title: Chronic hyperinsulinemia contributes to insulin resistance under dietary restriction in association with altered lipid metabolism in Zucker diabetic fatty rats.
abstract: Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats.
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan ippei.morita@shionogi.co.jp.
authors.forename: Ippei
authors.initials: I
authors.lastname: Morita
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Naya
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Fujieda
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi and Company, Ltd., Osaka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yukioka
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D007328:Insulin
keywords: dietary restriction; hyperinsulinemia; insulin resistance; lipogenesis; type 2 diabetes mellitus