The present invention provides methods and compositions for preventing hyperinsulinemia that can result from therapeutic administration of growth hormone. The methods are carried out by imposing a restricted high-fat diet and/or by administering one or more drugs that lower serum lipids.

SUMMARY OF THE INVENTION

The present inventors have found that the insulin response in a subject to administration of GH can be modulated, for example, by varying diet composition and caloric intake, and/or by administering a drug which brings about a reduction in blood lipid levels (more precisely a reduction in the level of one or more blood lipid components), and that this influences adipose tissue loss and serum leptin levels. Among blood lipid components, free fatty acids (FFA) are of particular interest since high FFA levels often are associated with a decrease in insulin sensitivity leading to a compensatory hyper-secretion of insulin. A broad aspect of the invention thus relates to a method for substantially preventing hyperinsulinemia in an animal or human subject undergoing treatment with growth hormone (GH), the method comprising subjecting the subject, during the growth hormone treatment period, to one or more measures (such a diet regimen and/or a drug treatment) which cause a reduction in blood lipid levels (more precisely a reduction in the level of one or more blood lipid components). Further aspects of the invention include, inter alia: (i) a method for achieving breakdown of adipose tissue in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst subjecting the subject to one or more measures which cause a reduction in blood lipid levels (more precisely a reduction in the level of one or more blood lipid components); (ii) a method for reducing blood lipid levels (more precisely reducing the level of one or more blood lipid components) in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst inhibiting lipolysis in the subject; and (iii) a method for reducing blood lipid levels (more precisely reducing the level of one or more blood lipid components) in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst stimulating lipid clearance from circulation.

Other aspects of the invention include medical kits suitable for use in methods according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods and compositions for minimizing the risk of development of diabetes as a consequence of excessive overloading of insulin-producing beta-cells.

One aspect of the present invention relates to a method for substantially preventing hyperinsulinemia in an animal or human subject undergoing treatment with growth hormone (GH), the method comprising subjecting the subject, during the growth hormone treatment period, to one or more measures which cause a reduction in blood lipid levels. The method in question is believed to be of general applicability, irrespective of the underlying rationale for treatment of the subject with growth hormone. Thus, for example, the method of the invention may be used in the context of established GH treatments of immature humans (children or adolescents), such as for the purpose of stimulating growth to counteract development of short stature or dwarfism, as well as of mature (adult) humans.

A closely related further aspect of the invention relates to a method for achieving breakdown of adipose tissue in an animal or human subject--particularly an obese human subject--substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst subjecting the subject to one or more measures which cause a reduction in blood lipid levels.

Measures of the type referred to in relation to methods of the invention include, without limitation, diet regimens or drug treatments. In one embodiment, the subject is provided with restricted amounts of a high-fat (HF) diet as sole food source (nutrition source). Appropriate drug treatments include, without limitation, treatment with agents such as the antihyperlipoproteinemic Acipimox.TM. (Olbetam.TM.), i.e. 5-methylpyrazinecarboxylic acid 4-oxide, and related compounds (see U.S. Pat. No. 4,002,750); statins, such as Fluvastatin.TM., Lovastatin.TM., Pravastatin.TM. or Simvastatin.TM.; and fibrates, such as Bezafibrat.TM., Clofibrat.TM. or Gemfibrozil.TM., in amounts and dosage regimens that are effective in lowering blood lipid levels.

Another, related aspect of the present invention relates to a method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst providing the subject with restricted amounts of a high-fat (HF) diet as sole food source.

A still further aspect of the invention provides another method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst inhibiting lipolysis in the subject. In this connection, inhibition of lipolysis may be reflected in inhibition of the lipase known as Hormone-Sensitive Lipase (HSL), although inhibition of other families of lipases may also be of relevance in the context of the method in question according to the invention. Non-limiting examples of substances capable of inhibiting the lipolytic effect of HSL include those disclosed in U.S. Pat. No. 6,596,742 B1 (corresponding to WO 01/17981), WO 01/66531, WO 03/051841, WO 03/051842 and WO 03/105860.

Yet another aspect of the invention relates to a method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst stimulating lipid clearance from the circulation. In this connection, stimulation of clearance of lipid from the circulation may, for example, be achieved by administration of a substance which acts to stimulate, activate or potentiate a lipase such as Lipoprotein Lipase (LPL). Non-limiting examples of LPL-potentiating substances include those described in WO 01/27088.

With regard to what constitutes "restricted" amounts of a HF diet in the context of the invention, it is generally preferable that the energy content (caloric content) of the amount of HF diet with which the subject is provided does not exceed (i.e. is below or is equal to or at least approximately equal to) the theoretical maintenance level for the subject in question. In the case of human subjects, there is an extensive body of published data which enables the establishment of the theoretical maintenance level for an individual on the basis of parameters such as age, gender, weight, height, ethnicity and level of physical activity. Published sources of such data include: Ritz, P., Factors affecting energy and macronutrient requirements in elderly people, Public Health Nutrition 4 (2001) pp. 561 569; and Lin et al., Estimation of energy requirements in a controlled feeding trial, Am. J. Clin. Nutr. 77 (2003) pp. 639 645.

With regard to animal species, particularly "farm" animals (animals of importance in relation to production of meat products, dairy products, eggs and the like, such as cattle, pigs, goats and poultry), and other domestic animals, such as horses, data are available from sources such as the UK Agricultural Research Council (ARC), the Commonwealth Agricultural Bureau, and the US National Research Council (NRC; e.g. data from 1988 and 1998, published by National Academy Press, Washington D.C.).

