Alterations in insulin-signaling and coagulation pathways in platelets during hyperglycemia-hyperinsulinemia in healthy non-diabetic subject

- Diabetes mellitus is a prothrombotic and proinflammatory state.
- Hyperglycemia (HG)-hyperinsulinemia (HI) in healthy subjects activates coagulation mechanisms.
- We studied effect of HG-HI on platelets and monocytes in non-diabetic healthy state.
- We used cell expression profiling before and after 24 hours of HG and HI.
- Even in healthy state HG + HI induces major changes in platelet and monocytes.

IntroductionDiabetes mellitus (DM) is a prothrombotic and proinflammatory state. Hyperglycemia (HG) is encountered even in patients without DM. We have shown that combined HG and hyperinsulinemia (HI) in healthy non-diabetic subjects increased circulating tissue factor (TF) and thrombin generation. To understand the changes in platelet and monocyte pathways induced by combined HG and HI in healthy non-diabetic state, we performed whole genome expression profiling of leukocyte-depleted platelets and monocytes before and after 24 hours of combined HG (glucose ~ 200 mg/dL) and HI by glucose infusion clamp in a healthy non-diabetic subject.ResultsWe defined time-dependent differential mRNA expression (24 versus 0 hour fold change (FC) ≥ 2) common to platelets and monocytes. Ingenuity Pathways Analysis revealed alterations in canonical insulin receptor signaling and coagulation pathways. A preliminary group of 9 differentially expressed genes was selected for qRT-PCR confirmation. Platelet 24 hour sample was compared to the 0 hour sample plus 4 controls. Five transcripts in platelets and 6 in monocytes were confirmed. Platelet GSK3B and PTPN1 were upregulated, and STXBP4 was downregulated in insulin signaling, and F3 and TFPI were upregulated in coagulation pathways. Monocyte, PIK3C3, PTPN11 and TFPI were downregulated. Platelet GSKβ3 and PTPN11 protein and TF antigen in platelets and monocytes was increased.ConclusionsEven in non-diabetic state, HG + HI for 24 hours induces changes in platelets and monocytes. They suggest downregulation of insulin signaling and upregulation of TF. Further studies are needed to elucidate cellular alterations leading to the prothrombotic and proinflammatory state in DM.