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WO1997026005A9 - 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

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Publication number
WO1997026005A9
WO1997026005A9 PCT/US1997/000085 US9700085W WO9726005A9 WO 1997026005 A9 WO1997026005 A9 WO 1997026005A9 US 9700085 W US9700085 W US 9700085W WO 9726005 A9 WO9726005 A9 WO 9726005A9
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WIPO (PCT)
Prior art keywords
igf
insulin
glucose
sulfonylurea
rats
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PCT/US1997/000085
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English (en)
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WO1997026005A1 (fr
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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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  • Type II, non- ⁇ nsul ⁇ n-dependentd ⁇ abetesmell ⁇ tus(NIDDM) which constitutesabout 80-90% of the total incidence of diabetes (Type I insulin- dependent diabetes mellitus ( IDDM ) makes up the rest) continues to grow rapidly, with respect to its incidence, prevalence, and cost
  • Diabetic therapy has a numberof goals, includingrelievingsymptoms of hyperglycemiaand preventing long-term complications of diabetes such as microvascular and macrovascular disease
  • the incidence and severity of these complications in IDDM are related at least in part to the degree of glycemic control, as confirmed by the results of the Diabetes Control and ComplicationsT ⁇ al (DCCT)
  • DCCT Diabetes Control and ComplicationsT ⁇ al
  • the medical managementof NIDDM is a progressive process F ⁇ rstly,d ⁇ et control (hypocalonc/eucaloric) and exercise is attempted to achieve weight loss especially in obese subjects, secondly oral hypoglycemic drugs are used and finally, treatment with
  • the sulfonylurea are oral hypoglycemics that are used to stimulate pancreatic insulin release Sulfonylureaare 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 (Gerich. 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 sulfonylureaare 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
  • the second generation drugs include glybu ⁇ de (gl ⁇ benclam ⁇ de),gl ⁇ p ⁇ z ⁇ de and gl ⁇ claz ⁇ de
  • Second generation sulfonylurea show 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 of the second generation sulphonylureas
  • the sulfonylurea have similar qualitative activities, their pharmacokinetics may also define their potency After absorption from the gut sulfonylureaare all present in plasma bound greater than 90% to protein, especially to albumin
  • the first generation sulfonylurea vary greatly in their serum half- lives with that of chloropropamidebemg 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, causing the large discrepancy between half- life and duration of action of the 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 of action, remain to be explained
  • pancreatic beta cells exhibit a maintained drug effect or because peripheral target tissues become more sensitive to insulin in response to the sulfonylurea (Kolterman.DiabetesMetab Rev 3.399-414f l9871)
  • IGF-1 and IGF-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 of the peptide, and are mitogenic for the cells in reproductive tissue, muscle, skeletal tissue and a wide variety of other tissues
  • the IGF- 1 and -2 peptides were originally named somatomedins indicative of their growth promoting or mitogenic effect
  • IGF's are present m high concentrations in the circulation, but only a small fraction of IGF is not protein bound
  • the overwhelmingmajo ⁇ ty of IGF circulatesas part of a non- covalently associated ternary complex composed of IGF- 1 or IGF-2, and insulin like growth factor binding prote ⁇ n-3 (IGFBP-3), and a large protein termed the acid labile subunit (ALS)
  • IGFBP-3 insulin like growth factor binding prote ⁇ n-3
  • ALS acid labile subunit
  • This complex is composed of equimolar amounts of each ofthe three components
  • 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-1 is believed to be synthesized in the liver
  • IGF- 1 may be purified from natural sources or produced from recombinant sources
  • IGF- 1 can be purified from human serum (Rmderknecht and Humbel J Biol Chem 251,2769-2773 [1978])
  • Recombinant IGF- 1 processes are exhibited in Patent EPO 128,733, published in December 1984
  • a suppression of blood insulin levels was observed (Guler et al.NEJM 317.137- 140[ 1987])
  • the most pertinent data was demonstrated in the studies carried out in Type II diabetics by Schlach et al fJ Clin.Metab 77.1563- 1568f 1993]) which demonstrated a fall in both serum insulin as well as a paralleled decrease in C peptide levels which indicated a fall in pancreatic insulin secretion after five days of IGF- 1 treatment This effect has been independently confirmed by Froesch et al (Horm Res 42.66-71 f 1994]) In vivo
  • 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 of the 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 of the sulfonylurea class
  • the literature describes a complex role for insulin secretagogues in controlling blood glucose in diabetes.
