The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression

Metabolomics analysis reveals that inosine monophosphate, a purine metabolite, promotes myelopoiesis and contributes to severe acute pancreatitis in db/db mice. Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1(+) granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.

Automated summary

Metabolomics analysis reveals that inosine monophosphate (IMP) promotes myelopoiesis and contributes to severe acute pancreatitis. These findings provide a potential therapeutic target for the control of vascular complications in diabetes.