqMan® assay for expression of GFP by the known ARE inducing agent tert-butyl hydroquinone (tBHQ) and found to be responsive to tBHQ. Cell line ARE10c1 was also evaluated for expression of insulin by quantitative RT-PCR using a TaqMan® assay. This cell line, ARE10c1 , allows for the determination of transcriptional induction by putative ARE stimulating conditions or drugs. Analysis of insulin expression by quantitative RT-PCR using a TaqMan® assay was also performed in the RIN-0146-38 cell line as a positive control for insulin expression. Cell line RIN- 0146-38 is an insulinoma cell line known to express high levels of insulin in culture. Cell line RIN-0146-38 does not express GFP and was used as a negative control for GFP expression analysis.

[0053] As shown in FIG. 1 , treatment with ebselen causes expression of the GFP reporter construct by ARE activation. Treatment with 200 uM of the positive control compound tBHQ also caused expression of the GFP mRNA, while the negative control cell line RIN1046-38 did not express GFP.

[0054] As shown in FIG. 2, ARE10c1 cells treated with 50 uM ebselen have insulin mRNA levels more than 600% of the insulin mRNA levels present in cells not treated with ebselen. ARE10c1 cells treated with 35 uM, 20 uM, and 10 uM ebselen have insulin mRNA levels of approximately 300%, 300%, and 200%, respectfully, of the insulin mRNA levels present in cells not treated with ebselen.

Example 2-Glucose Tolerance in Ebselen Treated Rats

[0055] Administration of ebselen in an animal model of Type II diabetes improved glucose tolerance. Zucker diabetic fatty (ZDF) rats were tested using an oral glucose tolerance test. At 6 weeks of age the ZDF rats were divided into six experimental groups (n=6-12 per group) and treated with ebselen (8 mg/kg, 32 mg/kg, or 128 mg/kg per day by oral gavage), negative control, or DMSO (vehicle).

[0056] Results of the glucose tolerance test are shown in FIGs. 3-4. From 6-12 weeks of age, the untreated and DMSO-treated ZDF rats showed a drastic decrease in glucose tolerance. However, the 12-week old ZDF rats treated with 128 mg/kg per day of ebselen showed a much better glucose tolerance with plasma glucose levels almost as low as that of the ZDF rats at 6 weeks of age. The ZDF rats treated with 32 mg/kg and 8 mg/kg per day of ebselen showed better glucose tolerance than the untreated and DMSO-treated rats. As shown in FIG. 4, the area under the curve (AUC) for glucose of the untreated 12-week old ZDF rats is substantially increased over the untreated 6-week old ZDF rats. Conversely, the ZDF rats treated with 128 mg/kg of ebselen per day have an AUC for glucose only slightly higher than the untreated 6-week old rats. The ZDF rats treated with 32 mg/kg and 8 mg/kg of ebselen per day also showed better glucose tolerance than the untreated 12-week old rats.

Example 3— Blood Glucose Levels in Ebselen Treated ZDF Rats

[0057] Blood glucose levels were measured in 6-12 week old ZDF rats that were treated daily with 128 mg/kg of ebselen. At 6 weeks of age the ZDF rats were divided into four experimental groups (n=9-10 per group): ebselen fasted, ebselen fed (both treated with 128 mg/kg of ebselen per day by oral gavage), and control fasted and control fed (not treated with ebselen). Each week, for the next six weeks, plasma glucose levels were measured in each group.

[0058] As shown in FIG. 5, the ebselen fed ZDF rat treatment group had glucose levels consistently lower than the control fed rats showing an improved glucose tolerance over the control group. Furthermore, after weeks 1 1 and 12 the ebselen fasted rats showed a better glucose tolerance than the control fasted group.

Example 4— Insulin Levels in Ebselen Treated ZDF Rats

[0059] The effect of ebselen treatment on blood insulin levels in 6-12 week old ZDF rats was measured. Beginning at 6 weeks of age, ZDF rats were given 128 mg/kg of ebselen daily by oral gavage. Each week, for the next six weeks, blood insulin levels were measured in the untreated and treated ZDF rats. [0060] As shown in FIG. 6, beginning with week 9, the ebselen fed ZDF rat treatment group had blood insulin levels higher than those of the untreated ZDF rats.

Example 5— Glucose-Stimulated Insulin Secretion in Ebselen Treated ZDF Rats

[0061] Insulin secretion from islet cells isolated from ZDF rats previously treated with ebselen was compared to insulin secretion from islet cells isolated from ZDF rats that had received no ebselen. As seen in FIG. 7, islets isolated from 12-week- old ZDF rats were exposed to increasing concentrations of glucose. The results show that a 6-week ebselen treatment with 128 mg/kg/day substantially increased the insulin expression nearly 3-fold when compared to isolated islets from ZDF rats not treated with ebselen.

Example 6— Effects of Ebselen Treatment on ZDF Rat Body Weight

[0062] The effects of ebselen treatment on the body weights of ZDF rats between 6 and 12 weeks old were measured. At 6 weeks of age the ZDF rats were divided into four experimental groups (n=9-10 per group): ebselen fasted, ebselen fed (both treated with 128 mg/kg of ebselen per day by oral gavage), and control fasted and control fed (not treated with ebselen). As shown in FIG. 8 and Table 1 , the ebselen treated ZDF rats had mean body weights significantly lower than the control rats (p=0.0319). Therefore, treatment with ebselen appears to limit an increase in body weight associated with the progression of hyperglycemia and diabetes.

