NL2022291B1

NL2022291B1 - Compound for Use in Treatment and Prevention of Type I Diabetes

Info

Publication number: NL2022291B1
Application number: NL2022291A
Authority: NL
Inventors: F Nijhoff Michiel; J P De Koning Eelco
Original assignee: Academisch Ziekenhuis Leiden
Priority date: 2018-12-21
Filing date: 2018-12-21
Publication date: 2020-07-21

Abstract

14 @ The present invention relates to diazoxide or a pharmaceutically acceptable salt thereof for use as a medicament in combination with an immunosuppressive 5 compound and/or an anti-inflammatory compound, particularly a corticosteroid, in a treatment of a mammal afflicted with Type I diabetes.

Description

Compound for Use in Treatment and Prevention of Type | Diabetes The present invention relates to diazoxide or a pharmaceutically acceptable salt thereof for use as a medicament at low doses to treat type | diabetes and to compositions containing diazoxide for use in the treatment of a mammal afflicted with, or at risk of developing type | diabetes.

BACKGROUND OF THE INVENTION Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic disorders in which a mammal’s blood contains high levels of sugar, also referred to as hyperglycemia, over a prolonged period.

Diabetes is due to a mammal’s pancreas not producing enough insulin or the mammal’s somatic cells not responding properly to the insulin produced by the mammal.

There are three main types of diabetes mellitus: Type | results from the failure of the mammal’s pancreas to produce enough insulin due to loss of beta cells.

Type 2 begins with insulin resistance, a condition in which the mammal’s cells fail to respond to insulin properly; as the disease progresses, a lack of insulin can also develop.

Gestational diabetes occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.

US5284845B describes the use of diazoxide for the treatment of disorders caused by defects in glucose metabolism, including hyperglycemia and hypoglycemia and to delay or prevent onset of insulin dependency in Type ll diabetic subjects.

EP2422787 describes the use of diazoxide for hypoglycaemia, as well as amyotrophic lateral sclerosis (ALS) and hypertension. In this regard, the principal use of diazoxide in diabetes therapy currently is for the treatment of hyperinsulinemia leading to hypoglycaemia, wherein hyperinsulinemia is characterised as excess levels of insulin circulating in blood relative to glucose.

There has been an unfilled need, therefore, for a treatment of the onset and progression of Type ll diabetes which will substantially prevent further deterioration of beta cells in the mammal’s pancreas.

Related to this, there has been an unfilled need for a treatment to protect beta cells during and shortly after islet transplantation against loss due to ischemia and against loss due to rejection after pancreas or islet transplantation.

Summary of the Invention Accordingly, in a first aspect, the present invention relates to diazoxide or a pharmaceutically acceptable salt thereof for use as a medicament in combination with an immunosuppressive compound and/or an anti-inflammatory compound, preferably a corticosteroid, in a treatment of a mammal afflicted with Type | diabetes. Preferably, the treatment substantially prevents further deterioration of beta cells in the mammal’s pancreas and/or protects beta cells in the mammal’s pancreas during and shortly after islet transplantation against loss due to ischemia and/or protects beta cells in the mammal’s pancreas against loss due to rejection after pancreas or islet transplantation.

In a second aspect, the present invention relates to a pharmaceutical composition comprising diazoxide or a pharmaceutically acceptable salt thereof and an immunosuppressive compound and/or an anti-inflammatory compound, preferably a corticosteroid, for use in the treatment of a mammal afflicted with, or prone to develop Type | diabetes.

Detailed description of the invention The present invention relates to the use of diazoxide for preventing or treating the onset and progression of Type | diabetes when a large mass of beta cells is still present in the mammal’s pancreas which will likely quickly deteriorate. Applicants have surprisingly found that the administration of diazoxide, preferably in combination with an immunosuppressive compound and/or an anti-inflammatory compound, preferably a corticosteroid, may protect beta cells from the auto-immune reaction considered as the underlying cause for this ailment.

