PROJECT SUMMARY/ABSTRACT A role for glycemic variation in optimizing management of diabetes and vascular complications It is well demonstrated that high glucose levels lead to more rapid development of macrovascular and microvascular complications in people with diabetes. However, there is less consistent evidence that lowering glucose levels to near normal levels prevent or slows vascular complications, particularly in more advanced stages of type 2 diabetes. The recent VADT, ACCORD, and ADVANCE trials demonstrated that intensive efforts to lower glucose had only modest effects on the rate of vascular complications. Why glycemic control strategies that focused on reduction of glucose levels and HbA1c did not have the anticipated success in reducing vascular outcomes is not clear. This has raised the possibility that (1) there are glycemic metrics beyond those that reflect average glucose control, such as HbA1c, that can explain this paradox, and (2) there exists heterogeneous treatment effects of intensive glycemic therapy for macrovascular and microvascular complications, with subgroups of patients who do less well with intensive treatment counter-balancing those that do respond. In recent reports we have demonstrated long-term glycemic variability was associated with risk of cardiovascular disease (CVD) events, even after adjusting for traditional markers of glycemic control. Importantly, this appeared most relevant to those receiving intensive glycemic control. These preliminary findings support careful examination of determinants and consequences of glycemic variability. In this proposal, we therefore propose to (a) evaluate and compare the importance of glycemic variation, both short-term measured by 1,5-anhydroglucitol and long-term in the development of macro and microvascular complications; (b) to study whether intensive treatment is beneficial in preventing vascular outcomes when glycemic variation is constrained; (c) genetic variants associated with glycemic variation in T2D patients will explain additional risk in progression to vascular complications beyond the genetic variants associated with mean glycemic levels.