4.7 Article

Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia, Glucose Intolerance, and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

Journal

DIABETES
Volume 63, Issue 2, Pages 688-700

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db13-0558

Keywords

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Funding

  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development [K99/R00]
  2. Pediatric Endocrine Society
  3. Canadian Institutes of Health Research
  4. American Diabetes Association
  5. Graetz Foundation
  6. Marie-Curie International Outgoing Fellowship for Career Development [MC-IOF-2009-253131]
  7. Joslin Diabetes Research Center [DK-036836]
  8. Vanderbilt Mouse Metabolic Phenotyping Center [DK-59637]

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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.

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