Accordingly, the present invention in a first instance relates to a process a composition comprising a combination of diazoxide as a beta cell protective agent with the immunosuppressive compound and/or the anti-inflammatory compound, preferably a corticosteroid.. Preferably, the process relates to a treatment with 100 — 1600mg per day, more preferably 200 — 1200 mg per day, more preferably of from 300 to 800mg per day of diazoxide. Preferably, the process also relates to a treatment with one or more immunosuppressive compounds and/or one or more anti-inflammatory compounds selected from the group consisting of: ° a corticosteroid, particularly methylprednisolone {dose range 5 — 2000 mg per day), prednisolone (dose range 1,25 — 120 mg per day}, dexamethasone (0.25 — 24 mg per day),

cortisone (10 — 1000 mg per day), or hydrocortisone (10 — 1000 mg per day), or combinations thereof; . a calcineurin-inhibitor, particularly tacrolimus (dose range 0.5 — 24 mg per day) or cyclosporine and its derivatives (dose range 25 — 750mg per day); eo an antimetabolite, particularly azathioprine and its derivatives (dose range 25 — 1000 mg per day), mycophenolate mofetil (dose range 250 — 4000 mg per day); mycophenolic acid (dose range 180 — 2880 mg per day,) and/or methotrexate (dose range 0.5 — 20 mg per day); . an mTOR inhibitor, particularly everolimus {dose range 0.25 — 10 mg per day) or sirolimus (dose range 0.5 — 80 mg per day); . an anti-lymphocyte antibody, particularly alemtuzumab {dose range 0.1 — 100 mg), rituximab {200 — 2000 mg) or thymoglobulin (dose range 10 — 500 mg per day}; and/or ° an anti-cytokine antibody, particularly basiliximab (dose range 10 — 100 mg), anakinra (dose range 10 — 500 mg per day), tocilizumab {dose range 8 — 1600 mg), etanercept (dose range 1 — 10 mg per day}, Adalimumab (dose range 5 -640 mg), infliximab {dose range 5 — 2000 mg), golimumab (dose range 25 — 800 mg), certolizumab (dose range 50 — 1600 mg).

Without wishing to relate to any particular theory, it is believed that this combination therapy may protect the beta cell from both the beta cell stress and the inflammation. A first situation whereby the combination may be applied is during the onset and progression of Type | diabetes, i.e. when a majority or at {east large group of beta cells is still present, but shows a fast deterioration, whereby applicants have found that diazoxide treatment ameliorates this deterioration.

More preferably, by also treating the ongoing insulitis, by combining the diazoxide with an immunosuppressive compound and/or an anti-inflammatory compound, in particular a corticosteroid, these beta cells may be kept alive.

A second situation in which beta cell protection may be applied is during, and shortly after islet transplantation, since transplanted islets require several weeks to be fully vascularized and a large portion of transplanted islets are lost due to ischemia, whereby the combination therapy may advantageously be employed.

A third situation in which beta cell protection may be applied is in the case of a rejection after pancreas or islet transplantation.

A fourth situation in which beta cell protection may be applied is in the case of a person having a substantially increased risk of developing Type | diabetes, as indicated by biomarkers or genetic predisposition.

In accordance with this invention, diazoxide or a pharmaceutically acceptable salt thereof is used as a medicament in combination with one or more immunosuppressive compounds and/or anti-inflammatory compounds, particularly one or more corticosteroids, in a treatment of a mammal afflicted with Type | diabetes or the onset thereof, and/or at risk of developing Type | diabetes.

A pharmaceutical composition comprising diazoxide or a pharmaceutically acceptable salt thereof and the one or more immunosuppressive compounds and/or anti- inflammatory compounds, particularly one or more corticosteroids, as the active compounds is preferably administered to the mammal in this treatment.

As used herein, the term “corticosteroid” preferably means a glucocorticoid, more preferably a natural glucocorticoid or a synthetic corticosteroid-like compound, such as betamethasone, prednisone, dexamethasone, cortisone, hydrocortisone, methylprednisolone and prednisolone, as well as amcinonide, betamethosone diproprionate, clobetasol, clocortolone, diflorasone, dutasteride, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone, fluticasone propionate, fluticasone propionate, fluticasone propionate, flurandrenolide and hydroflumethiazide As also used herein, the term “mammal” preferably means a primate, a human ora domestic or farm animal, such as a cow, horse, pig, sheep, goat, dog, cat or rodent, more preferably a human.

