WO2019186297A1 - Methods for treating high blood glucose - Google Patents

Abstract

A method for treating high blood sugar disorders such as diabetes and metabolic syndrome in a patient in need of such treatment or diagnosed with high blood sugar through the administration of an effective amount of lutropin receptor antagonist, human chorionic gonadotropin (hCG) antagonist or luteinizing hormone (LH) antagonist to the patient, optionally in combination with an additional bioactive agent that is effective in ameliorating the symptoms of the disorder.

Description

Methods for Treating High Blood Glucose

This application claims benefits of U.S. Provisional Application 62/650,000, filed on March 29, 2018.

FIELD OF THE INVENTION

The present invention relates generally to the field of treating high blood sugar or obesity disorders. More specifically, the present invention is a method for treating high blood glucose in patients with diabetes mellitus and metabolic syndrome.

BACKGROUND OF THE INVENTION

Hyperglycemia, also known as high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma (See“hyperglycemia” in Wikipedia). This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/L (-250-300 mg/dL). A subject with a consistent range between -5.6 and -7 mmol/L (100-126 mg/dL) (according to American Diabetes Association guidelines) is considered slightly hyperglycemia, while above 7 mmol/L (126 mg/dL) is generally held to have diabetes mellitus.

Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels (> 126 mg/dL or 7 mmol/L) over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger.

There are three main types of diabetes mellitus:

1. Type 1 DM results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". Type 1 DM is treated with insulin. 2. Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as "non-insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The development of Type 2 DM is strongly linked to overweightness or obesity. Type 2 DM is usually treated with oral medication with and without the addition of insulin therapy.

3. Gestational Diabetes is the third main form of diabetes and occurs when

women (without pre-existing diabetes) develop high blood sugar levels during pregnancy.

Classes of Medication Used for Treatment of Type 2 DM:

• Glucagon-like peptide- 1 (GLP-l) receptor agonists: slow digestion and prevent conversion of carbohydrates (such as starch and table sugar) into simple sugars to limit their absorption through the intestine;

• Biguanides: suppress excessive hepatic glucose production, improve the sensitivity of body tissues to insulin and increase glucose utilization in peripheral tissues;

• Sulfonylureas: stimulate the pancreas to secrete more insulin;

• Meglitinides: stimulate the pancreas to secrete more insulin;

• Thiazolidinediones: improve the sensitivity of body tissues to insulin;

• Dipeptidyl peptidase-4 (DPP-4) inhibitors: block DPP-4, an enzyme which destroys the hormone incretin;

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors: preventing the kidneys from reabsorbing sugar into the blood so that increased glucose is secreted in the urine;

• Sympatholytic D2-dopamine agonists are approved for Type 2 DM, though the mode of action is not known. They may prevent insulin resistance;

• Glucagon-like peptides (incretin mimetics): increase B-cell growth, insulin and glucagon utilization, decrease appetite and slow gastric emptying.

Metabolic syndrome is a clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low levels of HDL (high-density-lipoproteins). Metabolic syndrome is associated with the risk of developing Type 2 DM and cardiovascular disease.

The following references are related to the use of human chorionic gonadotropin (hCG) antagonist, luteinizing hormone (LH) antagonist, or hCG/LH lutropin receptor antagonist to treat various diseases. For example, the patents (Movsas, CA 2954893 Al; Movsas, US20170136093 Al) teach a method for treating diabetic retinopathy, an ocular complication of diabetes, by administering human chorionic gonadotropin (hCG) antagonist, luteinizing hormone (LH) antagonist or lutropin receptor antagonist to treat retinal neovascularization. However, diabetic retinopathy is well known to be secondary to elevated levels of vascular endothelial growth factor (VEGF) arising from ischemic retina (and not directly from high glucose), the reference does not teach a method of treating high blood sugar. Another reference (Mckenna et al., WO 2007/047829A2) teaches methods for making hybrid protein antagonist which includes linkage to a stable molecule such hCG. The reference mentions that (a) interferon alpha may be involved in the pathogenesis of diabetes and that (b) VEGF is involved in tumor growth. Though the reference mentions the hybrid proteins have antagonist activity of VEGF or IFN-alpha in treating various diseases such as cancer and insulin-dependent diabetes, it does not teach these hybrid proteins are hCG/LH antagonists in treating high blood sugar. The reference (Lustbader, US20080039372A1) teaches how to make an hCG/LH receptor antagonists and suggests that they may be useful for hCG producing tumors. It does not teach the use of these antagonists to lower blood sugar. The patent (Groendahl, US6297243B1) teaches the use of hCG/LH receptor antagonists for preventing hot flashes, not for glucose control. The reference (Cole, US20070020274A1) teaches the use of inhibitors of H-hCG or beta-H-hCG for preventing pregnancy, not related to glucose control. The reference (Cole, US20050260196A1) teaches use of inhibitors of H-hCG or beta-H-hCG for preventing cancer, not for glucose control. The reference (Moyle,

