EP0986397A1 - Utilisation d'antagonistes de leptine pour traiter le diabete - Google Patents
Utilisation d'antagonistes de leptine pour traiter le diabeteInfo
- Publication number
- EP0986397A1 EP0986397A1 EP97923840A EP97923840A EP0986397A1 EP 0986397 A1 EP0986397 A1 EP 0986397A1 EP 97923840 A EP97923840 A EP 97923840A EP 97923840 A EP97923840 A EP 97923840A EP 0986397 A1 EP0986397 A1 EP 0986397A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- leptin
- treatment
- insulin
- mice
- antagonist
- 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- Withdrawn
Links
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
-
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- 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
- 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
Definitions
- the invention relates to a novel use, in particular a use for the treatment of diabetes and complications thereof.
- NIDDM non-insulin-dependent diabetes
- IIDDM insulin resistance
- an inadequate insulin secretion from the beta-cells of the Islets of Langerhans in the pancreas Thus, despite hyperinsulinaemia there is insufficient insulin to compensate for the insulin resistance and to maintain blood glucose in the desirable range.
- Pelleymounter et al (Science, 1995, 269, 540-543) have reported that the ob polypeptide or "leptin” lowers both plasma insulin and glucose levels in the genetically obese ob/ob mouse.
- United Kingdom patent application, Publication Number 2292382 relates ter alia to polypeptides, OB polypeptides, and antagonists thereof and their use for modulating body weight.
- the disclosures of GB 2292382 are incorporated herein by reference.
- leptin directly inhibits insulin release from both isolated islets and the perfused pancreas of the ob/ob mouse.
- An antagonist of leptin is therefore indicated to be of value in enhancing insulin secretion and thereby assisting in the control of blood glucose levels.
- leptin inhibits basal and insulin-stimulated glycogen synthesis in isolated soleus muscle of ob/ob mice.
- An antagonist of leptin is therefore also indicated to be of value in enhancing glucose utilisation and the action of insulin to enhance glucose utilisation.
- Antagonists are therefore indicated to be of direct use in the treatment of disorders resulting from deficiencies in insulin secretion and action and of hyperglycaemia, such as non-insulin- dependent diabetes.
- an antagonist which enhances insulin secretion and assists in blood glucose control may be useful in the treatment of diabetic complications, such as retinopathy, nephropathy and angiopathy.
- the invention provides the use of an antagonist of leptin for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non-insulin-dependent diabetes (NIDDM).
- NIDDM non-insulin-dependent diabetes
- NIDDM non-insulin-dependent diabetes
- Suitable antagonists of leptin are as disclosed in GB2292382 and may be prepared according to methods disclosed therein.
- Particular antagonists include protein antagonists.
- Particular antagonists include non-protein antagonists, especially small organic molecule antagonists.
- the present invention also extends to a method for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non- insulin-dependent diabetes (NIDDM), in a human or non-human mammal, which method comprises the administration to human or non-human mammal in need of such treatment, an effective, pharmaceutically acceptable, non-toxic amount of an antagonist of leptin.
- NIDDM non- insulin-dependent diabetes
- the present invention also extends to a pharmaceutical composition
- a pharmaceutical composition comprising an antagonist of leptin, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
- Particular compositions of the invention are those used for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non-insulin-dependent diabetes (NIDDM).
- NIDDM non-insulin-dependent diabetes
- Suitable pharmaceutically acceptable carriers are as dictated by conventional practice such as those disclosed in GB 2292382 or in International Patent Application, Publication Number WO 94/01420.
- compositions of the invention are prepared according to conventional practice, such as described in the above mentioned patent applications
- the dosages of the antagonists may be determined according to conventional methodology such as those described in the above mentioned patent applications.