Table 1 .

^*p=0.0319, showing significantly lower mean body weight in ebselen treated rats.

Example 7— Ebselen Toxicology Study in Rats

[0063] The toxicokinetic parameters of ebselen were studied in female and male Strague-Dawley rats. The rats were administered a single oral ebselen dose of 100 mg/kg, 500 mg/kg, or 2000 mg/kg. Table 2 shows the results of the study.

Table 2.

RTiast (hr) 3.5 4.1 6.3 5.8 8.6 10.6

[0064] From this study, the micromolar blood plasma concentration of ebselen was calculated. The following calculation was used: 1 ug/mL ebselen in plasma = (1 ug/mL)x(1000mL/L)x(1 umol/274ug) = 3.65uM ebselen in plasma. With reference to Table 1 , for the 100mg/kg dose group: 0.8 ug/mL in plasma of female rats = 2.92uM ebselen. For the 500mg/kg dose group: 1 .7 ug/mL in plasma of female rats = 6.21 uM ebselen. For the 2000mg/kg dose group: 4.2ug/ml_ in plasma of female rats = 15.33 uM ebselen.

[0065] It will be obvious to those having skill in the art that many changes may be made to the details of the above-described embodiments without departing from the underlying principles of the invention. The scope of the present invention should, therefore, be determined only by the following claims.

Claims

1 . A method for treating impaired insulin production in a subject, the method comprising:

administering a therapeutically effective amount of an insulin-promoting composition to a subject, the insulin-promoting composition comprising at least one seleno-organic compound and at least one of a pharmaceutically acceptable carrier, excipient, and diluent.

2. The method of claim 1 , wherein administering a therapeutically effective amount of an insulin-promoting composition comprises administering a

therapeutically effective amount of an insulin-promoting composition comprising a glutathione peroxidase mimetic.

3. The method of claim 1 , wherein administering a therapeutically effective amount of an insulin-promoting composition comprises administering a

therapeutically effective amount of an insulin-promoting composition comprising a glutathione peroxidase mimetic selected from one or more of ebselen, 6A,6B- diseleninic acid-6A',6B'-selenium bridged β-cyclodextrin (6-diSeCD), and 2,2'- diseleno-bis- -cyclodextrin (2-diSeCD), including pharmaceutically acceptable salts, esters, isomers or solvates thereof.

4. The method of claim 1 , wherein administering a therapeutically effective amount of the insulin-promoting composition comprises administering a

therapeutically effective amount of an insulin-promoting composition comprising ebselen, including pharmaceutically acceptable salts, esters, isomers or solvates thereof.

5. The method of any preceding claim, wherein administering a therapeutically effective amount of the insulin-promoting composition comprises administering the insulin-promoting composition to the subject in a manner that results in

administration of a dose of the at least one seleno-organic compound selected from about 5 to about 500 mg/kg/day, about 25 to about 300 mg/kg/day, and about 25 to about 150 mg/kg/day.

6. The method of any preceding claim, wherein administering a therapeutically effective amount of the insulin-promoting composition comprises administering the insulin-promoting composition to the subject in a manner that results in

administration of a dose of the at least one seleno-organic compound selected from about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, and 500 mg/kg/day.

7. The method of any preceding claim, wherein administering a therapeutically effective amount of the insulin-promoting composition comprises administering the insulin-promoting composition to the subject in a manner that results in

administration of the at least one seleno-organic compound in an amount sufficient to achieve a blood plasma concentration selected from about 0.5 to about 100 μΜ, about 5 to about 75 μΜ, and about 10 to about 50 μΜ.

8. The method of any preceding claim, wherein administering a therapeutically effective amount of the insulin-promoting composition comprises administering the insulin-promoting composition to the subject in a manner that results in

administration of the at least one seleno-organic compound in an amount sufficient to achieve a blood plasma concentration selected from about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 uM.

9. The method of any preceding claim, wherein treating impaired insulin production in a subject comprises treating Type II diabetes in a subject.

10. The method of claim 9, wherein treating Type II diabetes in a subject comprises promoting insulin secretion in the subject.

1 1 . The method of any preceding claim, wherein the method comprises identifying a subject suffering from impaired insulin secretion and administering a therapeutically effective amount of the insulin-promoting composition comprises administering the insulin-promoting composition to the subject such that the subject experiences an increase in insulin production.

12. The method according to any of claims 1 -8, wherein treating impaired insulin production in the subject comprises inhibiting hyperglycemia in the subject.

13. The method of claim 12, wherein the method comprises identifying a subject suffering from hyperglycemia and administering a therapeutically effective amount of the insulin-promoting composition.

14. The method of claim 12 and claim 13, wherein the insulin-promoting composition is administered such that the blood glucose levels in the subject are returned to a level within 10% of a normal physiological level.

15. The method of any of claims 12-14, wherein the insulin-promoting

composition is administered such that the blood glucose levels in the subject are maintained at a level within 10% of a normal physiological level

16. The method of any of claims 12-15, wherein the insulin-promoting

composition is administered such that a blood glucose level in the subject ranging from about 100 mg/dl to about 200 mg/dl is achieved.

17. The method according to any of claims 1 -16, wherein treating impaired insulin production comprises promoting glucose tolerance in the subject.

18. The method of any preceding claim, wherein treating impaired insulin production in a subject comprises inhibiting weight gain in a subject.