US20110189316A1 - Composition for controlling increase in blood glucose - Google Patents

Composition for controlling increase in blood glucose Download PDF

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US20110189316A1
US20110189316A1 US13/055,281 US200913055281A US2011189316A1 US 20110189316 A1 US20110189316 A1 US 20110189316A1 US 200913055281 A US200913055281 A US 200913055281A US 2011189316 A1 US2011189316 A1 US 2011189316A1
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gte
egcg
glucose
peg
blood glucose
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Dae-Kyu SONG
Jinho Lee
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Nuc Electronics Co Ltd
Industry Academic Cooperation Foundation of Keimyung University
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Assigned to NUC ELECTRONICS CO., LTD. reassignment NUC ELECTRONICS CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEE, JINHO, SONG, DAE-KYU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/25—Synthetic polymers, e.g. vinylic or acrylic polymers
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to catechin-related compositions to lower postprandial blood glucose elevation.
  • the present invention also relates to functional foods for blood glucose control containing green tea extracts (GTE) with gallated catechins (GC) and macromolecules that prevent intestinal absorption of GC.
  • GTE green tea extracts
  • GC gallated catechins
  • One purpose of this invention is to take blood glucose lowering compositions after a meal without any side effects by inhibiting intestinal glucose absorption as well as lipid absorption using a different mechanism from available hypoglycemic agents.
  • Type 2 diabetes is characterized by two main features: peripheral insulin resistance and beta-cell dysfunction. Both hereditary and environmental factors, such as obesity and prolonged hyperglycemia, may trigger or exaggerate human type 2 diabetes. Hyperglycemia causes both beta-cell damage and peripheral insulin resistance via multiple mechanisms, collectively referred to as glucotoxicity (Borona, 2008). In MODY-2 diabetes, functional defects in glucokinase genes restrict hepatic glucose uptake, bringing about prolongation of postprandial hyperglycemia (Jiang et al, 2008), and eventually result in beta-cell overload. Hence, efforts to minimize postprandial hyperglycemia, as well as fasting blood glucose control, are of importance for the prevention and treatment of type 2 diabetes.
  • amylase inhibitors or glucosidase inhibitors are available to date to decrease postprandial hyperglycemia, the usage can induce some gastrointestinal side effects, as they block the conversion to monosaccharide.
  • the leaves of green tea Camellia sinensis ) contain polyphenols, in which catechin family is the most major polyphenol.
  • Catechins extracted with water from green tea leaves contain gallated catechins (GC), which mainly include gallate, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG).
  • GC gallated catechins
  • ECG epicatechin gallate
  • EGCG epigallocatechin gallate
  • type 2 diabetes the effects of green tea extracts (GTE) or EGCG in in vitro and in vivo studies were intensively investigated.
  • GC Gallated catechins
  • ECG epicatechin-3-gallate
  • SGLT1 Na-glucose co-transporters
  • the amount of GC that needs to be ingested to exert the luminal effect appears to be endurable in humans (Kobayashi et al, 2000; Van Amelsvoort et al, 2001), probably due to the lower oral bioavailability of these molecules.
  • GC in the circulation increased blood glucose levels and thus induced insulin hypersecretion. Therefore, a combinatorial application of GTE with an inhibitor of intestinal GTE absorption could effectively obtain the positive GTE effect in the intestinal lumen to lower postprandial blood glucose elevation.
  • GTE green tea extract
  • Glucose intolerance was ameliorated by gallated catechin-deficient GTE or GTE mixed with polyethylene glycol, which was used as an inhibitor of intestinal absorption of gallated catechins.
  • the invention is directed to a composition for blood glucose control containing green tea extracts (GTE) with gallated catechins (GC) and macromolecule to prevent the intestinal absorption of GC.
  • GTE green tea extracts
  • GC gallated catechins
  • the GC component may comprise at least one of EGCG or ECG.
  • the macromolecule may be polyethylene glycol (PEG), PEG derivatives, PEG copolymer, water-soluble copolymer, methoxy PEG (mPEG) or polypropylene glycol (PPG).
  • the macromolecule may have a molecular weight of 1,000-2,000,000 daltons.
