Glucolipotoxicity of the pancreatic beta-cell: myth or reality?
The glucolipotoxicity hypothesis postulates that chronically elevated levels of glucose and fatty acids adversely affect pancreatic beta-cell function and thereby contribute to the deterioration of insulin secretion in Type 2 diabetes. Whereas ample experimental evidence in in vitro systems supports the glucolipotoxicity hypothesis, the contribution of this phenomenon to beta-cell dysfunction in human Type 2 diabetes has been questioned. The reasons for this controversy include: differences between in vitro systems and in vivo situations; time-dependent effects of fatty acids on insulin secretion (acutely stimulatory and chronically inhibitory); and the ill-defined use of the suffix '-toxicity'. In vitro, prolonged exposure of insulin-secreting cells or isolated islets to concomitantly elevated levels of fatty acids and glucose impairs insulin secretion, inhibits insulin gene expression and, under certain circumstances, induces beta-cell death by apoptosis. Recent studies in our laboratory have shown that cyclical and alternate infusions of glucose and Intralipid in rats impair insulin gene expression, providing evidence that inhibition of the insulin gene under glucolipotoxic conditions is an early defect that might indeed contribute to beta-cell failure in Type 2 diabetes, although this hypothesis remains to be tested in humans.
Poitout
Vincent
V
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Technopole Angus, 2901 Rachel Est, Montréal, QC, Canada, H1W 4A4. vincent.poitout@umontreal.ca
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*
D005227:Fatty Acids; D005947:Glucose
J Biol Chem. 2003 Aug 8;278(32):30015-21
12771145
Biochemistry. 1993 Jul 27;32(29):7574-80
8338853
J Lipid Res. 1995 Feb;36(2):229-40
7751810
Diabetologia. 1985 Mar;28(3):119-21
3888754
Diabetes. 1999 Mar;48(3):524-30
10078552
Diabetes. 2003 Oct;52(10):2461-74
14514628
Diabetologia. 2006 Sep;49(9):2120-30
16868750
Diabetes. 1995 Oct;44(10):1239-42
7556964
Diabetologia. 2001 Nov;44(11):1989-97
11719829
J Clin Invest. 2006 Jul;116(7):1802-12
16823478
Am J Physiol. 1999 Jun;276(6):E1055-66
10362618
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8319-24
15148392
Nature. 1998 Mar 26;392(6674):398-401
9537324
Diabetes. 1995 Aug;44(8):863-70
7621989
J Biol Chem. 2005 Sep 16;280(37):32413-8
15944145
Diabetes. 2002 Dec;51 Suppl 3:S405-13
12475783
Endocrinology. 2003 Dec;144(12):5159-65
12960011
Lancet. 1998 Sep 12;352(9131):837-53
9742976
Endocr Rev. 2008 May;29(3):351-66
18048763
Diabetologia. 2004 Feb;47(2):204-13
14712348
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1775-81
17299078
Diabetes. 2000 Mar;49(3):399-408
10868961
Diabetes. 2008 Feb;57(2):424-31
17991758
Diabetes. 1999 Mar;48(3):577-83
10078559
Diabetes. 2004 Oct;53(10):2610-6
15448091
Diabetologia. 2007 Jan;50(1):74-83
17093947
Diabetes. 2002 Apr;51(4):977-87
11916915
Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E549-60
17003242
J Biol Chem. 2001 Apr 13;276(15):12162-8
11154699
Diabetes. 2003 Jan;52(1):102-10
12502499