EP1009232A1 - Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque - Google Patents

Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque

Info

Publication number
EP1009232A1
EP1009232A1 EP97953324A EP97953324A EP1009232A1 EP 1009232 A1 EP1009232 A1 EP 1009232A1 EP 97953324 A EP97953324 A EP 97953324A EP 97953324 A EP97953324 A EP 97953324A EP 1009232 A1 EP1009232 A1 EP 1009232A1
Authority
EP
European Patent Office
Prior art keywords
igf
patient
amount
serum
insulin resistance
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.)
Withdrawn
Application number
EP97953324A
Other languages
German (de)
English (en)
Other versions
EP1009232A4 (fr
Inventor
Fred I. Chasalow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astex Pharmaceuticals Inc
Original Assignee
Amur Pharmaceuticals Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Amur Pharmaceuticals Inc filed Critical Amur Pharmaceuticals Inc
Publication of EP1009232A1 publication Critical patent/EP1009232A1/fr
Publication of EP1009232A4 publication Critical patent/EP1009232A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism

Definitions

  • This invention pertains to methods and compositions for treating insulin resistance and for ameliorating pathological conditions associated with insulin resistance. Also disclosed herein are methods for identifying patients at risk for developing non- insulin dependent diabetes melitis or insulin resistance. The invention also pertains to methods for identifying patients at risk for developing or suffering from reactive hypoglycemia and methods of treatment thereof.
  • Insulin resistance is an extremely common pathophysiological phenomenon that is implicated in non- insulin- dependent diabetes (NIDDM) , atherosclerotic cardiovascular disease, syndrome X, obesity, hypertension, dyslipidemias , and polycystic ovarian syndrome, among other pathological conditions (Moller et al . , Diabetes Care ⁇ :396, 1996). At least in some instances, insulin resistance is likely to be caused by competition between insulin and IGF-2 for binding to the insulin receptor, which is present on a large number of different cell rypes and which mediates the body's response to insulin. This is based in part on the correlation between IGF-2 concentrations and insulin requirements in children with diabetes (Chasalow et al., A_77er.Ped.S0c.
  • the present invention encompasses methods for treating insulin resistance in a patient in need of such treatment, which involve: (a) determining the concentration of IGF-2 in the patient's serum and (b) lowering the serum concentration of IGF-2 in the patient.
  • the methods are carried out by administering an agent selected from the group consisting of:
  • nucleic acid sequences encoding human 20K-GH or variants or derivatives thereof in a context that allows cells comprising said nucleic acids to express pharmacologically active 20K-GH or variants or derivatives thereof; (iii) antibodies specific to human 20K-GH that stabilize 20K-GH in the circulation; and
  • the agent (which may, in combination with a pharmaceutically acceptable carrier or diluent, comprise a pharmaceutical formulation) is administered in an amount and for a time sufficient to reduce the concentration of IGF-2 in the patient's circulation. Administration may be via any suitable method, including without limitation subcutaneous, intravenous, intramuscular, oral, intranasal, and mucosal modes of administration .
  • Non-limiting examples of pathological conditions to which the methods of the invention may be applied include non- insulin-dependent diabetes (NIDDM) , syndrome X, obesity, polycystic ovarian disorder, hair-AN syndrome, AIDS wasting, intra-uterine growth failure, post-natal growth failure, and Prader-Willi syndrome.
  • NIDDM non- insulin-dependent diabetes
  • syndrome X obesity
  • polycystic ovarian disorder obesity
  • hair-AN syndrome AIDS wasting
  • intra-uterine growth failure post-natal growth failure
  • Prader-Willi syndrome Prader-Willi syndrome.
  • human 20K-GH produced from a recombinant gene, or a pharmacologically active variant or derivative thereof is administered in an amount and for a time sufficient to reduce the concentration of IGF-2 in the serum of said patient .
  • humanized monoclonal antibodies specific for 20K-GH which stabilize 20K-GH in the circulation, are administered in an amount and for a time sufficient to reduce the concentration of IGF-2 in the serum of said patient.
  • the present invention provides a method for identifying a patient at risk for developing insulin resistance comprising the steps of:
  • the present invention provides a method for identifying a patient at risk for developing insulin resistance comprising the steps of: 5 (a) determining the amount of IGF-2 in said patients serum; and
  • IGF-2 present in said control.
  • the present invention provides a method for identifying a patient at risk for ⁇ developing reactive hypoglycemia comprising the steps of quantifying the amount of IGF- 2 in the patient's serum and comparing the amount with the amount of IGF- 2 in age and sex matched controls, wherein the patient is at risk for developing reactive hypoglycemia if the levels of IGF-2 are significantly lower than those present in said control .
  • the present invention provides methods for treating patients suffering from reactive hypoglycemia by administering an effective amount for treating reactive hypoglycemia of an agent selected from the group consisting of:
  • nucleic acid sequences encoding human 22K-GK or variants or derivatives thereof in a context that allows cells comprising said nucleic acids to express pharmacologically active 22K-GH or variants or derivatives thereof;
  • IGF-2 or derivatives or variants thereof in a context that allows cells comprising said nucleic acids to express pharmacologically active IGF- 2, and
  • 20K-GH refers to the isoform of human growth hormone that has a molecular weight of 20,200 and lacks amino acids 32-46 of the larger human growth hormone isoform, which is designated "22K-GH".
  • the mRNA encoding 20K-GH is formed from the
  • a "pharmacologically active variant" of 20K-GH is a polypeptide having a sequence 0 related to authentic 20K-GH that is capable of increasing insulin sensitivity in patients to whom it is administered.
  • an "effective treatment” for insulin resistance is a treatment that results in the lessening or amelioration of at least one symptom of the pathological 5 condition or syndrome that is caused or exacerbated by insulin resistance, or that results in a directly measurable increase in insulin sensitivity in the patient .
  • the present invention provides a method for treating insulin resistance in humans.
  • a C patient who exhibits one or more symptoms of insulin resistance or otherwise suffers from a pathological condition that is caused or exacerbated by insulin resistance is administered a treatment that lowers the serum concentration of IGF-2.
  • a reduction in the circulating level of IGF-2 is 5 achieved by administration of 20K-GH.
  • Increased insulin sensitivity is believed to result from a lowering of IGF-2.
  • the invention takes advantage of the different physiological effects of the two primary human GH isoforms and the pharmacokinetics of the IGFs to achieve a reversal of insulin resistance .
  • (i) Differen tial effects of GH isoforms The two GH isoforms, 22K-GH and 20K-GH, appear to differ in their effects on the synthesis and secretion of IGFs.
  • 22K-GH is known to stimulate both IGF-1 and IGF-2.
  • 20K-GH by contrast, appears to stimulate only IGF-1 and not IGF-2, based on the observation that 20K-GH does not exert the lipolytic effects which are observed with 22K-GH and which are believed to result from GH-mediated stimulation of IGF-2 ( Juarez -Aguilar et al . , Biochem. Biophys . Res . Comm . 211 :28 , 1995).
  • the present invention encompasses the administration of 20K-GH to modulate circulating levels of IGF-2.
  • IGF pharmacokinetics IGFs in serum interact with a family of binding proteins designated binding proteins 1-6
  • the major IGF binding protein in serum is bp3.
  • IGF-1 and IGF-2 bind with equal affinity to bp3.
  • binding of an IGF polypeptide to bp3 confers stability on the bound IGF; unbound IGFs have a half -life in serum of about 20 min, while bp3-bound IGFs have a half-life of 24-36 hours.
  • an increase in serum IGF-1 will displace bp3 -bound IGF-2. Since the displaced IGF-2 is unstable, displacement of IGF-2 from a bound to a free fraction should result in a decrease in the serum concentration of IGF-2.
  • At least one possible cause of insulin resistance in humans is an increased level of IGF-2 which competes with insulin for binding to the insulin receptor and thus decreases insulin sensitivity. Accordingly, the methods of the present invention, by lowering circulating IGF-2 levels, promote increased insulin sensitivity/decreased insulin resistance. Any detectable increase in insulin sensitivity is useful, whether by providing direct therapeutic benefit or by allowing the further optimization of treatment regimens.