In some embodiments, the present invention relates to the treatment of humans, in particular obese humans. In these embodiments, the growth hormone to be employed will preferably be human growth hormone (hGH).

In the light of the above methods of the invention, still further aspects of the present invention include the following: (i) Pharmaceutical compositions comprising, as active ingredients, a growth hormone and an agent selected from: agents capable of reducing blood lipid levels; lipolysis-inhibiting agents (e.g. HSL inhibitors); and lipase-activating or -potentiating agents (e.g. LPL activators or potentiators); (ii) Medical kits suitable for use in methods according to the invention and comprising a growth hormone preparation and one or more measures which cause a reduction in blood lipid levels, such as, e.g., a medical kit comprising a growth hormone preparation and a high-fat diet, a medical kit comprising a growth hormone preparation and a drug which causes a reduction in blood lipid levels, a medical kit comprising a growth hormone preparation and a lipolysis-inhibiting agent (such as an HSL inhibitor), or a medical kit comprising a growth hormone preparation and a lipolysis-activating or -potentiating agent (such as a LPL activator or potentiator).

Also encompassed by the invention is the use of a substance which acts as a growth hormone secretagogue (GHS; also known, inter alia, as a growth hormone releasing substance), i.e. a substance which, when administered to a subject by an appropriate route, is capable of stimulating the release of growth hormone from the pituitary of the subject, as an alternative to a GH per se in the various aspects of the invention (i.e. as an active ingredient in methods, pharmaceutical compositions, medical kits etc. as described above). Non-limiting examples include the synthetic hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2, also known as GHRP-6 (see, e.g., Bowers et al. in Endocrinology 114 (1984) pp. 1537 1545 and in Endocrinology 128 (1991) pp. 2027 2035) and the peptide derivatives described in WO 95/17423. Naturally occurring growth hormone releasing substances of potential relevance in the context in question include so-called "growth hormone releasing hormone" (often abbreviated GHRH or GHRH(1 44)NH.sub.2) and truncated forms thereof (see, e.g., Guillemin et al., Science 218 (1982) pp. 585 587 and Rivier et al., Nature 300 (1982) pp. 276 278).

Pharmaceutical Administration

The regimen for treatment of a given subject/patient with growth hormone and, where appropriate, with another drug, in the manner described herein, may be determined by one skilled in the art. The daily dose to be administered can be determined by a physician and will depend on the particular substance employed, on the route of administration and on the age and the condition of the subject or patient. A convenient daily dosage of GH is typically in the range of from about 0.001mg/kg body weight to about 2.0 mg/kg body weight, often from about 0.01 mg/kg body weight to about 1.0 mg/kg body weight. The therapeutic dose of the substance will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

GH may be administered in a single dose or in repeated doses during the day. Administration in the manner described herein should continue until the treated individual is no longer in need of such treatment, for example, until an initially obese individual is no longer obese.

The route of GH administration may be any route that effectively transports the active compound to the appropriate or desired site of action, such as by infusion (continuous or pulsatile), injection, pulmonary inhalation, or by oral or nasal administration. Presently preferred routes include parenteral routes (e.g. via intramuscular, intraperitoneal, intravenous or subcutaneous injection, or by implant). The growth hormone can be formulated in dosage forms appropriate for each route of administration. The compositions or dosage forms may be in conventional forms, e.g. aerosols, solutions or suspensions.

A GH composition may be in a form suited for systemic injection or infusion, and may, as such, be formulated with a suitable liquid vehicle such as sterile water or an isotonic saline or glucose solution. The compositions may be sterilized by conventional sterilization techniques which are well known in the art. The resulting aqueous solutions may be packaged for use as such, or they may be filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with the appropriate sterile aqueous vehicle prior to administration. The composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as buffering agents, tonicity-adjusting agents and the like. Non-limiting examples of buffering agents include citrate salts and histidine; non-limiting examples of tonicity adjusting agents include sugars, such as sucrose and mannitol, and salts, such as alkali metal and alkaline earth metal chlorides, e.g. sodium, potassium or calcium chloride, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Aqueous liquid formulations, in particular, may advantageously contain a non-ionic surfactant, e.g. a polysorbate [such as polysorbate 20 (e.g. Tween.TM. 20) or a poloxamer [such as poloxamer 188 (e.g. Pluronic.TM. F68) or poloxamer 407 (e.g. Lutrol.TM. F127)], and a preservative, such as benzyl alcohol, phenol or a cresol (e.g. m-cresol), will often be incorporated.

It may be advantageous to provide GH in the form of a sustained release formulation. As such, the composition may be formulated as microcapsules or microparticles containing the growth hormone encapsulated in, or dispersed in, a suitable pharmaceutically acceptable biodegradable polymer, such as polylactic acid, polyglycolic acid or a lactic acid/glycolic acid copolymer.

For nasal administration, the GH preparation may contain growth hormone dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents (e.g. propylene glycol), surfactants, absorption-enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.

Growth hormone may be formulated by any of the established methods of formulating pharmaceutical compositions, e.g. as described in Remington: The Science and Practice of Pharmacy (1995).

A liquid hGH formulation which is well suited, in particular, for administration by injection in the context of the present invention is Norditropin.TM. SimpleXx.TM. (Novo Nordisk).

 

Claim 1 of 6 Claims

1. A method for reducing the incidence of a statistically significant rise in plasma insulin levels in an animal or human subject undergoing treatment with growth hormone (GH), comprising providing the subject, during the growth hormone treatment period, with a restricted amount of a high-fat (HF) diet as the sole food source.

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