Template to improve glycemic control without reducing adiposity or dietary fat.
Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.
Infections and Obesity Laboratory, Pennington Biomedical Research Center, Louisiana State Univ. System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA. nikhil.dhurandhar@pbrc.edu
R
R
Krishnapuram
E J
EJ
Dhurandhar
O
O
Dubuisson
H
H
Kirk-Ballard
S
S
Bajpeyi
N
N
Butte
M S
MS
Sothern
E
E
Larsen-Meyer
S
S
Chalew
B
B
Bennett
A K
AK
Gupta
F L
FL
Greenway
W
W
Johnson
M
M
Brashear
G
G
Reinhart
T
T
Rankinen
C
C
Bouchard
W T
WT
Cefalu
J
J
Ye
R
R
Javier
A
A
Zuberi
N V
NV
Dhurandhar
D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D004041:Dietary Fats / Q000494:pharmacology*; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D001786:Blood Glucose; D004041:Dietary Fats; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012333:RNA, Messenger
Am J Clin Nutr. 2006 Sep;84(3):646-54; quiz 673-4
16960181
JAMA. 2007 Dec 12;298(22):2634-43
18073359
Biochem Soc Trans. 2001 May;29(Pt 2):310-6
11356173
JAMA. 1990 Jun 6;263(21):2893-8
2338751
Metabolism. 2008 Dec;57(12):1655-62
19013287
Am J Clin Nutr. 2007 Jun;85(6):1478-85
17556682
Clin Gastroenterol Hepatol. 2006 Aug;4(8):1048-52
16814613
Biosci Biotechnol Biochem. 2007 Jan;71(1):206-14
17213668
Arch Virol. 1980;64(3):225-33
7406681
Diabetes. 2008 Sep;57(9):2321-31
18599527
J Appl Physiol (1985). 2009 Apr;106(4):1079-85
19196913
J Physiol Pharmacol. 2009 Dec;60 Suppl 7:57-66
20388946
Curr Cancer Drug Targets. 2007 Mar;7(2):133-9
17346104
J Physiol Pharmacol. 2009 Dec;60(4):135-40
20065507
J Clin Invest. 2001 Oct;108(8):1167-74
11602624
Obesity (Silver Spring). 2010 Aug;18(8):1510-5
20395947
Biochemistry. 1999 Jun 8;38(23):7532-44
10360951
Diabetologia. 2010 Nov;53(11):2406-16
20652679
Med Sci Sports Exerc. 1995 May;27(5):721-9
7674877
Diabetes Care. 2009 Feb;32(2):287-94
19017771
J Clin Invest. 1995 May;95(5):2195-204
7537758
J Lipid Res. 1999 Nov;40(11):2134-9
10553017
Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E506-15
20570822
Dig Dis. 2010;28(1):169-78
20460907
Int J Obes (Lond). 2005 Mar;29(3):281-6
15611785
Hepatology. 2005 Sep;42(3):568-77
16108051
Pharmacol Res. 2009 Sep;60(3):151-9
19646654
J Nutr. 2002 Oct;132(10):3155-60
12368411
Int J Pediatr Obes. 2010;5(1):51-5
19579147
Liver Int. 2010 Feb;30(2):184-90
19840251
Gastroenterology. 2007 May;132(6):2191-207
17498512
Dig Dis. 2010;28(1):155-61
20460905
N Engl J Med. 2007 Jun 14;356(24):2457-71
17517853
Endocrinology. 2008 May;149(5):2270-82
18202126
Biol Chem. 2010 Sep;391(9):1005-18
20536390
Diabetes Technol Ther. 2010 Mar;12(3):207-12
20151771
J Biol Chem. 2002 Dec 13;277(50):48115-21
12351658
Science. 1996 Oct 18;274(5286):373-6
8832876
J Clin Invest. 2007 Sep;117(9):2621-37
17717599
N Engl J Med. 2010 May 6;362(18):1675-85
20427778
FASEB J. 2001 Oct;15(12):2099-111
11641236
N Engl J Med. 2001 May 3;344(18):1343-50
11333990
Diabetes Care. 2007 May;30(5):1212-8
17277038
Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E170-6
11739098
J Clin Invest. 2009 Feb;119(2):315-22
19164855
Diabetes Care. 2008 May;31(5):977-9
18299442
Gastroenterology. 2005 Jul;129(1):113-21
16012941
Int J Obes Relat Metab Disord. 2001 Jul;25(7):990-6
11443497
Obesity (Silver Spring). 2006 Nov;14(11):1905-13
17135605
Nutrition. 2009 Jul-Aug;25(7-8):818-27
19268533
Nat Med. 2002 Nov;8(11):1288-95
12368907
Mol Pharmacol. 2007 Oct;72(4):947-55
17628011
Curr Drug Discov Technol. 2007 Aug;4(2):133-40
17691915
Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E485-93
17003244
J Biol Chem. 2006 Apr 14;281(15):10105-17
16492665
Hepatology. 2006 Oct;44(4):865-73
17006923
J Clin Invest. 2000 Jul;106(2):165-9
10903329
Int J Obes Relat Metab Disord. 2000 Aug;24(8):989-96
10951537
Int J Antimicrob Agents. 2007 Aug;30(2):118-28
17566713
Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15430-5
19706383
Genes Dev. 2007 Jun 15;21(12):1443-55
17575046
J Diabetes Complications. 2010 Sep-Oct;24(5):289-96
19577936
Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):363-73
11747141
Obesity (Silver Spring). 2009 Apr;17(4):657-64
19165154
Diabetes. 2008 Jul;57(7):1805-13
18420488
Life Sci. 2008 Nov 7;83(19-20):638-43
18824177
Curr Diab Rep. 2003 Jun;3(3):207-13
12762967