  • IGF-2 levels are decreased by increasing the circulating levels of IGF-1.
  • This increase ir. circulating IGF-1 levels is preferably achieved by an indirect method, such as, for example, by treatments that increase the circulating levels of 20K-GH.
  • treatments include without limitation administration of any or all of the following: (i) 20K-GH polypeptide or pharmacologically active variants or derivatives thereof; (ii) nucleic acids encoding 20K-GH in a context that allows cells comprising the nucleic acids to express pharmacologically active 20K-GH polypeptide; and (iii) monoclonal anti-20K-GH antibodies.
  • the invention encompasses any treatment that increases the short-term or steady-state concentration of circulating 20K-GH, whether acting primarily by increasing the production of 20K-GH from an endogenous or recombinant gene (such as in methods (i) or (ii) above) or by stabilizing 20K-GH in the circulation (such as in method (iii) above) .
  • 20K-GH polypeptide 20K-GH or a pharmacologically active variant or derivative thereof for use in the present invention may be isolated from its native source or, preferably, from recombinant cells that have been programmed to produce it.
  • U.S. Patent No. 5,496,713 discloses methods for producing recombinant 20K-GH in E. coli ; however, any suitable host cell may be used.
  • 20K-GH or its derivatives may be chemically synthesized by commercially available automated procedures, including, without limitation, exclusive solid phase synthesis, partial solid phase methods, fragment condensation or classical solution synthesis.
  • any method for polypeptide purification well-known in the art may be used to isolate 20K-GH or a derivative, including without limitation preparative disc-gel electrophoresis , isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution.
  • Recombinant 20K-GH may also be produced containing an additional amino acid sequence that acts as a "tag" to facilitate purification, such as, but not limited to, a polyhistidine sequence.
  • the 20K-GH can then be purified from a crude lysate or extracellular medium of the host cell by chromatography on an appropriate solid-phase matrix.
  • anti-20K-GH antibodies can be used as purification reagents.
  • Other purification methods are possible. General protein purification methods are described in Protein Purifica tion : Principles and Practi ce, R.K. Scopes, Ed., 1987, Springer-Verlag, New York, NY.
  • Natural variants of 20K-GH have been reported, for example, 20K-GH with divergent sequences at codon 14 (Masuda et al . , Biochi . Biophys . Acta 949 : 125, 1988; and Martial et al . , Science 205 : 602, 1979) .
  • Another known variant is Met-20K-GH, which contains an additional methionine residue at the aminoterminus .
  • 20K-GH for use in the invention may also be conjugated to other molecules, such as, for example, polyethylene glycol, fatty acids, and the like.
  • the polypeptide may also be modified by, for example, N-acetylation, deamidation, phosphorylation, sulfation, and the like.
  • any variant or conjugate of 20K-GH may be used in practicing the invention, with the proviso that it is pharmacologically active, i.e., mediates an increase in insulin sensitivity in a patient to whom it is administered.
  • a particular 20K-GH variant may be identified as useful in practicing the invention by assessing whether it is capable of mediating one or more of the following activities: an increase in IGF-1, a decrease in IGF-2, or an increase in insulin sensitivity.
  • cultured human cells that secrete both IGF-1 and IGF-2 in response to 22K-GH and secrete only IGF-1 in response to 20K-GH are used to test the suitability of a particular 20K-GH.
  • 2OK-GH-encoding nucleic acids 20 K - GH - encoding nucleic acids may be DNA or RNA, and include sense and antisense sequences.
  • the nucleic acids may be flanked by their native regulatory sequences, or may be associated with heterologous sequences, including promoters, enhancers, response elements, signal sequences, polyadenylation sequences, introns, 5'- and 3'- noncoding regions, and the like.
  • the nucleic acids may also be modified by many means known in the art.
  • Non-limiting examples of such modifications include methylation, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates , phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates , etc.) .
  • uncharged linkages e.g., methyl phosphonates , phosphotriesters, phosphoroamidates, carbamates, etc.
  • charged linkages e.g., phosphorothioates, phosphorodithioates , etc.
