US20060199761A1 - Insulin resistance improving agent - Google Patents

Insulin resistance improving agent Download PDF

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US20060199761A1
US20060199761A1 US10/502,051 US50205104A US2006199761A1 US 20060199761 A1 US20060199761 A1 US 20060199761A1 US 50205104 A US50205104 A US 50205104A US 2006199761 A1 US2006199761 A1 US 2006199761A1
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adiponectin
mice
insulin
insulin resistance
diabetes
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Takashi Kadowaki
Toshimasa Yamauchi
Junji Kamon
Hironori Waki
Ryozo Nagai
Satoshi Kimura
Motto Tomita
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Japan Science and Technology Agency
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Japan Science and Technology Agency
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Assigned to JAPAN SCIENCE AND TECHNOLOGY AGENCY reassignment JAPAN SCIENCE AND TECHNOLOGY AGENCY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WAKI, HIRONORI, KIMURA, SATOSHI, TOMITA, MOTOO, NAGAI, RYOZO, KAMON, JUNJI, KADOWAKI, TAKASHI, YAMAUCHI, TOSHIMASA
Publication of US20060199761A1 publication Critical patent/US20060199761A1/en
Priority to US12/041,279 priority Critical patent/US7850976B2/en
Priority to US12/906,374 priority patent/US20110065780A1/en
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    • 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
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an insulin resistance improving agent useful for the prevention and treatment of obesity, diabetes, and cardiovascular diseases, as well as to a drug for treating type 2 diabetes.
  • adipose tissue has been considered a mere storage medium for excess energy.
  • the physiologically active substances are collectively called adipocytokines, and specific members which have been known to date include leptin, tumor necrosis factor- ⁇ (TNF- ⁇ ), plasminogen-activator inhibitor type 1 (PAI-1), adipsin, and resistin.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • PAI-1 plasminogen-activator inhibitor type 1
  • resistin resistin.
  • Adiponectin has recently been identified as an adipocytokine. Adiponectin was originally identified independently by four research groups that used different approaches. Adiponectin cDNA was isolated by large-scale random sequencing of a 3′-directed, human-adipose-tissue cDNA library. Mouse cDNAs for adiponectin termed AcrpSO and AdipoQ were cloned through differential display before and after differentiation of mouse 3T3-L1 and 3T3-F442A cells, respectively. Human adiponectin was also purified from plasma as gelatin-binding protein 28.
  • Insulin resistance induced by high-fat diet and accompanied with obesity is a major risk factor for diabetes and cardiovascular diseases, and therefore, capacity to improve insulin resistance is a key factor for determining that a certain drug is effective for the treatment of diabetes.
  • an object of the present invention is to provide a novel drug which improves insulin resistance and thus is useful in the treatment of diabetes.
  • the present inventors have investigated effects of adiponectin through use of model mice of different types; i.e., mice in which insulin sensitivity had been modified, obese mice, and type 2 diabetes mice, and have found that decrease in expression or loss of expression of adiponectin is a cause for development of insulin resistance, and that administration of adiponectin or a fragment of adiponectin, or introduction of any of their genes, is effective for the treatment of insulin-resistant diabetes and type 2 diabetes, thereby leading to completion of the invention.
  • the present invention provides an insulin resistance improving agent containing, as an active component, a C-terminal globular region, adiponectin, or a gene for the globular region or adiponectin.
  • the present invention also provides a therapeutic drug for type 2 diabetes, containing, as an active component, a C-terminal globular region, adiponectin, or a gene for the globular region or adiponectin.
  • FIG. 1 shows the amounts of adiponectin mRNA in WAT (a) and serum adiponectin levels (b) of db/db mice.
  • FIG. 2 shows the calculated areas under (a) the glucose curves and (b) the insulin curves obtained through a glucose tolerance test of db/db mice.
  • FIG. 3 shows the amounts of adiponectin mRNA in 3T3L1 adipocytes.
  • FIG. 4 shows the amounts of LPL mRNA in WAT.
  • FIG. 5 is a graph showing the epididymal WAT weight.
  • FIG. 6 shows images of the abdominal cavities of mice, which show loss of WAT.
  • FIG. 7 shows the results of immunoblotting through use of anti-adiponectin antibody.
  • FIG. 8 shows insulin resistance indices.
  • FIG. 9 shows expression of mRNAs of CD36, ACO, UCP2, and PPAR- ⁇ in the mouse skeletal muscle.
  • FIG. 10 shows expression of mRNAs of CD36, ACO, UCP2, and PPAR- ⁇ in the mouse liver.
  • FIG. 11 shows insulin-induced tyrosine phosphorylation and insulin (Ins)-stimulated phosphorylation of Akt of insulin receptor (IR) and insulin receptor substrate (IRS)-1 in the mouse skeletal muscle.
  • FIG. 12 shows serum adiponectin levels obtained through a glucose tolerance test of C57 and db/db mice.
  • FIG. 13 shows the calculated areas under the glucose curves obtained through glucose tolerance test of C57 and db/db mice.
  • FIG. 14 shows calculated areas under the insulin curves obtained through glucose tolerance test of C57 and db/db mice.
  • FIG. 15 shows serum adiponectin levels obtained through a glucose tolerance test of KK and KKA y mice.
  • FIG. 16 shows calculated areas under the glucose curves obtained through a glucose tolerance test of KK and KKA y mice.
  • FIG. 17 shows calculated areas under the insulin curves obtained through a glucose tolerance test of KK and KKA y mice.
  • Adiponectin to be used in the present invention has already been cloned [Maeda, K. et al., Biochem. Biophys. Res. Commun. 221, 286-296 (1996), Nakano, Y. et al., J. Biochem. (Tokyo) 120, 802-812 (1996)], and therefore, is available through known means.
  • SEQ ID NOs: 1 and 2 show the amino acid sequence and the nucleotide sequence of human adiponectin, respectively.
  • Adiponectin consists of an N-terminal collagen-like domain (cAd) and a C-terminal globular domain (gAd; in SEQ ID NO: 1, amino acid Nos. 114 to 239 or 111 to 242).
  • the C-terminal globular domain (gAd) is highly preferred, as it provides stronger effect in alleviating high blood sugar and hyperinsulinemia.
  • SEQ ID NOs: 3 and 4 show the amino acid sequence and nucleotide sequence of mouse adiponectin, respectively.
  • the cAd domain of mouse adiponectin extends from the 45th to 109th amino acid residues, and the gAd domain of the same extends from the 110th to 247th amino acid residues.
  • proteins that can be employed in the present invention are not limited to a protein having any of amino acid sequences of SEQ ID NOs: 1 to 4 or a protein having an amino acid sequence exhibiting the gAd domain; any other protein may be employed, even though it is a protein derived therefrom through substitution, deletion, or addition of one or more amino acid residues, so long as it exhibits effects equivalent to those of adiponectin.
  • Examples of the amino acid sequence derived through substitution, deletion, or addition of one or more amino acid residues in the amino acid sequence include those sequences having 80% or more homology, more preferably 90% or more homology, to the sequence of SEQ ID NO: 1.
  • genes which may be used in the present invention include a gene encoding adiponectin of SEQ ID NO: 1, and a gene encoding gAd. Moreover, genes having a nucleotide sequence capable of being hybridized with any of these genes under stringent conditions may also be used.
  • a polypeptide of adiponectin or a portion thereof may be separated from the cells containing it.
  • the polypeptide since a cloned gene capable of encoding adiponectin has already become available, the polypeptide may be prepared by means of the DNA recombinant technique. Specifically, an expression vector is prepared by use of the gene, and the vector is used to create transformant cells.
  • model mice in which insulin sensitivity had been modified were found to exhibit a reduction in expression of adiponectin and development of insulin resistance simultaneously.
  • Adiponectin reduces insulin resistance by lowering the triglyceride content of the muscles and the liver of an obese mouse. This mechanism is based on an elevated expression of a molecule which participates in both burning of fatty acids and energy consumption in the muscles.
  • the insulin resistance in lipoatrophic mice was alleviated by single use of either adiponectin or leptin. However, when adiponectin and leptin were used in combination, full alleviation was attained.
  • adiponectin In any of obese model mice and lipoatrophic model mice, reduced adiponectin participates in the manifestation of insulin resistance. Therefore, adiponectin has thus been proven to serve as a new type of remedy for alleviation of insulin resistance and treatment of type 2 diabetes.
  • a pharmacologically acceptable carrier may be added to the aforementioned active component, thereby forming pharmaceutical compositions suitable for different manners of administration.
  • a preferred manner of administration is injection.
  • the pharmacologically acceptable carrier include distilled water, a solubilizer, a stabilizer, an emulsifier, and a buffer.
  • the dose of any of the drugs differs depending on the pathological condition, sex, body weight, etc. of the patient, and may be approximately 0.1 ⁇ g to 10 mg/day as reduced to the amount of adiponectin.