  • IGF-1 is being investigated as a treatment for diabetes as it has direct hypoglycemicactivity.
  • IGF-1 has been reported to have the opposite effect to sulfonylurea on insulin secretion. Sulfonylurea stimulate insulin secretion whereas IGF- 1 inhibits insulin secretion.
  • IGF-1 inhibits insulin secretion.
  • IGF-1 inhibits insulin secretion.
  • This confusion provides no clear basis to predict the effect of the co-administration of insulin secretagogues and IGF- 1 on insulin secretion or glucose control. in many patients the insulin secretagogues either fail initially (primary failure), or fail subsequently
  • IGF- 1 did not oppose the insulin release caused by an insulin secretagogue such as a sulfonylurea. Even more surprisingly, when islets were cultured in the setting of long- term high glucose exposure in the presence of a sulfonylurea, IGF-1 had the opposite effect in that it actually stimulated rather than inhibited insulin secretion. Further, IGF- 1 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.
  • 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 either to prevent this failure from occurring or to restore glycemic control if failure has already occurred.
  • FIG.1. shows a bar graph of the effect of glucose and tolbutamide on insulin secretion over a 24 hour period by isolated rat pancreatic islets (means +/-SE).
  • FIG.2. showsa bar graph of the 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 of the 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, following 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 glybunde 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 glybunde treated rats depicted in FIG 7 (means +/SE)
  • FIG 9 shows 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 glybunde), IGF-1 treated group no glybunde,a glybunde treated group with no IGF-1 treatment and a group treated with both glybunde and IGF- I (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 of the 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- l 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 representsthe change in Hemoglobin A l c(%) over 12 weeks in Typell Diabetic patients being treated with IGF- 1 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)
  • HA oral hypoglycemic agent
  • FIG 16 represents the change in Hemoglobin A lc(%) over 12 weeks in Typell diabetic patients being treated with IGF- 1 subsequentto 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, ovme, 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-1 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 published Dec 19, 1984 or EP 288,451 published Oct 26,
  • IGF-I variants are those described in PCT WO 87/01038 published Feb 26, 1987 and m PCT WO 89/05822 published June 29, 1989, l e , those wherein at least the glutamic acid residue is absent at position 3 from the N-terminusof the mature molecule or those that have a deletion of up to five amino acids at the N-terminus
  • the most preferred variant has the first three ammo acids from the N-terminus deleted
  • brain IGF (variously designated as brain IGF, tIGF-I, des(l -3)-IGF-I or des-IGF-I)
  • treatment refers to therapeutic and prophylactictreatment Those in need of treatment include those already with the disorder as well as those in which treatment of the disorder has failed As used herein, "diabetic'Vefers 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 glybunde, 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, lntraartal, 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 IGI--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, which is described in WO 89/09268 published Oct 5, 1989 and by Martin and Baxter, J Biol Chem 261 8754-8760 ( 1986)
  • IGFBP-3 which is described in 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 of the second agent
  • Phasic administration includes multiple administrations of one agent followed by multiple administrationsof the second agent
  • the total pharmaceutically effective amount of IGT-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
  • the IGF-I is typically administeredat 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 administered by 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 (Sid an et al , Biopolvmers 22
  • IGF- 1 compositions also include liposomally 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, a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i e ,one that is non toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation
  • a pharmaceutically acceptable carrier i e ,one that is non toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation
  • the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides
  • the formulations are prepared by contactingthe 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 materials 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 ⁇ mmunoglobul ⁇ ns,hydrophil ⁇ cpolymers such as poly-vmyl -pyrrolidone, ammo acids, such as glycine, glutamic acid, aspartic acid, or arginine, monosaccha ⁇ des, disacchandes, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dext ⁇ ns, chelating agents such as EDTA,
  • the IGF- 1, preferably the full- length IGF- 1 is suitably formulated in an acceptable carrier vehicle to 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- I 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 surfactantthat increases the solubility of the IGF-1 at this pH, such as 0 1% polysorbate20 or poloxamer 188
  • the 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 ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution, or as a lyophilized formulation for reconstitution
  • 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-1 in bacte ⁇ ostatic Water-for-lnjection
  • the insulin secretagogue or hypoglycemic agent is administered to the mammal by any suitable
  • rhIGF-I at both 13nM and 65nM enhanced 5 mM and 16 mM glucose stimulated insulin secretion, reaching significance for high dose rhIGF-I (3.6 ⁇ 0.8 and 10.1 ⁇ 1.34 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-I; respectively). Therefore acute exposure to rhlGF- 1 did not affect glucose- stimulated insulin secretion. Unexpectedly, 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 l6mM glucose.
