Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity

Diabetologia. 2015 Oct;58(10):2392-402. doi: 10.1007/s00125-015-3676-7. Epub 2015 Jul 9.


Aims/hypothesis: Hyperinsulinaemia is associated with obesity but its causal role in the onset of obesity remains controversial. In this study, we tested the hypothesis that transient attenuation of diet-induced insulin hypersecretion in young mice can provide sustained protection against obesity throughout adult life.

Methods: Using 'genetically humanised' mice lacking both alleles of rodent-specific Ins1, we compared mice heterozygous for the ancestral insulin gene Ins2 with Ins2(+/+) controls. Female Ins1(-/-):Ins2(+/-) and Ins1(-/-):Ins2(+/+) littermates were fed chow or high-fat diet (HFD). Insulin secretion, metabolic health variables and body mass/composition were tracked for over 1 year. We examined islet function and adipose transcript levels of adipogenic, lipogenic and lipolytic genes at two time points.

Results: In control Ins1(-/-):Ins2(+/+) mice, HFD resulted in elevated fasting and glucose-stimulated insulin secretion between 8 weeks and 27 weeks of age. Hyperinsulinaemia was reduced by nearly 50% in Ins1(-/-):Ins2(+/-) mice during this period, without lasting adverse effects on glucose homeostasis. This corresponded with attenuated weight gain and adiposity. White adipose tissue from Ins1(-/-):Ins2(+/-) mice had fewer large lipid droplets, although transcriptional changes were not detected. Importantly, Ins1(-/-):Ins2(+/-) mice remained lighter than Ins1(-/-):Ins2(+/+) littermates despite reaching an equivalent degree of hyperinsulinaemia on HFD by 52 weeks.

Conclusions/interpretation: These data demonstrate that attenuation of hyperinsulinaemia in young, growing female mice provides a long-lasting protection against obesity. This protection persists despite a late-onset emergence of hyperinsulinaemia in HFD-fed Ins1(-/-):Ins2(+/-) mice. Given the evolutionary conserved roles of insulin, it is possible that suppressing hyperinsulinaemia early in life may have far-reaching consequences on obesity in full-grown adult humans.

Keywords: Adolescence; Diet-induced obesity; Glucose homeostasis; Insulin; Knockout mice; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism
  • Alleles
  • Animals
  • Body Composition / genetics
  • Diet, High-Fat
  • Female
  • Glucose / metabolism
  • Hyperinsulinism / genetics*
  • Hyperinsulinism / metabolism
  • Insulin / genetics*
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Mice
  • Mice, Knockout
  • Obesity / genetics*
  • Obesity / metabolism


  • Ins1 protein, mouse
  • Ins2 protein, mouse
  • Insulin
  • Glucose