US20090209453A1) teaches the use of glycoprotein hormone analogs as agonists, antagonists, targeting vectors and immunogens, it does not teach the use of these antagonists for glucose control. The reference (Prasad and Soman, WO2013102921A4) teaches the method of utilizing hCG (not hCG antagonists) for treating diabetes. This is opposite to what the instant invention teaches, which is a good example of how the instant invention (the use of hCG antagonists to lower blood sugar) is non-obvious. The present invention is a method for treating high blood sugar disorders such as diabetes and metabolic syndrome through the administration of an effective amount of lutropin receptor antagonist, hCG antagonist or LH antagonist. It is proposed that this treatment blocks LH/hCG-induced VEGF synthesis by intestinal epithelial cells, thus, limiting intestinal epithelial cell proliferation and intestinal endothelial cell recruitment; and that the treatment also blocks LH/hCG induced glucose transport through intestinal glucose transporters (such as Glut 1). Thus, with less intestinal absorption of glucose, blood sugar and glycated hemoglobin (also known as HgbAlC, HbAlC or A1C) levels will decrease. In addition, since less glucose is absorbed into the body, obesity can also be treated by this method.

Terminology:

For the purposes of promoting an understanding of the principles of the invention, reference will be made to preferred embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alteration and further modifications of the invention and such further applications of the principles of the invention as illustrated herein, being contemplated as would normally occur to one skilled in the art in which the invention is related.

The following terms shall be used to describe the preferred embodiments for this invention. In the absence of a specific definition set forth herein, the terms used to describe the present invention shall be given their common meaning as understood by those of ordinary skill in the art.

Human chorionic gonadotropin (hCG) and luteinizing hormone (FH) share the same receptor in the body and we shall refer to this receptor as the lutropin receptor. The term“hCG” will refer to any isoform of naturally-occurring or synthetic human chorionic gonadotropin and the term“FH” will refer to any isoform of naturally occurring or synthetic luteinizing hormone. In this patent, when we refer to hCG/FH antagonists, we define hCG/EH antagonist as an“lutropin receptor antagonist’, as“hCG antagonist’ or as “LH antagonist”. These terms are used interchangeably and are intended to include appropriate effective derivatives or fragments of the named compounds, including for example physiologically acceptable cations or anions.

The term“high blood sugar” as used herein refers to the level of blood sugar higher than 126 mg/dL or 7 mmol/L in a patient.

The term“hCG/LH antagonist” as used herein refers to a disabling moiety which binds either to the hCG or LH hormone or to the lutropin receptor thereof.

The term“active ingredient” refers to the hCG/LH antagonist.

The term“bioactive agent” refers to an agent that is effective in reducing high blood sugar or ameliorating the symptoms of high blood sugar disorder. For example, the medication to treat type 2 DM.

As used herein, the term“obesity” shall refer to any overweight condition of a subject defined by a body mass index (BMI) considered above normal for a patient’s age and gender.

As used herein, the term“metabolic syndrome” will include the condition of “prediabetes”.

As used herein, the term“diabetes” will include all types of diabetes such as but not limited to: Type 1 Diabetes mellitus, Type 2 Diabetes mellitus, and Gestational Diabetes.

As used herein, the term“pharmaceutically acceptable carrier”,“diluent” “additive” or“excipient” means a chemical composition with which the active ingredient either alone or in combination, can be used to administer the appropriate compound(s) to a patient or subject in therapeutic methods according to the preferred embodiments of the present invention.

As used herein, the term“physiologically acceptable” ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.

As used herein, an“oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. The term“patient” or“subject” is used throughout the specification to describe an animal, generally a human, in need of such treatment or diagnosed with high blood sugar, in which the hCG/LH antagonist is administered to affect an intended result in that patient or subject. The age of the patient may range from neonate through adult. In the case of a female patient, the patient may be pregnant or non-pregnant.

