CP-91149 is a selective inhibitor of glycogen phosphorylase (GP) with an IC50 value of 0.13 μM. A series of benzazepinones have also been reported as potent GP inhibitors. Glycogen phosphorylase (GP) is the key enzyme for glycogen degradation.  |  Synonym: 1-(3-(3-(2-Chloro-4,5-difluorobenzoyl)ureido)-4-methoxyphenyl)-3-methylurea, Glycogen Phosphorylase Inhibitor - CAS 648926-15-2 - Calbiochem. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. on the catalytic and structural properties of glycogen phosphorylase a has been studied. Expert Opin Ther Pat. 1.2 Diabetes Diabetes is the most common hormonal deficiency disease in the world. Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). Probing the catalytic site of rabbit muscle glycogen phosphorylase using a series of specifically modified maltohexaose derivatives. Goyard D, Kónya B, Chajistamatiou AS, Chrysina ED, Leroy J, Balzarin S, Tournier M, Tousch D, Petit P, Duret C, Maurel P, Somsák L, Docsa T, Gergely P, Praly JP, Azay-Milhau J, Vidal S. Eur J Med Chem. Epub 2015 Dec 10. glycogen phosphorylase glycogen debranching enzyme phosphoglucomutase Glycogen phosphorylase (phosphorylase) - phosphorolysis of glucose residues at least 5 units from branch point Glycogen + Pi glycogen + glucose-1-phosphate (n residues) (n-1 residues) homodimer of 842-residues (92-kD) subunits allosteric regulation - inhibitors (ATP, glucose-6- The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Glucose-based inhibitors have found potential applications since they now reach low nanomolar Ki values. The cloning of the human liver glycogen phosphorylase (HLGP) revealed a new allosteric binding site near the subunit interface that is not present in the rabbit muscle glycogen phosphorylase (RMGP) normally used in studi… Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase. Please enable it to take advantage of the complete set of features! Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. Chem Biol. Stathi A, Mamais M, Chrysina ED, Gimisis T. Molecules. The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. When glucose concentrations get too high, phosphorylase a is converted to its inactive, T state. This substance, [R- (R*,S*)]-5-chloro- N - [3- (dimethylamino)-2-hydroxy-3-oxo-1- (phenylmethyl)propyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC 50 of 0.13 μM in the presence of 7.5 mM glucose. Epub 2020 Jan 10. A structural analogy between glucose-based GP inhibitors and C-glucosides targeting sodium glucose co-transporter 2 (SGLT2) is intriguing. 2010 Oct;10(12):1139-55. doi: 10.2174/1389557511009011139.  |  In mammals, glycogen phosphorylase is abundant in muscle, liver, and brain tissues. Areas covered: Glucose-based inhibitors have found potential applications since they now reach low nanomolar Ki values. Mini Rev Med Chem. Glycogen phosphorylase (EC 2.4.1.1) catalyzes the rate-limiting step in glycogenolysis using glycogen and inorganic phosphate to produce glucose-1-phosphate (G1P). COVID-19 is an emerging, rapidly evolving situation. Selleck's CP-91149 has been cited by 3 publications Cells, 2020, 9 (3) J Biol Chem, 2020, 295 (1):83-98 Areas covered: Top Curr Chem (Cham). Nakamura M, Makino Y, Takagi C, Yamagaki T, Sato M. Glycoconj J. Another set of patents disclose cholic acid/7-aza-indole conjugates for targeted drug delivery to the liver. 2020 Nov 22;25(22):5463. doi: 10.3390/molecules25225463. In the Search of Glycoside-Based Molecules as Antidiabetic Agents. Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition. 2019 Jun 5;377(4):19. doi: 10.1007/s41061-019-0243-6. The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. 2000 Sep;7(9):677-82. doi: 10.1016/s1074-5521(00)00004-1. 1. Human liver glycogen phosphorylase inhibitors bind at a new allosteric site. C-glycoside; Type 2 diabetes; carbohydrate; glycogen phosphorylase; inhibitor; steroids. Curr Protein Pept Sci. Therefore, suppression of glucose output from the liver may be achieved by inhibition of glycogen phosphorylase. CAS Number 648926-15-2. Advances in glycogen phosphorylase inhibitor design. Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes. Inhibits glucagon-induced glyocgenolysis in hepatocytes in vitro. Active Inhibitor 1 protein and direct phosphorylation by cAMP-dependent protein kinase keep protein phosphatase 1 in the inactive state so that is does not remove the activating phosphate group from glycogen phosphorylase. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). Please enable it to take advantage of the complete set of features! Control of glycemia is crucial in the treatment of type 2 diabetes complications. 2019 Apr 3;24(7):1322. doi: 10.3390/molecules24071322. Nagy L, Béke F, Juhász L, Kovács T, Juhász-Tóth É, Docsa T, Tóth A, Gergely P, Somsák L, Bai P. PLoS One. Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes. NLM 2018 Mar 15;23(3):666. doi: 10.3390/molecules23030666. 2020 Oct 30;10:592455. doi: 10.3389/fonc.2020.592455. Glycogen phosphorylase (GP) catalyzes the hydrolysis of glycogen to generate glucose-1-phosphate and shortened glycogen molecule and is considered the rate limiting step in the degradation of glycogen. Epub 2017 Jun 8. The Glycogen Phosphorylase Inhibitor, also referenced under CAS 648926-15-2, controls the biological activity of Glycogen Phosphorylase. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes. Cholic acid/7-aza-indole conjugates are promising in vivo drug delivery systems to the liver. Glycogen phosphorylase is a phosphorylase enzymes that can catalize phosphorolytic cleavage of the glycosidic linkages of glycogen by releasing glucose-1-phosphate from the terminal alpha-1, 4 … While industry has slowed down on GP inhibitors design, academic groups are pursuing investigations and have provided potential drug candidates which will resuscitate the interest for GP, including its potential for targeting cancer. potential inhibitors of glycogen phosphorylase, an enzyme implicated in type 2 diabetes. Approximately 90 – 95% of all diabetes mellitus diagnoses are classified as type 2 / non-insulin dependant diabetes mellitus (NIDDM).1 Currently in Australia, diabetes Such inhibitors may be of use for therapy of the non-insulin dependent form of diabetes (NIDDM or Type II diabetes). 3,5,6-tricarboxylate~W1807! 2020 Sep 22;15(9):e0236081. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. 2010 Oct;10(12):1156-74. doi: 10.2174/1389557511009011156. By shifting phosphorylase a to its T state, PP1 dissociates from the complex. Benzazepinones were very recently described and no associated literature is available, making it very difficult to comment at present. Glycogen Phosphorylase Inhibitor | C17H15ClF2N4O4 | CID 10070301 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more. Glycogen phosphorylase inhibitor N-(3,5-dimethyl-Benzoyl)-N′-(β-D-glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism. Glycogen phosphorylase inhibitor, 2,3-bis[(2E)-3-(4-hydroxyphenyl)prop-2-enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells.  |  Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes. NIH 2010 Oct;10(12):1102-26. Epub 2013 Apr 30. This site needs JavaScript to work properly. Increasing doses (50–100 μ M) of the glycogen phosphorylase inhibitor CP-320626 inhibited [1,2-13C2]glucose stable isotope substrate re-distribution among glycolysis, pentose and … Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. Computation as a tool for glycogen phosphorylase inhibitor design. The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. 2008 Apr;9(4):379-95. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error.  |  Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Mavreas KF, Neofytos DD, Chrysina ED, Venturini A, Gimisis T. Molecules. Glycogen phosphorylase ~GP! Mini Rev Med Chem. The X-ray structure of screening hit 1 (IC50 = 2 μM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). Epub 2016 Feb 29. Mavreas KF, Neofytos DD, Chrysina ED, Venturini A, Gimisis T. Molecules. Rath VL, Ammirati M, Danley DE, Ekstrom JL, Gibbs EM, Hynes TR, Mathiowetz AM, McPherson RK, Olson TV, Treadway JL, Hoover DJ. 2020 Nov 22;25(22):5463. doi: 10.3390/molecules25225463. Keywords: An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. Inhibition of glycogen phosphorylase in the context of type 2 diabetes, with focus on recent inhibitors bound at the active site. Crystallographic studies indicate, however, that selectivity between glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Expert opinion: Parmenopoulou V, Manta S, Dimopoulou A, Kollatos N, Schols D, Komiotis D. Med Chem Res. Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to … CP-91149 is a selective glycogen phosphorylase (GP) inhibitor with IC50 of 0.13 μM in the presence of glucose, 5- to 10-fold less potent in the absence of glucose. Glycogen phosphorylase is the enzyme that catalyzes this process. With the rapid increase of type 2 diabetic patients recently, it is becoming an interesting field to discover GP inhibitor for potential antidiabetic drugs. The inhibition of glycogen phosphorylase has been proposed as one method for treating type 2 diabetes. Abstract: Glycogen phosphorylase (GP) has been firmly proved as an important target for treatment of type 2 diabetes. HHS 1 It blocks glucagon-induced hepatic glycogenolysis in vivo. Glycogen metabolism has implications in beta cell function. The glucose-1-phophate is then fur… Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. is an allosteric enzyme whose activity is primarily controlled by reversible phosphory-lation of Ser14 of the dephosphorylated enzyme ~GPb, less active, predominantly T-state! Clipboard, Search History, and several other advanced features are temporarily unavailable. 2016;25(5):932-940. doi: 10.1007/s00044-016-1539-5. PloS ONE 8 (7): e69420 Crossref , Medline , ISI , Google Scholar . Glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents: recent developments. Glycogen phosphorylase as a molecular target for type 2 diabetes therapy. Curr Opin Investig Drugs.  |  Pałasz A, Cież D, Trzewik B, Miszczak K, Tynor G, Bazan B. 2, 3, 4 Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover Gerald A. Dienel, Kelly K. Ball and Nancy F. Cruz Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Abstract Mini Rev Med Chem. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed. Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. doi: 10.1371/journal.pone.0236081. Fischer T, Koulas SM, Tsagkarakou AS, Kyriakis E, Stravodimos GA, Skamnaki VT, Liggri PGV, Zographos SE, Riedl R, Leonidas DD. Activation of glycogen phosphorylase and phosphorolysis of glycogen: The active form of glycogen phosphorylase kinase phosphorylates and activates glycogen phosphorylase. Glycogen phosphorylase inhibitor is a cell-permeable acyl urea first identified as an inhibitor of human liver glycogen phosphorylase (IC 50 = 53 nM). Glycogen phosphorylase …. 2019 Jun 25;24(12):2327. doi: 10.3390/molecules24122327. Introduction: Khan T, Sullivan MA, Gunter JH, Kryza T, Lyons N, He Y, Hooper JD. USA.gov. Since glucose production in the liver has been shown to increase in type 2 diabetes patients, inhibiting the release of glucose from the liver's glycogen's supplies appears to be a valid approach. The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. Kun S, Bokor É, Sipos Á, Docsa T, Somsák L. Molecules. 2017 Aug;34(4):563-574. doi: 10.1007/s10719-017-9776-5. Would you like email updates of new search results? 2003;9(15):1177-89. doi: 10.2174/1381612033454919. There are two forms of glycogen phosphorylase, namely glycogen phosphorylase a and b forms. NLM This site needs JavaScript to work properly. Clipboard, Search History, and several other advanced features are temporarily unavailable. In vitro data are reported for GP inhibition but the in vivo biological data at the cellular or animal levels are often missing, even though the literature reported for these molecules is also discussed. Anomeric Spironucleosides of β-d-Glucopyranosyl Uracil as Potential Inhibitors of Glycogen Phosphorylase. Enhances glucose sensitivity in chow-fed, obese, diabetic mice and increasing hepatic glucose uptake. High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-. Glycogen Phosphorylase Inhibitor is a cell-permeable urea compound that acts as a potent and AMP-competitive inhibitor of PYGB (glycogen phosphorylase); IC 50 = 53 nM). Recent advances in the allosteric inhibition of glycogen phosphorylase. Reduces blood glucose levels and increases hepatic glycogen content in C57/BL6J mice. Glycogen phosphorylase inhibitors: a patent review (2008 - 2012). eCollection 2020. Glycogen phosphorylase is a dimer composed of two identical subunits, molecular weight 97,444 (842 amino acids), and an ... Glucose is an inhibitor that binds to the catalytic site and stabilizes the T state. 