  • Nucleic acids may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.) , and alkylators .
  • proteins e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.
  • intercalators e.g., acridine, psoralen, etc.
  • chelators e.g., metals, radioactive metals, iron, oxidative metals, etc.
  • alkylators e.g., alkylators.
  • the sequences are present in appropriate nucleic acid vectors operably linked to regulatory sequences that allow their expression in the recipient cells.
  • the expression may be transient or long-term, depending upon the expression system that is utilized. Any appropriate means for delivering the 20K-GH-encoding nucleic acids to the recipient cells may be used, including packaging in liposomes or recombinant viruses.
  • both in vivo and ex vivo approaches may be used.
  • the nucleic acids are introduced directly into the patient; for ex vivo approaches, appropriate recipient cells are first removed from the patient and contacted with the 20K-GH-encoding nucleic acids under conditions appropriate for uptake and expression, after which the transformed cells are re- introduced into the patient.
  • Monoclonal anti-20K-GH antibodies An increase insulin sensitivity according to the present invention may also be achieved by increasing the stability of serum 20K-GH and thereby raising its steady- state concentration.
  • any compound may be administered that binds to circulating 20K-GH and retards its degradation, with the proviso that the complex retains the pharmacological activity of 20K-GH in reducing insulin resistance.
  • monoclonal antibodies specific for 20K-GH are used.
  • antibodies "specific for 20K- GH” recognize and bind to 20K-GH with a sufficient affinity to stabilize it; but, conversely, do not recognize and/or bind tc 22K-GH with sufficient affinity to stabilize it.
  • the antibodies are "humanized", i.e., human Fc sequences are present in the antibody molecule to prevent an adverse immune response in a patient to whom the antibodies are administered. (See below.)
  • the present invention can be applied to any syndrome or disorder that is associated with insulin resistance, low serum levels of 20K-GH, and/or high serum levels of IGF-2, including without limitation non- insulin-dependent diabetes (NIDDM) , syndrome X, obesity, polycystic ovarian disorder, hair-AN syndrome, AIDS wasting, intra-uterine growth failure, post-natal growth failure, and Prader-Willi syndrome.
  • NIDDM non- insulin-dependent diabetes
  • Therapeutic administration can be determined by experimentation known in the art, such as by establishing a matrix of dosages and frequencies and comparing a group of experimental units or subjects to each point in the matrix. It will be understood that the administration regimen
  • amount and frequency of administration will vary depending upon the agent itself, the syndrome being treated, and the age, gender, and physical condition of the patient. Any lessening or amelioration of any clinical signs or symptoms of a particular condition or syndrome caused or exacerbated by insulin resistance pursuant to treatment as disclosed herein is within the scope of the invention. Included are any treatments that allow a reduction in the amount and frequency of administration of other drugs used to treat the syndromes, such as, e.g., sulfonylureas , biguanides, ⁇ -glucosidase inhibitors, and insulin (Tan et al . , Mayo Clin . Proc . 71:763, 1996).
  • Administration may be via any suitable method, including without limitation subcutaneous, intravenous, intramuscular, oral, intranasal, and mucosal modes of administration.
  • mucosal administration encompasses the use of suppositories.
  • 20K-GH is administered in an effective amount ranging between about 0.0001 and about 0.06 mg/kg/day, preferably between about 0.0005 and about 0.005 mg/kg/day.
  • the dosage and administration regimen of long-acting 20K-GH derivatives is modified to take advantage of this property.
  • humanized antibody specific for 20K-GH is administered in sufficient amounts and at sufficient intervals to achieve a detectable increase in circulating 20K-GH. It will be understood that the particular amounts and times of administration will depend upon the particular properties of the antibody being used, including, for example, relative affinities for 20K-GH and 22K-GH and half-life in the circulation.
  • the agents of the invention may, in combination with a pharmaceutically acceptable carrier or diluent, comprise pharmaceutical formulations.
  • a pharmaceutically acceptable carrier or diluent comprise pharmaceutical formulations.