The term“effective amount” is used throughout the specification to describe an amount of the present composition (hCG/LH antagonist) which is used to affect an intended result when used in the methods of the preferred embodiments. In numerous aspects of the present invention, the term effective amount is used in conjunction with the treatment of a patient.

As used herein,“pharmaceutically acceptable additives” include, but are not limited to, one or more of the following: surface active agent; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents;

sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents;

demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; nanoparticles; and pharmaceutically acceptable polymeric or hydrophobic materials. Other“additives” may be included in the pharmaceutical compositions of the invention which are known in the art.

As used herein, the term“a or an” means more than one.

DESCRIPTION OF THE DRAWINGS

Figures 1A and 1B describe the theory of LH receptor (LHR) over-signaling in the pathogenesis of diabetes mellitus.

Figure 2 shows FHR signaling impacts glucose regulation by comparing HgbAlC in FHR knockouts (KO) to wildtype (WT) siblings.

Figure 3 shows over-stimulation of the FH/hCG receptor in the intestine increases glucose uptake. DETAIL DESCRIPTIONS OF THE INVENTION

All illustrations of the drawings are for the purpose of describing selected versions of the present invention and are not intended to limit the scope of the present invention.

The present invention is a method for treating high blood glucose in diabetes mellitus and metabolic syndrome. The method can also be used to treat obesity. The treatment involves the administration of an effective amount of lutropin (LH/hCG) receptor antagonist, human chorionic gonadotropin (hCG) antagonist or luteinizing hormone (LH) antagonist, optionally in combination with at least one additional bioactive agent in reducing high blood glucose.

The methods of the preferred embodiment may be used to treat a patient either diagnosed with or at risk for diabetes, metabolic syndrome or obesity. The method of treatment involves the administration of an effective amount of LH/hCG antagonist (lutropin receptor antagonist, hCG antagonist or LH antagonist), optionally in combination with at least one additional bioactive agent. The active ingredient will be repeatedly administered at an interval of time that is determined to be necessary to maintain the active ingredient at a therapeutic blood level.

Theoretical Discussion

Some relevant background information is described as follows. Dr. Bernardo Alberto Houssay was awarded the Nobel Prize for his discovery that pituitary extract regulates blood glucose in 1947. In later years, pituitary-derived growth hormone was partially credited for Houssay’s observations (Holly et ah, 1988). However, despite 75 years of research since Houssay’s experiments, the pituitary hormones primarily responsible for glucose regulation have remained unidentified. For reasons described below, the inventor proposes that (a) luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are the two hormones that largely account for the Houssay discovery and (b) by utilizing therapeutics to antagonize these gonadotropins, diabetes can be more effectively managed. Pituitary-derived hCG and LH are present in all adults (men and non-pregnant women) (Choi and Smitz, 2014), The classical targets of LH and hCG in women are the ovary and uterus. Levels of these gonadotropins significantly increase after menopause. During pregnancy, additional placental-derived hCG is found in maternal blood. Both LH and hCG activate the same receptor, here on in referred to as the LH receptor (LHR) (Cole, 2010). A key function of these hormones in the gonadal organs is the regulation of vascular endothelial growth factor (VEGF). VEGF is the major regulator of angiogenesis in the body. The role of these hormones in promoting VEGF expression in non-gonadal organs has not been well explored. In recent years, LHRs have been found in many non- gonadal organs (intestine, kidney, eye) (Cole, 2010). The inventor has been the first to report that LHR signaling participates in VEGF regulation during eye development (Movsas et ah, 2018a). That said, the potential role of these gonadotropins in most non- gonadal organs is unknown. A key component of the inventor’s current theory is that LH and hCG participate in VEGF regulation in the intestine. Important to this theory is the fact that LHRs are abundantly expressed in the intestine (Sand et ah, 2013).

Inventor’s gonadotropin-glucose theory:

It is well established that intestinal endothelial cells“talk” with enterocytes to promote the efficient absorption of glucose from the intestinal lumen into the blood (Pappenheimer and Michel, 2003). It is also well known that intestinal VEGF regulates intestinal endothelial cell proliferation and mucin production (Kamba et ah, 2006). The inventor proposes that overactivation of intestinal LHRs results in high levels of intestinal VEGF and that this plays a role in diabetic pathogenesis, especially when LH and hCG levels are significantly elevated ( pregnancy , menopause, polycystic ovarian syndrome ).