2013 Aug;23(8):1017-32. doi: 10.1517/13543776.2013.794790. This dissociation activates glycogen synthase and converts phosphorylase a to phosphorylase b. Phosphorylase b does not bind PP1 allowing PP1 to remain activated. One of the merits of the glycogen phosphorylase inhibition approach is that certain glycogen phosphorylase inhibitors (GPi) have been shown to be more potent at reducing hepatic glucose output in the presence of high glucose concentrations. Goyard D, Kónya B, Czifrák K, Larini P, Demontrond F, Leroy J, Balzarin S, Tournier M, Tousch D, Petit P, Duret C, Maurel P, Docsa T, Gergely P, Somsák L, Praly JP, Azay-Milhau J, Vidal S. Org Biomol Chem. Displays a mixed type of inhibition. Somsák L, Nagya V, Hadady Z, Docsa T, Gergely P. Curr Pharm Des. USA.gov. One class of phosphorylase inhibitors consists of glucose analogs which stabilise the inactive T-form of the enzyme. Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase. 1 Glycogen phosphorylase inhibitor has been used to study glycogen utilization in human liver HepG2 cells, retinal explants, and human T lymphocyte Kit 225 cells. Molecules. Advances in glycogen phosphorylase inhibitor design. Introduction: Glycogen phosphorylase (GP) is the enzyme responsible for the synthesis of glucose-1-phosphate, the source of energy for muscles and the rest of the body. to form the phosphorylated COVID-19 is an emerging, rapidly evolving situation. 2002 Dec;3(6):561-86. doi: 10.2174/1389203023380422. Front Oncol. 2016 Jan 27;108:444-454. doi: 10.1016/j.ejmech.2015.12.004. It is a part of the glucosyltransferase family and acts on the α-1,4-glycosidic linkage; the phosphorylase comes to a standstill 4 residues from an α-1,6-branchpoint, where debranching enzyme takes over . Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition. GP inhibitors (GPi‐s) are glucose lowering agents that cause the accumulation of glucose in the liver as glycogen. Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation.  |  2020 Feb 7;18(5):931-940. doi: 10.1039/c9ob01190k. Curr Opin Investig Drugs. Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. HHS Glycogen phosphorylase …. 3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles were prepared by acylation of O-perbenzoylated N1-tosyl-C-β-d-glucopyranosyl formamidrazone and subsequent removal of the protecting groups. eCollection 2020. 2008 Apr;9(4):379-95. NIH National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. A glucopyranosyl urea compound that acts as an inhibitor of muscle glycogen phosphorylase (K i = 930 nM). Glycogen phosphorylase inhibitors are considered as potential antidiabetic agents. Would you like email updates of new search results? Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. 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Of rabbit muscle glycogen phosphorylase ( GP ) releases glucose from the liver probing the catalytic site rabbit... -5-Substituted-1,2,4-Triazoles were prepared by acylation of O-perbenzoylated N1-tosyl-C-β-d-glucopyranosyl formamidrazone and subsequent removal of the complete set of!. Á, Docsa T, Lyons N, He Y, Takagi C, Yamagaki T, N... Catalytic and structural properties of glycogen phosphorylase ( GP ) has been linked to type 2 diabetes N-β-d-Glucopyranosyl Derivatives Imidazole... Inhibitor of muscle glycogen phosphorylase is the key enzyme for glycogen phosphorylase inhibitors consists of glucose analogs which the... Indicating the importance of this enzyme, which may lead to antihyperglycaemic drugs, has received attention. Diabetes through glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes, Google.!