  • pharmaceutical formulations for general information concerning formulations, see, e.g., Gilman et al . (eds.), 1990, Goodmans and Gilman ' s : The Pharmacological Basis of Therapeu tics , 8th Ed., Pergamon Press; and Remington ' s Pharmaceutical Sciences , 17th ed. , 1990, Mack Publishing Co., Easton, PA; Avis et al . (eds.), 1993, Pharmaceu tical Dosage Forms : Parenteral Medi ca tions , Dekker, New York; Lieberman et al . (eds), 1990, Pharmaceutical Dosage Forms : Disperse Systems, Dekker, New York.
  • the invention also encompasses diagnostic tests that are performed to identify patients at risk for developing insulin resistance or non-insulin dependent diabetes melitus (NIDDM) and/or those patients whose pathological conditions are likely to respond to the methods of the invention.
  • NIDDM non-insulin dependent diabetes melitus
  • serum levels of 20K-GH will be low in individuals suffering from NIDDM or insulin resistance.
  • an assay for serum levels of 20K-GH can be used to evaluate the risk of a patient developing NIDDM or insulin resistance as set forth below.
  • the determination involves (i) obtaining a serum sample from the patient; (ii) measuring the absolute amount of 20K-GH in the sample; and (iii) comparing the amount measured in step (ii) with pre-determined levels of 20K-GH in normal subjects matched with the patient with respect to age, gender, etc. If the amount of 20K-GH is significantly lower than that present in the normal subjects, the patient is at risk for developing insulin resistance.
  • 20K-GH and 22K-GH may be measured using any method known in the art, including without limitation immunological methods such as radioimmunoassay, receptor binding assay, physical methods such as gel electrophoresis or chromatography, or combinations of the foregoing. It will be understood that normal levels of 20K-GH and 22K-GH for comparison will be determined using the same assay method, or, in the alternative, that normalization factors will be used to allow a comparison of GH levels.
  • antibodies specific for 20K- GH will be generated as follows.
  • the growth hormone gene codes for the expression of two proteins which differ by an internal 15 amino acid deletion.
  • the cause of the deletion is the expression of an alternate splice in one of the non-translated portions of the gene.
  • peptides will be selected across the bridge of the deletion (between the Phe and the Agn aminc acid residues disclosed below) .
  • Non-limiting examples of useful peptides are set forth below in Table I .
  • Each peptide will be coupled to an antigen and used to immunize rabbits for polyclonal antibody production or to mice for monoclonal antibody production. It should be noted that direct administration of 20K-GH to either rabbits or mice yields antibodies that cross-react with both 20K-GH and 22K-GH.
  • the antibodies can be used to generate an assay for 20K-GH in several different formats.
  • the peptides will be coupled to thyroglobulin using commercially available reagents (Pierce, Rockford, IL) and bound to a 96-well ELISA plate (as described in Steroids 12.:682-687, 1996) .
  • a sample standard, control or unknown
  • the antibody would be added, incubated and washed. The amount of antibody remaining on the plate would be quantitated with ELISA techniques.
  • the wells with standards would be used to generate a standard curve and use to evaluate controls and unknowns .
  • 20K-GH could be bound to each well.
  • the peptides would be radioiodinated, and used as a tracer in a standard RIA format.
  • 20K-GH could be iodinated and used in an RIA format.
  • a sandwich assay the 20K-GH specific antibody could be bound to the well and incubated with standards, controls and unknowns. After washing, a second antibody specific for both 20K-GH and 22K-GH could be added. The amount of the second antibody could be determined by ELISA or by radioiodination of the second antibody.
  • data will be generated on the normal values of 20K-GH. This would include evaluating ranges in normal subjects of different ages, sexes, degrees of adiposity, blood pressure and health history. It will also be necessary to evaluate time of day, time of month (women) , exercise status, and estimated dietary fat content as variables. Serum obtained from subjects with family histories of NIDDM and newly diagnosed patients would be compared with the normal curve . Other studies to validate the assay will correlate 20K-GH levels with IGF-1, IGF-2, IGF-bp3, hemoglobin A1C, serum glucose levels, and insulin requirements in patients with NIDDM.
