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. 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. Adult livers (n=4-9) had similar Igf2 mRNA expression between genotypes, with undetectable preptin expression in KO mice. Metabolic phenotypes were evaluated by weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44-weeks of age, and 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; immature), 14-weeks (n=10-12/sex/genotype; peak bone mass), and 47-weeks of age (n=12-14/sex/genotype; aging).
Bodyweights were similar between genotypes at all ages. Blood glucose concentrations returned to baseline quicker following ITT in female KO than 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 bone microarchitecture at 6-weeks of age. By 14-weeks of age, trabecular bone volume fraction (BV/TV) was increased by 21%, trabecular number was increased 17%, and cortical bone area was increased 8% in male KO vs. WT mice. These effects were absent in females. At 47-weeks of age, males had similar bone microarchitecture; however, trabecular bone volume fraction was increased by 29% (p=0.09), and trabecular number was increased by 30% in female KO vs. WT mice.
Male preptin KO mice had increased trabecular bone volume at 14-weeks of age only, whereas female preptin KO mice developed this phenotype as they aged. Mechanistic evaluation of this phenotype is ongoing.