• The inventor proposes that LH and hCG (both of which bind to the same receptor) regulates physiologic VEGF production in the intestine. In turn, (LH-induced) VEGF exerts its known effects on the intestinal endothelium and mucin production (See Fig. 1A).

• The inventor proposes that LHR over-signaling elevates intestinal VEGF, which in turn hyper-vascularizes the intestine and over-thickens the mucus layer. It is further proposed that these LHR-induced effects promote over- absorption of glucose by the intestine, leading to hyperglycemia (high HgbAlc) (See Fig. IB).

The instant invention is the use of hCG/LH antagonists to decreases glucose uptake then to decrease blood sugar.

Innovation:

( a ) Pioneering hypothesis that VEGF expression in the intestine is under gonadotropin control.

The inventor’s proposal that VEGF expression in the intestine is controlled by LH receptor signaling. In recent decades, LH receptors have been identified in many non- gonadal organs. However, because the only overt abnormality in LHR knockouts (LHRKOs) is hypoplastic gonads (Lei et ah, 2001), no role was attributed to LHRs outside of the gonadal system. To counter this, the inventor set out to investigate whether LHR signaling may regulate VEGF in non-gonadal organs. After all, LH and hCG are both known to upregulate VEGF in gonadal tissue; thus, the inventor reasoned that a similar process may occur in non-gonadal tissues, despite the lack of obvious anomalies in non-gonadal LHRKO organs. The inventor has been the first to show that LH regulates VEGF levels in the eye (Movsas, 2018a, 2018b). Now the inventor proposes that antagonizing intestinal LHRs with LH/hCG antagonists, VEGF levels in the intestine will be reduced as well.

(b) Innovative hypothesis that LHR antagonism reduces intestinal vascularization, which in turn decreases slucose absorption from the intestinal lumen into the bloodstream.

The correlation between high ocular VEGF and increased retinal vascularization is well established; in fact, retinal neovascularization is the hallmark of proliferative diabetic retinopathy. However, the presence of a similar correlation between high intestinal VEGF and increased intestinal vascularization has never before been suggested. The inventor proposes that a similar process to what happens in the eye also happens in the intestine. In other words, the inventor proposes that elevated intestinal VEGF leads to a proliferative enteropathy. It is further proposed that as the intestine hyper-vascularizes, the glucose-absorbing capabilities of the villi increase. Villus capillaries are specialized nutrient-absorbing structures. The capillaries of human villus tips weigh only a few grams, yet they absorb >400 grams of sugar each day (Pappenheimer and Michel, 2003). Thus, even a small increase in intestinal vascular density may enhance the absorptive capacity of the capillaries to the point of overwhelming the insulin response and thus potentially leading to diabetic status. The instant invention involves slowing the rate of glucose absorption with LH/hCG antagonists to mitigate hyperglycemia.

Examples: To show that hCG/LH signaling plays an important role in glucose control.

Example 1: It is aimed to show that LHR signaling impacts glucose regulation by comparing HgbAlc in LHR knockouts to wildtype (WT) siblings.

At 21 days of age, blood was collected from 12 male WTs and 12 age- and gender-matched homozygous LHR knockout (KO) mice ( Lhrko [B6;l29Xl- Lhcgr^tmlZmle 7J]. HgbAlc (also known as glycated hemoglobin, A1C, or HbAlC) levels were assessed by a commercially-available murine HgbAlc ELISA. HgbAlc levels were -25% lower in in the KOs than the WTs (Fig. 2). Thus, the elimination of LHRs in neonatal mice chronically lowered glucose levels (reflected by lower HgbAlc), supporting the inventor’s hypothesis that LH/hCG receptor signaling participates in the physiological regulation of glucose.

Example 2: It is aimed to show that over-stimulation of the LH/hCG receptor in the intestine increases glucose uptake.

The MatTek Epi-intestinal model is a metabolically active 3D tissue model derived from human intestinal cells. These cells were cultured for 24 hours were then treated with either Vehicle (0.1% BSA in PBS) or hCG (5 IU/ml) (added to the culture medium) for 24 hours. [Of note, hCG is an LH analogue. Both hCG and LH bind to the hCG/LH receptor.] The cells were treated with 100 m M fluorescent-labelled glucose (2- NBDG) for 60 min. Then the cells were washed, fixed and mounted with Prolong gold overnight. The cells were then imaged with a Nikon Al Spectral Confocal Microscope. We found 6-fold more glucose uptake in the intestinal cells treated with hCG compared to untreated controls (Fig. 3). This supports inventor’s theory that increased LHR activation in the intestine increases glucose absorption.

