Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice.

Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from ß-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of Igf2 was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but Igf2 exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, ß-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts ß-cell function.NEW & NOTEWORTHY This is the first study to describe a model in which the preptin-coding portion of the Igf2 gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with Igf2 knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature Igf2. Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.

Determining insulin sensitivity from glucose tolerance tests in sheep.

A mathematical model of the dynamics of insulin and glucose during a frequently sampled intravenous glucose tolerance test (IVGTT) in sheep was developed that characterizes the large second-phase insulin secretion response in sheep during IVGTT. The model was fit to measurements of the glucose and insulin dynamics during standard IVGTT ( = 42) and modified IVGTT ( = 40), where insulin was injected 60 min after the initiation of the IVGTT. The correlation between log insulin sensitivity determined by hyperglycemic clamps (HGC) and standard IVGTT was = 0.43 ( = 0.005). The correlation between log insulin sensitivity determined by HGC and modified IVGTT was = 0.51 ( = 0.002). The model, therefore, provides a method to determine insulin sensitivity through a cheaper and more easily performed IVGTT. We validated our estimation procedure using 2 independent experiments on the effect of 1) pregnancy and 2) being born preterm and exposed to dextrose or dextrose with insulin on HGC-derived insulin sensitivity. The IVGTT-derived insulin sensitivity was significantly greater in pregnant ewes than in prepregnant ewes (difference of 0.39 ± 0.12 log n ng mL; < 0.05), and this was consistent with the significantly greater hyperinsulinemic euglycemic clamp-derived insulin sensitivity in pregnant ewes than in prepregnant ewes (difference of 4.03 ± 0.66 µmol mL kg min ng; < 0.001). There was no significant effect of being born preterm on IVGTT/HGC-derived insulin sensitivity. Basal insulin, insulin sensitivity, insulin production, and insulin clearance were lower in prepregnant ewes ( < 0.05). That is, prepregnant ewes have a lower insulin equilibrium status and less responsive insulin turnover. There was also a significant effect of insulin therapy on the rate of insulin clearance in preterm lambs ( < 0.05). This effect was independently significant of its covariance with all other model parameters. Therefore, it can be interpreted as a direct effect on the rate of insulin clearance by the insulin treatment. All other parameter responses to the insulin treatment effect can be regarded as being due to the covariance between these parameters. These analyses demonstrate that treatment effects on insulin sensitivity can be detected using IVGTT experiments.