  • the invention is directed to a pharmaceutical composition that includes a blood glucose controlling amount of the composition described above, and a pharmaceutically acceptable excipient thereof.
  • the GC may include EGCG or ECG or both.
  • the macromolecule may be PEG, PEG derivatives, PEG copolymer, water-soluble copolymer, methoxy PEG (mPEG) or PPG.
  • the macromolecule may have a preferable molecular weight of 1,000-50,000 daltons.
  • the invention is directed to a method for controlling blood glucose level in a subject, comprising administering to the subject the composition described above.
  • FIGS. 2A-2B show effects of circulating GC on glucose tolerance.
  • FIGS. 3A-3D show EGCG-mediated decreases in glucose uptake.
  • 2-Deoxy-[ 3 H] glucose was added after a 20-min incubation with the indicated concentrations of EGCG with or without 100 nM insulin in the media containing differentiated L6 myoblasts (A), HepG2 hepatocytes (B), differentiated 3T3-L1 adipocytes (C) and INS-1 beta cells (D).
  • Data are shown as the percentage of each control value in the absence or presence of insulin.
  • * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, as compared to the corresponding control without insulin, and # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001, as compared to each control with insulin, using ANOVA with Bonferroni correction. n 3 for each group.
  • FIGS. 4A-4D show representative data showing that neither basal nor insulin-stimulated PKB phosphorylation is altered by pretreatment with EGCG in differentiated L6 myoblasts (A), HepG2 hepatocytes (B), differentiated 3T3-L1 adipocytes (C) and INS-1 beta cells (D).
  • FIGS. 5A-5D show effect of circulating EGCG on blood glucose levels and insulin resistance.
  • EGCG injection (10 mg/kg, i.v.) was performed in 4-h fasted rats (A and C) and Kir6.2 k/o mice (B and D). Control animals received PBS alone. Significant increase in blood glucose level was observed 30 min after EGCG injection. Then insulin (1 IU/kg, i.p.) was injected at the time indicated by the arrows. The percent change in blood glucose levels was shown in C and D; the values of the two groups obtained immediately before the insulin injection were normalized to 100.
  • FIGS. 6A-6D show that GC-deficient GTE diminishes effects of natural GTE in the circulation and the alimentary tract.
  • A In 4-h fasted rats, PBS as control, natural GTE (100 mg/kg) or GC-deficient GTE (100 mg/kg) was intravenously injected 30 min before insulin injection (1 IU/kg, i.p.).
  • FIGS. 7A-7D show ingestion of PEG with GTE blocks the circulating effect of GTE.
  • FIG. 8 shows an illustration showing the ambivalent effects of GC in the intestine and in circulation.
  • the dotted lines represent movement of the molecules; the solid arrow line represents facilitation by insulin; the solid block lines represent inhibition by GC.
  • carriers include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
  • pharmaceutically acceptable carrier is an aqueous pH buffered solution.
  • Examples of pharmaceutically acceptable carriers include without limitation buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as
  • an effective amount is an amount sufficient to effect beneficial or desired clinical or biochemical results.
  • An effective amount can be administered one or more times.
  • an effective amount of an inhibitor compound is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • mammal for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, and so on.
  • the mammal is human.
  • pharmaceutically acceptable carrier and/or diluent includes any and all solvents, dispersion media, coatings antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired.
  • the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.5 ⁇ g to about 2000 mg. Expressed in proportions, the active compound is generally present in from about 0.5 ⁇ g/ml of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • subject is a mammal, more preferably a human.
  • the method to manufacture the compositions with blood glucose lowering effect as to this invention contains the step to extract GC, which possesses at least one of either EGCG or ECG, from green tea; the step of mixing the GC-containing extract solution or powder with at least one of polyglycol (PG), such as polyethylene glycol (PEG), PEG derivatives (e.g., PEG-alkyl, PEG-dialkyl, PEG-ester, PEG-diester, etc), PEG copolymer (e.g., PEG-PPG, PEG-PPG-PEG (poloxamer, Pluronic)), water-soluble copolymer (e.g., polyvinyl pyrrolidine etc), or macromolecules to selectively bind GC.
