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1 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States
2 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States; Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, United States
3 Pharmacology, Medical University of Ohio, Toledo, Ohio, United States
4 Preventive Medicine, Columbia University Medical Center, New York, New York, United States
5 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States; Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, New Haven, Connecticut, United States
6 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States; Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, United States; Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: jason.kim{at}psu.edu.
Mice with liver-specific overexpression of dominant-negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-hour hyperinsulinemic-euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of CEACAM1 caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by 1H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.
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