WO2016209659A1 - Inversion de génération de ros persistante après une hyperglycémie transitoire - Google Patents

Inversion de génération de ros persistante après une hyperglycémie transitoire Download PDF

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WO2016209659A1
WO2016209659A1 PCT/US2016/037334 US2016037334W WO2016209659A1 WO 2016209659 A1 WO2016209659 A1 WO 2016209659A1 US 2016037334 W US2016037334 W US 2016037334W WO 2016209659 A1 WO2016209659 A1 WO 2016209659A1
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agent
subject
hyperglycemia
ros
production
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Michael Alan BROWNLEE
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Albert Einstein College Of Medicine, Inc.
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K38/26—Glucagons
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5064—Endothelial cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/84—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving inorganic compounds or pH

Definitions

  • Diabetic and pre-diabetic hyperglycemia continue to be a major cause of blindness, renal failure, heart attacks, and lower limb amputation.
  • Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species (ROS) initiates many of the complex series of molecular events that result in diabetic tissue damage.
  • ROS mitochondrial reactive oxygen species
  • the assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbAlc, prevents microvascular complications.
  • recent analyses by the DCCT/EDIC study group showed that 89% of variation in risk of retinopathy, microalbuminuria or albuminuria is due to elements of glycemia not captured by mean HbAlc values.
  • HbAlc time-averaged glucose concentrations
  • technologies targeting diabetic complications mostly target HbAlc values by providing improved insulin secretion or action.
  • Developing technologies include iPSC differentiation, mechanical insulin or insulin-glucagon devices, and a variety of monomelic peptides engineered to be agonists for multiple peptide-hormone receptors. Small molecular weight compounds and peptides that increase tissue sensitivity to insulin action are also in development. None, to the inventor's knowledge, address the long-term effects of brief spikes of hyperglycemia.
  • ROS reactive oxygen species
  • a method for obtaining an agent which reduces hyperglycemia- induced ongoing or persistent or post-hyperglycemic spike reactive oxygen species (ROS) production in a cell in a subject, wherein the agent inhibits an ROS production feedback loop,
  • ROS reactive oxygen species
  • a method for obtaining an agent which reduces hyperglycemia- induced ongoing reactive oxygen species (ROS) production in a cell in a subject, wherein the agent inhibits an ROS production feedback loop,
  • ROS reactive oxygen species
  • ROS hyperglycemia-induced ongoing reactive oxygen species
  • ROS reactive oxygen species
  • the method further comprises physically recovering the candidate agent identified as reducing ROS production so as to obtain an agent which reduces reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • ROS reactive oxygen species
  • Also provided is a method of treating diabetes complication in a subject comprising administering to the subject an amount of an agent effective to inhibit reactive oxygen species production by a cell of a subject.
  • ROS reactive oxygen species
  • Also provided is a method for treating diabetes complication in a subject comprising administering to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK-3beta, to inhibit phosphorylation of VDAC threonine, or to increase association of VDAC with HK-II.
  • Also provided is a method for treating diabetes or prediabetic hyperglycemia in a subject comprising administering to the subject an amount of an agent effective to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK- 3beta, to inhibit phosphorylation of VDAC threonine, or to increase association of VDAC with HK-II.
  • FIG. 1A-1D Transient exposure to high glucose induces persistent mitochondrial ROS production by shifting the glucose concentration-ROS curve to the left.
  • IB ROS levels in HAEC exposed to 25mM glucose for varying times.
  • FIG. 2A-2H Persistent mitochondrial ROS production after transient exposure to high glucose is maintained by activation of a multi-component feedback loop.
  • Upper panel Representative photomicrographs of increased JC-1 red fluorescence indicating increased mitochondrial membrane potential.
  • Lower panel ROS production measured by CM-H2DCFDA.
  • (2B-G) HAEC were exposed to 25 mM glucose for the indicated times with (red bars) or without (green bars) subsequent incubation in 5 mM glucose for 2 days. Cells exposed to 5mM glucose were used as controls (blue bars).
  • Lower panel Quantitation of IP-WB data from upper panel.
  • Free iron in HAEC was measured by Electron Paramagnetic Spectroscopy (EPR).
  • EPR Electron Paramagnetic Spectroscopy
  • HAEC were exposed to 5mM glucose for 6 hrs after infection with adenoviral vectors expressing either Akt-DN, GSK-3 -CA, or vector alone.
  • Upper panel Representative photomicrographs of increased JC-1 red fluorescence indicating increased mitochondrial membrane potential.
