AU2001239635A1 - Use of growth hormone in low dose - Google Patents
Use of growth hormone in low doseInfo
- Publication number
- AU2001239635A1 AU2001239635A1 AU2001239635A AU3963501A AU2001239635A1 AU 2001239635 A1 AU2001239635 A1 AU 2001239635A1 AU 2001239635 A AU2001239635 A AU 2001239635A AU 3963501 A AU3963501 A AU 3963501A AU 2001239635 A1 AU2001239635 A1 AU 2001239635A1
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- Australia
- Prior art keywords
- growth hormone
- day
- less
- dose
- low dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 73
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 73
- 239000000122 growth hormone Substances 0.000 title claims abstract description 72
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 23
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 102000002265 Human Growth Hormone Human genes 0.000 claims abstract description 12
- 108010000521 Human Growth Hormone Proteins 0.000 claims abstract description 12
- 239000000854 Human Growth Hormone Substances 0.000 claims abstract description 12
- 230000002950 deficient Effects 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 11
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 13
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 10
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 8
- 230000006872 improvement Effects 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 230000035945 sensitivity Effects 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 5
- 230000003915 cell function Effects 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- 102000004374 Insulin-like growth factor binding protein 3 Human genes 0.000 description 3
- 108090000965 Insulin-like growth factor binding protein 3 Proteins 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000013632 homeostatic process Effects 0.000 description 3
- 230000035879 hyperinsulinaemia Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 2
- 102000043296 Lipoprotein lipases Human genes 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000004190 glucose uptake Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 201000009104 prediabetes syndrome Diseases 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 208000029422 Hypernatremia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 101150088952 IGF1 gene Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000026928 Turner syndrome Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940063135 genotropin Drugs 0.000 description 1
- 238000009578 growth hormone therapy Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/12—Growth hormone, growth factor other than t-cell or b-cell growth factor, and growth hormone releasing factor; related peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to treatment of patients in need of increasing insulin sensitivity by administration of growth hormone or analogues thereof, preferably human growth hormone, in a low dose and the use of growth hormone or analogues thereof, preferably human growth hormone, for the manufacturing of a medicament useful for increasing insulin sensitivity in low dose therapy. The patient is preferably a normal subject, i.e. not growth hormone deficient patient and/or a non-obese patients. By low dose therapy is preferably meant less than 0.008 mg/kg/day, preferably 0.007 mg/kg/day or less, more preferably 0.005 mg/kg/day or less and most preferably 0.003 mg/kg/day or less. The therapy is preferably performed during short term treatment, preferably less than one month.
Description
USE OF GROWTH HORMONE IN LOW DOSE
The present invention relates to treatment of patients in need of increasing insulin sensitivity by administration of growth hormone or analogues thereof, preferably human growth hormone, in a low dose and the use of growth hormone or analogues thereof, preferably human growth hormone, for the manufacturing of a medicament useful for increasing insulin sensitivity in low dose therapy.
BACKGROUND Human Growth hormone, hGH, is a protein consisting of a single chain of 191 amino acids. The molecule is cross-linked by two disulfide bridges and the monomeric form has a molecular weight of 22 kDa. hGH preparations have been prepared from human pituitaries, but nowadays the products on the market are produced by recombinant methods, rhGH. Two types of therapeutically useful recombinant hGH preparations are present on the market: the authentic one, e.g. Genotropin®, Pharmacia AB, and an analogue with an additional methionine residue at the N-terminal end, e.g. Somatonorm®. hGH is used to stimulate linear growth in patients with hypopituitary dwarfism or Turner's syndrome but other indications have also been suggested.
Growth hormone therapy is used in children to promote growth and in adults to improve muscle strength, reduce fat mass and improve metabolic profiles, which could predispose to cardiovascular disease. In contrast to the growth promoting effects of growth hormone, the metabolic effects have been less often studied, yet they may be very important to the risk- benefit assessment of GH therapy in adults.
GH therapy is known to counter insulin actions and is contra-indicated for individuals with diabetes mellitus..
At present GH therapy in adults is monitored using serum IGF-I levels, but it is possible that it is the metabolic effects which are more relevant to improvements in symptomatology and disease risk profiles and there is a need to develop ways of formally assessing these responses.
PRIOR ART Growth hormone replacement supplementation to hypophysectomized rats has been shown to improve glucose uptake in the diaphragm muscle, see Diabetes, 1962. Vol. 1 1 (3), pp. 171-178. By contrast, pharmacological treatment with GH. resulting in supra-physiological circulating levels of the hormone, is known to produce a decrease in total body glucose uptake and disposal as well as a blunted metabolic response to insulin (i.e. insulin resistance) in skeletal muscle, see Hettiarachchi M et al., Diabetes 45(4):415-21, 1996. However, in tissues which are metabolically markedly different from the muscle, like adipose tissue, GH could induce glucose up-take, as reported in Endocrinology, 1996, Vol. 137(11), pp. 4650-5 M Ridderstrale et al.
Koller J et al, Acta Chirurgiae Plasticae, (1998) 40/3 (76-78) disclose the growth hormone effect in burn treatment. rhGH was administered at daily doses of 0.52 i.u./kg starting on day 19 post-burn for 15 consecutive days. It is stated that the treatment was well tolerated except for mild insulin resistance.
Initial studies of GH replacement in hypopituitary adults used high daily GH doses (0.07 IU/kg BW; ~ 3 IU/m2; ~ 5 IU/day) based on experience in children (Salomon F et al. NEJM 1989; 321 : 1797-1803.). However, these studies were associated with an increased incidence of side-effects (mainly salt and water retention), which usually resolved on reduction in dosage. In sequential studies using half this dose (0.035 IU/kg BW; ~ 1.5 IU/m2; ~ 2.5 IU/day), the incidence of side-effects decreased significantly (Mardh G. et al. Endocrinol Metab 1995: 2: 1 1-16.). This is also in agreement with using lower doses in adults than in children as physiological GH production decreases with ageing (Iranmanesh
A et al. ./ Clin Endocrinol Metab 1991 : 73 : 1081-1088.). Rosenfalck et al recently demonstrated the beneficial effects of a relatively low dose of GH replacement therapv (mean dose of 1.6 IU/day) in GH-deficient adults on bod)' composition with an increase in lean body mass and a reduction in body fat. In spite of these favourable changes, a deterioration in insulin sensitivity was observed with a quarter of the patients developing impaired glucose tolerance (Rosenfalck AM. et al J Clin Endocrinol Metab 2000; 1 1 : 4173- 4181). In 1998, the Growth Hormone Research Society recommended that GH replacement was commenced at a low dose (0.45-0.9 IU/day). and increased gradually on the basis of biochemical and clinical response at intervals greater than 1 month (Carroll PV et al. J Clin Endocrinol Metab 1998; 83: 382-395.). Murray et al recently demonstrated that baseline serum IGF-1 SD is the only determinant required for optimal GH replacement therapy in GH-deficient adults (Murray RD et al. Clinical Endocrinology 2000; 52: 537-542.).
WO9409813 discloses a method for treating obesity by the administration of GH and IGF-I. The dose of GH should be at least 0.01 mg/kg/day.
W09532991 discloses the combined administration of human growth hormone and dehydroepiandrosterone to regenerate human thymus to allow intra-thymic transplantation to eliminate organ and tissue rejection. The hyperinsulinaemia side effects of growth hormone are thereby eliminated e.g.hyperinsulinaemia in children, i.e. no elevation in blood levels of insulin are observed.
In WO97/38709 obese subjects have been treated with GH to find the potential for growth hormone to reduce central obesity. The subjects treated had a body mass index between 25 and 35 kg/m^, an IGF-I less that
160 μg/L (low normal) and a waist hip ratio of more that 0.95. The study was performed for 9 months with the administration of rhGH. The daily rhGH dose was 0.0095 mg/kg (0.20 IU/kg body weight/week), administrated subcutaneously before bedtime. Lipoprotein lipase (LPL) activity and Glucose disposal rate (GDR) were observed in this studv.
The patients in WO97/38709 are obese and rhGH was given for 9 months. No conclusion can be drawn from this study for treatment of normal individuals with low dose GH treatment.
WO9901 151 relates to a therapy involving administration of human growth hormone for improving cellular function in the heart challenged by insulin resistance and thereby treating or protecting the heart from complications derivable from this condition. Only complications resulting from insulin resistance in the heart are mentioned.
