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WO1997026005A1 - Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants - Google Patents

Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants Download PDF

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Publication number
WO1997026005A1
WO1997026005A1 PCT/US1997/000085 US9700085W WO9726005A1 WO 1997026005 A1 WO1997026005 A1 WO 1997026005A1 US 9700085 W US9700085 W US 9700085W WO 9726005 A1 WO9726005 A1 WO 9726005A1
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igf
insulin
glucose
sulfonylurea
rats
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PCT/US1997/000085
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WO1997026005A9 (fr
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Ross G. Clark
Yan Hui Ma
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Genentech, Inc.
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Priority to AU15709/97A priority Critical patent/AU1570997A/en
Publication of WO1997026005A1 publication Critical patent/WO1997026005A1/fr
Publication of WO1997026005A9 publication Critical patent/WO1997026005A9/fr

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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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2

Definitions

  • NIDDM non- ⁇ nsul ⁇ n-dependentd ⁇ abetesmell ⁇ tus
  • the sulfonylurea are oral hypoglycemics that are used to stimulate pancreatic insulin release Sulfonylurea are the most widely prescribed of the oral hypoglycemic agents currently approved for use in the United States Approximately 30 percent of patients initially treated with sulfonylureahave a poor response, and in the remaining 70 percent the subsequent failure rate is approximately 4 to 5 percent per year (Defronzo et al , NEJM.333.541 -549,[ 1995]) and has been reported as high as 10 percent (Ge ⁇ ch. NEJM 321.1231-1245,[ 1989]) This indicates that there is a clear need to improve sulfonylurea therapy
  • Sulfonylurea are divided into two classes loosely based on their chemistry and potency All sulfonylurea are substituted arylsulfonylureas which differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety
  • the first generation sulfonylurea include acetohexamide, chloropropamide tolazamide and tolbutamide, while the second generation drugs include glybu ⁇ de
  • Second generation sulfonylurea shows increased potency partly because they are larger and non - polar compared to the smaller, polar, first generation molecules Therefore, improved lipid solubility may account for the greater potency ofthe second generation sulphonylureas
  • the sulfonylurea have similar qualitative activities, their pharmacokinetics may also define their potency After abso ⁇ tion from the gut sulfonylureaare all present in plasma bound greaterthan 90% to protem, especially to albumin
  • the first generation sulfonylurea vary greatly in their serum half- lives with that of chloropropam ide being long at 24-48 hours, and that of tolbutamide being 4-7 hours Despite this variation in half- life their duration of action is uniformly short, so that they need to be given in divided daily doses
  • the second generation molecules are 100 times as potent and even though their half-lives are short ( 1 -5 hours) they have a long duration of hypoglycemic action and thus may be administered only once daily
  • the exact mechanisms.causmg the large discrepancy between half- life and duration of action ofthe sulphonylureas, are not known Therefore, despite this class of drug being widely used, simple concepts, such as the relationship between persistence in the body and duration
  • IGF-1 and 1GF-2 are growth factors with molecular weights of approximately 7500 daltons Both IGF- 1 and IGF-2 have insulin - like activities as indicated by the chosen name ofthe peptide, and are mitogenic for
  • IGF- 1 and -2 peptides were originally named somatomedins indicative of their growth promoting or mitogenic effect.
  • IGF insulin like growth factor binding protein-3
  • ALS acid labile subunit
  • the ternary complex of IGF plus IGFBP-3 plus ALS has a molecular weight of approximately 150,000 daltons, and it has been suggested that the function of this complex in the circulation may be to serve as a reservoir and buffer for IGF- 1 and IGF-2 preventing rapid changes of free IGF-1.
  • IGF- 1 is produced in many tissues, most circulating IGF- I is believed to be synthesized in the liver.
  • IGF- 1 may be purified from natural sources or produced from recombinant sources.
  • IGF- I can be purified from human serum (Rinderknecht and Humbel J Biol. Chem. 253:2769-2773 [19781). Recombinant IGF-1 processes are exhibited in Patent EPO 128,733, published in December 1984.
  • recombinant human IGF- 1 was first given to normal human subjects a suppression of blood insulin levels was observed (Guler et al.NEJM.3 17: 137-140[ 1987] ). The most pertinent data was demonstrated in the studies carried out in Type II diabetics by Schlach et al.