  • Lower panel ROS production measured by CM- H2DCFDA.
  • ROS data are the mean +/- S.E.M from 3 independent experiments with at least 8 technical replicates. All data shown are the mean +/- S.D. from 5 independent experiments. * p ⁇ 0.05.
  • FIG. 3 Schematic representation of the multi-component feedback loop which maintains persistently increased ROS production after transient exposure to high glucose.
  • Transient exposure to high glucose induces a transient increase in ETC flux increasing ⁇ and thereby increasing mitochondrial superoxide production.
  • this superoxide causes release of Fe 2+ from ferritin and iron sulfur cluster-containing proteins.
  • This released free iron reacts with diffused superoxide-derived hydrogen peroxide to form hydroxyl radicals, which increase PP2A activity.
  • Activated PP2A then dephosphorylates Aktl, decreasing its activity. Decreased Aktl activity increases GSK-3 activity, which then increases VDAC threonine phosphorylation.
  • Glucose concentration-ROS dose response curve from HAEC exposed to 12mM for 6 hrs followed by 2 days of 5mM glucose, and then transiently treated with a peptide GSK-3 inhibitor (gold curve). This curve is shown in comparison to the glucose concentration-ROS curves from cells exposed to 5mM glucose for 2 days (blue curve), and the curve from cells exposed to 6 hrs 12mM glucose followed by 5mM glucose for 2 days (red curve) from Figure ID. ROS levels were measured by CM- H2DCFDA. ROS data are the mean +/- S.E.M from 3 independent experiments with at least 8 technical replicates. * p ⁇ 0.05. (4B-4E) Effect of GLP-1 (9-36)amide on feedback loop components.
  • HAEC were exposed to 12 mM glucose for 6 hrs with or without 100 pM GLP-1 (9-36)amide. Cells exposed to 5mM glucose were used as controls (blue bars).
  • GLP-1 (9-36)amide reverses the persistent reduction of prostacyclin synthase caused by transient hyperglycemia in vivo.
  • Upper panel Experiment schematic.
  • IP glucose
  • a micro-osmotic pump with GLP-1 (9-36)amide 300 ⁇ g/ml was inserted in the mice for 24 hours and then removed.
  • ROS overproduction during hyperglycemia involves increased glucose metabolism causing increased mitochondrial electron leak, which can also activate other ROS -generating proteins such as NADPH oxidases and monomeric ENOS.
  • glucose levels are normal, there is no increased glucose metabolism in target cells of complications.
  • a method for obtaining an agent which reduces hyperglycemia- induced ongoing reactive oxygen species (ROS) production in a cell in a subject, wherein the agent inhibits an ROS production feedback loop,
  • ROS reactive oxygen species
  • ROS reactive oxygen
  • the cell is a vascular cell.
  • candidate agents are selected from a peptide library.
  • candidate agents are selected from a peptide library wherein the peptiodes are from 5 to 40 amino acids in length.
  • Hyperglycemic glucose and normoglycemic glucose are easily determined by the species of mammal the cell being tested.
  • the cells are human cells, and the hyperglycemic glucose and normoglycemic glucose are hyperglycemic glucose for a human and normoglycemic glucose for a human.
  • the cells are previously exposed to hyperglycemic glucose for 5.75 - 6.25 hours.
  • the cells are previously exposed to hyperglycemic glucose for 6 hours.
  • the cells are exposed to normoglycemic glucose for over 1.5 days with the candidate agent.
  • the cells are exposed to normoglycemic glucose for 2.0 days with the candidate agent.
  • a method for obtaining an agent which reduces hyperglycemia- induced ongoing reactive oxygen species (ROS) production in a cell in a subject, wherein the agent inhibits an ROS production feedback loop,
  • ROS reactive oxygen species
  • the cell is a vascular cell.
  • the VDAC, a GSK-3beta or an Akt is contacted with the candidate agent.
  • the cell is
  • the method further comprises physically recovering the candidate agent identified as reducing ROS production so as to obtain an agent which reduces hyperglycemia-induced ongoing ROS production in a vascular cell or an agent which reduces ROS production in a vascular cell, respectively.
  • VDAC phosphorylation, GSK-3beta activity or Akt activity are experimentally quantified using Western blot and/or immunoprecipitation.
  • the candidate agent is a peptide. In an embodiment of the methods, the candidate agent is a peptide of less than 20 amino acid residues. In an embodiment of the methods, the candidate agent is a peptide of less than 10 amino acid residues.