In none of these references has a low dose of growth hormone been given to normal subjects and no conclusion regarding insulin sensitivity can be drawn from the earlier reported findings.
FIGURES The Figures illustrates the invention.
Figure 1 % Insulin sensitivity (HOMA, Day 1 = 100%) (0.003 and 0.008 mg/kg/day)
Figure 2 mean IGF-I levels on GH therapy I (0.003 and 0.008 mg/kg/day)
Figure 3 mean IGFBP-3 levels on GH therapy (0.003 and 0.008 mg/kg/day)
Figure 4. Insulin levels on GFI therapy ( 0.0016 mg/kg/day) Figure 5 Glucose levels on GH therapy ( 0.0016 mg/kg/day)
Figure 6 HOMA beta cell function on GH therapy ( 0.0016mg/kg/day)
THE INVENTION
We have now found that low dose growth hormone (GH) therapy can induce sustained improvements in insulin sensitivity in normal subjects. This is in contrast to current dogma which indicates that that GH only has transient insulin-like effects and generally leads to insulin resistance. One would predict from prior art, that giving GH to normal subjects would lead to peripheral insulin resistance and compensatory hyperinsulinaemia, and certainly this was not what was observed at the lower dose here administrated. Our observation of improved insulin sensitivity in these normal subjects given the lower dose of GH is a novel finding and quite unpredictable.
The msulm resistance obseπ ed in adult GH deficient sublets is paiadoxical because gtowth hormone
young children leads to increased msulm sensitivity In the GH deficient children studied, younger children tend to be insulm sensitive wheieas the older ones become msulm resistant Thus when we tieat adult GH deficient patients with GH, improvements in msulm sensitivity could result |ust from redistribution oi fat oi from increased IGF- 1 levels
Oui finding that the effects of low dose GH in normal sub]ects, (non-obese, non-GH deficient), in particular, subjects who may be msulm resistant and geneticallv predisposed to syndrome X is of great importance The ability to improve msulm sensitivity in these subjects using low doses of GH is an unexpected finding
This invention relates to the findings that ultra-low dose GH may paradoxically improve insulin sensitivity in contrast to higher doses which cause a decline in insulm sensitivity and these differences may relate to different bio-availabihty and inhibition of IGF-I by binding proteins in these normal subjects These data indicate a novel and unique indication for low dose GH treatment in subjects with impaired glucose tolerance or msulm resistance who are subsequently prone to develop type 2 diabetes and syndrome X as such treatment might reduce msulm resistance and susceptibility to disease m these subjects
Our invention relates to a method for treatment of patients in need of increasing insulm sensitivity which method comprises the administration of growth hormone or analogues thereof in a low dose The growth hormone is preferably human growth hormone and more preferably recombinant growth hormone
The patient is preferably a normal subject, l e not growth hormone deficient patient and/or a non-obese patients
By low dose therapy is preterably meant less than 0 008mg/kg/day, preferably 0 007 mg/kg/day or less, more pielerabh 0 005mg/kg/day or less and most pieferably 0 003mg/kg/day or less
The therapy is preferably performed during short term treatment, prefeiab less than one month
The invention also relates to the use of growth hormone, preferably human growth hormone or analogues thereof for the manufacturing of a medicament useful for increasing insulin sensitivity, preferably in non-obese patients, more preferably in non growth hormone deficient patients when given as low dose therapy, preferably less than 0.008mg/kg/day and 5 more preferably 0.007 mg/kg/day or less, preferably during less than one month.
The homeostasis model assessment (HOMA) is a model used to estimate insulin sensitivity (and also beta-cell function) from fasting plasma glucose levels and insulin concentrations. (See Matthews DR et al. 1985. Homeostasis model assessment: insulin resistance and beta- l o cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28:412-419).
EXAMPLE 1
Twelve GH normal adults, age between the ages of 16 and 40 years and normal body mass 5 index were used for the study.
A dose of 0.003 mg/kg/day of GH was given for a period of 7 days, followed by a wash out period for 1 week and thereafter a GH treatment of 0.008 mg/kg/day during 7 days.
