Suppression of hyperinsulinaemia in growing female XXXX provides long-term protection against @entity28 .

@entity1 @entity28 @entity19 @entity2690 @entity1017 @entity413 @entity15979 @entity15981 @entity1386
AIMS/HYPOTHESIS: Hyperinsulinaemia is associated with @entity28 but its causal role in the onset of @entity28 remains controversial. In this study, we tested the hypothesis that transient attenuation of diet-induced @entity2690 hypersecretion in young @entity19 can provide sustained protection against @entity28 throughout adult life. METHODS: Using 'genetically humanised' @entity19 lacking both alleles of rodent-specific @entity15981 , we compared @entity19 heterozygous for the ancestral @entity2690 gene @entity15979 with @entity15979 (+/+) controls. Female @entity15981 (-/-): @entity15979 (+/-) and @entity15981 (-/-): @entity15979 (+/+) littermates were fed chow or @entity1386 ( @entity1386 ). @entity2690 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 @entity15981 (-/-): @entity15979 (+/+) @entity19 , @entity1386 resulted in elevated fasting and @entity413 -stimulated @entity2690 secretion between 8  weeks and 27  weeks of age. Hyperinsulinaemia was reduced by nearly 50% in @entity15981 (-/-): @entity15979 (+/-) @entity19 during this period, without lasting adverse effects on @entity413 homeostasis. This corresponded with attenuated @entity1017 and adiposity. White adipose tissue from @entity15981 (-/-): @entity15979 (+/-) @entity19 had fewer large lipid droplets, although transcriptional changes were not detected. Importantly, @entity15981 (-/-): @entity15979 (+/-) @entity19 remained lighter than @entity15981 (-/-): @entity15979 (+/+) littermates despite reaching an equivalent degree of hyperinsulinaemia on @entity1386 by 52  weeks. CONCLUSIONS/INTERPRETATION: These data demonstrate that attenuation of hyperinsulinaemia in young, growing female @entity19 provides a long-lasting protection against @entity28 . This protection persists despite a late-onset emergence of hyperinsulinaemia in @entity1386 -fed @entity15981 (-/-): @entity15979 (+/-) @entity19 . Given the evolutionary conserved roles of @entity2690 , it is possible that suppressing hyperinsulinaemia early in life may have far-reaching consequences on @entity28 in full-grown adult @entity1 .