  • 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 Glybu ⁇ dewas incorporated into the food to give a dose of 2 5 mg/kg/d of glybunde, or the rats were fed the 5001 diet without glybunde Osmotic minipumps (Alzet 2001 TMpumps, 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,
  • Figure 10 shows the GTT data
  • Figure 1 1 the insulin concentrations after the GTT given 3 days following the beginning of drug dosing.
  • Glucose tolerance was worsened by glyburide 30 and 60 minutes after the GTT.
  • the insulin concentrations in the glyburide treated rats did not rise with a glucose challenge.
  • IGF- 1 had little effect on glucose tolerance.
  • IGF-1 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 responseto a glucose load in glyburide- treated rats.
  • the GTT was then repeated after 7 days of treatment.
  • This experiment produced su ⁇ rising results. Insulin secretion was stimulated by glyburide after a 6- hour food withdrawal and blood glucose concentrations were reduced. IGF- 1 suppressed basal insulin concentrations in the presence of glyburide, but by itself had no effect on basal blood glucose. Despite the rise in basal insulin concentrations, indicating that glyburide was stimulating insulin secretion, glyburide suppressed the insulin secretory response to a simulated meal (the GTT) and compared to control animals worsened glucose tolerance. IGF-1 plus glyburide, despite suppressing basal insulin levels, allowed an insulin response to the GTT and improved glucose tolerance compared to treatment with glyburide alone.
  • IGF- 1 which is generally thought to inhibit insulin secretion and did so in the fasted state, equally su ⁇ risingly allowed insulin secretion to be recovered in response to the GTT both in the presence and the absence of the sulfonylurea.
  • Osmotic minipumps (Alzet 2002TMpumps, Alza Palo Alto, CA) were implanted sub-cutaneously into the rats to deliver des(l -3)IGF-l at a dose of 270 ⁇ g/rat/d or 1 1 mg/kg/d while other pumps were filled with the IGF- 1 excipient
  • the analog of IGF- 1 , des( l -3)IGF-l was used at a lower dose than was used for IGF- 1 m Study 5, as des( l-3)IGF-l is more potent than IGF- 1
  • the blood glucose concentrationsbefore the GTT were lower in the glipizide- treated rats ( 1 l ⁇ 7 mg/dl in control vs 133 ⁇ 4 mg/dl, p ⁇ 0 05), were not affected by des( l-3)IGF- l , and were not reduced in the group treated with both drugs ( 167 ⁇ 12 mg/dl)
  • the low blood glucose before the GTT m the glipizide rats was not associated with a change blood insulin concentration (control, 1 4 ⁇ 0 14 vs glipizide, 1 3 ⁇ 0 14 ng/ml), but des( l-3)IGF-l reduced basal insulin levels
  • 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)IGF- 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 glybunde
  • Example 1 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, IGF- I 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.
  • Example 3 a study in Type II diabetic humans produced very compelling evidence supporting the use of the combination of IGF- I and oral hypoglycemics.
  • diabetics who were being treated with either sulfonylurea or insulin and were poorly controlled, and therefore were considered treatment failures, were then treated with IGF-I .
  • IGF- I therapy can be combined with insulin secretagogue therapy to improve the regulation of blood glucose in diabetes.
  • IGF- 1 can be used either to prevent this failure from occurring or to restore glucose regulation if failure has already occurred.
  • IGF- 1 can be used either to prevent this failure from occurring or to restore glucose regulation if failure has already occurred.

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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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
WO2002060473A2 (fr) * 2001-01-31 2002-08-08 Colorado State University Research Foundation 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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