  • Rosiglitazone (PPAR- ⁇ agonist) and HX531 (PPAR- ⁇ /RXR inhibitor) were synthesized as described in the literature (Chem. Pharm. Bull. (Tokyo) 47, 1778-1786 (1999), Diabetes 47, 1841-1847 (1998)).
  • PPAR- ⁇ +/ ⁇ mice were prepared in a manner which had already been reported (Mol. Cell 4, 597-609 (1999)). All other animals were purchased from Nippon CREA. Six-week-old mice were fed powdered chow, and drugs were given as feed admixtures as described (Mol. Cell 4, 597-609 (1999)).
  • Serum adiponectin levels were determined by immunoblotting with the polyclonal antibody against gelatin-binding protein 28 (raised against the peptide of CYADNDNDSTFTGFLLYHDTN, which corresponds to the C-terminal 20 amino acid residues of human adiponectin with an extra cysteine at its N terminus) through use of a recombinant adiponectin as standards (J. Biochem. (Tokyo) 120, 802-812 (1996)). The procedures used for immunoprecipitation and immunoblotting have been described (Mol. Cell. Biol. 16, 3074-3084 (1996)). The data from one of three independent experiments are shown as representative data.
  • Plasma glucose, serum FFA, and triglyceride levels were determined through a glucose B-test, nonesterified fatty acid (NEFA) C-test, and triglyceride L-type (Wako Pure Chemicals), respectively.
  • Plasma insulin was measured by insulin immunoassay (Morinaga Institute of Biological Science) (Diabetes 47, 1841-1847 (1998)). Leptin was assayed with an ELISA-based Quantikine M mouse leptin immunoassay kit (R&D Systems) according to the manufacturer's instructions.
  • Bacterial extracts were prepared using standard methods, and the fusion proteins were purified by elution by use of a nickel-ion agarose column (Diabetes 47, 1841-1847 (1998)). ActiClean Etox affinity columns (Sterogene Bioseparations) were used to remove potential endotoxin contaminations.
  • Adiponectin or leptin was administered to mice through intraperitoneal injection or continuous systemic infusion as described (Nature 401, 73-76 (1999)).
  • An Alzet micro-osmotic pump (model 1002, Alza) was inserted subcutaneously in the back of each mouse.
  • a daily dose shown in Figures
  • recombinant leptin (Sigma) or adiponectin was dissolved in a total volume of 0.1 mL of PBS, and the solution was delivered to mice through the pump for twelve days.
  • the insulin resistance index was calculated from the product of the areas of glucose and insulin ⁇ 10 ⁇ 2 in glucose tolerance test (Mol. Cell 4, 597-609 (1999)). The results are expressed as the percentage of the value of each control.
  • adiponectin is reported to be decreased in obesity
  • FIG. 1 shows amounts of the adiponectin mRNA in WAT ( FIG. 1 a ) or serum levels of adiponectin ( FIG. 1 b ) of db/db mice on the high-carbohydrate diet (HC), on the high-fat diet (HF), or on the high-fat diet and treated with rosiglitazone (HF+Rosi).
  • FIG. 2 shows values of area under the glucose curve ( FIG. 2 a ) and area under the insulin curve ( FIG. 2 b ) obtained through a glucose tolerance test of db/db mice which had been subjected to the high-carbohydrate diet (HC), to the high-fat diet (HF), or to the high-fat diet and treated with rosiglitazone (HF+Rosi). Results are expressed as the percentage of the value based on that of untreated mice on the HC diet.
  • FIG. 3 shows amounts of adiponectin mRNA in 3T3L1 adipocytes which were untreated ( ⁇ ) or treated with 1 ⁇ M rosiglitazone (Rosi) for 24 hours.
  • a high-fat diet reduced the mRNA levels in white adipose tissue (WAT) ( FIG. 1 a ) and serum levels of adiponectin ( FIG. 1 b ) in mice with hyperglycemia ( FIG. 2 a ) and hyperinsulinemia ( FIG. 2 b ). Rosiglitazone significantly increased the mRNA levels in WAT ( FIG. 1 a ) and serum levels of adiponectin ( FIG. 1 b ) in mice on high-fat diet, and, at the same time, ameliorated hyperglycemia ( FIG. 2 a ) and hyperinsulinemia ( FIG. 2 b ).