  • the teratureon treatingwith combinationsof insulin and sulfonylurea provides no guidance as to the efficacy of combinationsof IGF- 1 and sulfonylurea
  • the medical management of diabetic patients who have failed sulfonylureatreatment would not be expected to be improved by combination treatment with IGF- I and sulfonylurea
  • This invention provides a method for treating diabetes in a mammal comprising administering to the mammal an effective amount of a hypoglycemic agent, preferably an insulin secretagogue ofthe sulfonylurea class, with an effective amount of IGF- 1 so as to improve glycemic control and limit the progression of the disease
  • a hypoglycemic agent preferably an insulin secretagogue ofthe sulfonylurea class
  • insulin secretagogues either fail initially (primary failure), or fail subsequently
  • IGF- 1 did not oppose the insulin release caused by an insulin secretagoguesuch as a sulfonylurea
  • IGF- I had the opposite effect in that it actually stimulated rather than inhibited insulin secretion Further.
  • IGF- l was tested during secretagogue failure in animals and in human diabetics In animals, in a situation where glucose tolerance was worsened by sulfonylurea, the co-administrationof IGF- 1 was found to prevent the failure and maintain glucose tolerance
  • diabetics who were poorly controlled while on either sulfonylurea or insulin therapy and were thus deemed treatment failures, were then treated with IGF- 1
  • IGF- 1 In the patients previously treated with an insulin secretagogue, in this case a sulfonylurea, there was a surprising!) large, dramatic, and highly significant improvement in glycemic control compared to that seen in patients previously treated with insulin
  • IGF-1 therapy can be combined with insulin secretagogue therapy to improve the ongoing regulation of blood glucose during the progression of diabetes Additionally, when the insulin secretagogue exhibits a failure to adequately regulate glucose, IGF- 1 can be used eitherto prevent this failure from occurring or to restore glycemic control if failure has already occurred
  • FIG 1 shows a bar graph ofthe effect of glucose and tolbutamide on insulin secretion over a 24 hour period by isolated rat pancreatic islets (means +/-SE)
  • FIG 2 shows a bar graph ofthe effect of glucose and IGF- 1 on insulin secretion over a 24 hour period by isolated rat pancreatic islets (means+/-SE)
  • FIG 3 shows a bar graph ofthe effect of the combination of IGF- 1 and tolbutamideon insulin secretion, over a 24 hour period (means +/-SE)
  • FIG 4 representsthe % change in blood glucose over 90 minutes following a bolus administration of glucose after a fast (a glucose tolerance test) in one group of normal rats pretreated with alcohol as placebo (control) or in a group of rats pretreated with tolbutamide at either 25 or 125 mg kg (means+/-SE)
  • FIG 5 represents the % change in blood glucose over 90 minutes in normal rats, following a glucose tolerance test, either pretreated with alcohol as placebo (control), or pretreated with tolbutamide at 25 mg kg (means +/-SE)
  • FIG 6 represents the % change in blood glucose over 90 minutes in normal rats follow ing a glucose tolerance test either pretreated with alcohol as placebo (control) or pretreated with tolbutamide at 50 mg/kg (means+/-SE)
  • FIG 7 represents the % change in blood glucose over 90 minutes in normal rats, following a glucose tolerance test, in a group pretreated with normal rat chow (control) or a group that were pretreated with glyburide mixed in their food for 6 days (means+/-SE , * represents statistical significance, p ⁇ 0 05)
  • FIG 8 representsthe serum insulin concentrationstaken during the glucose tolerance test performed in the control and glyburide treated rats depicted in FIG 7 (means +/SE)
  • FIG 9 show s a bar graph representing basal serum blood glucose (mg%) and insulin concentration (ng/m l) in four groups of rats, control group (placebo continuously administered-no oral glyburide), IGF-1 treated group no glybu ⁇ de.a glyburide treated group with no IGT-l treatment and a group treated with both glyburide and IGF- 1 (means+/-SE)
  • FIG 10 representsthe %change in blood glucose over 120 minutes, following a glucose tolerance test, in the four groups of rats depicted in FIG 9 (means+/-SE) after 3 days ofthe study
  • FIG 1 1 represents the serum insulin concentration over the same 120 minutes following the glucose tolerance test given to the four groups of rats depicted in FIG 9 (means+/-SE) after 3 days of study
  • FIG 12 representsthe %change in blood glucose over 120 minutes, following a glucose tolerance test given to four groups of normal rats, a control group (placebo continuously administered for 14 days-no oral glipizide), a des( l -3)IGF-l treated group with no glipizide, a glipizide treated group with no des( l -3)IGF- l treatment and a group treated with both des( l -3)IGF- I and glipizide after 3 days of treatment (means+/-SE)
  • FIG 13 represents the serum insulin concentration over the same 120 minutes following the glucose tolerance test given to the four groups of rats depicted in FIG 12 (means+/-SE) after 3 days of study
  • FIG 14 represents the blood glucose over 120 minutes, following a glucose tolerance test, in all four groups of rats depicted in FIG 12 (means+/-SE) after 7 days of study
  • FIG 15 represents the change in Hemoglobin A l c(%) over 12 weeks in Typell Diabetic patients being treated with IGF-I subsequent to a period of treatment with an oral hypoglycemic agent (HA).