0 The results can be seen on Figures 1 to 3.
Figure 1 shows that HOMA (Day 1 = 100%) was higher after the first day when 0.003 mg/kg/day was given in comparison to 0.008 mg/kg/day. This clearly shows the increase in insulin sensitivity effect when the low dose was given in comparison to the higher dose of 0.008 mg/kg/day. 5 Figure 2 shows mean IGF-I levels, which increase significantly from baseline on both 0.003 mg/kg/day and 0.008 mg/kg/day doses). In contrast IGFBP-3 levels remained unchanged on the 0.003 mg/kg/day dose, and only showed an increase on the higher 0.008 mg/kg/day dose.
0 This study shows that in GH normal adults, low dose GFI therapy (0.003 mg/kg/day or at least less than 0.008 mg/kg/day) results in improvement in insulin sensitivity. This is accompanied by a significant increase in IGF-I levels but not in the IGF-1 major binding
protein IGFBP-3, suggesting that the changes in msulm sensitπ it λ may relate to improvement in IGF-I bιoa\aιlabιlιty
EXAMPLE 2 A dose of 0 0016 mg/kg d (0 005IU kg/d) of GH was given foi 15 days to normal \ olunteeis
Glucose levels fell consistently over the treatment period (p=0 00017), wheieas msulm els were unchanged Figure 4 shows the Insulm levels. Figure 5 shows the Glucose levels and Figure 6 shows HOM beta cell function
er the period The glucose levels fell significantly over the 15 day period which is an unexpected finding of high therapeutic value
This even lower dose GH therapy (0 0016 mg/kg/day) again resulted in an impiovement in glucose-insulin homeostasis HOMA interpreted this as an improvement in beta-cell function (p=0 00017), which is reminiscent of reports of GH on beta-cell function and induction of hypoglycaemia), rather than in msulm sensitivity However, we suspect that this could be an anomaly of HOMA which was not designed to detect improvements in insulm sensitivity beyond the normal range
Claims (14)
1. Method for treatment of patients in need of increasing insulin sensitivity which method comprises the administration of growth hormone or analogues thereof, preferably human growth hormone, in a low dose.
2. Method according to claim 1 in which the patient is a non-obese patient.
3. Method according to claim 1 or 2 in which the patient is not a growth hormone deficient patients.
4. Method according to any of claims 1 to 3 in which the dose is less than 0.008 mg/kg/day. preferably 0.007 mg/kg/day or less.
5. Method according to any of claims 1 to 4 in which the dose is 0.005 mg/kg/day or less.
6. Method according to any of claims 1 to 5 in which the dose is 0.003 mg/kg/day or less.
7. Method according to any of claims 1 to 6 in which the administration is performed during less than one month
8. Use of growth hormone or analogues thereof, preferably human growth hormone, for the manufacturing of a medicament useful for increasing insulin sensitivity for low dose therapy.
9. Use of growth hormone according to claim 8 in non-obese patients.
10. Use of growth hormone according to claim 8 or 9 in not growth hormone deficient patients.
1 1. Use of growth hormone according to any of claims 8 to 10. in which the dose is less than 0.008 mg/kg/d, preferably 0.007 mg/kg/day or less.
