Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
OBJECTIVE
To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db) mouse strain.


METHODS
Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains.


RESULTS
Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities.


CONCLUSIONS
Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of beta-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.
Davis
Richard C
RC
Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Castellani
Lawrence W
LW
Hosseini
Maryam
M
Ben-Zeev
Osnat
O
Mao
Hui Z
HZ
Weinstein
Michael M
MM
Jung
Dae Young
DY
Jun
John Y
JY
Kim
Jason K
JK
Lusis
Aldons J
AJ
Péterfy
Miklós
M
D000704:Analysis of Variance; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008049:Lipase / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
D005227:Fatty Acids; D007328:Insulin; D008049:Lipase
Science. 1966 Sep 2;153(3740):1127-8
5918576
Endocr Rev. 2007 Feb;28(1):48-83
17018838
Arterioscler Thromb. 1993 Jan;13(1):1-10
8422330
J Biol Chem. 1983 Jan 25;258(2):938-45
6822515
Diabetes. 2004 Apr;53(4):1060-7
15047622
Methods Enzymol. 1975;35:279-87
1121283
J Pharmacol Toxicol Methods. 1997 Oct;38(2):59-69
9403776
J Biol Chem. 2004 Jun 11;279(24):25039-49
15028732
Science. 1996 Feb 16;271(5251):994-6
8584938
J Clin Invest. 2003 Mar;111(5):737-47
12618528
Curr Opin Lipidol. 2009 Jun;20(3):206-10
19421055
Diabetes. 2005 Apr;54(4):1191-9
15793261
Methods Cell Biol. 1976;13:29-83
177845
J Biol Chem. 2003 Feb 7;278(6):3992-9
12456680
Annu Rev Med. 2002;53:319-36
11818477
Jpn J Pharmacol. 2000 Oct;84(2):113-23
11128033
J Clin Invest. 2005 Mar;115(3):718-27
15711641
Mamm Genome. 1995 Feb;6(2):131-3
7766997
Diabetologia. 1973 Aug;9(4):287-93
4588246
J Biol Chem. 2003 Jan 10;278(2):1131-6
12414791
Biochim Biophys Acta. 1991 Nov 5;1086(2):197-208
1932102
Proc Natl Acad Sci U S A. 1982 Jan;79(2):630-4
6210909
Diabetes Metab. 2004 Feb;30(1):13-9
15029093
J Lipid Res. 1999 Nov;40(11):2134-9
10553017
J Clin Invest. 1997 Dec 15;100(12):3164-72
9399964
Cell. 1996 Feb 9;84(3):491-5
8608603
Annu Rev Physiol. 2006;68:123-58
16460269
Biochem Genet. 1972 Aug;7(1):1-13
4557514
Diabetologia. 1984 Oct;27(4):464-7
6439585
Diabetes. 2001 Nov;50(11):2425-30
11679417
Diabetes. 1998 Jan;47(1):13-23
9421369
Diabetologia. 1970 Jun;6(3):207-15
4914661
Diabetes. 1977 Oct;26(10):916-20
143386
J Biol Chem. 2004 Jul 9;279(28):29558-64
15123608
Isr J Med Sci. 1975 Jul;11(7):708-13
1099054
Biochim Biophys Acta. 2006 Apr;1762(4):440-6
16481151
Mol Cell. 2000 Jul;6(1):87-97
10949030
Diabetologia. 1979 Sep;17(3):187-91
510832
Diabetologia. 1989 Sep;32(9):636-43
2676665
J Hepatol. 2001 Jul;35(1):17-23
11495036
Biochem Cell Biol. 2004 Feb;82(1):201-11
15052338
J Clin Invest. 1992 Nov;90(5):1839-49
1331176
Nature. 1998 Mar 26;392(6674):398-401
9537324
J Biol Chem. 2008 Dec 12;283(50):34511-8
18845532
Diabetes. 2003 Mar;52(3):688-700
12606510
Methods Mol Biol. 1999;109:81-94
9918014