title: Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice.
abstract: Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring.
authors.affiliation: Division of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA.
authors.forename: Elvira
authors.initials: E
authors.lastname: Isganaitis
authors.forename: Melissa
authors.initials: M
authors.lastname: Woo
authors.forename: Huijuan
authors.initials: H
authors.lastname: Ma
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Kong
authors.forename: Aristides
authors.initials: A
authors.lastname: Lytras
authors.forename: Vicencia
authors.initials: V
authors.lastname: Sales
authors.forename: Jennifer
authors.initials: J
authors.lastname: Decoste-Lopez
authors.forename: Kyung-Ju
authors.initials: KJ
authors.lastname: Lee
authors.forename: Cianna
authors.initials: C
authors.lastname: Leatherwood
authors.forename: Deborah
authors.initials: D
authors.lastname: Lee
authors.forename: Connor
authors.initials: C
authors.lastname: Fitzpatrick
authors.forename: Walter
authors.initials: W
authors.lastname: Gall
authors.forename: Steven
authors.initials: S
authors.lastname: Watkins
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Patti
mesh_terms: D000375:Aging; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D050171:Dyslipidemias / Q000209:etiology*; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000209:etiology*; D006239:Haplotypes; D006946:Hyperinsulinism / Q000209:etiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism; D011297:Prenatal Exposure Delayed Effects
chemical_list: D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse