Abstract
Backgroundp8 was initially described as being overexpressed in acute pancreatitis and encoding a ubiquitous stress protein. Analysis of insulin sensitivity and glucose tolerance in p8-knockout and haplodeficient mice revealed counterintuitive results. Thus, we determined glycemic control of p8 in mice fed with standard (SD) and high-fat diet (HFD).Methodsp8-/- and wild type (p8+/+) mice were used for analysis of glucagon (immunohistochemistry), insulin levels (ELISA) and beta cell mass. Hyperinsulinemic- euglycemic glucose clamp technique, i.p. glucose tolerance test (ipGTT), i.p. insulin tolerance test (ipITT) and metabolic chamber analysis were performed in SD (4% fat) and HFD (55% fat) groups.Resultsp8-/- mice showed no differences in glucagon or insulin content but higher insulin secretion from pancreatic islets upon glucose stimulation. p8 deficiency resulted in elevated beta cell mass but was not associated with increased insulin resistance in ipGTT or ipITT. Glucose clamp tests also revealed no evidence of association of p8 deficiency with insulin resistance. Metabolic chamber analysis showed equal energy expenditure in p8-/- mice and wild type animals.Conclusionp8 depletion may contribute to glucose metabolism via stress-induced insulin production and elevated beta cell mass. Nevertheless, p8 knockout showed no impact on insulin resistance in SD and HFD-fed mice.
Highlights
Nuclear Protein 1, Transcriptional Regulator gene (NUPR1, p8; OMIM: 614812) encodes a ubiquitous nuclear and cytoplasmic stress-activated protein and shares structural similarities with high-mobility group box proteins [1]
Hyperinsulinemic- euglycemic glucose clamp technique, i.p. glucose tolerance test, i.p. insulin tolerance test and metabolic chamber analysis were performed in standard deviation (SD) (4% fat) and high-fat diet (HFD) (55% fat) groups
Additional studies indicate interaction of p8 with transcriptional cofactors including p300 and PTIP [2], as well as binding of p8 to DNA upon phosphorylation [3]. p8 has been shown to be implicated in oxidative stress via regulation of anti-oxidative enzyme heme-oxigenase-1 (HO-1) [4], and p8 is overexpressed in sepsis and pancreatitis [5,6]
Summary
P8 was initially described as being overexpressed in acute pancreatitis and encoding a ubiquitous stress protein. We determined glycemic control of p8 in mice fed with standard (SD) and high-fat diet (HFD)
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