As also used herein, the term “pharmaceutically acceptable salt thereof” preferably means a free compound or, for example, a pharmaceutically acceptable, non-toxic organic or inorganic acid or base addition salt of diazoxide.

As also used herein, the term “mammal … at risk of developing Type | diabetes” preferably means a mammal testing positive for one or more diabetes-associated antibodies and/or with a positive family history for Type { diabetes in one or more first-degree relatives and/or with an increased risk for Type | diabetes based on gene analysis thereof as described by: Redondo MJ, Oram RA, Steck AK. Genetic Risk Scores for Type | Diabetes Prediction and Diagnosis. Curr Diab Rep, 2017; Regnell SE, Lernmark A. Early prediction ofautoimmune (Type |) diabetes. Diabetologia, 2017; Bonifacio E. Predicting Type | diabetes using biomarkers. Diabetes Care 2015.

In accordance with this invention, diazoxide or a pharmaceutically acceptable salt thereof and an immunosuppressive compound and/or an anti-inflammatory compound, 5 particularly a corticosteroid, or preferably a pharmaceutical composition thereof can be administered to the mammal orally, topically, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation. Depending upon the mammal to be treated and the route of administration, varying doses of a pharmaceutical composition of this invention comprising diazoxide or a pharmaceutically acceptable salt thereof and the immunosuppressive compound and/or anti-inflammatory compound, particularly the corticosteroid, can be suitably administered. Preferably, this treatment substantially prevents further deterioration of beta cells in the mammal’s pancreas and/or protects beta cells in the mammal’s pancreas during and shortly after islet transplantation against loss due to ischemia and/or protects beta cells in the mammal’s pancreas against loss due to rejection after pancreas or islet transplantation.

Typically, a pharmaceutical composition of this invention can be administered orally or parenterally. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a mammal. Generally, the pharmaceutical composition will also contain one or more pharmaceutically acceptable diluents, excipients or carriers.

Actual dosage levels of the pharmaceutical composition of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response. The selected dosage level will depend upon the route of administration, the severity of the condition being treated, and the condition and prior medical history of the mammal being treated.

Preferably, the components of the subject composition are administered such that they develop their respective effects such that the best protection for the beta cells in the pancreas is ensured. Without wishing to refer to any particular theory, it is believed that the immunosuppressive compound and/or an anti-inflammatory compound or composition is present in an amount sufficient to limit the mammal’s immune response, whereas thediazoxide concentration is increased to a suitable level when the presence of the immunosuppressive compound and/or an anti-inflammatory compound is ensured. In this way, it believed that the subject composition develops a strongly synergistic effect.

In the treatment of a mammal afflicted with, or at risk of developing Type | diabetes, an appropriate dosage of the pharmaceutical composition of this invention can generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.

The dosage level will preferably be about 0.1 to about 250 mg/kg per day, more preferably about 0.5 to about 100 mg/kg per day. For oral administration, this composition can be provided in the form of tablets containing 1.0 to 1000 milligrams of each of the active ingredients, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,

250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of each active ingredient. This composition can be administered on a regimen of 1 to 4 times per day, e.g. once or twice per day. The dosage regimen can be adjusted to provide the optimal therapeutic response.

The pharmaceutical composition of this invention or compositions in the case where the two components are administered separately, for parenteral injection can be in the form of a pharmaceutically acceptable sterile agueous or non-aqueous solution, dispersion, suspension or emulsion. The composition can also be in the form of a sterile powder for reconstitution into a sterile injectable solution or dispersion just prior to use.

Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols {such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils {such as olive oil} and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

The pharmaceutical composition or compositions of this invention can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It can also be desirable to include isotonic agents, such as sugars or sodium chloride.

Prolonged absorption of the injectable pharmaceutical form can be effected by the inclusion of agents such as aluminium monostearate and gelatine which delay absorption.

To prolong the effects of the pharmaceutical composition of this invention, it can be desirable to slow the absorption of the composition from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the composition then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered composition can be accomplished by dissolving or suspending it in an oil vehicle.