  • PPAR- ⁇ +/ ⁇ mice were treated with HX531 for six weeks (+) or untreated ( ⁇ ), recombinant full-length adiponectin (Ad), gAd, or leptin (Lep) was administered to each mouse at a predetermined dose ( ⁇ g/day). Unless otherwise described herein, administration was performed through continuous systemic infusion (pump) in combination with a high-fat (HF) diet for the final twelve days of the six-week HX531 treatment.
  • HF high-fat
  • FIG. 4 shows amounts of LPL mRNA in WAT.
  • FIG. 5 shows epididymal WAT weight.
  • FIG. 6 presents images of the abdominal cavities of the mice illustrating loss of WAT.
  • FIG. 7 shows serum adiponectin levels determined by immunoblotting with anti-adiponectin antibody through use of recombinant adiponectin as standards.
  • lane 9 shows the serum adiponectin level when 50 ⁇ g of Ad was administered to mice through intraperitoneal (ip) injection.
  • FIG. 8 shows insulin resistance indices. The results are expressed as the percentage of the value based on that of untreated PPAR- ⁇ +/ ⁇ mice on the high-fat diet.
  • a PPAR- ⁇ /RXR inhibitor such as an RXR antagonist HX531 to PPAR- ⁇ +/ ⁇ mice for three weeks markedly lowered expression of genes responsive to PPAR- ⁇ /RXR, such as lipoprotein lipase (LPL) in WAT (about 90% or further; FIG. 4 ), indicating that PPAR- ⁇ /RXR activity was likely to be significantly decreased.
  • LPL lipoprotein lipase
  • Adiponectin was completely absent in sera from the lipoatrophic mice, whereas adiponectin was detected as a 35-kD protein with an antibody against adiponectin in sera from control mice ( FIG. 7 , lanes 6 and 7).
  • Tissue triglyceride content and free fatty acid in serum in the lipoatrophic mice were also determined.
  • PPAR- ⁇ +/ ⁇ mice were treated with HX531 for six weeks (+) or untreated ( ⁇ ), recombinant full-length adiponectin (Ad), gAd, or leptin (Lep) was administered to each PPAR- ⁇ +/ ⁇ mouse at a predetermined dose ( ⁇ g/day). Administration was performed through continuous systemic infusion in combination with the high-fat (HF) diet for the final twelve days of the six-week HX531 treatment (six weeks).
  • HF high-fat
  • the lipoatrophic mice showed increased serum free fatty acid (FFA) levels, increased triglyceride levels, increased tissue triglyceride content in skeletal muscle and liver (Table 1) as well as hyperinsulinemia and hyperglycemia ( FIG. 8 ).
  • FFA serum free fatty acid
  • adiponectin was administered to the mice.
  • Continuous systemic infusion of recombinant adiponectin at a physiological concentration significantly ameliorated hyperglycemia and hyperinsulinemia ( FIG. 8 ).
  • Adiponectin is composed of an N-terminal collagen-like sequence (cAd) and a C-terminal globular domain (gAd) (see SEQ ID NO: 1). An analysis was performed to determine which domain exerts these physiological effects. As a result, gAd ameliorated hyperglycemia and hyperinsulinemia much more potently than full-length adiponectin ( FIG. 8 ). A 25-kD protein recognized by an antibody against C-terminal portion of adiponectin was present in the serum, albeit in a very small amount, suggesting that full-length adiponectin might undergo proteolytic processing.
  • adiponectin is one of such adipocytokines.
  • Administration of adiponectin at a physiological concentration was not sufficient to completely ameliorate insulin resistance in mice without adipose tissue.
  • Leptin has also been known to be such an adipocytokine. Serum leptin levels were undetectable in these mice (upper limit: 0.2 ng/ml).
  • Administration of leptin to these mice at a physiological concentration did indeed alleviate their insulin resistance, albeit partially ( FIG. 8 ).
  • Administration of adiponectin and leptin in combination at a physiological concentration almost completely removed insulin resistance synergistically ( FIG. 8 ).
  • FIGS. 9 and 10 show mRNAs of fatty-acid translocase (FAT)/CD36, ACO, UCP2, and PPAR- ⁇ in mouse skeletal muscle and in liver, respectively.
  • FIG. 11 shows insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS)-1 in skeletal muscle, and insulin-stimulated phosphorylation of Akt in skeletal muscle.
  • IR insulin receptor
  • IRS insulin receptor substrate
  • Increased tissue triglyceride content has been reported to interfere with insulin-stimulated activation of phosphatidylinositol-3-kinase and subsequent translocation of glucose-transporter protein 4 to surfaces of cell membrane and uptake of glucose, which leads to development of insulin resistance.
