Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in c57bl/6 Mice

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 12; pp. 3530 - 3540
• Main Authors: PARK, So-Young, CHO, You-Ree, RUSSELL, Kerry S, KIM, Jason K, KIM, Hyo-Jeong, HIGASHIMORI, Takamasa, DANTON, Cheryl, LEE, Mi-Kyung, DEY, Asim, ROTHERMEL, Beverly, KIM, Young-Bum, KALINOWSKI, April
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-12-2005
• Subjects: Adipose Tissue - anatomy & histology; Animal Feed; Animals; Biological and medical sciences; Blood Glucose - metabolism; Body fat; Cardiovascular disease; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Diagnosis; Dietary Fats; Drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - metabolism; Glucose Clamp Technique; Heart - drug effects; Heart diseases; Heart Diseases - physiopathology; Insulin - physiology; Insulin resistance; Insulin Resistance - physiology; Kinases; Medical sciences; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Organ Specificity; Risk factors; United Kingdom; Endocrinopathy; Human; Vertebrata; Mammalia; Diet; Mouse; Dysfunction; Animal; Diabetes mellitus; Rodentia; Insulin resistance; Feeding
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.12.3530

Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in c57bl/6 Mice
So-Young Park 1 ,
You-Ree Cho 1 ,
Hyo-Jeong Kim 1 ,
Takamasa Higashimori 1 ,
Cheryl Danton 1 ,
Mi-Kyung Lee 1 ,
Asim Dey 2 ,
Beverly Rothermel 2 ,
Young-Bum Kim 3 ,
April Kalinowski 4 ,
Kerry S. Russell 4 and
Jason K. Kim 1 5
1 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
3 Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts
4 Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, Connecticut
5 Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Prof. Jason K. Kim, Pennsylvania State University College of Medicine, Department
of Cellular and Molecular Physiology (H166), 500 University Dr., Room C4600D, Hershey, PA 17033-0850. E-mail: jason.kim{at}psu.edu
Abstract
Type 2 diabetes is a heterogeneous disease characterized by insulin resistance and altered glucose and lipid metabolism in
multiple organs. To understand the complex series of events that occur during the development of obesity-associated diabetes,
we examined the temporal pattern of changes in insulin action and glucose metabolism in individual organs during chronic high-fat
feeding in C57BL/6 mice. Insulin-stimulated cardiac glucose metabolism was significantly reduced after 1.5 weeks of high-fat
feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling and GLUT4 levels. Insulin
resistance in skeletal muscle, adipose tissue, and liver developed in parallel after 3 weeks of high-fat feeding. Diet-induced
whole-body insulin resistance was associated with increased circulating levels of resistin and leptin but unaltered adiponectin
levels. High-fat feeding caused insulin resistance in skeletal muscle that was associated with significantly elevated intramuscular
fat content. In contrast, diet-induced hepatic insulin resistance developed before a marked increase in intrahepatic triglyceride
levels. Cardiac function gradually declined over the course of high-fat feeding, and after 20 weeks of high-fat diet, cardiac
dysfunction was associated with mild hyperglycemia, hyperleptinemia, and reduced circulating adiponectin levels. Our findings
demonstrate that cardiac insulin resistance is an early adaptive event in response to obesity and develops before changes
in whole-body glucose homeostasis. This suggests that obesity-associated defects in cardiac function may not be due to insulin
resistance per se but may be attributable to chronic alteration in cardiac glucose and lipid metabolism and circulating adipokines.
2-[14C]DG, 2-deoxy-d-[1-14C]glucose
AMPK, AMP-activated protein kinase
CVD, cardiovascular disease
GSK-3β, glycogen synthase kinase-3β
HGP, hepatic glucose production
1H-MRS, 1H-magnetic resonance spectroscopy
Footnotes
S.-Y.P. is currently affiliated with the Department of Physiology, Yeungnam University College of Medicine, Yeungnam, South
Korea.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 6, 2005.
Received March 11, 2005.
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