Injectable forms of the pharmaceutical composition of this invention can be made by forming microencapsulate matrices of the composition in biodegradable polymers, for example polylactide-polyglycolide. Depending upon the ratio of the composition to the polymer and the nature of the particular polymer employed, the rate of release of the composition can be controlled. Examples of biodegradable polymers include poly{orthoesters) and poly({anhydrides). Depot injectable formulations can also be prepared by entrapping the composition in a liposome or microemulsion which is compatible with body tissues of the mammal. The injectable formulations can be sterilized, for example, by filtration through a bacterial retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.

Solid dosage forms of the pharmaceutical composition or compositions of this invention for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the composition is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; ¢) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h} absorbents, such as kaolin and bentonite clay and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycols, sodium lauryl sulfate and mixtures thereof. In the capsules, tablets and pills, the solid dosage form can also comprise buffering agents. The composition can also be used as a filler in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.

Solid dosage forms of the pharmaceutical composition(s) of this invention for oral administration can contain a dissolution aid. Examples of dissolution aids include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters {eg sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkyamine oxides; bile acid and salts thereof (eg chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsufonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.

Solid dosage forms of the pharmaceutical composition(s) of this invention in the form of tablets, dragees, capsules, pills, or granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. The coatings can optionally contain opacifying agents and can also be of a composition such that they release the active compound(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.

The active compounds of the pharmaceutical composition of this invention can also be in microencapsulated form with one or more of the above-mentioned excipients. The active compounds can also be in finely divided form, for example, they can be micronized.

Liquid dosage forms of the pharmaceutical composition of this invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions,

syrups and elixirs.

In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the liquid dosage forms “can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.

The pharmaceutical composition(s) of this invention can also be administered in the form of a liposome.

As is known in the art, liposomes are generally derived from phospholipids or other lipid substances.

Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium, Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.

The composition in liposome form can contain, in addition to the active compounds of the invention, stabilizers, preservatives, excipients and the like.

The preferred lipids are the phospholipids and the phosphatidyl cholines ({lecithins}, both natural and synthetic.

Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p33 et seq.. Formulations of the pharmaceutical composition{s} of this invention can also contain inactive components.

Suitable inactive components are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8thEd., Gilman et al, Eds.

Pergamon Press (1990), and Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa. {1990}, both of which are incorporated by reference herein in their entirety.

The following, non-limiting example section illustrates the invention further.

Example Isolated human islets are cultured in vitro for 48-72 hours in a control medium containing either methylprednisolone (2 mg/L) or diazoxide {325 pmol/L), or both diazoxideand methylprednisolone.

After culturing, viability of the human islets is tested by FDA-PI and PrestoBlue.

Islet damage is assessed with a micro-RNA kit, GAD and PPP IRIA concentrations in the culture medium.

Mitochondrial function is assessed by Sea Horse or OUROBOROS.

In addition, islet functionality is assessed by static and dynamic glucose-stimulated insulinsecretion (GSIS) according to standard procedures in the human islet isolation unit.

Human islets cultured in vitro in the control medium containing both diazoxide and methylprednisolone were shown to be significantly more viable than those culture in only diazoxide or methylprednisolone.

Claims

CONCLUSIONS

Diazoxide or a pharmaceutically acceptable salt thereof, for use as a medicament in combination with an immunosuppressant and / or an anti-inflammatory compound, more particularly a corticosteroid, in the treatment of a mammal suffering from type II diabetes or at risk of developing to develop them.

Diazoxide or a pharmaceutically acceptable salt thereof, for use as a medicament in combination with an immunosuppressant and / or an anti-inflammatory compound, in particular a corticosteroid, according to claim 1, to substantially reduce beta cells in the pancreas of the brain. mammal.

Diazoxide or a pharmaceutically acceptable salt thereof, for use as a medicament in combination with an immunosuppressant compound and / or an anti-inflammatory compound, in particular a corticosteroid, according to claim 1 or 2, in order to produce beta cells in the pancreas of the mammal. protect against loss due to ischemia during and shortly after islet transplantation of Langerhans.

Diazoxide or a pharmaceutically acceptable salt thereof, for use as a medicament in combination with an immunosuppressant compound and / or an anti-inflammatory compound, in particular a corticosteroid, according to any one of claims 1 to 3, to inhibit beta cells in the pancreas of protect the mammal against pancreatic or islet loss following transplantation of the pancreas or islets of Langerhans.