  • PG polyglycol
  • PEG polyethylene glycol
  • PEG derivatives e.g., PEG-alkyl, PEG-dialkyl, PEG-ester, PEG-diester, etc
  • PEG copolymer
  • the above compositions can also be manufactured by mixing PG with GC which is commercially concentrated and available.
  • the above compositions contain GC at concentrations between 10-2000 mg and PG (0.01-50 g/gGC).
  • the molecular weight of the above PG is 100-2,000,000 daltons, more appropriately 500-100,000 daltons, the most appropriately, 1,000 to 80,000, 1,000-50,000 daltons, or 1,000 to 8,000 daltons as it is better to be ingested without discomfort and control blood glucose.
  • the chemical structure of used PG can be various PG derivatives with one or two substitution; C1-C6 alkyl, aryl, acetyl, acetyl substituted for C1-C6alkyl or aryl, sulfone substituted for C1-C6alkyl or aryl on the terminus of PG.
  • the method to manufacture the above GC include
  • Step 1 green tea leaves were added to hot water (80-95° C., 10-50 times of leaves weight), stirred gently for 5 min-1 hour for extraction and filtered.
  • step 2 the powder containing polyphenols of green tea was obtained by lyophilizing the above extract solution.
  • step 3 to purify and obtain polyphenol chemicals in the powder, column chromatography was performed.
  • This invention employed high porosity polystyrene gel column chromatography (particle size, 75-150 ⁇ m, Diaion HP-20, Mitsubishi Kagaku Co., Japan; Column, 25 ⁇ 1,000 mm).
  • the extraction solvent was 100 ml methanol:H 2 O (1:5), and the extract was extracted once more with 100 ml methanol:H 2 O (2:5).
  • the flow rate was 5 ml/min
  • GC contained in manufactured compositions inhibits the activity of SGLT (sodium-dependent glucose transporter) in the intestinal lumen and thus suppresses intestinal glucose absorption. It has fewer side effects than now available hypoglycemic drug to inhibit amylase activity.
  • SGLT sodium-dependent glucose transporter
  • the intestinal absorption of GC itself which increases blood glucose in the circulation, can be suppressed by co-administered polyglycol (PG). Therefore, this invention, by decreasing postprandial blood glucose levels, may offer diabetic prevention of normal individuals, inhibition of diabetic progression of individuals predisposed to diabetes, and relief of diabetic complications of diabetic patients.
  • compositions of this invention are applied orally with commercially available types. They can be applied before or during a meal, but preferably to be applied just before a meal.
  • the GC-contained compositions of this invention are natural bioactive materials extracted from natural green tea and not absorbed into the circulation, when orally applied in animals and humans, they are safe without side effects and acute toxicity. Therefore, this invention offers food or functional healthy food, containing GC and PG, to control postprandial blood glucose.
  • GC and PG in the case of manufacturing as a pharmaceutical agent, can be mixed and formed with commercially and pharmaceutically available material to make tablets, rigid or soft capsules, chewing tablets, powder, liquid or immersion on the purpose of oral ingestion.
  • compositions In the formation of tablets, rigid or soft capsules, chewing tablets, powder, liquid or immersion as an orally applicable material using the compositions, it can contain Arabian gum, corn starch, bonding material like fine grain cellulose or gellatin, vehicle like calcium phosphate or lactose, disintegrator like alginic acid, corn starch or potato starch, lubricant like stearic acid magnesium, sweetener like sucrose or saccharine, and flavor like methyl salicylate or fruits flavor.
  • it can contain liquid materials like fat oil in addition to the above materials.
  • supplementary materials can be mixed and used for the formation of orally applicable materials with GC and PG, if they are pharmaceutically pure, substantially non-toxic, and do not affect the action of bioactive materials.
  • the dose for achieving the effect as a blood glucose controller can be determined by doctors with the consideration in the type of diseases, disease severity, gender, age, body weight, health status, application type, application frequency and time, the presence of combinatorial drugs, and other related environment.
  • This pharmacological drug in this invention which contains GC and PG (0.01-50 gram GC), in the case of oral ingestion, 0.5-100 mg EGCG, ECG or its mixed compounds per kg body weight, more appropriately 1-50 mg, can be applied once or several times a day, more appropriately 1-3 times a day, just before, during, or just after a meal.