  • group p is the placebo treated group
  • groups 1, 2, 4 and 8 are the IGF- 1 treated groups, (being 10,20,40,80 ⁇ g/kg,respect ⁇ vely) (means+/-SE)
  • FIG 16 represents the change in Hemoglobin A lc(%) over 12 weeks in Typel I diabetic patients being treated with IGF-lsubsequentto a period of treatment with insulin (mean+/-SE) Groupdesignationsare the same as those depicted in FIG 15
  • mammal signifies humans as well as other mammals, and includes animals of economic importance such as bovine, ovine, and porcine animals
  • the preferred mammal herein is a human
  • IGF-1 refers to insulin-like growth factor- 1 from any species, including bovine, ovine, porcine equine and preferably human, in native-sequence or in variant form, and from any source, whether natural, synthetic, or recombinant
  • Preferred herein for animal use is IGF-I from the particular species being treated, such as porcine IGF-I to treat pigs, ovine IGF-I to treat sheep bovine IGF-I to treat cattle etc
  • Preferred herein for human use is human native-sequence, mature IGF-I, more preferably without a N-terminal methionine, prepared, e g , by the process described in EP 230,869 published Aug 5, 1987, EP 128,733 pub shed Dec 19, 1984 or EP 288,451 published Oct 26, 1988 More
  • IGF-I variants are those described in PCT WO 87/01038 published Feb 26, 1987 and in PCT WO 89/05822 published June 29, 1989, i e , those wherein at least the glutamic acid residue is absent at position 3 from the N-terminus ofthe mature molecule or those that have a deletion of up to five amino acids at the N-terminus
  • the most preferred va ⁇ ant has the first three amino acids from the N-termmus deleted
  • brain IGF (variously designated as brain IGF, tIGF-I, des(l-3)-IGF-l or des-IGF-I)
  • treatment refers to therapeutic and prophylactic treatment Those in need of treatment include those already with the disorder as well as those in which treatment ofthe disorder has failed As used herem,”d ⁇ abet ⁇ c”refers to a progressive disease of carbohydrate metabolism involving inadequate production or utilization of insulin and is characterized by hyperglycemia and glycosu ⁇ a
  • hypoglycemic agent is a secretagogue, preferably an oral agent, excluding insulin, which causes the secretion of insulin by the pancreas More preferred herein for human use are the sulfonylurea class of oral hypoglycemic agents Examples include glyburide, glipizide and gliclazide B Modes for carrying out the invention
  • the IGF-I is directly administered to the mammal by any suitable technique, including parenterally, intranasal ly, orally, or by any other effective route
  • parenteral administration include subcutaneous, intramuscular, intravenous, intraarterial, and intraperitonealadministration
  • the administration is by continuous infusion (using, e g , minipumps such as osmotic pumps), or by injection (using e g , intravenous or subcutaneous means)
  • the administration is subcutaneous and by injection for IGF-1
  • the administration may also be as a single bolus or by slow-release or depot formulation
  • the IGF-1 is suitably administered together with one of its binding proteins for example, IGFBP-3.
