Revisiting the membrane-centric view of diabetes.
Fundamental questions remain unresolved in diabetes: What is the actual mechanism of glucose toxicity? Why is there insulin resistance in type 2 diabetes? Why do diets rich in sugars or saturated fatty acids increase the risk of developing diabetes? Studying the C. elegans homologs of the anti-diabetic adiponectin receptors (AdipoR1 and AdipoR2) has led us to exciting new discoveries and to revisit what may be termed "The Membrane Theory of Diabetes". We hypothesize that excess saturated fatty acids (obtained through a diet rich in saturated fats or through conversion of sugars into saturated fats via lipogenesis) leads to rigid cellular membranes that in turn impair insulin signalling, glucose uptake and blood circulation, thus creating a vicious cycle that contributes to the development of overt type 2 diabetes. This hypothesis is supported by our own studies in C. elegans and by a wealth of literature concerning membrane composition in diabetics. The purpose of this review is to survey this literature in the light of the new results, and to provide an admittedly membrane-centric view of diabetes.
Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9, Box 462, S-405 30, Göteborg, Sweden. marc.pilon@cmb.gu.se.
Marc
http://orcid.org/0000-0003-3919-2882
M
Pilon
AdipoR1; AdipoR2; Diabetes; Diet; Fatty acids; Lipidomics; Membrane fluidity; PAQR-2; Phospholipid
Diabetes. 1978 Sep;27(9):895-901
689301
PLoS Biol. 2011 Jun;9(6):e1000623
21666801
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3579-84
24522108
Curr Opin Lipidol. 2012 Feb;23(1):4-10
22123669
Biochim Biophys Acta. 1982 Sep 9;690(2):157-64
6751393
Microvasc Res. 2001 May;61(3):231-9
11336534
Annu Rev Biophys Biomol Struct. 2006;35:177-98
16689633
Biol Cell. 1991;71(3):293-6
1933025
Lipids. 1967 May;2(3):284-5
17805784
J Biol Chem. 2015 Apr 24;290(17):11075-92
25762724
Mol Cell Biochem. 2003 Jul;249(1-2):175-82
12956413
PLoS Genet. 2016 Apr 15;12 (4):e1005982
27082444
Biochem Biophys Res Commun. 2001 May 4;283(2):323-6
11327701
Clin Chim Acta. 1990 May;188(3):211-9
2387073
Diabet Med. 2008 Apr;25(4):400-6
18294218
Diabetes. 1983 Jul;32(7):585-91
6305749
Nat Rev Endocrinol. 2014 Mar;10(3):143-56
24393785
Acta Diabetol. 2006 Dec;43(4):109-13
17211560
Diabetes Metab. 1999 Jun;25(2):110-27
10443322
PLoS One. 2011;6(6):e21343
21712952
Annu Rev Physiol. 2000;62:207-35
10845090
Diabetes. 1979 Dec;28(12):1138-40
510812
Diabetes. 1990 Feb;39(2):241-4
2227132
Biochim Biophys Acta. 2012 Mar;1818(3):467-73
22024024
Am J Physiol Regul Integr Comp Physiol. 2012 Mar 1;302(5):R598-605
22204953
Diabetes. 1979 May;28(5):479-85
437377
J Bacteriol. 2004 May;186(9):2655-63
15090506
J Biol Chem. 2010 Feb 26;285(9):6044-52
20032470
Obesity (Silver Spring). 2007 Jul;15(7):1732-40
17636091
Diabetes. 1981 Sep;30(9):773-80
6266903
J Bacteriol. 2004 Oct;186(20):6681-8
15466018
Annu Rev Physiol. 1995;57:19-42
7778864
Lancet Diabetes Endocrinol. 2014 Oct;2(10):810-8
25107467
Metabolism. 1990 Aug;39(8):794-8
2377077
Diabetes. 2006 Mar;55(3):856-61
16505255
Science. 2015 Sep 18;349(6254):1343-7
26383953
Diabetes. 1990 Apr;39(4):466-70
2138577
Clin Chem. 2011 Feb;57(2):241-54
21119033
Diabetes Res Clin Pract. 1992 Apr;16(1):1-6
1576926
Metabolism. 2005 Feb;54(2):240-6
15789505
Am J Clin Nutr. 2002 Dec;76(6):1222-9
12450886
Nature. 2014 Jun 5;510(7503):48-57
24899304
N Engl J Med. 2006 Apr 13;354(15):1601-13
16611951
Clin Sci (Lond). 2012 Mar;122(6):253-70
22117616
Biol Direct. 2011 Jul 06;6:37
21733186
EMBO Rep. 2001 Apr;2(4):282-6
11306547
Lipids. 2004 Nov;39(11):1061-5
15726820
Diabetes. 1993 Sep;42(9):1303-9
7688706
Mol Cell Biochem. 2003 Oct;252(1-2):125-32
14577585
FEBS Lett. 2006 Oct 9;580(23):5477-83
16824520
J Nutr Biochem. 1990 Feb;1(2):68-79
15539188
Diabetologia. 2005 Nov;48(11):2282-91
16205883
J Nutr. 1993 Mar;123(3):512-9
8463854
Curr Diabetes Rev. 2012 Sep;8(5):390-400
22698081
Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
18216768
Nat Med. 2011 Jan;17(1):55-63
21186369
Diabetes. 1986 May;35(5):604-11
3956887
Annu Rev Physiol. 1992;54:557-77
1314046
Science. 1985 May 31;228(4703):1101-3
3992247
Br J Haematol. 1986 Jan;62(1):111-6
3942692
PLoS Genet. 2013;9(9):e1003801
24068966
Mol Biotechnol. 2004 Jun;27(2):127-38
15208455
Biochim Biophys Acta. 2012 May;1818(5):1309-17
22285120
Diabetologia. 1993 Sep;36(9):850-6
8405757
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6353-8
25941408
J Endocrinol. 2007 Jan;192(1):229-36
17210760
Nature. 2003 Jun 12;423(6941):762-9
12802337
Curr Biol. 2010 Sep 14;20(17 ):1539-44
20705470
Eur J Pharmacol. 1997 Oct 15;337(1):103-10
9389387
Diabetes Care. 1995 Jan;18(1):60-3
7698049
J Biol Chem. 2016 Feb 12;291(7):3658-67
26663081
Am J Clin Nutr. 2010 Mar;91(3):794-801
20032495
J Comp Physiol B. 2008 Sep;178(7):795-809
18506451
Biochim Biophys Acta. 1984 Jan 27;779(1):89-137
6229284
Biochim Biophys Acta. 2006 Dec;1758(12):1945-56
16901461
Clin Endocrinol (Oxf). 2009 Jan;70(1):66-74
18466348
Neuroscience. 2009 Aug 18;162(2):349-58
19426784
J Cell Commun Signal. 2007 Sep;1(2):113-25
18481202
Nat Med. 2007 Mar;13(3):332-9
17268472
Worm. 2013 Oct 1;2(4):e27123
24744984
Am J Clin Nutr. 2011 Jan;93(1):127-42
20980488
Cell Metab. 2013 Feb 5;17(2):185-96
23352188
N Engl J Med. 1993 Jan 28;328(4):238-44
8418404
Curr Opin Clin Nutr Metab Care. 1998 Nov;1(6):559-63
10565410
Nature. 2015 Apr 16;520(7547):312-6
25855295
Prostaglandins Leukot Essent Fatty Acids. 1998 Sep;59(3):191-4
9844992
Mol Cell. 2016 Jul 7;63(1):49-59
27320200
Mol Pharmacol. 2009 Apr;75(4):866-75
19066337
Diabetologia. 2015 Feb;58(2):282-9
25344391
Biochemistry. 2004 May 25;43(20):6344-51
15147219
J Mol Cell Biol. 2016 Apr;8(2):93-100
26993047
Nat Rev Mol Cell Biol. 2002 Apr;3(4):267-77
11994746
Diabetologia. 2002 Mar;45(3):369-77
11914742
EMBO J. 2001 Apr 2;20(7):1681-91
11285232
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1189-94
20153289
Biol Rev Camb Philos Soc. 2005 Feb;80(1):155-69
15727042
Ann Nutr Metab. 1999;43(5):290-300
10749029
J Biol Chem. 1985 Oct 15;260(23):12405-9
3900076