  • GC and PG in this invention can be manufactured for a supplementary material of commercial beverages, mineral water, alcoholic beverages, chewing gum, caramel, candy, ice cream, and cookies. In addition, it can be applied in healthy food or food supplements with vitamins and minerals in order to lower postprandial blood glucose.
  • GC of green tea such as EGCG and ECG
  • EGCG green tea polyphenols
  • ECG ECG
  • GC may not be the major inhibitor because the inhibitory effect of green tea was weaker than that of black tea which has smaller amount of GC (19).
  • the intestinal glucose uptake is mediated by SGLT1, and GTE or GC has been found to be a competitive inhibitor of SGLT1 of human intestinal epithelial cells (9, 20).
  • the blood glucose uptake into metabolically-important cells was also inhibited in the presence of EGCG.
  • the latter amplification may be due to the other constituents, such as ECG and gallic acid, which may exert additional effects, or may be due to the delayed catabolism of EGCG in the presence of other green tea components (16). Therefore, it is expected that the accumulation of glucose in the circulation caused by green tea catechins may induce insulin hypersecretion. It is not surprising that long-term beta-cell overload represents a detrimental consequence that leads to eventual beta-cell impairment.
  • GTE was effective at blood EGCG concentrations of 1-2 ⁇ M, which is readily achievable by daily oral administration of green tea (24).
  • rats are more likely to overlook this circulating effect, because rats have a much lower oral bioavailability of EGCG (15, 16).
  • GTE hindered return of the glucose level to the control value.
  • An in vivo report which examined the circulating EGCG effect within a concentration range applicable to human showed that relatively long-term intraperitoneal EGCG application led to weight loss in rats (17). However, they found significant deterioration in the sexual organs.
  • the beneficial effects of EGCG in treatment of some cancers may be, at least partly, due to the glucose deprivation effect that EGCG may inflict on cancer cells which are more metabolically active and glycolytic-dependent than normal cells (26).
  • Other polyphenols, such as quercetin and myricetin, seem to have relatively broader safety margins because they inhibit cellular glucose uptake around 10 ⁇ M (27).
  • Dulbecco's modified Eagle's medium (DMEM), phosphate-buffered saline (PBS), fetal bovine serum (FBS) and fetal calf serum (FCS) were purchased from Gibco (Carlsbad, Calif.).
  • RPMI-1640 medium was purchased from Welgene (Daegu, Korea).
  • Polyethylene glycol (PEG; Novasyn TG hydroxy resin) was delivered from Novabiochem (Darmstadt, Germany) for animal study.
  • PEG for human study was kindly gifted from Taejoon (Seoul, Korea).
  • Green tea leaves (BOSUNG SEIJAK) were purchased from Bosung green tea Co. (Jeonnam, Korea).
  • Epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epicatechin (EC) were purchased from Sigma-Aldrich (St. Louis, Mo.). All other chemicals were obtained from Sigma-Aldrich.
  • Rat L6 myoblasts were cultured in low-glucose DMEM with 10% (v/v) FBS until they reached 80% confluency. To induce differentiation, cells were further cultured in DMEM (24.9 mM glucose) containing 2% FBS for 7 days. Cell viability was assessed by the trypan blue viability test. Myogenic differentiation to myotube status was evaluated both morphologically and biochemically.
  • Mouse 3T3-L1 preadipocytes were grown to confluence at 37° C. in 35-mm culture dishes in DMEM containing 10% FCS with no added biotin or pantothenate in incubators equilibrated with 5% CO 2 .
  • Rat insulin-secreting INS-1 cells were grown in RPMI-1640 media supplemented with 10% FBS, 10 mM N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES), 1 mM sodium pyruvate, 50 mM 2-mercaptoethanol, 100 IU/ml penicillin, and 100 mg/ml streptomycin.
  • GTE-GC GC-deficient GTE
  • Plasma insulin levels were measured using the Glucocard test strip II (Arkray Inc., Kyoto, Japan). Plasma insulin levels were measured using an immunoradiometric kit (INSULIN MYRIA, Techno genetics, Sesto, Italy). Before the study began, its purpose and risks were carefully explained, and written informed consent was obtained from all participants. The protocol was approved by the IRB Keimyung University Ethics Committee, Daegu, Korea, regulating human research.