  • IGFBP-3 which is described m WO 89/09268 published Oct 5, 1989 and by Martin and Baxter. J Biol Chem 261 8754-8760 ( 1986)
  • the IGF-I may also be suitably coupled to a receptor or antibody or antibody fragment for administration
  • the treatment regimen or pattern of administration of the agents may be one of simultaneous administration with the hypoglycemic agent and the IGF-1
  • the treatment regimen may be phasic with an alternating pattern of administration of one agent followed at a later time by the administration ofthe second agent
  • Phasic administration includes multiple administrations of one agent followed by multiple administrationsof the second agent
  • the total pharmaceutically effective amount of IGF-I administered parenterally per dose will be in the range of about 10 ⁇ g/kg/day to 200 ⁇ g/kg/day of patient body weight. although this will be subject to therapeutic discretion If given continuously, the IGF-I is typically administered at a dose rate of about 0 5 ⁇ g/kg/hour to about 10 g/kg/hour, either by 1 -2 injections per day or by continuous subcutaneous release, for example, using a minipump, patch, implant, or a depot formulation
  • the IGF- 1 is also suitably admintsteredby sustained- release systems Suitable examples of sustained- release compositions include semi-permeable polymer matrices in the form of shaped articles, e g films, or microcapsules Sustained-release matrices include polylactides (U S Pat No 3,773,919), copolymers of L- glutamic acid and gamma-ethyl-L-glutamate (Sidman et al , Bio
  • IGF- 1 compositions also include posomally entrapped IGF-1 Liposomes are prepared by methods known per se DE3,218, 121 ,U S Pat Nos 4,485,045 and 4,545,545 Ordinarily, the liposomes are of small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal IGF- 1 therapy
  • the IGF- 1 is formulated by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, l e ,one that is non toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation I he formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides
  • the formulations are prepared by contacting the IGF- 1 uniformly and intimately with liquid carriers or finely divided solid carriers or both Then, if, necessary, the product is shaped into the desired formulation
  • the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient Examples include water, saline, Ringers solution, and dextrose solution
  • Non- aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes
  • the carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability
  • additives such as substances that enhance isotonicity and chemical stability
  • Such mate ⁇ als are non- toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) polypeptides, e g , polyarginine or t ⁇ peptides, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as poly-vinyl -pyrrolidone, amino acids, such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccha ⁇ des, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins, chelating agents such as EDTA, sugar alcohols such as manni
  • the IGF- 1 preferably the full- length IGF- 1
  • an acceptable carrier vehicleto form a pharmaceutical composition preferably one that does not contain cells
  • the buffer used for formulation will depend on whether the composition will be employed immediately upon mixing or stored for later use If employed immediately, the full length IGF- 1 can be formulated in mannitol glycine. and phosphate at pH 7 4 If this mixture is to be stored, it is formulated in a buffer at a pH of about 6 such as surfactant that increases the solubility of the IGF-I at this pH, such as 0 1% polysorbate20 or poloxamer 188 1 he final preparation may be a stable liquid or a lyophilized solid
  • IGF- 1 to be used for therapeutic use must be sterile Sterility is readily accomplished by filtration through sterile filtration membranes (e g 0 2 micron membranes)
  • Therapeutic IGF- 1 compositions generally are placed into a container having a sterile access port, for example, a vial having a stopper pierceable by a hypodermic injection needle IGF-1 ordina ⁇ lywill be stored in unit or multi-dosecontainers, for example, sealed ampoules or vials, as an aqueous solution, or as a lyophilized formulation for reconstitution
  • a lyophilized formulation 10-ml vials are filled with 5 ml of sterile-filtered 1 % (w/v) aqueous IGF-1 solution, and the resulting mixture is lyophilized
  • the infusion solution is prepared by reconstituting the lyophilized IGF- I in bactenostatic Water- for-Injection
  • the insulin secretagogue or hypoglycemic agent is administered to
