Abstract
AimsIntra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral insulin sensitivity in mice that underwent IUGR followed by postnatal catch-up growth and investigate potential molecular mechanisms underpinning their physiology.MethodsWe used a C57BL/6J mouse model of maternal diet-induced IUGR (maternal diet, 8% protein) followed by cross-fostering to a normal nutrition dam (maternal diet, 20% protein) and litter size manipulation to cause accelerated postnatal catch-up growth. We performed intracerebroventricular insulin injection and hyperinsulinaemic–euglycaemic clamp studies to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real-time PCR and western blotting to examine the expression of key insulin-signalling components in discrete regions of the hypothalamus.ResultsIUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these ‘recuperated’ animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the p110β subunit of phosphoinositide 3-kinase (PI3K) and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Expression of the gene encoding protein tyrosine phosphatase 1B (PTP1B; Ptpn1) was also increased specifically in this region of the hypothalamus.Conclusions/interpretationMice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin, as well as the impaired glucose homeostasis seen in these animals.
Highlights
Obesity and type 2 diabetes are increasing globally at an unprecedented rate across all ages and sexes
We used a rodent model to show that animals that undergo Intra-uterine growth restriction (IUGR) followed by rapid postnatal catch-up growth display whole-body insulin resistance in adulthood
This is associated with peripheral insulin resistance, as demonstrated by the results of the hyperinsulinaemic–euglycaemic clamps
Summary
Obesity and type 2 diabetes are increasing globally at an unprecedented rate across all ages and sexes. Numerous studies have shown that low birthweight is associated with increased risk of developing impaired glucose tolerance and, subsequently, type 2 diabetes [4, 5]. It is well established that the accelerated growth that often follows low birthweight, as well as accelerated postnatal growth alone, are important risk factors for type 2 diabetes and obesity [6, 7]. The combination of low birthweight with rapid weight gain, if the baby crosses growth percentiles, is strongly linked to developing type 2 diabetes and obesity later in life [8, 9]
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