Diabetes (type 1 & 2) is a major risk factor for cardiovascular disease (CVD) which represents the major cause of mortality in this group. Patients with diabetes present with reticulated thrombocytosis (increased immature platelets), which lower the efficacy of current anti-platelet therapies. We suggest that the reticulated thrombocytosis observed in people with diabetes plays an important role in atherogenesis. Thus we investigated the mechanisms contributing to increased reticulated platelets in diabetes. WT mice made diabetic with streptozotocin (STZ) had significantly higher levels of reticulated platelets. This was paralleled by an increase in the population of megakaryocyte progenitors (MkPs) and megakaryocytes in the BM. We also found an increase in thrombopoietin (TPO) levels in the plasma, but no change in the TPO receptor, c-MPL, on any of the BM progenitor cells or circulating platelets. The expression of TPO is generally upregulated by Kupffer cell derived IL-6. We found more Kupffer cells in the liver of diabetic mice which expressed higher levels of cell surface RAGE and produced more IL-6. Depletion of Kupffer cells using clodronate liposomes normalized the levels of total and reticulated platelets along with MkPs in the BM. Rage-/- BM transplantation (BMT) into mice that were then rendered diabetic were protected from diabetes-induced thrombocytosis. We noted that Kupffer cells from diabetic Rage-/- BMT mice failed to express IL-6 and plasma TPO levels remained similar to the non-diabetic mice. Rage-/- BMT mice also had normal levels of MkPs in the BM. Thus we have identified a role for RAGE in the liver Kupffer cells of diabetic mice that triggers IL-6 expression, which inturn promotes TPO production. TPO then enhances proliferation and expansion of MkPs in the BM, resulting in an increase in the abundance of reticulated platelets which could contribute to accelerated atherogenesis in diabetes.