  • Rat islets of Langerhans were freshly isolated from pancreata of normal male Sprague Dawley rats (SD) by collagenase digestion followed by batch incubation in a modified RPMI media using a shaking water bath at 37°C under 5% COi - 95% 0 2 After recovery for an hour in media without glucose, islets were incubated in different concentrationsof glucose, recombinant human IGF- 1 (rhIGF- 1 ) or the sulfonylurea, tolbutamide The media were changed hourly, before the experiment, to obtain a basal release rate and then during the experiment (at 1, 2, 3. 20, 21, 22, 23, and 24 h) and insulin secretion was determined by assaying the insulin concentration by RI ⁇ (Linco Research) in these samples Data are means ⁇ SEM (n ⁇ 3/g ⁇ ) Results
  • rhIGF-I at 65nM more than doubled glucose ( 16 mM) stimulated insulin secretion ( 1 22 -O 33 vs 2 87 ⁇ 0 42 p ⁇ 0 05)
  • rhIGF-I at both 13nM and 65nM enhanced 5 mM and 16 mM glucose stimulated insulin secretion, reaching significance for high dose rhlGF-I (3 6 ⁇ 0 8 and 10 l ⁇ l 34 for 5 and 16mM glucose respectively, vs 6 1 ⁇ 0 96 and 15 3 ⁇ 1 75 ng /islet, for 5 and 16mM glucose plus rhIGF-1, respectively)
  • I herefore acute exposure to rhlGF- I did not affect glucose- stimulated insulin secretion
  • chronic exposure to rhIGF-I, even when islets were desensitized by high glucose resulted in an increased release of insulin
  • IGF- 1 suppresses insulin secretion by acting directly on the pancreas
  • concentrations 100-500 ng/ml
  • rhIGF-I does not affect acute glucose-stimulatedinsulin secretion
  • rhIGF-I does not antagonize tolbutamide-stimulated insulin secretion at either 5mM or 16mM glucose
  • rhIGF-I assisted insulin secretion in islets that were desensitized by chronic hyperglycemia This situation mimics, in v ⁇ t ⁇ o,ti ⁇ e diabetic state In this situation rhlGF- 1 also enhanced insulin secretion induced by a maximal stimulation
  • Study 3 This experiment used a higher dose of tolbutamide (50 mg/kg) than the 25 mg/kg dose used in Study 2
  • the object was to study the short-term effects of tolbutamideadministrationon blood glucose and the effects on the glucose concentrations after a glucose tolerance test
  • mice Twenty-eight SD rats (250 g) were housed in individual cages and their intake of powdered food (diet 5001) was measured Glyburide was inco ⁇ orated into the food to give a dose of 2 5 mg/kg/d of glyburide, or the rats were fed the 5001 diet without glyburide Osmotic minipumps (Alzet 2001TMpumps, Alza Palo Alto CA) were implanted sub-cutaneously into the rats to deliver IGF- 1 at a dose of 670 ⁇ g/rat/d or 2 5 mg/kg/d, while other pumps were filled with the IGF-1 excipient There were 4 groups of rats,
  • IGF- 1 had little effect on glucose tolerance
  • IGF- I and glyburide were given in combination
  • IGF- 1 reversed the deterioration in glucose tolerance caused by glyburide Therefore, although IGF- 1 caused a reduction in basal insulin levels, it restored insulin secretion in response to a glucose load in glyburide- treated rats
  • the GTT was then repeated after 7 days of treatment By this time the response to the failure of glyburide was more evident in terms of glucose clearance
  • Basal insulin secretion was significantly suppressed by IGF- 1 alone but not by the combination of IGF- 1 and glyburide
  • glyburide allowed insulin secretion, glucose tolerance was dramatically impaired This suggests that the sulfonylurea failure is not totally dependent on a pancreatic mechanism
  • Glucose clearance was not affected by IGF- 1 compared to that of controls, but the combination of glybu ⁇ deand IGF- 1 showed an improvement in glucose clearance compared to glyburide alone
  • Figure 12 shows the GTT data
  • Figure 13 the insulin concentrations after the GTT given 3 days following the beginning of drug dosing Glucose tolerance was worsened by glipizide at 30 and 60 minutes
  • IGF- 1 and glipizide caused a reduction in insulin levels, only glipizide reduced glucose clearance glipizide and des( 1 -3)IGF- 1 plus glipizide (control, 154 ⁇ 7 mg%, des( 1 -3)1GF- 1 , 148 ⁇ 6 mg%, glipizide, 127 ⁇ 6 mg%, IGF- 1 + glipizide, 131 ⁇ 7 mg%)
  • glucose tolerance was dramatically impaired
  • the treatment period was twelve weeks Patients had either previously been treated with insulin or with a hypoglycemic agent, in most cases glyburide
  • Results indicate that the patients pretreated with an oral hypoglycemic agent (Figure 15) followed by IGF-I treatment were in better glycemic control than the group that had received insulin (Figure 16) followed by IGF- 1 treatment
  • This is depicted by a dose- related fall in hemoglobin A I C, the best indicatorof successful medical management of diabetes (Crofford Ann Rev Med 46.267-279[ 1995])
