EP1126831A1 - Procede pour traiter la resistance insulinique par le monoxyde d'azote hepatique - Google Patents

Procede pour traiter la resistance insulinique par le monoxyde d'azote hepatique

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Publication number
EP1126831A1
EP1126831A1 EP99951765A EP99951765A EP1126831A1 EP 1126831 A1 EP1126831 A1 EP 1126831A1 EP 99951765 A EP99951765 A EP 99951765A EP 99951765 A EP99951765 A EP 99951765A EP 1126831 A1 EP1126831 A1 EP 1126831A1
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EP
European Patent Office
Prior art keywords
insulin
rist
liver
insulin resistance
nitric oxide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99951765A
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German (de)
English (en)
Other versions
EP1126831A4 (fr
Inventor
Wilfred Wayne Lautt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Diamedica Therapeutics Inc
Original Assignee
University of Manitoba
Kohn Kenneth I
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Publication date
Application filed by University of Manitoba , Kohn Kenneth I filed Critical University of Manitoba
Publication of EP1126831A1 publication Critical patent/EP1126831A1/fr
Publication of EP1126831A4 publication Critical patent/EP1126831A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to a compound and method for the treatment of insulin resistance.
  • NIDDM non-insulin dependent diabetes mellitus
  • the neural pathway connecting the sensory and effector branches of the reflex is not known but, in this unique preparation, could only occur through two sources.
  • One route is from the liver along the portal vein through the posterior hepatic plexus to the intestine.
  • the other involves transmission through the celiac ganglion which remained intact in this preparation.
  • this is an example of a splanchnic reflex that does not pass through the central nervous system. This mechanism likely serves the function of assuring that maximum glucose absorption only occurs at a time when the organs sensitive to insulin-induced uptake have also been stimulated.
  • RIST rapid insulin sensitivity test
  • Cats showed a dose-related development of insulin resistance using atropine (11) that was of a similar magnitude to that produced by surgical denervation.
  • the dose of atropine required to produce a full insulin resistance is 3 mg/kg (4 ⁇ mol/kg) administered into the portal vein.
  • a similar degree of insulin resistance was achieved with 10 "7 mmol/kg of the Iv ⁇ muscarinic selective antagonist, parenzepine, and with 10 "6 ⁇ mol/kg of the M 2 selective antagonist, methoctramine.
  • the data suggest that the response may be mediated by the M ⁇ muscarinic receptor subtype (21).
  • liver was clearly the organ that produced the insulin resistance, it was not clear that the liver was the resistant organ.
  • a further series was done in cats that measured arterial-venous glucose responses across the hindlimbs, extrahepatic splanchnic organs, and liver (22).
  • the intestine was unresponsive to the bolus insulin administration both before and after atropine or anterior plexus denervation or the combination of both.
  • the hepatic response was also not notably altered whereas the glucose uptake across the hindlimbs, primarily representing skeletal muscle uptake, was decreased following atropine or hepatic parasympathetic denervation.
  • HISS hepatic insulin sensitizing substance
  • HISS release in response to insulin is minimal or absent so that if insulin is released in this situation, there is a minimal metabolic effect.
  • the parasympathetic reflex mechanism is amplified so that HISS release occurs and results in the majority of the ingested glucose being stored in skeletal muscle.
  • HISS release results in severe insulin resistance.
  • the pancreas is required to secrete substantially larger amounts of insulin in order that the glucose in the blood is disposed of to prevent hyperglycemia from occurring. If this condition persists, insulin resistance will progress to a state of type 2 diabetes (non-insulin dependent diabetes mellitus) and eventually will lead to a complete exhaustion of the pancreas thus requiring the patient to resort to injections of insulin. Thus, any condition in which the hepatic parasympathetic reflex is dysfunctional will result in insulin resistance.
  • the liver Normally after a meal, the liver takes up a small proportion of glucose and releases HISS to stimulate skeletal muscle to take up the majority of the glucose load. In the absence of HISS, the skeletal muscle is unable to take up the majority of glucose thus leaving the liver to compensate.
  • the hepatic glycogen storage capacity is insufficient to handle all of the glucose, with the excess being converted to lipids which are then incorporated into lipoproteins and transported to adipose tissue for storage as fat. Provision of HISS to these individuals would restore the nutrition partitioning so that the nutrients are stored primarily as glycogen in the skeletal muscle rather than as fat in the adipose tissue.
  • acetylcholine infused directly into the portal vein resulted in a complete reversal of the insulin resistance induced by surgical denervation.
  • Administration of the same dose of acetylcholine intravenously produced no reversal.
  • Intraportal administration directly targets the liver whereas intravenous infusion bypasses the liver and is not organ selective.
  • This demonstration is extremely important in that the data indicate that the signal from the liver to skeletal muscle is blood-borne. This blood- borne signal is referred to as the hepatic insulin sensitizing substance (HISS).
  • HISS hepatic insulin sensitizing substance
