Approximately 100,000 IDM are born in the United States annually, some of whom may be at increased risk for metabolic and other complications [1
]. The biochemical mechanisms leading to these complications are not completely understood. Recent studies suggest that hyperketonemia, oxidative stress and vascular inflammation may each play a role in the development of fetal complications during diabetic pregnancies. Ketone bodies can cross the placenta and their levels have been found to be elevated in fetuses of diabetic mothers in pregnant Ewe [12
]. At birth, an increase in inflammatory markers, such as CRP and ICAM-1 has been reported in the offspring of type I diabetic mothers [14
]. However, the effect of hyperketonemia on markers of vascular inflammation and oxidative stress in infants of diabetic mothers has not been investigated. For the first time, this study demonstrates increased levels of MCP-1 and protein oxidation levels in the cord blood of IDM (p<0.05) but not in cord blood of infants born to normal mothers. The level of MCP-1 significantly correlated (p=0.01) with the concentration of aceotoacetate in the cord blood of IDM. A significant correlation of MCP-1 with aceotoacetate levels in the blood and increased secretion of MCP-1 in acetoacetate treated monocytes suggests that hyperketonemia may contribute to elevated MCP-1 levels in IDM.
Monocyte chemotactic protein-1 (MCP-1) is a chemokine secreted by different cell types [16
]. It attracts and monocytes into an area of inflammation and then activates them. Several studies have examined its role during normal and abnormal pregnancies and during the neonatal period [17
]. Denison et al. found that MCP-1 is important in the development of the placenta and thus, maintaining a normal pregnancy [18
]. Briana et al estimated maternal and cord blood MCP-1 levels, and reported significantly lower levels in growth retarded infants compared to healthy controls [18
]. MCP-1 levels are increased in women with type 1 and 2 diabetes [19
]. Two separate studies from Poland reported that women with gestational diabetes showed increased levels of the chemokine MCP-1, possibly leading to adverse pregnancy outcomes [21
]. This study did not find significant increase in the levels of IL-8 in the cord blood of IDM or the cord blood of infants born to normal mothers.
This study observed elevated levels of protein carbonyl, a marker of oxidative stress. Kinalski et al study in diabetic mothers suggest that their fetuses experience increased oxidative stress (23). The results show that acetoacetate, but not β-hydroxybutyrate, increased MCP-1 secretion in U937 monocytes exposed to high glucose. The reasons that one ketone body as opposed to the other affect inflammation differently remain unclear. We speculate that effects caused by AA may be due to the generation of oxygen radicals either directly or indirectly. It has been shown that AA but not BHB can generate oxygen radicals in a cell free system [24
], which may ultimately lead to an oxidative environment. It is also possible that AA is indirectly producing ROS by being fed into the electron transport chain, creating an overload of electrons similar to that seen with hyperglycemia [24
]. Since studies have also shown a decrease in the mitochondrial membrane potential in monocytes treated with AA, it seems likely that the mitochondria would be the second source of ROS in monocytes treated with AA. Another possibility is that AA is converted to BHB, which in turn can alter the redox state of the cell by affecting both NADH and GSH levels. Structurally the two compounds are very similar, but there is no ketone functional group present in BHB. AA contains two keto groups whereas BHB does not, suggesting that the difference in chemical structure of the two ketone bodies may play a role in mediating the effects caused by AA and not BHB. Acetoacetate is much less stable than β-hydroxybutyrate. Previous studies have also reported that the ketone body aceotoacetate can increase oxygen radical formation and oxidative stress [24
]. However, we found no correlation between levels of acetoacetate and protein oxidation levels in IDM. The long term outcomes of IDM exposed to oxidative stress is unknown.
In conclusion, this study demonstrate that increase in circulating MCP-1 and protein oxidation levels in the cord blood of IDM compared to those of normal infants suggest increased inflammation and oxidative stress. The hyperglycemic environment reflected by higher HbA1c and fructosamine levels in diabetic mothers and the presence of the acetoacetate ketone may be a factor in the increased MCP-1 levels in the cord blood of IDM. The increase in oxidative stress may also result from elevated acetoacetate levels and/or glycosylation of antioxidative defense enzymes due to hyperglycemia. The role of elevated MCP-1 levels in the metabolic complications common to diabetic pregnancies needs further investigation in a larger patient population.