Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.
OBJECTIVE
Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10).


METHODS
MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses.


RESULTS
MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-alpha, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle.


CONCLUSIONS
These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.
Hong
Eun-Gyoung
EG
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Ko
Hwi Jin
HJ
Cho
You-Ree
YR
Kim
Hyo-Jeong
HJ
Ma
Zhexi
Z
Yu
Tim Y
TY
Friedline
Randall H
RH
Kurt-Jones
Evelyn
E
Finberg
Robert
R
Fischer
Matthew A
MA
Granger
Erica L
EL
Norbury
Christopher C
CC
Hauschka
Stephen D
SD
Philbrick
William M
WM
Lee
Chun-Geun
CG
Elias
Jack A
JA
Kim
Jason K
JK
D000818:Animals; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology
D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; D016753:Interleukin-10; D003402:Creatine Kinase
J Clin Endocrinol Metab. 2001 Mar;86(3):965-71
11238470
Diabetes. 2005 Sep;54(9):2514-24
16123338
Mol Cell Biochem. 1998 May;182(1-2):3-11
9609109
Diabetes. 1994 Aug;43(8):1066-84
8039601
J Biol Chem. 2003 Nov 21;278(47):46494-505
12968024
Annu Rev Immunol. 2004;22:929-79
15032600
Clin Immunol Immunopathol. 1994 May;71(2):169-75
8181185
J Immunol. 2002 Jun 15;168(12):6479-85
12055268
Diabetes. 2002 Apr;51(4):1088-92
11916930
J Clin Invest. 2004 Sep;114(6):823-7
15372106
J Biol Chem. 2004 Aug 13;279(33):34733-40
15181014
J Biol Chem. 2006 Sep 8;281(36):26602-14
16809344
Diabetologia. 1998 Oct;41(10):1241-8
9794114
Diabetes Care. 2004 May;27(5):1047-53
15111519
Lancet. 1963 Apr 13;1(7285):785-9
13990765
Science. 2008 Dec 5;322(5907):1539-43
19056984
Diabetes. 2006 May;55(5):1529-33
16644716
J Clin Invest. 2007 Jan;117(1):175-84
17200717
Diabetes Care. 2005 Aug;28(8):2036-7
16043753
Neuromuscul Disord. 2002 Oct;12 Suppl 1:S23-9
12206791
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E327-36
17616608
J Lipid Res. 2005 Nov;46(11):2347-55
16150820
J Biol Chem. 2003 Nov 21;278(47):46654-60
13129912
Mol Cell Biol. 1996 Sep;16(9):5058-68
8756664
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Mol Ther. 2007 Feb;15(2):320-9
17235310
Diabetes. 2002 Dec;51(12):3391-9
12453891
Diabetes. 2005 Aug;54(8):2305-13
16046295
Diabetes. 2006 Oct;55(10):2688-97
17003332
J Clin Invest. 2000 Jul;106(2):171-6
10903330
Am J Physiol Endocrinol Metab. 2001 May;280(5):E745-51
11287357
Diabetes. 2005 Dec;54(12):3530-40
16306372
Diabetes. 1997 Jan;46(1):3-10
8971073
Diabetes. 1999 Jun;48(6):1270-4
10342815
Science. 1993 Jan 1;259(5091):87-91
7678183
Diabetes. 2004 Apr;53(4):1060-7
15047622
Annu Rev Immunol. 2001;19:683-765
11244051
Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E166-74
16926380
J Appl Physiol (1985). 2007 Feb;102(2):814-6
17068210
J Biol Chem. 2002 Sep 20;277(38):35466-74
12107190
EMBO J. 1996 Apr 1;15(7):1557-65
8612579
Biochem Biophys Res Commun. 2006 Mar 10;341(2):507-14
16427608
J Clin Invest. 2006 Jun;116(6):1494-505
16691291
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7522-7
11390966
J Clin Endocrinol Metab. 2003 Mar;88(3):1055-8
12629085
Diabetes. 1988 Jun;37(6):667-87
3289989
J Clin Invest. 2005 May;115(5):1111-9
15864338
Pharmacol Res. 2006 Jun;53(6):469-77
16632376
Diabetes. 1988 Dec;37(12):1595-607
3056758
Cell Metab. 2006 Dec;4(6):465-74
17141630
Immunology. 2001 Jun;103(2):131-6
11412299
J Clin Invest. 2006 Jan;116(1):115-24
16341265