  • a method of increasing insulin sensitivity by administering an effective amount of a compound which stimulates nitric oxide production in the liver.
  • a pharmaceutical composition having an effective amount of a compound which stimulates nitric oxide production in the liver and a pharmaceutically acceptable carrier.
  • Figure 1 is a bar graph showing the rapid insulin sensitivity test (RIST) index before and after intravenous L-NAME administration and two hours after administration;
  • RIST rapid insulin sensitivity test
  • Figure 2A and 2B are graphs showing (A) the control RIST index versus the change from control after L-NAME administration; and (B) the control RIST index versus the change from control after parasympathectomy and intraported atropine administration;
  • Figure 3 is a bar graph showing the RIST index in a control, after intraportal or intravenous L-NAME administration, and after intraportal atropine administration;
  • Figure 4 is a bar graph showing the RIST index in control, after parasympathetic denervation, and after intraportal L-NMMA administration;
  • Figure 5 is a bar graph showing the RIST index in a control, and after intravenous L-NAME and intraportal L-arginine administration;
  • Figure 6 is a bar graph showing the RIST index in a control, after intraportal L-NMMA administration and two hours post L-NMMA administration;
  • Figure 7 is a bar graph showing the RIST index in a control and after intraportal L-NMMA and intraportal SIN-1 administration;
  • Figure 8 is a bar graph showing the RIST index in a control and after intraportal L-NMMA and intraportal SIN-1 administration.
  • Figure 9 is a bar graph showing the RIST index in a control, after parasympathetic denervation, and after intraportal SIN-1 administration.
  • the present invention provides a compound and method of increasing insulin sensitivity by administering an effective amount of a compound which stimulates nitric oxide production in the liver. More specifically, the compound can be administered as a nitric oxide donor or as a stimulus that generates nitric oxide within the liver. Therefore, this compound and method can be useful in treating obesity, insulin resistance, and other diseases associated with insulin resistance.
  • the compounds of the present invention can be considered, generally, as members of the groups of nitric oxide agonists and NO donors.
  • Examples of such compounds include, but are not limited to: 3- morpholinosyndnonimine (SIN-1), sodium nitrite, nitroprusside, S-nitroso-N- acetyl-D, L-penicillamine (SNAP).
  • SIN-1 3- morpholinosyndnonimine
  • SNAP L-penicillamine
  • Insulin results in a hepatic parasympathetic activation of cholinergic muscarinic receptors which lead to release of a hepatic insulin sensitizing substance (HISS) that enters the bloodstream and regulates insulin sensitivity in skeletal muscle.
  • HISS hepatic insulin sensitizing substance
  • Virtually all of the variability in insulin sensitivity in fed rats is demonstrated to be due to variability in the hepatic parasympathetic-dependent insulin response.
  • Insulin resistance is produced by surgical or pharmacological blockade of the hepatic parasympathetic nerves and is easily demonstrated using a new insulin sensitivity test.
  • the insulin resistance so produced does not affect the splanchnic organs but appears to be restricted to skeletal muscle and, therefore, strongly resembles the sort of insulin resistance seen in non- insulin-dependent diabetes mellitus and in patients with chronic liver disease.
  • Insulin resistance produced by surgical denervation of the liver or the chronic bile duct ligation model of liver disease can be restored completely to normal levels by intraportal but not intravenous administration of acetylcholine. It is shown that many forms of insulin resistance in different disease states are secondary to hepatic parasympathetic neuropathy. This pathway shows an unexpected but major role for hepatic parasympathetic nerves in physiological and pathological regulation of glucose metabolism.
  • HISS hepatic insulin sensitizing substance
  • RIST rapid insulin sensitivity test
  • L-NAME N-nitro-L-arginine methyl ester
  • L-NMMA N-monomethyl-L-arginine
  • NOS in the liver interrupts the parasympathetic reflex, resulting in insulin resistance and that NO delivered to the liver can restore insulin sensitivity to normal levels when insulin resistance is produced by blockade of NO production in the liver or surgical destruction of hepatic nerves.
  • Nitric oxide can be administered to the liver by provision of nitric oxide donors or nitric oxide agonists or compounds that generate nitric oxide within the liver when administered orally, intravenously, intramuscularly, subcutaneously, or by delivery through a pump system directly into the portal vein.
  • the present invention therefore provides a pharmaceutical composition containing an effective amount of a compound which stimulates nitric oxide production in the liver and a pharmaceutically acceptable carrier.
  • PCR Polymerase chain reaction
  • the compound of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
  • the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound or as pharmaceutically acceptable salt and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.
  • the compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful.
  • the patient being treated is a warm-blooded animal and, in particular, mammals including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the doses may be single doses or multiple doses over a period of several days, but single doses are preferred.
  • the doses may be single doses or multiple doses over a period of several days. Additionally, dosing can be single doses or multiple doses prior to each meal for the duration of the disease.
