Prolonged
physiological stress which causes over secretion of insulin can result in
β-cell dysfunction and ultimately type 2 diabetes. We have previously shown
that the gene, Herpud1 has a function
in the islet β-cell and insulin secretion. Herpud1
encodes the ER-resident protein HERP which plays a protective role in ER-stress
related pathways. To determine the function of Herpud1 in the islet β-cell we obtained a knock-out mouse model
with global deletion of Herpud1. These
mice were studied at 8 weeks of age to determine whether the deletion of Herpud1 affected body weight and basal
glucose and insulin levels as well as insulin secretory responses in vivo (using the intravenous glucose
tolerance test - IVGTT). The data show
that there was no difference in body weight (Negative littermates: 21.4 ± 0.9
grams, Knockout: 19.8 ± 0.3 grams, p=0.08, n=5-7) or basal insulin levels (Negative
littermates: 0.6 ± 0.1 ng/ml, Knockout: 0.5 ±0.1 ng/ml, p=0.20, n=5-7) between
the Herpud1 knockout mice and their
negative littermates. Basal glucose concentrations were lower in the knockout compared
with the negative littermates (10.4 ± 0.8 mmol/L vs 8.3 ± 0.6 mmol/L, p=0.04,
n=5-6). Following the IVGTT Herpud1-deficient mice had a decrease in
glucose-mediated insulin secretion compared with their negative littermates (AUC
- negative littermates: 54.3 ± 6.7 ng/ml x 30min, Knockout 42.6 ± 3.3 ng/ml x
30 min, p = 0.03, n=5-6). We conclude
that the preliminary data suggest that Herpud1
plays an important role in the islet β-cell since its genetic deletion caused
reduced insulin secretion in response to glucose. Further studies will be performed to
determine the mechanism of this reduction in secretion and whether a high fat
diet worsens the phenotype of the mice.