  • the candidate agent is a small organic molecule of 1,500 daltons or less.
  • the hyperglycemia of the hyperglycemia- induced ongoing ROS production or the hyperglycemia associated with the ROS production is transient. In an embodiment of the methods, the hyperglycemia is from about 4 to 6 hours. In an embodiment of the methods, the hyperglycemia is undetectable using HbAlc quantification. In an embodiment of the methods, the hyperglycemia does not increase HbAlc production in the subject.
  • the candidate the agent does not affect glycemia in the subject. In an embodiment of the methods, the candidate the agent does not affect insulin production or affect insulin activity in a subject.
  • the method further comprises physically recovering the candidate agent identified as reducing ROS production so as to obtain an agent which reduces reactive oxygen species (ROS).
  • the cell is a vascular cell.
  • the cell is a vascular cell.
  • the HAEC has been obtained from a diabetic human. In an embodiment, the HAEC has been obtained from a non-diabetic human.
  • the elevated glucose concentration is equivalent to over 190 mg/dL blood. In an embodiment, the elevated glucose concentration is equivalent to over 210 mg/dL blood. In an embodiment, the elevated glucose concentration is equivalent over 20 mM. In an embodiment, the elevated glucose concentration is 23 - 27 mM. In an embodiment, the elevated glucose concentration is 25 mM.
  • the candidate agent is a peptide. In an embodiment, the candidate agent is a peptide of less than 20 amino acid residues. In an embodiment, the candidate agent is a peptide of less than 10 amino acid residues. In an embodiment, the candidate agent is a small organic molecule of 1,500 daltons or less. In an embodiment, the candidate agent is a small organic molecule of 1,000 daltons or less. In an embodiment, the candidate agent is a small organic molecule of 500 daltons or less.
  • ROS levels are quantified using CM-H2DCFDA. In an embodiment, ROS levels are quantified using fluorimetry.
  • ROS reactive oxygen species
  • the cell is a vascular cell.
  • ROS reactive oxygen species
  • the cell is a vascular cell.
  • a method of treating diabetes complication in a subject comprising administering to the subject an amount of an agent effective to inhibit reactive oxygen species production by a cell of a subject.
  • Normal fasting plasma glucose is generally understood to be ⁇ 100 mg/dL (5.6 mmol/L).
  • Two-hour glucose during oral glucose tolerance test (OGTT) has blood glucose ⁇ 140 mg/dL (7.8 mmol/L).
  • the subject has an increased risk for diabetes.
  • Subjects with increased risk for diabetes include those with impaired fasting glcose (IFG) - which is generally understood to be a fasting plasma glucose of between 100 and 125 mg/dL (5.6 to 6.9 mmol/L).
  • Subjects with increased risk for diabetes also include those with impaired glucose tolerance (IGT) - a two-hour plasma glucose value during a 75 g oral glucose tolerance test between 140 and 199 mg/dL (7.8 to 11.0 mmol/L).
  • ITT impaired glucose tolerance
  • the subject has diabetes type 2 diabetes or diabtes mellitus.
  • Subjects with diabetes mellitus have an FPG at or above 126 mg/dL (7.0 mmol/L), a two-hour value in an OGTT (2-h PG) at or above 200 mg/dL (11.1 mmol/L), or a random (or "casual") plasma glucose concentration >200 mg/dL (11.1 mmol/L) in the presence of symptoms.
  • the subject has near normal FPG.
  • the subject has diabetes. "Near normal" FPG in someone who already has diabetes would be 100-145 or 150 mg/dL, while 200-250 would be quite high but not unusual in many ambulatory diabetic patients.
  • the cell is a vascular cell.
  • the complication is a retinopathy, an albuminuria or a microalbuminuria.
  • the complication is a peripheral neuropathy, a non-healing diabetic foot ulcer, a cognitive decline, a diabetic cardiomyopathy, an atherosclerosis, or a post-myocardial infarction arrhythmia.
  • a method of reducing reactive oxygen species (ROS) production in a cell in a subject, wherein the ROS production is fatty acid-induced ROS comprising administering to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK-3beta, to inhibit phosphorylation of VDAC threonine, or to increase association of VDAC with HK-II.
  • ROS reactive oxygen species
  • a method of treating diabetes or prediabetic hyperglycemia in a subject comprising: a) receiving an identification of the subject as having a persistent or an ongoing fatty acid- induced ROS;
  • Also provided is a method of treating diabetes or prediabetic hyperglycemia in a subject comprising administering to the subject an amount of an agent effective to inhibit reactive oxygen species production by a cell of a subject.