  • the treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Non-aqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
  • Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
  • a pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • a pharmacological formulation of the compound utilized in the present invention can be administered orally to the patient.
  • Conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
  • Known techniques which deliver it orally or intravenously and retain the biological activity are preferred.
  • the compound of the present invention can be administered initially by intravenous injection to bring blood levels to a suitable level.
  • the patient's levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition and as indicated above, can be used.
  • the quantity to be administered will vary for the patient being treated.
  • the left jugular vein was cannulated for glucose infusion. Spontaneous respiration was allowed through a tracheal tube.
  • the blood samples (25 ⁇ l) were obtained through a right femoral arterial- venous loop (30).
  • the right femoral artery was cannulated with the arterial side of the loop.
  • the right femoral vein was cannulated with the venous side of the arterial-venous loop.
  • Arterial blood pressure was monitored via the arterial-venous loop by clamping the silicon sleeve on the venous side of the loop.
  • the arterial blood continuously flows through the loop into the venous side.
  • the portal vein was cannulated with a 24G (OPTIVATM, Johnson & Johnson Medical Inc.) intravenous catheter for intraportal drug administration.
  • the rats were allowed to stabilize from the surgical interventions for at least 30 minutes before any procedures were carried out.
  • Arterial blood samples were taken every five minutes, and glucose concentrations were immediately analyzed by the oxidase method with a glucose analyzer (model 27, Yellow Springs Instrumentals) until three successive stable glucose concentrations were obtained. The mean of these three concentrations is referred to as the basal glucose level.
  • RIST Rapid Insulin Sensitivity Test
  • insulin 50 mU/kg in 0.5 ml saline
  • Euglycemia was maintained by a variable glucose infusion.
  • the glucose solution was prepared in saline (100 mg/ml) and infused by a variable infusion pump (Harvard Apparatus).
  • the glucose infusion (5mg/kg/min) was started one minute after insulin infusion.
  • the infusion rate of the glucose pump was adjusted whenever required to clamp the arterial glucose levels as close to the basal value as possible.
  • the amount of glucose infused over 30 minutes following insulin administration represents the magnitude of insulin sensitivity and is referred to as the RIST index. This method has previously been described (30) and a standard operating procedure is given (11).
  • a stable basal arterial glucose concentration was determined and a RIST was performed as described above. After 30 minutes of restabilization, basal arterial glucose concentrations were determined and a second post L-NAME RIST was repeated to measure the duration of action of each dose.
  • Rapid Insulin Sensitivity Test in control, after L-NAME intravenously or intraportally and after Atropine.
  • Atropine (3.0 mg/kg) was infused intraportally over five minutes and the RIST was repeated.
  • L-NAME, L-NMMA, L-arginine and atropine were purchased from Sigma Chemical (St. Louis, MO).
  • SIN-1 was purchased from Alexis Corporation (San Diego, CA).
  • the human insulin was obtained from Eli Lilly & Company (Indianapolis, IN). All the chemicals were dissolved in saline.
  • Data analysis Data were analyzed using repeated-measures analysis of variance followed by Tukey-Kramer multiple comparison test in each group or, when applicable, paired and unpaired Student's t tests. The analyzed data were expressed as means ⁇ SE throughout. Some results were analyzed using linear regression analysis. Differences were accepted as statistically significant at p ⁇ 0.05. Animals were treated according to the guidelines of the Canadian Council on Animal Care.
  • the index used to express insulin sensitivity is the total amount of glucose (mg/kg) infused over 30 minutes after insulin (50 mU/kg) administration in order to maintain euglycemia at the baseline level and is referred to as the RIST index.
  • RIST in time controls Three consecutive control RISTs were performed in the same animal.
  • the RIST indexes were 207.0 ⁇ 17.1 mg/kg, 202.4 ⁇ 25.7 mg/kg and 200.5 ⁇ 35.0 mg/kg, respectively.
  • the mean coefficient of variance (standard deviation/mean RIST index for each rat) between the tests was 8.8 ⁇ 1.5%.
  • the basal glucose levels before each RIST (106.1 ⁇ 8.0 mg/dl, 99.4 ⁇ 10.8 mg/dl, 106.1 ⁇ 11.3 mg/dl, respectively) were not significantly different.
  • the blood pressure was stable (110 ⁇ 6.9 mmHg, 111.7 ⁇ 9.0 mmHg, 107.5 ⁇ 9.8 mmHg, respectively) throughout each test. Thus, all three RISTs were similar.
  • the basal glucose was similar before each RIST (117.9 ⁇ 3.3 mg/ml, 107.4 ⁇ 3.4 mg/ml, 115.6 ⁇ 5.3 mg/ml, respectively).
  • both 2.5 mg/kg and 5.0 mg/kg L- NAME produce similar insulin resistance but the duration of action is less than two hours with the low dose but was maintained for at least two hours for the high dose.
  • Intraportal infusion of L-NMMA (0.73 mg/kg) caused significant insulin resistance and reduced the RIST index to 129.7 ⁇ 14.3 mg/kg and caused (54.5 ⁇ 2.0% inhibition)(Fig. 7).
  • Intraportal SIN-1 (5.0 mg/kg) partially reversed the inhibition caused by L-NMMA (24.0 ⁇ 11.6%).
  • NO production in the liver can partially reverse insulin resistance caused by NOS antagonism.
  • Intraportal SIN-1 (10.0 mg/kg) completly reversed the inhibition caused by L-NMMA (0.6 ⁇ 5.8%) ( Figure 8).