- the following is a brief description of the figures ( Figures 1-5 and Table 1) of the application:
- Figure 1 and Table 1 show the effect of leptin (lOOnM) on basal insulin secretion from the perfused pancreas of ob mice;
- Figure 2 shows the effect of leptin (100 nmol/1) on glucose stimulated (16.7 mmol/1) insulin secretion from ob/ob islets;
- Figure 3 shows the dose - dependency of inhibitory effects of recombinant leptin on glucose-stimulated (16.7 mmol/1) insulin secretion from isolated pancreatic islets of ob/ob mice;
- Figure 4 shows the effect of leptin on glycogen synthesis in isolated soleus muscle of ob/ob mice.
- Figure 5 shows the effect of leptin on the glycogen synthesis in isolated soleus muscle of ob/ob mice.
- an especially useful antagonist would be one that antagonizes the action of leptin at the islet and/or skeletal muscle receptor, but does not antagonize other leptin receptors (e.g. in the hypothalamus) and thereby exacerbate insulin resistance.
- the leptin receptor has several alternatively spliced variants.
- One of these spliced variants is expressed at a high level in hypothalamus, and is believed to be the functional receptor in the regulation of energy balance. It is abnormally spliced in C57B1/KSJ db/db mice (Nature (Lond.) 379, 622-635 (1996); Cell
- leptin has both central and peripheral actions.
- the diabetic (db) gene product in mice has been identified as the receptor for leptin. At least six alternatively spliced forms of the leptin message have been identified
- Ob-Rb has an extensive intracellular region containing a Box 2 sequence motif, which is required for the binding of JAK protein kinases and is believed to encode the functional receptor.
- Short antisense oligodeoxynucleotide probes (Trayhurn et al, Biochem. Soc. Trans. Vol 23 page 4945, 1995) 30-34 mers, were designed to hybridise with different domains in the mouse leptin
- oligonucleotide probe sequence was unique to the leptin receptor and had no significant homology to any other known sequence.
- Total leptin receptor mRNA, standardised to poly(A) mRNA levels was over-expressed in ob/ob mice relative to the lean littermates. However, there were tissue specific differences in overexpression. Thus, hypothalamus which shows the highest level of expression in lean mice was only 2-fold
- this leptin receptor Ob-Rb gave a single sharp band. This contrasted with the multiple bands when the blot was probed with the 33-mer corresponding to bases 1877-1910, which is a sequence common to all the known splice variants of the leptin receptor. Molecular weight markers indicated that the 34-mer hybridised to a mRNA fragment of approximately 3400 b.p. consistent with the putative functional leptin receptor. This was
- Leptin (lOOnM) produced an immediate reduction in the insulin release from the isolated pancreas.
- leptin in the perfused pancreas preparation could be either direct on
- leptin islets or via the release of a further mediator from the vasculature.
- leptin completely inhibited the stimulatory effect of 16.7mM glucose on insulin release in islets isolated from overnight-fasted mice (Fig.2).
- the inhibitory effect of leptin was dose-related over the range 1-lOOnM (Fig. 3). Also leptin
- Obesity is the commonest nutritional disorder in Western Society and in many
- leptin overproduction associated with obesity may be one
- the present invention provides the use of an antagonist of leptin for the treatment of insulin resistance, especially that associated with obesity.
- a method for the treatment of of insulin resistance, especially that associated with obesity, in a human or non-human mammal comprises the administration to human or non-human mammal in need of such treatment, an effective, pharmaceutically acceptable, non-toxic amount of an antagonist of leptin.
- a further particular pharmaceutical composition of the invention is therefore a pharmaceutical composition useful for the treatment of of insulin resistance, especially that associated with obesity.
- pancreatic islets we have also detected the long-form of the leptin receptor in liver, kidney and lung. The functional effects of leptin in these tissues are at 210 present unknown.
