Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity.
High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα-/-null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα-/-mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity.
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614.
Sadeesh K
SK
Ramakrishnan
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614.
Lucia
L
Russo
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614.
Simona S
SS
Ghanem
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614.
Payal R
PR
Patel
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614.|the Department of Pharmacology and Experimental Therapeutics College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, Ohio 43614, and.
Ana Maria
AM
Oyarce
the Department of Pharmacology and Experimental Therapeutics College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, Ohio 43614, and.
Garrett
G
Heinrich
From the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio 43614, najjar@ohio.edu.|the Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701.
Sonia M
SM
Najjar
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology
D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D007328:Insulin; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D011345:Fenofibrate
fatty acid oxidation; fatty acid synthase (FAS); fenofibrate; insulin clearance; insulin metabolism; insulin resistance; insulin secretion; peroxisome proliferator-activated receptor (PPAR)
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