  • Hypoglycemia is an abnormally low blood glucose level.
  • "Reactive hypoglycemia” is abnormally low blood glucose levels in response to specific factors such as a meal, nutrients, or drugs. It is distinguished from spontaneous hypoglycemia in that it occurs following administration of exogenous factors such as meals (e.g. containing carbohydrates), specific nutrients which inhibit hepatic glucose output, drugs which lead to excess glucose utilization (such as insulin) or those leading to deficient glucose production (alcohol, salicylates, aminobenzoic acid, etc.) as described in The Merck Manual of Diagnosis and Therapy, Vol. 1, 15th Edition, pp.
  • the present invention provides a method for identifying a patient at risk for or suffering from reactive hypoglycemia comprising the steps of determining the amount of IGF- 2 in the patient's serum and comparing the amount of IGF-2 in the patient's serum with the amount of IGF- 2 present in age and sex matched control serum, wherein the patient is at risk for reactive hypoglycemia if the amount of IGF-2 present in the patient's serum is significantly lower than the amount of IGF-2 present in the control serum.
  • the present invention provides a method for treating reactive hypoglycemia in a patient by administering an agent selected from the group consisting of 22K-GH, a pharmacologically active variant or a derivative thereof in an amount and for a time sufficient to increase the concentration of IGF-2 in the serum of said patient.
  • an effective amount for treating reactive hypoglycemia of IGF-2 or variants thereof can be (directly or indirectly) administered.
  • Direct administration comprises introducing the protein whereas indirect administration comprises introducing a recombinant gene encoding IGF-2.
  • the gene can be administered ex vivo .
  • the DNA and amino acid sequence IGF-2 is disclosed in Rinderknect et al . FEBS Letters 89 (2) :283-286, 1978. Variants of IGF-2 have been described in FEBS Letters 179 : (2) ,-243-246, 1985.
  • Example 1 is intended to serve as non- limiting illustrations of the present invention.
  • Example 1 is intended to serve as non- limiting illustrations of the present invention.
  • a patient suffering from non- insulin dependent diabetes A patient suffering from non- insulin dependent diabetes
  • the treatment results in a reduction in the amount of 0 insulin that the patient requires on a daily basis to maintain euglycemia .
  • Another patient suffering from non-insulin dependent diabetes who currently takes 3.75 mg of Glyburide per day, receives a daily intramuscular injection of controlled release 5 formulation containing 20K-GH in sterile buffered saline.
  • the patient receives about 0.07 mg 20K-GH per dose, equivalent to 0.001 mg/kg/day 20K-GH.
  • the treatment results in (a) reduction in the amount of Glyburide needed; (b) the patient no longer needs Glyburide to C maintain euglycemia or has improved euglycemia control. Therapy need not be on an every day basis.
  • the following experiments are performed to evaluate the suitability of 20K-GH variants or derivatives for use in practicing the present invention.
  • the primary determination is achieved by comparing a particular 20K-GH variant or derivative with authentic 20K-GH itself with respect to the ability to differentially stimulate the release of IGF-1 and not IGF-2 from human cells in culture.
  • a human hepatocyte cell culture such as, e.g., HepG2 , is incubated individually with 22K-GH, 20K-
  • the stimulatory effect on IGF-1 and IGF-2 is assessed after different times of incubation by: (1) quantifying mRNA encoding IGF-1 and IGF-2; and/or
  • Both determinations are performed using methods well- known in the art, such as, for example, Northern blot hybridization (to measure mRNA) and radioimmunoassay (to measure secreted polypeptides) .
  • Example 3 Treatment of Reactive Hypoglycemia
  • IGF-1 levels are normal but IGF-2 levels are more than two standard deviations below the expected levels for a person of the same age, sex and body weight.
  • the patient is treated by administering IGF-2 or 22K-GH in a long-acting controlled release formulation.
  • the result of the above treatment is that IGF-2 levels are increased and hypoglycemic episodes become less frequent .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Rehabilitation Therapy (AREA)
  • Rheumatology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Obesity (AREA)
  • Microbiology (AREA)
  • Emergency Medicine (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)