  • the cell is a vascular cell.
  • Also provided is a method of preventing or reducing development of diabetes, or preventing or reducing development of prediabetic hyperglycemia, in a subject comprising administering to the subject an amount of an agent effective to inhibit reactive oxygen species production by a cell of a subject.
  • the cell is a vascular cell.
  • the method is for treating diabetes. In an embodiment, the method is for treating prediabetic hyperglycemia. In an embodiment, the agent comprises a peptide.
  • the peptide is a non-hypoglycemic peptide.
  • the agent comprises glucagon like peptide- 1 (9-36) amide. In an embodiment, the agent does not comprise glucagon like peptide-1 (9-36) amide. In an embodiment, the glucagon like peptide-1 (9-36) amide has the sequence EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2 (SEQ ID NO: l).
  • the agent comprises glucagon like peptide-1 (9-37). In an embodiment, the agent does not comprise glucagon like peptide-1 (9-37). In an embodiment, the glucagon like peptide-1 (9- 37) has the sequence EGTFTSDVSSYLEGQAAKEFIAWLVKGRG.
  • the agent is directly administered to a retinal tissue for treating the retinopathy.
  • the agent comprises glucagon like peptide-1 (9-36) amide, the agent comprises a small organic molecule.
  • the agent is administered during or subsequent to a hyperglycemic event. In an embodiment, the agent is administered by self-administration. In an embodiment, the agent is administered continuously by a pump. [0055] Also provided is a method of treating diabetes or prediabetic hyperglycemia in a subject comprising administering to the subject an amount of an agent effective to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK- 3beta, to inhibit phosphorylation of VDAC threonine , or to increase association of VDAC with HK-II.
  • the subject is a human.
  • Also provided is a method of treating diabetes or prediabetic hyperglycemia in a subject comprising:
  • a method of treating diabetes or prediabetic hyperglycemia in a subject comprising:
  • the agent comprises a peptide.
  • the agent comprises glucagon like peptide- 1 (9-36) amide.
  • the agent comprises glucagon like peptide- 1 (9-37).
  • the agent comprises a small organic molecule.
  • the agent is administered during or subsequent to a hyperglycemic event.
  • the agent is administered by self-administration. In an embodiment, the agent is administered continuously by a pump. In an embodiment, the amount of agent administered decreases Akt inhibition in the vascular cells of the subject. In an embodiment, the amount of agent administered reduces the extent of VDAC phosphorylation associated with hyperglycemia in the subject. In an embodiment, the amount of agent administered reduces the extent of GSK-3P activation associated with hyperglycemia in the subject. In an embodiment, the amount of agent administered reduces the extent of PGI2 inactivation associated with hyperglycemia induced ROS production in the subject.
  • the subject is identified as undergoing a hyperglycemic spike by means of a blood glucose monitor.
  • the agent is administered within 5 minutes of a hyperglycemia threshold being crossed.
  • a hyperglycemia threshold is crossed when the glucose level in a subject's blood exceeds a predetermined threshold value, which is indicative of hyperglycemia.
  • the hyperglycemia threshold is l lmmol/L.
  • the hyperglycemia threshold is 12mmol/L.
  • the hyperglycemia threshold is 13mmol/L.
  • the hyperglycemia threshold is 14mmol/L.
  • the hyperglycemia threshold is 15mmol/L.
  • the hyperglycemia threshold is 16mmol/L.
  • the hyperglycemia threshold is 17mmol/L. In an embodiment, the hyperglycemia threshold is 18mmol/L. In an embodiment, the hyperglycemia threshold is 19mmol/L. In an embodiment, the hyperglycemia threshold is 20mmol/L. In an embodiment, the hyperglycemia threshold is 25mmol/L. In an embodiment, the agent is administered within 10 minutes of a hyperglycemia threshold being crossed. In an embodiment, the agent is administered within 15 minutes of a hyperglycemia threshold being crossed. In an embodiment, the agent is administered within 20 minutes of a hyperglycemia threshold being crossed. In an embodiment, the agent is administered within 25 minutes of a hyperglycemia threshold being crossed. In an embodiment, the agent is administered within 30 minutes of a hyperglycemia threshold being crossed.
  • the method is for treating diabetes. In an embodiment, the method is for treating prediabetic hyperglycemia.