  • the high- dose group 80 ⁇ g/kg rhlGF- 1 per day
  • the placebo group there was a high drop- out rate due to an increased incidence of undesirable side effects, whereas at the lower doses of IGT-I drop- out rates were low, indicative of the beneficial effects of treatment
  • Improved glycemic control would be a desired effect in patients currently on hypoglycemictherapy in that it would prolong this period of management of their diabetes before resorting to exogenous insulin treatment by daily injections
  • therapy with IGF- 1 is clearly beneficial A direct result of this beneficial effect would be
  • Example I using cultured pancreatic islets of Langerhans, IGF- 1 did not oppose the insulin release caused by an insulin secretagogue sulfonylurea In fact, when the islets were cultured in the setting of high glucose exposure and in the presence of a sulfonylurea, to mimic the diabetic state, IG F- 1 had the opposite effect to that predicted in that it stimulated rather than inhibited insulin secretion The in vitro data would therefore predict that the combination treatment of IGF-1 and an insulin secretagogue would improve glycemic control in diabetic patients In Examples 2 and 3 IGF-1 was tested during secretagogue failure in animals and in humans In animals, a situation of secretagogue failure was induced in that glucose tolerance was worsened by a sulfonylurea In this situation the co- administration of IGI - I with a sulfonylurea was found to ameliorate the failure and maintain glucose tolerance These data in animals predict that combination treatment with IGF- I
  • Example 3 a study in Type II diabetic humans produced very compelling evidence supporting the use ofthe combination of IGF- 1 and oral hypoglycemics
  • diabetics who were being treated with either sulfonylureaor insulin and were poorly controlled, and therefore were considered treatment failures, were then treated with IGF-1
  • IGF- 1 therapy can be combined with insulin secretagogue therapy to improve the regulation of blood glucose in diabetes
  • insulin secretagogue shows a failure to regulate glucose
  • IGF- 1 can be used either to prevent this failure from occurring or to restore glucose regulation if failure has already occurred
  • treating diabetics with IGF- 1 and an insulin secretagogue would be an improvement on current medical practice

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Abstract

La présente invention concerne un traitement permettant de mieux gérer, chez les mammifères, l'évolution du diabète, et notamment du diabète de type II, et consistant en une administration d'IGF-1 en combinaison avec une administration d'hypoglycémiants. L'IGF-1 est de préférence un IGF-1 mature en séquence native et d'origine humaine, les hypoglycémiants étant des sécrétagogues tels que la sulfonylurée. Cette combinaison d'agents améliore la régulation glycémique dans des cas de diabète.
PCT/US1997/000085 1996-01-16 1997-01-10 Traitement anti-diabetique par une combinaison d'igf-1 avec des hypoglycemiants WO1997026005A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049894A1 (fr) * 1998-04-01 1999-10-07 Genentech, Inc. Antagonistes du gene 6 specifique de l'arret de croissance, et leur utilisation contre des troubles insulinoresistants
WO2002060473A3 (fr) * 2001-01-31 2003-10-16 Univ Colorado State Res Found Methode de traitement de la retinopathie diabetique a l'aide de facteurs de croissance semblables a l'insuline (igfs) naturels et d'analogues d'igfs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
O. G. KOLTERMAN: "Type II diabetes: Who has the keys", THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE, vol. 121, no. 4, April 1993 (1993-04-01), pages 534 - 535, XP000653482 *
OTA, A., ET AL.: "Insulin and IGF-I receptors in neuroblastoma cells: increases in mRNA and binding produced by glyburide", NEUROPEPTIDES, vol. 14, no. 3, 1989, pages 171 - 175, XP000653575 *
WANG P. H. ET AL.: "Augmentation of the effects of insulin and insulin-like growth factors I and II on glucose uptake in cultured rat skeletal muscle cells by sulfonylureas", DIABETOLOGIA, vol. 30, 1987, pages 797 - 803, XP000653480 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049894A1 (fr) * 1998-04-01 1999-10-07 Genentech, Inc. Antagonistes du gene 6 specifique de l'arret de croissance, et leur utilisation contre des troubles insulinoresistants
WO2002060473A3 (fr) * 2001-01-31 2003-10-16 Univ Colorado State Res Found Methode de traitement de la retinopathie diabetique a l'aide de facteurs de croissance semblables a l'insuline (igfs) naturels et d'analogues d'igfs

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