Florian Willecke1, Diego Scerbo1, Prabhakara Nagareddy1, Joseph C Obunike1, Tessa J Barrett1, Mariane L Abdillahi1, Chad M Trent1, Lesley A Huggins1, Edward A Fisher1, Konstantinos Drosatos1, Ira J Goldberg2. 1. From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.). 2. From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.). Ira.Goldberg@NYUMC.org.
Abstract
OBJECTIVE: Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. APPROACH AND RESULTS: To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance. CONCLUSIONS: Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.
OBJECTIVE: Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. APPROACH AND RESULTS: To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance. CONCLUSIONS: Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.
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