Abstract

La présente invention concerne des compositions et des méthodes destinées au traitement de l'insulinorésistance et à l'amélioration de conditions pathologiques liées à celle-ci. L'invention concerne également des procédés d'identification de patients susceptibles de développer un diabète sucré non insulinodépendant ou une insulinorésistance. L'invention concerne, en outre, des procédés d'identification de patients susceptibles de développer une hypoglycémie réactive ou d'en souffrir, et des méthodes de traitement de ceux-ci.
EP97953324A 1996-12-24 1997-12-23 Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque Withdrawn EP1009232A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US3450496P 1996-12-24 1996-12-24
US34504P 1996-12-24
US3741797P 1997-02-21 1997-02-21
US37417P 1997-02-21
PCT/US1997/023481 WO1998027813A1 (fr) 1996-12-24 1997-12-23 Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque

Publications (2)

Publication Number Publication Date
EP1009232A1 true EP1009232A1 (fr) 2000-06-21
EP1009232A4 EP1009232A4 (fr) 2002-06-12

Family

ID=26711037

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97953324A Withdrawn EP1009232A4 (fr) 1996-12-24 1997-12-23 Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque

Country Status (5)

Country Link
EP (1) EP1009232A4 (fr)
JP (1) JP2001508770A (fr)
AU (1) AU5709698A (fr)
CA (1) CA2276149A1 (fr)
WO (1) WO1998027813A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4228675A1 (fr) * 2020-10-13 2023-08-23 Betavive Ltd. Méthode et composés pour le traitement du diabète et des maladies métaboliques associées

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8920381D0 (en) * 1989-09-08 1989-10-25 Greater Glasgow Health Board Treatment of insulin-resistant diabetes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHASALOW F I ET AL: "CORRELATION OF IGF-2 CONCENTRATIONS WITH INSULIN REQUIREMENTS IN DIABETES MELLITUS" PEDIATRIC RESEARCH, WILLIAMS AND WILKINS, BALTIMORE, MD,, US, vol. 37, no. 4, PART 2, 1994, page 86A XP001024844 ISSN: 0031-3998 *
FROESCH ER ET AL.: "Insulin-like growth factor-I in the therapy of non-insulin-dependent diabetes mellitus and insulin resistance" DIABETES & METABOLISM (PARIS), vol. 22, 1996, pages 261-267, XP001041950 *
FROST RA ET AL.: "Wasting in the acquired immune deficiency syndrome is linked associated with multiple defects in serum inulin-like growth factor system" CLINICAL ENDOCRINOLOGY, vol. 44, May 1996 (1996-05), pages 501-514, XP001024899 *
JOHANSSON JO ET AL.: "Growth hormone deficient adults are insulin-resistant" METABOLISM, vol. 44, no. 9, 1995, pages 1126-1129, XP001041622 *
JUÁREZ-AGUILAR E ET AL.: "22-kDa and 20-kDa isoforms show differential effects when assayed in 3T3-F442A and T3-F442A/C4 adipiocytes" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATION, vol. 217, no. 1, 1995, pages 28-33, XP001024865 *
See also references of WO9827813A1 *