  • IPGTT Intraperitoneal Glucose Tolerance Test
  • OGTT Intraperitoneal Glucose Tolerance Test
  • Sprague-Dawley rats were provided by Hyochang Science Co. (Seoul, Korea). After a 12-h fast, rats were anesthetized using pentobarbital sodium (40 mg/kg, i.p.; Nembutal, 50 mg/ml, Hanlim Pharmaceutical Co., Seoul, Korea) and then injected with one of the epicatechins: EGCG, EGC, ECG, and EC (each 10 mg/kg in 300 ⁇ l PBS, i.v.). EC was dissolved in a minute amount of DMSO in advance before addition of PBS. In another experiment, rats were randomly divided into 3 groups: control, GTE and GTE-GC.
  • the rats in the GTE group were injected with natural GTE (100 mg/kg in 300 ⁇ l PBS, i.v.; 10 mg/kg as EGCG) through the tail vein, while the control rats were injected with only 300 ⁇ l PBS and rats in the GTE-GC group were given an equal amount of GC-deficient GTE (100 mg/kg in 300 ⁇ l PBS, i.v.; 2.6 mg/kg as EGCG).
  • glucose 2.0 g/kg in 600 ⁇ l distilled water, i.p.
  • the rats were ingested with 1-ml distilled water only (control), or 1-ml distilled water containing one of natural GTE (900 mg/kg), GC-deficient GTE (900 mg/kg), EGCG (90 mg/kg), natural GTE plus PEG (110 mg/100 mg EGCG) or PEG alone Immediately after the ingestion, each rat was orally given 1-ml distilled water containing glucose (2 g/kg). For the assay of blood glucose levels, blood was drawn from the tail vein at the indicated times. All the experiments were approved by the Keimyung University institutional ethics committee, Daegu, Korea for supervising animal research.
  • ITT Insulin Tolerance Test
  • Kir6.2 knock-out mice were kindly provided by Prof. Susumu Seino at Kobe University in Japan. Following a 4-h fast, Kir6.2 k/o mice or normal rats were intravenously injected with PBS (100 ⁇ l for mouse, 300 ⁇ l for rat) only, or PBS containing EGCG (10 mg/kg), natural GTE (100 mg/kg) or GC-deficient GTE (100 mg/kg). Thirty minutes after the injection, the mice and rats were injected intraperitoneally with normal saline (300 ⁇ l for mouse, 600 ⁇ l for rat) containing insulin (1 IU/kg; INSULIN LISPRO, Eli Lilly, Ind.). Blood samplings were done through the tail vein at the indicated times.
  • KRPH buffer 10 mM phosphate buffer, pH 7.4; 1 mM MgSO 4 , 1 mM CaCl 2 , 136 mM NaCl, 4.7 mM KCl, and 10 mM HEPES, pH 7.6] and then incubated with or without 100 nM insulin for 20 min in KRPH buffer that contained EGCG (0, 0.1, 1.0 or 10 ⁇ M).
  • Glucose transport was determined by the addition of 2-deoxy-[ 3 H] glucose (0.1 mM, 0.5 ⁇ Ci/ml; PerkinElmer Life and Analytical Science, Waltham, Mass.). After 10 min of incubation, the reaction was stopped by three quick washes with ice-cold PBS. The cells were then lysed in PBS containing 0.2 M NaOH, and glucose uptake was assessed by scintillation counting.
  • PKB protein kinase B
  • lysis buffer (10 mM Tris-Cl (pH 7.4), 130 mM NaCl, 5% (v/v) Triton X-100, 5 mM EDTA, 200 nM aprotinin, 20 mM leupeptin, 50 mM phenanthroline, 280 mM benzamidine-HCl) for 20 min at 4° C. Lysates were separated by SDS-PAGE and electrotransferred to an Immobilion-P membrane (Millipore, Billerica, Mass.).
  • HPLC analysis was conducted on a Waters Alliance 2695 liquid chromatograph equipped with a model 2487 dual absorbance detector (Waters Co., Milford, Mass.).
  • a Waters symmetry C18 reversed-phase packing column (4.5 mm ⁇ 250 mm, 5 ⁇ m) was used at 25° C. for separation throughout this study. Catechins were determined simultaneously at 235 nm.
