title: D-chiro-inositol glycans in insulin signaling and insulin resistance.
abstract: Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primary Tyr phosphorylated substrates-the insulin receptor substrate family of proteins. This scheme accounts for most, but not all, intracellular actions of insulin. Essentially forgotten is the previous literature and continuing work on second messengers generated in cells in response to insulin. Treatment and even prevention of diabetes and metabolic syndrome will benefit from a more complete elucidation of cellular-signaling events activated by insulin, to include the actions of second messengers such as glycan molecules that contain D-chiro-inositol (DCI). The metabolism of DCI is associated with insulin sensitivity and resistance, supporting the concept that second messengers have a role in responses to and resistance to insulin.
authors.affiliation: Allomed Pharmaceuticals, Charlottesville, Virginia, United States of America. jl6d@virginia.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Larner
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
mesh_terms: D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011134:Polysaccharides / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D011134:Polysaccharides; D011768:Pyruvate Dehydrogenase Complex; C068698:inositol-glycan; D007294:Inositol; D006006:Glycogen Synthase; D011972:Receptor, Insulin
references.citation: Biochemistry. 1973 Nov 6;12(23):4507-12
references.pmid: 4149348
references.citation: J Biol Chem. 2009 Apr 3;284(14):9443-57
references.pmid: 19188364
references.citation: Proc Natl Acad Sci U S A. 1986 Aug;83(16):5793-7
references.pmid: 3016721
references.citation: Cold Spring Harb Symp Quant Biol. 1988;53 Pt 2:965-71
references.pmid: 3076102
references.citation: Biochem Biophys Res Commun. 1988 Mar 30;151(3):1416-26
references.pmid: 2833261
references.citation: Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5924-8
references.pmid: 8392181
references.citation: Fed Proc. 1982 Sep;41(11):2730-5
references.pmid: 6811328
references.citation: J Biol Chem. 2008 Nov 28;283(48):33428-36
references.pmid: 18768479
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):217-22
references.pmid: 19143635
references.citation: J Biol Chem. 1992 Aug 25;267(24):16904-10
references.pmid: 1387397
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9988-92
references.pmid: 8234346
references.citation: J Clin Endocrinol Metab. 2006 Feb;91(2):709-17
references.pmid: 16332940
references.citation: FEBS Lett. 1999 Nov 12;461(1-2):120-4
references.pmid: 10561508
references.citation: Fed Proc. 1982 Sep;41(11):2724-9
references.pmid: 6288476
references.citation: Biochem J. 2005 Mar 1;386(Pt 2):237-44
references.pmid: 15461583
references.citation: Science. 1988 Apr 22;240(4851):509-11
references.pmid: 3282305
references.citation: J Clin Endocrinol Metab. 2004 Jan;89(1):242-9
references.pmid: 14715857
references.citation: Mol Cell Biol. 2000 Jul;20(13):4708-23
references.pmid: 10848597
references.citation: J Biol Chem. 1992 Feb 15;267(5):2864-7
references.pmid: 1346611
references.citation: Ann N Y Acad Sci. 1989;573:297-305
references.pmid: 2517463
references.citation: Diabetes Care. 2006 Feb;29(2):300-5
references.pmid: 16443877
references.citation: Biochim Biophys Acta. 1969 Apr 1;177(2):204-12
references.pmid: 4305362
references.citation: J Physiol. 2006 Jul 1;574(Pt 1):73-83
references.pmid: 16709629
references.citation: Yonsei Med J. 2005 Aug 31;46(4):532-8
references.pmid: 16127779
references.citation: J Biol Chem. 1980 Jul 25;255(14):6529-31
references.pmid: 6993474
references.citation: Science. 1979 Dec 21;206(4425):1407-8
references.pmid: 505013
references.citation: Biochem Biophys Res Commun. 1987 Jul 31;146(2):764-70
references.pmid: 3304285
references.citation: Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E374-82
references.pmid: 12110545
references.citation: Biochem Biophys Res Commun. 1992 Apr 30;184(2):1042-7
references.pmid: 1575723
references.citation: Biochemistry. 2005 Aug 23;44(33):11067-73
references.pmid: 16101290
references.citation: Endocrinology. 1993 Feb;132(2):640-5
references.pmid: 8425483
references.citation: Eur J Biochem. 1981 Oct;119(3):503-10
references.pmid: 6273162
references.citation: Diabetes. 2007 Feb;56(2):414-23
references.pmid: 17259386
references.citation: Bioorg Med Chem. 2005 Dec 15;13(24):6732-41
references.pmid: 16115771
references.citation: N Engl J Med. 1990 Aug 9;323(6):373-8
references.pmid: 2370888
references.citation: Biochem Biophys Res Commun. 2002 May 10;293(3):1092-8
references.pmid: 12051772
references.citation: J Clin Invest. 1954 Mar;33(3):326-32
references.pmid: 13143077
references.citation: Bull Soc Chim Biol (Paris). 1967;49(4):415-31
references.pmid: 6060514
references.citation: Science. 1979 Dec 21;206(4425):1408-10
references.pmid: 228395
references.citation: Diabetologia. 1997 May;40(5):557-63
references.pmid: 9165224
references.citation: Bioorg Med Chem. 2010 Feb;18(3):1103-10
references.pmid: 20079654
references.citation: J Clin Endocrinol Metab. 1998 Jun;83(6):2001-5
references.pmid: 9626131
references.citation: Adv Second Messenger Phosphoprotein Res. 1990;24:290-4
references.pmid: 2169809
references.citation: Am J Clin Nutr. 2005 Feb;81(2):341-54
references.pmid: 15699220
references.citation: J Biol Chem. 1980 Aug 25;255(16):7540-3
references.pmid: 6249805
references.citation: Nat Cell Biol. 2002 Sep;4(9):648-57
references.pmid: 12172553
references.citation: Mol Cells. 1998 Jun 30;8(3):301-9
references.pmid: 9666467
references.citation: Endocrinology. 1993 Feb;132(2):652-7
references.pmid: 8425485
references.citation: Biochem Biophys Res Commun. 2002 Jul 12;295(2):561-9
references.pmid: 12150987
references.citation: Ann N Y Acad Sci. 1989;573:285-96
references.pmid: 2699402
references.citation: J Biol Chem. 2004 May 21;279(21):22715-26
references.pmid: 15016818
references.citation: J Biol Chem. 1991 Dec 15;266(35):23670-5
references.pmid: 1748644
references.citation: J Comp Neurol. 1998 Aug 31;398(3):323-32
references.pmid: 9714146
references.citation: J Med Chem. 2003 Jul 17;46(15):3283-91
references.pmid: 12852758
references.citation: J Biol Chem. 2010 Jan 22;285(4):2245-57
references.pmid: 19897488
references.citation: Metabolism. 1997 Nov;46(11):1270-4
references.pmid: 9361684
references.citation: Biochem J. 1991 Mar 1;274 ( Pt 2):369-74
references.pmid: 2006906
references.citation: Lancet. 1962 Dec 29;2(7270):1348-51
references.pmid: 13982963
references.citation: Diabetes Care. 1994 Dec;17(12):1465-8
references.pmid: 7882818
references.citation: Biochem J. 1996 Dec 15;320 ( Pt 3):801-6
references.pmid: 9003365
references.citation: J Biol Chem. 2002 Sep 20;277(38):35219-24
references.pmid: 12133831
references.citation: J Biol Chem. 1992 Aug 15;267(23):16266-73
references.pmid: 1322896
references.citation: Diabetes. 1993 May;42(5):643-50
references.pmid: 8387037
references.citation: Diabetes Care. 1996 Jan;19(1):76-8
references.pmid: 8720541