It has already been established that crosstalk between epithelial and endothelial cells in the intestinal villus microcirculation plays a critical role in the intestinal absorption of glucose (Pappenheimer and Michel, 2003). Vascular endothelial growth factor (VEGF) plays an important role in this regard. VEGF has potent effects in intestinal mucosa, inducing a thickened, hypercellular mucosa with recruitment of endothelial cells and myofibroblasts and augmented proliferation of the epithelium (Boquoi et ah, 2009). VEGF receptors are present on vascular endothelial cells, where they contribute to endothelial cell survival, proliferation, mechanical properties, and migration (Olsson et ah, 2006). However, it has NOT been previously taught that activation of the lutropin receptor (by LH or hCG) in the intestine plays a role in VEGF stimulation in the intestinal circulation, which in turns leads to enhanced coupling of epithelial and endothelial glucose transport.

The present invention proposes that the activation of the lutropin receptor by its ligands (LH or hCG) stimulates intestinal epithelial cells to produce VEGF. The present invention teaches a novel method to decrease epithelial cell proliferation and endothelial cell recruitment by blocking LH/hCG induced VEGF synthesis in the intestinal epithelium. Over time, this treatment will lead to less vascular density of the intestine compared to untreated diabetic intestine. Less vascular density combined with less epithelial cell proliferation will limit intestinal absorption of glucose, and thus lower blood sugar and glycated hemoglobin (also known as HgbAlC, HbAlC, A1C), and limit weight gain.

Exemplary hCG/LH Antagonists Exemplary hCG/LH antagonists include small molecule antagonists, large molecule antagonists and macromolecule (very large) antagonists. Small molecule antagonists are molecules having molecular weight (MW) of less than 900 Daltons (See “Small molecule” in Wikipedia). Macromolecule antagonists are molecules with molecular weights more than 150 kDa, such as antibody antagonists (Movsas, 2017). We will define large molecules as molecules with MWs greater than small molecules but less than macromolecules (i.e. large molecule antagonists have MWs >900 daltons but less than or equal tol50 kDa). Small molecule antagonists are preferred. An example of a small molecule lutropin receptor antagonist is a substituted terphenyl compounds (Heitman et ah, 2009).

A different example of a lutropin receptor antagonist is a de-glycosylated hCG, a mutant hCG or an hCG molecule which is both de-glycosylated and mutant. A de- glycosylated hCG refers to hCG which has a reduced number of carbohydrates relative to naturally occurring hCG. In one embodiment, the de-glycosylated hCG comprises less N-linked carbohydrates than naturally occurring hCG (Movsas, 2017; Lustbader, 2008).

Lutropin receptor antagonists that have already been developed can be utilized for treatment. However, our invention of the method to utilize lutropin receptor antagonists, hCG antagonists or LH antagonists for high blood sugar does not restrict use to antagonists already developed. A high molecular weight antagonist for the lutropin receptor comprised of two fused beta subunits of hCG is described in the publication entitled: Translational fusion of two beta-subunits of human chorionic gonadotropin results in production of a novel antagonist of the hormone (Roy et ah, 2007).

The present invention’s preferred hCG/LH antagonist would be a low molecular weight antagonist of the lutropin receptor. Substituted terphenyl compounds are described as a class of low molecular weight allosteric inhibitors of the lutropin receptors and the materials and methods for their syntheses are described previously (Heitman et ah, 2009). The present invention’s preferred lutropin receptor antagonist is referred to as compound #24 in the publication referenced above.

Other hCG/LH antagonists that could be used are antibodies (either monoclonal or polyclonal) or antibody fragments that are directed against LH, against hCG and/or against the LH/hCG receptor. The methodology, technology and skills required for production of such antibodies are readily available. LH antibodies, LH antibodies and LH/hCG receptor antibodies are commercially available.

Exemplary Pharmaceutical Compositions

The pharmaceutical compositions to be administered in the preferred

embodiments include hCG/LH antagonists in an effective amount either alone, or in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, diluents, additives, excipients and/or one of more additional ingredients or some combination of these. Pharmaceutical compositions according to the preferred embodiments may be formulated and administered to deliver a dose of between 1 picogram/kg/day and 1 g/kg/day of hCG/LH antagonist or variant thereof to the patient or subject in need of therapy or otherwise described herein.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients and then, if necessary or desirable, shaping or packaging the product into a desired single or multi dose unit.