  • Administration can be one of, or any combination of, auricular, buccal, conjunctival, cutaneous, subcutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, via hemodialysis, interstitial, intrabdominal, intraamniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronary, intradermal, intradiscal, intraductal, intraepidermal, intraesophagus, intragastric, intravaginal, intragingival, intraileal, intraluminal, intralesional, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrae
  • the amount of agent administered decreases Akt inhibition in the vascular cells of the subject. In an embodiment, the amount of agent administered reduces the extent of VDAC phosphorylation associated with hyperglycemia in the subject. In an embodiment, the amount of agent administered reduces the extent of GSK-3P activation associated with hyperglycemia in the subject. In an embodiment, the amount of agent administered reduces the extent of PGI2 inactivation associated with hyperglycemia induced ROS production in the subject. In an embodiment of the methods of treatment, the hyperglycemia is undetectable using HbAlc quantification. In an embodiment of the methods, the hyperglycemia does not increase HbAlc production in the subject.
  • the ROS production is persistent ROS production following brief spike(s) of hyperglycemia.
  • ROS reactive oxygen species
  • ROS reactive oxygen species
  • a method for reducing reactive oxygen species (ROS) production in a cell in a subject, wherein the ROS production is associated with a hyperglycemia in a subject comprising administering to the subject an amount of an agent effective to normalize Aktl activity, to normalize PP2A activity, to normalize GSK-3beta activity, to normalize phosphorylation of VDAC threonine, or to normalize association of VDAC with HK-II.
  • ROS reactive oxygen species
  • a method for treating a diabetes complication in a subject comprising administering to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK-3beta, to inhibit phosphorylation of VDAC threonine, or to increase association of VDAC with HK-II.
  • the complication is a retinopathy, an albuminuria or a microalbuminuria.
  • Also provided is a method for treating diabetes or prediabetic hyperglycemia in a subject comprising administering to the subject an amount of an agent effective to activate Aktl, to inhibit PP2A, to inhibit GSK-3beta, to inhibit phosphorylation of VDAC threonine, or to increase association of VDAC with HK-II.
  • the subject is a human.
  • ROS reactive oxygen species
  • the method further comprises physically recovering the candidate agent identified as reducing ROS production so as to obtain an agent which reduces hyperglycemia-induced ongoing ROS production.
  • the non-human animal is a diabetes-model animal.
  • the animal is a rat or a mouse.
  • it is vascular cell ROS production that is quantified.
  • treating a diabetes means that one or more symptoms of the disease, such as the diabetes itself, or a resultant symptom of the diabetes such as blindness, heart damage, lower limb ischemia or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, placed in a state of remission, or maintained in a state of remission.
  • the method inhibits further development of the diabetes.
  • the method inhibits further development of a pathology that results from the diabetes.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes. This definition of treating a diabetes, mutatis mutandis, can apply to treating a diabetic complication, such as a retinopathy, albuminuria or microalbuminuria.
  • treating a prediabetes hyperglycemia means that one or more symptoms of the disease, such as ROS generation, or a damage resulting from hyperglycemia induced ROS generation or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, or maintained in a state of prediabetes.
  • the method inhibits further development of the prediabetes into diabetes.
  • the method inhibits further development of a pathology that results from the prediabetes hyperglycemia.
  • the subject treated has Hemoglobin Ale levels between 5.7% and 6.4% indicate increased risk of diabetes. In an embodiment, the subject treated has Hemoglobin Ale levels of 6.5% or higher.
  • a control amount is a value decided or obtained, usually beforehand, as a control.
  • the concept of a control is well-established in the field, and can be determined, in a non-limiting example, empirically from suitable systems, and may be normalized as desired (in non-limiting examples, for volume, mass, location, etc.) to negate the effect of one or more variables.
  • Hyperglycemia-induced overproduction of intracellular ROS initiates many of the complex series of molecular events that result in diabetic tissue damage, and transgenic expression of the antioxidant enzyme superoxide dismutase prevents each complication in experimental diabetes.
  • transient above-threshold spikes of hyperglycemia continue to generate excess ROS after they have ceased and thereby activate damaging mechanisms for days of subsequent normal glycemia. These brief spikes are too short to be reflected in the HbAlc values.
  • HbAlc values In human vascular cells and in mice, several hours' exposure to high glucose activates a positive multicomponent feedback loop which maintains persistent overproduction of oxygen free radicals for days of subsequent exposure to normal glucose concentrations. Disruption of this loop, e.g. by selected peptides as shown herein, rapidly normalizes both the persistent free radical overproduction and its pathologic consequences that otherwise persist for days of subsequent exposure to normal glucose concentrations.