  • a gradient elution was performed by varying the proportion of solvent A (water-trifluoroacetic acid, 99.9:0.1 v/v) to solvent B (acetonitrile-trifluoroacetic acid, 99.9:0.1 v/v), with a flow rate of 1 ml/min.
  • the mobile phase composition changed linearly from 9.5% to 14% solvent B in 10 min and then kept the same composition for 10 min, followed by a linear increase of solvent B to 27.5% within 15 min.
  • the mobile phase composition was then brought back to the initial conditions over a period of 5 min for the next run. All the prepared solutions were filtered through 0.45 ⁇ m membranes (Sartorius, Maisemore, UK), and the mobile phase was degassed before injection into the HPLC.
  • the results are expressed as mean ⁇ SEM.
  • the SPSS (release 14.0) software package (SPSS Inc., Chicago, Ill.) was used for the statistical analyses. Area under the curve was calculated by using Microcal Origin software (version 7.0; Northampton, Mass.). Comparisons between two groups were performed with the Student's two-tailed t-test for paired or unpaired data. For comparisons of more than two groups, significance was tested using an analysis of variance (ANOVA) with Bonferroni correction to deal with relatively small amounts of samples. Differences between groups were considered significant when P ⁇ 0.05.
  • ANOVA analysis of variance
  • the 1-h interval between GTE and glucose intake was chosen because the blood concentrations of tea ingredients, especially catechins, were known to peak between 1-2 h after GTE ingestion (4, 15).
  • plasma insulin levels were also significantly (P ⁇ 0.05) higher in the GTE group at the 60 min ( FIG. 1D ), implying that the higher blood glucose levels may induce a higher rate of insulin secretion.
  • IPGTT was performed with rat ( FIG. 2 ). Since epicatechins were studied intensively for its role in glucose tolerance, EGCG, ECG, EGC and EC were used for IPGTT. Each catechin was injected in rats 30 min before glucose administration. The amount of EGCG injected (10 mg/kg, i.v.) was chosen to achieve its blood concentrations around 1 ⁇ M at 30 min after injection (16, 17). Same amount of other catechins was used even though they had different pharmacokinetic profiles (10). EGCG and ECG caused more elevated blood glucose levels 30 min after glucose loading compared to control (P ⁇ 0.01) while EC and EGC had no effects.
  • Circulating EGCG Acutely Increases Blood Glucose Levels and Insulin Resistance
  • ITT revealed remarkable insulin resistance in the GTE group (P ⁇ 0.01 at the 20 min), whereas significant amelioration of insulin resistance was observed in the GTE-GC group ( FIG. 6B ).
  • Rats in another experiment were fasted for 12 h, not 4 h, to minimize elevation of blood glucose level by GTE itself. Then they were injected intravenously with PBS alone, or with PBS containing either natural GTE or GC-deficient GTE 30 min before glucose loading. As shown in FIG.
  • the GC-deficient GTE- or EGCG-administered group appeared to inhibit glucose absorption less efficiently than in the GTE-treated group, indicating that GC is also critical for the effect of GTE on blockade of glucose absorption in the intestinal lumen.
  • Example 3 an equal amount of the GTE solution was mixed with 2 g PEG (3,000-4,000) bead for 5 min at room temperature. After filtration, the supernatant was lyophilized (EGCG, ECG, EGC and EC were ⁇ 26, 14, 42 and 25 mg/g GTE, respectively) to obtain GC-deficient GTE (GTE-GC). The results indicated that the resin pretreatment preferentially reduced GC from the GTE solution.
  • a tablet containing 50 mg of EGCG, ECG or its mixed form; 50 mg PEG (4,000); 20 mg starch; adequate amount of stearic acid magnesium can be made as a blood glucose controller, according to general instruction for tablet production.
  • a capsule filled with 50 mg of EGCG, ECG or its mixed form; 50 mg PEG (4,000); 19 mg starch; 1 mg talc; adequate amount of stearic acid magnesium can be made as a blood glucose controller, according to general instruction for capsule production.
  • a granule can also be made as a blood glucose controller, according to general instruction for granule production.

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