- Levin et_al Proc. Natl, Acad. ScL, USA 93, 1726-1730
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Genetics & Genomics (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP1997/002240 WO1998055139A1 (fr) | 1997-06-06 | 1997-06-06 | Utilisation d'antagonistes de leptine pour traiter le diabete |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0986397A1 true EP0986397A1 (fr) | 2000-03-22 |
Family
ID=8166613
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97923840A Withdrawn EP0986397A1 (fr) | 1997-06-06 | 1997-06-06 | Utilisation d'antagonistes de leptine pour traiter le diabete |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0986397A1 (fr) |
JP (1) | JP2002504102A (fr) |
KR (1) | KR20010013414A (fr) |
AU (1) | AU2951797A (fr) |
CA (1) | CA2293504A1 (fr) |
HU (1) | HUP0003428A3 (fr) |
IL (1) | IL133136A0 (fr) |
TR (1) | TR199902980T2 (fr) |
WO (1) | WO1998055139A1 (fr) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7208572B2 (en) | 1998-08-21 | 2007-04-24 | Albany Medical College | Leptin-related peptides |
US6777388B1 (en) | 1998-08-21 | 2004-08-17 | Clf Medical Technology Acceleration Program, Inc. | Leptin-related peptides |
US20050272652A1 (en) | 1999-03-29 | 2005-12-08 | Gault Victor A | Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
CN1961000B (zh) | 2004-02-11 | 2011-05-04 | 安米林药品公司 | 具有可选择特性的杂合多肽 |
US8263545B2 (en) | 2005-02-11 | 2012-09-11 | Amylin Pharmaceuticals, Inc. | GIP analog and hybrid polypeptides with selectable properties |
CA2597649A1 (fr) | 2005-02-11 | 2006-08-17 | Amylin Pharmaceuticals, Inc. | Analogues de gip et polypeptides hybrides de gip aux proprietes selectionnables |
CA2617649A1 (fr) | 2005-08-11 | 2007-02-22 | Amylin Pharmaceuticals, Inc. | Polypeptides hybrides presentant des proprietes selectionnables |
BRPI0614649A2 (pt) | 2005-08-11 | 2011-04-12 | Amylin Pharmaceuticals Inc | polipeptìdeos hìbridos com propriedades selecionáveis |
US8497240B2 (en) | 2006-08-17 | 2013-07-30 | Amylin Pharmaceuticals, Llc | DPP-IV resistant GIP hybrid polypeptides with selectable properties |
US20120071401A1 (en) | 2009-04-10 | 2012-03-22 | Amylin Pharamaceuticals, Inc. | Amylin agonist compounds for estrogen-deficient mammals |
DK3241558T3 (da) | 2010-09-28 | 2021-04-26 | Aegerion Pharmaceuticals Inc | Højopløselige leptiner |
JP6040464B2 (ja) | 2011-07-08 | 2016-12-07 | アエゲリオン・ファーマシューティカルズ・インコーポレイテッドAegerion Pharmaceuticals, Inc. | 作用持続期間が増大し、免疫原性が減少した操作されたポリペプチド |
EP2900230B1 (fr) | 2012-09-27 | 2018-08-15 | The Children's Medical Center Corporation | Composés pour le traitement de l'obésité et méthodes d'utilisation de ceux-ci |
AU2014354831B2 (en) | 2013-11-26 | 2017-10-26 | The Children's Medical Center Corporation | Compounds for the treatment of obesity and methods of use thereof |
US20170209408A1 (en) | 2014-04-03 | 2017-07-27 | The Children's Medical Center Corporation | Hsp90 inhibitors for the treatment of obesity and methods of use thereof |
BR112019004715A2 (pt) | 2016-09-12 | 2019-07-16 | Aegerion Pharmaceuticals Inc | métodos para detectar anticorpos neutralizantes anti-leptina |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6309853B1 (en) * | 1994-08-17 | 2001-10-30 | The Rockfeller University | Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof |
PL324284A1 (en) * | 1995-06-30 | 1998-05-11 | Lilly Co Eli | Methods of treating diabetes |
-
1997
- 1997-06-06 AU AU29517/97A patent/AU2951797A/en not_active Abandoned
- 1997-06-06 CA CA002293504A patent/CA2293504A1/fr not_active Abandoned
- 1997-06-06 TR TR1999/02980T patent/TR199902980T2/xx unknown
- 1997-06-06 WO PCT/EP1997/002240 patent/WO1998055139A1/fr not_active Application Discontinuation
- 1997-06-06 EP EP97923840A patent/EP0986397A1/fr not_active Withdrawn
- 1997-06-06 HU HU0003428A patent/HUP0003428A3/hu unknown
- 1997-06-06 JP JP50135299A patent/JP2002504102A/ja active Pending