  • higher NO production in the liver can completely reverse insulin resistance caused by NOS antagonism.
  • the parasympathetic reflex release of HISS is concluded to be NO-mediated.
  • the rapid insulin sensitivity test is a modified euglycemic clamp method (11 ,30). Insulin (50 mU) is infused over five minutes and the total amount of glucose infused (RIST index) in order to maintain arterial glucose at the baseline level during the 30 minutes of the test is used to express insulin sensitivity in each test.
  • the difference between a control RIST and the RIST index after surgical hepatic denervation or atropine is used to determine the hepatic parasympathetic component of insulin action (27, 29).
  • Three RISTs were performed, as time controls, in the same rat during one experiment with a coefficient of variance of 8.8 ⁇ 1.5%.
  • the basal glucose levels before each RIST were not significantly different.
  • the blood pressure was stable throughout and between each test.
  • the RIST is sensitive and shows inhibition by L-NAME, L-NMMA, atropine and hepatic denervation in anesthetized animals.
  • L-NAME is both a NOS inhibitor and a muscarinic receptor antagonist (2). Although the mechanism or location of action was not described, it was previously determined that L-NAME produces insulin resistance that does not act through muscarinic antagonism (22), thus indicating that both L-NAME and L-NMMA are suitable tools for the present purpose.
  • Insulin resistance caused by NOS antagonism is not a result of reduction in skeletal muscle perfusion but rather is caused by blockade of the parasympathetic reflex release of a hepatic factor that is released in response to insulin.
  • This putative hepatic insulin sensitizing substance amplifies the skeletal muscle response to insulin (28) and hepatic NOS inhibition interrupts this pathway.
  • Vasodilatory effect of insulin Insulin-mediated vasodilation increases glucose uptake in skeletal muscles (5,18,24).
  • Scherrer et al. (23) showed that L-NMMA, when infused into one arm, reduces forearm blood flow and increases blood pressure, but does not alter the whole-body glucose uptake (24). Natali et al.
  • NOS antagonism produced insulin resistance secondary to blocking vascular responses to insulin in skeletal muscle
  • the insulin resistance caused by hepatic denervation should have been made worse by the addition of this peripheral effect.
  • Insulin resistance produced by denervation was not affected by addition of a NOS antagonist.
  • the data are consistent with insulin resistance following NOS antagonism being secondary to a hepatic, rather than peripheral, effect.
  • L-arginine did not produce the anticipated reversal of insulin resistance produced by L-NAME, but rather L- arginine, by itself, caused insulin resistance (48.8 ⁇ 8.2%) (Figure 5).
  • L-NAME not only blocks NOS but also blocks arginine uptake across the hepatocyte plasma membrane (8).
  • L-arginine is metabolized by NOS to NO, and by arginase to urea and L-ornithine (6). Since the liver has a very high arginase activity, most L-arginine administered is converted to L-ornithine by the liver, although L-arginine can reverse the vascular effects of L-NAME in the liver (12).
  • L-arginine also causes release of growth hormone (7,14) and glucagon; both hormones reduce insulin sensitivity. This explains why insulin resistance caused by L-NAME could not be reversed with L-arginine and why L-arginine caused insulin resistance.
  • the NO donor SIN-1
  • SIN-1 As an alternative to using L-arginine to reverse the effect of NOS blockade, the NO donor, SIN-1 , was used.
  • administration of a higher dose of SIN-1 (10.0 mg/kg) to the liver completely reversed the insulin resistance caused by L-NMMA Figure 8
  • administration of intraportal SIN-1 after denervation of the liver completely restored insulin sensitivity ( Figure 9).
  • NO production in the liver is confirmed to be essential for insulin sensitivity.
  • This pathway is shown to consist of an insulin-induced hepatic parasympathetic reflex, acting through muscarinic receptors, resulting in production of NO in the liver, leading to release of the putative hormone, HISS, that sensitizes the skeletal muscle to the action of insulin. Interruption of this NO-mediated reflex inhibits HISS release from the liver and insulin resistance follows.
  • An insulin sensitivity test showing amount of glucose needed to be administered after insulin (50 mU/kg i.v.) in order to maintain arterial glucose steady is analyzed.
  • group 1 a nitric oxide synthase blocker (blocks production of nitric oxide), L-NAME, was given into the portal vein and produced a 54.9 ⁇ 5.2% inhibition of insulin response.
  • Atropine in a dose known to produce full blockade of the hepatic parasympathetic nerves, was administered intravenously after L-NAME and produced a modest further resistance (67.2 ⁇ 4.9%).
  • the same dose of L- NAME was given intravenously and did not produce significant insulin resistance (19.8 ⁇ 7.5%).
  • the blockade of muscarinic receptors with atropine produced normal insulin resistance (56.0 ⁇ 8.9%) expected from parasympathetic interruption.
  • the data show conclusively that insulin resistance produced by blockade of NO synthase did so by acting on the liver rather than other tissues.
  • Insulin resistance (45.0 ⁇ 3.0% of normal response) is produced by the blockade of nitric oxide synthase (eliminates production of nitric oxide) which is not reversed by administration of a nitric oxide donor intravenously but is fully reversed by administration of the same dose directly to the liver via the portal vein.
  • This response conclusively shows that the liver is the site of nitric oxide regulation of insulin sensitivity.
  • HISS hepatic insulin sensitizing substance

