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

Abstract

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 β-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-weeks of age, and an oral glucose tolerance test (GTT) at 45-weeks of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared to 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 bodyweight, body composition, β-cell area and fasted glucose concentrations compared to WT mice in both sexes up to 47-weeks 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 β-cell function.

Preptin Deficiency Does Not Protect against High‐Fat Diet‐Induced Metabolic Dysfunction or Bone Loss in Mice

“…This fits with our previous data showing that preptin ablation in female mice led to diminished GSIS. (34) In this study, nonfasted blood glucose concentrations were lower in male KO mice than in WT mice at the start and end of the dietary intervention period in the LFD study arm despite the absence of major differences in weight and fat mass. This suggests that preptin deficiency may improve overall physiological glucose regulation in a nonstressed state in males specifically.…”

“…(59) In contrast, we have been unable to detect preptin in adult mouse serum. (34) Nevertheless, it would be of interest to investigate whether preptin is affected by feeding mice a HFD and whether preptin concentrations are related to any of the bone parameters measured in our study.…”

“…(43)(44)(45)(46) In addition, we have already noted sexually dimorphic phenotypes in preptin KO mice. (34) We therefore examined our male and female mice separately. We found that this HFD intervention increased bodyweight and fat mass and increased liver triglycerides and lowered BMD in mice of both sexes relative to the LFD.…”

“…Global preptin KO mice in a C57BL/6J background were generated as described previously. ( 34 ) In this mouse, exons 3 and 4 of Igf2 were truncated to remove the preptin sequence and intervening intron. All experimental mice were generated using heterozygous breeding pairs with maternal inheritance of the preptin KO allele.…”

Preptin: A New Bone Metabolic Parameter?

“…Multiple sources of preptin secretion besides beta cells, such as the kidneys, liver, salivary gland and mammary tissue, have been found since its discovery [ 1 ]. Female preptin knockout mice exhibit reduced glucose-enhanced insulin secretion, but not males [ 4 ]. Early clinical studies reported higher plasma preptin concentrations in patients with type 2 diabetes mellitus (T2M) compared to patients with impaired glucose tolerance and controls, respectively.…”