Preptin is a 34-amino acid peptide derived from the E-peptide of pro-IGF-II. Preptin is co-secreted with insulin from β-cells, can increase glucose-stimulated insulin secretion, and promotes proliferation and differentiation of osteoblasts. Understanding the function and mechanism of action of preptin in vivo may enable development of novel osteoporosis therapeutics. We tested the hypothesis that preptin deficiency alters bone metabolism by evaluating a preptin knockout (KO) mouse.
Experimental KO and wild type (WT) mice were generated by heterozygous breeders. RT-qPCR on adult livers (n=4-9) confirmed similar Igf2 expression between genotypes, whereas KO mice had undetectable preptin expression.
Metabolic phenotypes were evaluated by weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44-weeks of age, and an oral glucose tolerance test (GTT) at 45-weeks of age (n=12-14/sex/genotype). Bone phenotypes were evaluated by femoral microCT at 6-weeks (n=8-12/sex/genotype), 14-weeks (n=10-12/sex/genotype), and 1-year of age (n=7, males only).
Bodyweights were similar between genotypes at all ages. Blood glucose concentrations returned to baseline quicker following ITT in female KO compared to WT mice at 9-weeks of age only. Female KO had increased blood glucose concentrations 15- and 30-minutes post-glucose during GTT compared to WT mice. There were no metabolic differences in males.
There were no differences between genotypes in trabecular or cortical bone parameters at 6-weeks of age. By 14-weeks of age, trabecular bone had a 21% increase in bone volume fraction (BV/TV), a 17% increase in trabecular number, and an 8% increase in cortical bone area in male KO compared to WT mice. These effects were absent in females. At 1-year of age, BV/TV was increased 47%, and trabecular number was increased 45% in male KO mice.
Male preptin KO mice demonstrated increased bone volume in the absence of overt metabolic dysfunction. Mechanistic evaluation of this phenotype is ongoing.