- 1997-06-06 KR KR19997011415A patent/KR20010013414A/fr not_active Application Discontinuation
- 1997-06-06 IL IL13313697A patent/IL133136A0/xx unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9855139A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU2951797A (en) | 1998-12-21 |
HUP0003428A2 (hu) | 2001-05-28 |
WO1998055139A1 (fr) | 1998-12-10 |
KR20010013414A (fr) | 2001-02-26 |
CA2293504A1 (fr) | 1998-12-10 |
IL133136A0 (en) | 2001-03-19 |
HUP0003428A3 (en) | 2001-12-28 |
TR199902980T2 (xx) | 2000-05-22 |
JP2002504102A (ja) | 2002-02-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0986397A1 (fr) | Utilisation d'antagonistes de leptine pour traiter le diabete | |
Yip et al. | Functional GIP receptors are present on adipocytes | |
Haffner et al. | The role of behavioral variables and fat patterning in explaining ethnic differences in serum lipids and lipoproteins | |
Roman et al. | Central leptin action improves skeletal muscle AKT, AMPK, and PGC1α activation by hypothalamic PI3K-dependent mechanism | |
Ladyman et al. | Region-specific reduction in leptin-induced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy | |
Baldelli et al. | Glucose homeostasis in acromegaly: effects of long‐acting somatostatin analogues treatment | |
Carvalheira et al. | Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver | |
Garcia-Vicente et al. | Oral insulin-mimetic compounds that act independently of insulin | |
Alemzadeh et al. | Modification of insulin resistance by diazoxide in obese Zucker rats | |
Yun et al. | PVN galanin increases fat storage and promotes obesity by causing muscle to utilize carbohydrate more than fat | |
AU645076B2 (en) | Use of 3-guanidinopropionic acid in the treatment and prevention of metabolic disorders | |
Bell-Anderson et al. | Leptin as a potential treatment for obesity: progress to date | |
Henry et al. | Energy metabolic profile of mice after chronic activation of central NPY Y1, Y2, or Y5 receptors | |
Zhang et al. | Aged-obese rats exhibit robust responses to a melanocortin agonist and antagonist despite leptin resistance | |
US20080020974A1 (en) | Somatostatin and somatostatin agonists for treating insulin insensitivity and syndrome x | |
Wang et al. | Skeletal muscle mRNA for IGF-IEa, IGF-II, and IGF-I receptor is decreased in sedentary chronic hemodialysis patients | |
EP2872124B1 (fr) | Peptides lipidés en tant qu'agents anti-obésité | |
Tessari | Changes in protein, carbohydrate, and fat metabolism with aging: possible role of insulin | |
Wasan et al. | Emerging pharmacological approaches to the treatment of obesity | |
US20040142868A1 (en) | Method of treating liver steatosis in a mammal | |
Baltaci et al. | Pinealectomy and melatonin administration in rats: their effects on plasma leptin levels and relationship with zinc | |
Judge et al. | Prolonged hyperphagia with high-fat feeding contributes to exacerbated weight gain in rats with adult-onset obesity | |
Miller et al. | Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles of ob/ob mice | |
Salvatore et al. | Decreased insulin clearance as a feature of essential hypertension | |
US20020160935A1 (en) | Use of leptin antagonists for the treatment of diabetes |
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: 19991124 |
|
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 |
|
AX | Request for extension of the european patent |
Free format text: SI PAYMENT 19991124 |
|
17Q | First examination report despatched |
Effective date: 20000728 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7A 61K 38/22 A, 7C 07K 16/28 B, 7A 61P 3/10 B, 7A 61P 5/50 B |
|
RTI1 | Title (correction) |
Free format text: USE OF LEPTIN ANTAGONISTS FOR THE TREATMENT OF DIABETES |
|
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: 20030103 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1027742 Country of ref document: HK |