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Abstract

L'invention concerne un procédé permettant d'augmenter la sensibilité insulinique par une administration d'une quantité efficace d'un composé destiné à stimuler la production de monoxyde d'azote dans le foie. Cette invention concerne également une composition pharmaceutique renfermant une quantité efficace d'un composé destiné à stimuler la production de monoxyde d'azote dans le foie, ainsi qu'un excipient pharmaceutiquement acceptable.
EP99951765A 1998-10-06 1999-10-05 Procede pour traiter la resistance insulinique par le monoxyde d'azote hepatique Withdrawn EP1126831A4 (fr)

Applications Claiming Priority (3)

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US10317098P 1998-10-06 1998-10-06
US103170P 1998-10-06
PCT/US1999/023098 WO2000019992A1 (fr) 1998-10-06 1999-10-05 Procede pour traiter la resistance insulinique par le monoxyde d'azote hepatique

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XIE H ET AL: "INSULIN RESISTANCE CAUSED BY HEPATIC CHOLINERGIC INTERRUPTION AN REVERSED BY ACETYLCHOLINE ADMINISTRATION" AMERICAN JOURNAL OF PHYSIOLOGY, AMERICAN PHYSIOLOGICAL SOCIETY, BETHESDA, MD, US, vol. 271, no. 3, PART 1, 1996, pages E587-E592, XP009011012 ISSN: 0002-9513 *

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CA2381095A1 (fr) 2000-04-13
WO2000019992A9 (fr) 2000-09-21
EP1126831A4 (fr) 2004-10-06
WO2000019992A1 (fr) 2000-04-13

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