Diazoxide or a pharmaceutically acceptable salt thereof, for use as a medicament in combination with an immunosuppressant compound and / or an anti-inflammatory compound, according to any one of claims 1 to 4, wherein the immunosuppressant compound and / or the anti-inflammatory compound is selected. from the group consisting of a corticosteroid, a calcineurin inhibitor; an mTOR inhibitor; an anti-lymphocyte antibody and / or an anti-cytokine antibody; or combinations thereof.

A composition for use according to claim 5, wherein the immunosuppressant compound and / or the anti-inflammatory compound comprises or comprises one or more corticosteroids.

A composition for use according to any one of claims 5 or 6, wherein the corticosteroid comprises a natural glucocorticoid or a synthetic corticosteroid-like compound such as beta-methasone, dexamethasone, cortisone, hydrocortisone, methylprednisolone, and prednisolone, as well as amcinonide, beta-methosone diproprionate. , clobetasol, clocortolone, diflorasone, dutasteride, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone, fluticasone propionate, flurandrenolide, and hydroflumethiazide, each in a suitable dosage.

A composition for use according to any one of claims 5 to 7, wherein the corticosteroid is methylprednisolone in a preferred dosage range of 5 mg to 2000 mg per day, prednisolone in a preferred dosage range of 1.25 mg to 120 mg per day, dexamethasone in a preferred dose range of 0.25 mg to 24 mg per day, cortisone in a preferred dose range of 10 mg to 1000 mg per day, or hydrocortisone in a preferred dose range of 10 mg to 1000 mg per day.

Composition for use according to claim 5, wherein the calcineurin inhibitor comprises tacrolimus, preferably in a dose range of 0.5 mg to 24 mg per day, and / or cyclosporine and its derivatives, preferably in a dose range of 25 mg to 750 mg per day.

A composition for use according to claim 5, wherein the antimetabolite comprises azathioprine and its derivatives, preferably in a dosage range of 25 to 1000mg per day; mycophenolate mofetil, preferably in a dosage range of 250 mg to 4000 mg per day; mycophenolic acid, preferably in a dose range of 180 mg to 2880 mg per day, and / or methotrexate, preferably in a dose range of 0.5 mg to 20 mg per day.

A composition for use according to claim 5, wherein the mTOR inhibitor comprises everolimus, preferably in a dose range of 0.25 mg to 10 mg per day, or sirolimus, preferably in a dose range of 0.5 mg to with 80 mg per day.

A composition for use according to claim 5, wherein the anti-lymphocyte antibody is alemtuzumab, preferably in a dose range of 0.1 mg to 100 mg; rituximab, preferably in a dosage range of 200 mg to 2000; or thymoglobulin, preferably in a dosage range of 10 mg to 500 mg per day.

The composition of claim 5, wherein the anti-cytokine antibody comprises basiliximab, preferably in a dosage range of 10 mg to 100 mg; anakinra, preferably in a dosage range of 10 mg to 500 mg per day; tocilizumab, preferably in a dose range of 8 mg to 1600 mg; etanercept, preferably in a dosage range of 1 mg to 10 mg per day; adalimumab, preferably in a dosage range of 5 mg to 640 mg; infliximab, preferably in a dosage range of 5 mg to 2000 mg; golimumab, preferably in a dosage range of 25 mg to 800 mg; and / or certolizumab, preferably in a dosage range of 50 mg to 1600 mg per day.

Pharmaceutical composition, diazoxide or a pharmaceutically acceptable salt thereof and an immunosuppressant compound and / or an anti-inflammatory compound, in particular a corticosteroid, comprising, according to any one of claims 1 to 13, for use in the treatment of a mammal in suffering type II diabetes or are at risk of developing it.

A method of treating a mammal suffering from type II diabetes, the method comprising the step of administering to the mammal an effective amount of diazoxide or a pharmaceutically acceptable salt thereof, as well as an immunosuppressant compound and / or an anti-inflammatory compound. , in particular a corticosteroid, according to any one of claims 1 to 13.

A composition according to any one of claims 1 to 13 for the manufacture of a medicament for treating or type I diabetes in a mammal.