Also Published As

Publication number Publication date
AU5709698A (en) 1998-07-17
EP1009232A4 (fr) 2002-06-12
JP2001508770A (ja) 2001-07-03
WO1998027813A1 (fr) 1998-07-02
CA2276149A1 (fr) 1998-07-02

Similar Documents

Publication Publication Date Title
Cummins et al. Cardiac specific troponin-I release in canine experimental myocardial infarction: development of a sensitive enzyme-linked immunoassay
US6455267B1 (en) Methods and kits useful for determining the status of and detecting pancreatic B-cell associated autoimmune diseases
Benson et al. Familial amyloidotic polyneuropathy
Löfberg et al. Immunohistochemical characterization of the amyloid deposits and quantitation of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis.
US7815905B2 (en) Methods of increasing insulin sensitivity or decreasing insulin secretion by administering corticotropin releasing factor receptor-2 inhibitors
JP3666866B2 (ja) 神経保護治療をモニターする方法
US5512447A (en) Methods for the diagnosis and treatment of diabetes
Stein et al. Plasma neuropeptide Y in anxiety disorders: findings in panic disorder and social phobia
US11155584B2 (en) Unstructured non-repetitive polypeptides having LCST behavior
Fukui et al. Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy
US5919902A (en) Leptin bound to inter-alphatrypsin inhibitor and uses thereof
Osterman et al. Serum carbonic anhydrase III in neuromuscular disorders and in healthy persons after a long-distance run
EP1009232A1 (fr) Methodes de traitement de l'insulinoresistance et procedes d'identification de patients presentant ce risque
US20020165127A1 (en) Methods for treating insulin resistance and identifying patients at risk for the disease
JP2006523678A (ja) Ｓｌｕｒｐ−１組成物及びその使用方法
CN112368294A (zh) 用于治疗风湿性关节炎的肽以及其用途
Morano et al. Autoimmune markers and neurological complications in non-insulin-dependent diabetes mellitus
Maringhini et al. Is the plasma amino acid consumption test an accurate test of exocrine pancreatic insufficiency?
US5766856A (en) Diagnostic method for evaluating advanced glycosylation endproducts using MAC-2 receptor
Klein et al. High performance liquid chromatography used to distinguish the autoimmune hypoglycemia syndrome from factitious hypoglycemia
EP1171157B1 (fr) Utilisation de la glucose-6-phospate isomerase et de ses anticorps pour le diagnostic et le traitement de l'arthrite; essai de composes anti-arthritiques
Retegui et al. Specificities of antibodies to human growth hormone (hGH) in patients treated with hGH: longitudinal study and comparison with the specificities of animal antisera
US7662375B2 (en) Use of glucose-6-phosphate isomerase and antibodies thereto for the diagnosis and therapy of arthritis, and test of anti-arthritic compounds
Heaton et al. B-cell responses to intravenous glucose and glucagon in non-diabetic twins of patients with type 1 (insulin-dependent) diabetes mellitus
Tanaka et al. Levels of proelafin peptides in the sera of the patients with generalized pustular psoriasis and pustulosis palmoplantaris

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990727

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SUPERGEN, INC.

A4 Supplementary search report drawn up and despatched

Effective date: 20020503

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 01N 37/18 A, 7A 61K 38/00 B, 7A 61K 38/28 B, 7A 61K 38/27 B

17Q First examination report despatched

Effective date: 20021120

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030401