12. Use of growth hormone according to any of claims 8 to 1 1 , in which the dose is 0.005 mg/kg/d or less.
13. Use of growth hormone according to any of claims 8 to 12, in which the dose is 0.003 mg/kg/d or less.
14. Use of growth hormone according to any of claims 8-13 in which growth hormone is administrated during a period of less than one month.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2006200127A AU2006200127B2 (en) | 2000-03-13 | 2001-03-13 | Use of growth hormone in low dose |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0000837A SE0000837D0 (en) | 2000-03-13 | 2000-03-13 | New use |
| SE0000837 | 2000-03-13 | ||
| PCT/SE2001/000522 WO2001068127A1 (en) | 2000-03-13 | 2001-03-13 | Use of growth hormone in low dose |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001239635A1 true AU2001239635A1 (en) | 2001-09-24 |
Family
ID=20278800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001239635A Abandoned AU2001239635A1 (en) | 2000-03-13 | 2001-03-13 | Use of growth hormone in low dose |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US6696414B2 (en) |
| EP (1) | EP1265629B1 (en) |
| JP (1) | JP2003526675A (en) |
| AT (1) | ATE328604T1 (en) |
| AU (1) | AU2001239635A1 (en) |
| CA (1) | CA2402948A1 (en) |
| DE (1) | DE60120371T2 (en) |
| DK (1) | DK1265629T3 (en) |
| ES (1) | ES2263601T3 (en) |
| NZ (1) | NZ533844A (en) |
| PT (1) | PT1265629E (en) |
| SE (1) | SE0000837D0 (en) |
| WO (1) | WO2001068127A1 (en) |
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| US20020165127A1 (en) * | 1996-12-24 | 2002-11-07 | Supergen, Inc. | Methods for treating insulin resistance and identifying patients at risk for the disease |
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| US4670393A (en) | 1982-03-22 | 1987-06-02 | Genentech, Inc. | DNA vectors encoding a novel human growth hormone-variant protein |
| US5079345A (en) * | 1988-08-19 | 1992-01-07 | Eli Lilly And Company | Proteins having growth hormone anabolic properties with reduced effect on carbohydrate metabolism |
| EP0397834B1 (en) | 1988-10-28 | 2000-02-02 | Genentech, Inc. | Method for identifying active domains and amino acid residues in polypeptides and hormone variants |
| EP0441889A1 (en) | 1988-11-07 | 1991-08-21 | Commission des Communautés Européennes | Modified human growth hormone |
| IT1251895B (en) | 1991-09-27 | 1995-05-26 | Eniricerche Spa | HUMAN GROWTH HORMONE MUTANTS AND THEIR USE |
| ATE143267T1 (en) * | 1992-10-29 | 1996-10-15 | Genentech Inc | METHOD OF TREATING OR PREVENTING OBESITY |
| US5597709A (en) * | 1994-01-27 | 1997-01-28 | Human Genome Sciences, Inc. | Human growth hormone splice variants hGHV-2(88) and hGHV-3(53) |
| EP0766966A3 (en) * | 1995-09-08 | 2001-02-28 | Eli Lilly And Company | Method of treating insulin resistance |
| SE9601397D0 (en) | 1996-04-12 | 1996-04-12 | Pharmacia Ab | Use of growth hormone |
| AU737065B2 (en) | 1997-07-04 | 2001-08-09 | Pharmacia Ab | Use of growth hormone in compositions for treating insulin resistance in the heart and for enhancing protein kinase B (PKB) activity |
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2000
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2001
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- 2001-03-13 JP JP2001566691A patent/JP2003526675A/en active Pending
- 2001-03-13 AT AT01914289T patent/ATE328604T1/en not_active IP Right Cessation
- 2001-03-13 NZ NZ533844A patent/NZ533844A/en unknown
- 2001-03-13 EP EP01914289A patent/EP1265629B1/en not_active Expired - Lifetime
- 2001-03-13 PT PT01914289T patent/PT1265629E/en unknown
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- 2001-03-13 DE DE60120371T patent/DE60120371T2/en not_active Expired - Fee Related
- 2001-03-13 US US09/804,775 patent/US6696414B2/en not_active Expired - Fee Related
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- 2001-03-13 WO PCT/SE2001/000522 patent/WO2001068127A1/en active IP Right Grant
- 2001-03-13 CA CA002402948A patent/CA2402948A1/en not_active Abandoned
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| CA2402948A1 (en) | 2001-09-20 |
| SE0000837D0 (en) | 2000-03-13 |
| EP1265629A1 (en) | 2002-12-18 |
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| US6696414B2 (en) | 2004-02-24 |
| US20040147446A1 (en) | 2004-07-29 |
| EP1265629B1 (en) | 2006-06-07 |
| US7229965B2 (en) | 2007-06-12 |
| PT1265629E (en) | 2006-09-29 |
| DE60120371T2 (en) | 2007-05-16 |
| DE60120371D1 (en) | 2006-07-20 |
| ES2263601T3 (en) | 2006-12-16 |
| WO2001068127A1 (en) | 2001-09-20 |
| JP2003526675A (en) | 2003-09-09 |
| DK1265629T3 (en) | 2006-08-28 |
| US20010051601A1 (en) | 2001-12-13 |
| ATE328604T1 (en) | 2006-06-15 |
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