  • GLP-1 (9-36)amide e.g., EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2 (SEQ ID NO: l)
  • GLP-1 (9-36)amide reversed the persistent left shift of the glucose concentration-ROS dose- response curve caused by transient hyperglycemia, and thereby reversed the persistent ROS dependent inactivation of PGI2.
  • GLP-1 (9-36)amide is a cleavage product of the incretin hormone GLP-1 (7- 36)amide.
  • GLP-1 (9-36)amide has been reported to have unique extrapancreatic insulin-like actions in the heart, vasculature, and liver, which appear not to be mediated through the GLP-1 receptor.
  • GLP-1 (9-36)amide activated cardioprotective signaling pathways while GLP-1 receptor agonists did not.

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Abstract

L'invention concerne des méthodes pour le traitement du diabète et du prédiabète. L'invention concerne également des méthodes qui permettent de réduire la production de ROS induite par l'hyperglycémie transitoire. L'invention concerne en outre des méthodes d'obtention d'agents qui permettent de réduire la production de ROS induite par l'hyperglycémie transitoire.
PCT/US2016/037334 2015-06-25 2016-06-14 Inversion de génération de ros persistante après une hyperglycémie transitoire WO2016209659A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060100189A1 (en) * 2004-05-24 2006-05-11 Gurtner Geoffrey C Method of treating or preventing pathologic effects of acute increases in hyperglycemia and/or acute increases of free fatty acid flux
WO2014036528A2 (fr) * 2012-08-31 2014-03-06 Ixchel Pharma, Llc Agents utiles pour le traitement de l'obésité, du diabète et de troubles associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060100189A1 (en) * 2004-05-24 2006-05-11 Gurtner Geoffrey C Method of treating or preventing pathologic effects of acute increases in hyperglycemia and/or acute increases of free fatty acid flux
WO2014036528A2 (fr) * 2012-08-31 2014-03-06 Ixchel Pharma, Llc Agents utiles pour le traitement de l'obésité, du diabète et de troubles associés

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BYUN, H ET AL.: "GSK3 Inactivation is Involved in Mitochondrial Complex IV Defect in Transforming Growth Factor (TGF) beta1-Induced Senescence.", EXPERIMENTAL CELL RESEARCH., vol. 318, no. 15, 28 May 2012 (2012-05-28), pages 1808 - 1819, XP028404735 *
CICCONE, MM ET AL.: "Endothelial Function in Pre-diabetes, Diabetes and Diabetic Cardiomyopathy: A Review.", JOURNAL OF DIABETES AND METABOLISM., vol. 5, no. 4, 14 May 2014 (2014-05-14), pages 1 - 10, XP055341126 *
EDUAFO, AK: "Mechanisms of Hyperglycemia-Induced ROS Production in Osmotically Swollen Glial Cells", 12 May 2015 (2015-05-12), pages 1 - 83, XP055341102, Retrieved from the Internet <URL:https://etd.ohiolink.edu/!etd.send_file? accession=wright1433185840&disposition=inline> [retrieved on 20160819] *
EGGER, AE ET AL.: "Development of an Experimental Protocol for Uptake Studies of Metal Compounds in Adherent Tumor Cells.", JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY;, vol. 24, no. 1, January 2009 (2009-01-01), pages 1 - 29, XP055051941 *
GERO, D ET AL.: "Cell -Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction.", vol. 62, no. 3, 7 December 2012 (2012-12-07), pages 953 - 964, XP055341090 *
KANG, NS ET AL.: "Identification of Small Molecules that Inhibit GSK-3beta Through Virtual Screening.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS., vol. 19, no. 2, 5 November 2008 (2008-11-05), pages 533 - 537, XP025816982 *
TABIT, CE ET AL.: "Protein Kinase-C Beta Contributes to Impaired Endothelial Insulin Signaling in Humans with Diabetes Mellitus.", CIRCULATION., vol. 127, no. 1, 30 November 2012 (2012-11-30), pages 1 - 19, XP055341124 *
TOMAS, E ET AL.: "GLP-1-Derived Nonapeptide GLP-1(28-36) Amide Targets to Mitochondria and Suppresses Glucose Production and Oxidative Stress in Isolated Mouse Hepatocytes.", REGULATORY PEPTIDES., vol. 167, no. 2-3, 21 January 2011 (2011-01-21), pages 177 - 184, XP028160773 *

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