A pharmaceutical composition of the invention may be prepared, packaged or sold in bulk, as a single unit dose or as a plurality of single unit does. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise less than 0.001% to 100% (w/w) active ingredient. Controlled- or sustained-release formulation of a pharmaceutical composition of the invention may be made using conventional technology.

Pharmaceutical compositions that are useful in the methods of the preferred embodiments may be administered, prepared, packaged and/or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic (topical, intraocular, intravitreal, subconjunctival), suppository, aerosol or another route of administration. The route of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and severity of the disease being treated, the type and age of patient being treated and the like.

Formulation for oral administration is the preferred embodiment. A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged or sold in the form of a discrete solid dose unit including but not limited to a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution or an emulsion. Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

Other possible formulations such as nanoparticle, liposomes, immunologically based systems may also be used to administer, for example, peptides, fragments, or derivatives and/or a nucleic acid encoding the same according to the methods of the invention.

The compound (with active ingredient) can be administered to a subject as frequently as several times daily or it may be administered less frequently such as once a day, once a week, only with meals, once every two weeks, once a month or even less frequently such as once every several months or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors such as, but not limited to, the type and severity of the disease being treated, route of administration and age and body weight of the subject.

Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats and dogs.

It will be recognized by one of the skill in the art that the various embodiments of the invention as described above relating to specific methods of preventing or treating the disease state and/or condition or its symptoms may relate within context to the treatment or resolution of signs or symptomatology not specifically mentioned herein or may involve different circumstances of symptomatology.

Although the invention has been explained in relation to its preferred

embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention.

REFERENCES

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Holly JM, Amiel SA, Sandhu RR, Rees LH, Wass JA. The role of growth hormone in diabetes mellitus. J Endocrinol. 1988; 118(3):353-364.

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Claims

CLAIMS What is claimed is:

1. A method for treating a high blood sugar disorder comprising administering to a patient diagnosed with high blood sugar an effective amount of a lutropin receptor antagonist, a human chorionic gonadotropin (hCG) antagonist or luteinizing hormone (LH) antagonist to reduce the level of blood sugar, optionally in combination with an additional bioactive agent that is effective in ameliorating the symptoms of the disorder.

2. The method of claim 1 , wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is a hCG analog composed of two fused beta subunits of hCG.

3. The method of claim 1, wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is a substituted terphenyl compound.

4. The method of claim 1 , wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is an antibody or antibody fragment that is directed against hCG, LH or lutropin receptor.

5. The method of claim 1, wherein the high blood sugar disorder is diabetes or

metabolic syndrome.

6. The method of claim 5, wherein the diabetes is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus and gestational diabetes.

7. The method of claim 5, wherein the metabolic syndrome is selected from the medical conditions consisting of prediabetes, obesity, high blood pressure, high blood sugar, high serum triglycerides and low levels of high-density-lipoproteins (HDL).

8. The method of claim 1, wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is administered with an additional bioactive agent.

9. The method of claim 8, wherein the additional bioactive agent is a medication for type 2 diabetes mellitus.

10. The method of claim 1, wherein the lutropin receptor antagonist, the hCG antagonist or LH antagonist is a de-glycosylated hCG.

11. The method of claim 1 , wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is a small molecule.

12. The method of claim 1, wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is administered as an active ingredient of a pharmaceutical composition.

13. The method of claim 12, wherein the pharmaceutical composition comprises less than 0.001% to 100% active ingredient.

14. The method of claim 12, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, dilutes, additives or excipients.

15. The method of claim 12, wherein the pharmaceutical composition is administered to deliver a dose of between 1 picogram/kg/day and 1 g/kg/day of active ingredient to the patient.

16. The method of claim 12, wherein the pharmaceutical composition is prepared in formulation suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, aerosol or another route of administration.

17. The method of claim 12, wherein the pharmaceutical composition is prepared as an oral formulation of a tablet, a hard or soft capsule, a powdered or granular formulation, an aqueous or oily suspension, oily solution or an emulsion.

18. The method of claim 12, wherein the pharmaceutical composition is prepared in a formulation of nanoparticle, liposome or immunologically based system.

19. The method of claim 12, wherein the pharmaceutical composition is prepared as a controlled- or sustained-release formulation.

20. The method of claim 1 , wherein the lutropin receptor antagonist, the hCG

antagonist or LH antagonist is repeatedly administered at an interval of time that is determined to be necessary to maintain the active ingredient at a therapeutic blood level.