  • decreased triglyceride content in muscle might contribute to the improved insulin signal transduction, as demonstrated by increase in insulin-induced tyrosine phosphorylation of insulin receptor and insulin-receptor substrate 1, as well as increases in insulin-stimulated phosphorylation of Akt kinase in skeletal muscle of adiponectin-administered lipoatrophic mice ( FIG. 11 ).
  • adiponectin can improve insulin resistance and diabetes in db/db and KKA y mice (KK mice overexpressing agouti), two different mouse models of type 2 diabetes characterized by obesity, hyperlipidemia, insulin resistance, and hyperglycemia.
  • FIGS. 12 to 17 serum levels of adiponectin ( FIGS. 12 and 15 ), areas under the glucose curve ( FIGS. 13 and 16 ), and areas under the insulin curve ( FIGS. 14 and 17 ), obtained through glucose tolerance test (GTT) of C57 or db/db mice (FIGS. 12 to 14 ) or of KK or KKA y mice (FIGS. 15 to 17 ).
  • GTT glucose tolerance test
  • the mice were fed an HC or HF diet.
  • Ad or gAd was administered, or none of these was administered, to the mice at a predetermined dose ( ⁇ g/day).
  • Serum adiponectin levels were determined by immunoblotting with anti-adiponectin antibody through use of a recombinant adiponectin as standards ( FIGS. 12 and 15 ). The results are expressed as the percentage of the value based on untreated wild-type mice on the HC diet ( FIGS. 13, 14 , 16 , and 17 ).
  • serum adiponectin levels were decreased in wild-type mice on a high-fat diet ( FIG. 12 , lane 3) as compared with those in mice on a high-carbohydrate diet ( FIG. 12 , lane 1).
  • Serum adiponectin levels in db/db mice were also decreased as compared with wild-type controls on either high-carbohydrate or high-fat diet ( FIG. 12 , lanes 1 and 3).
  • Mice were fed with high fat diet, and full-length adiponectin (Ad) or adiponectin globular domain (gAd) was administered to each mice at a dose shown in Table 2 for two weeks.
  • mice In skeletal muscle, adiponectin-administered KKA y mice showed increased expression of enzymes involved in ⁇ -oxidation and UCP2. In mice to which adiponectin had been administered, ACO activities and fatty-acid combustion were increased in skeletal muscle but not liver (Table 2). These alterations decreased triglyceride content in skeletal muscle, and also decreased serum FFA and triglyceride levels (Table 2). These reductions in serum FFA and triglyceride levels seem to cause subsequent decreased expression of molecules involved in fatty-acid transport into hepatic tissues, thereby also reducing tissue triglyceride content in liver (Table 2).
  • adiponectin administered to wild-type mice did not alter the expression of leptin in WAT and serum leptin levels (vehicle: 11.1 ⁇ 2.1 ng/ml; gAd: 10.4 ⁇ 2.6 ng/ml).
  • the present invention reverses insulin resistance induced from a high fat diet and associated with obesity, and therefore, enables treatment of type 2 diabetes, which is the most common among other types of diabetes.

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EP1682172A4 (fr) * 2003-10-09 2009-08-12 Univ Boston Procedes et compositions utilisant de l'adiponectine pour le traitement de troubles cardiaques et pour la stimulation de l'angiogenese
US20110104666A1 (en) * 2009-11-02 2011-05-05 Toshiya Matsubara Insulin resistance marker
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JP4169777B2 (ja) 2005-09-30 2008-10-22 森永乳業株式会社 インスリン抵抗性改善剤
US8895011B2 (en) * 2010-05-27 2014-11-25 The University Of Tokyo Insulin-resistance-improving drug
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Publication number Priority date Publication date Assignee Title
EP1682172A4 (fr) * 2003-10-09 2009-08-12 Univ Boston Procedes et compositions utilisant de l'adiponectine pour le traitement de troubles cardiaques et pour la stimulation de l'angiogenese
US20070213282A1 (en) * 2004-11-08 2007-09-13 Arkray, Inc. Peroxisome proliferator-activated receptor (PPAR) activator, and drugs, supplements, functional foods and food additives using the same
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US20140228253A1 (en) * 2008-08-14 2014-08-14 Nestec Sa Compositions and methods for influencing satiety, lipid metabolism, and fat utilization
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US20100120674A1 (en) 2010-05-13
US7850976B2 (en) 2010-12-14
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CA2474964A1 (fr) 2003-08-07

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