Hyperglycemia and white blood cell biology
Several complications of diabetes may be exacerbated by inflammation. Whether this is due to hyperglycemia, defective insulin actions, or other metabolic alterations of diabetes is unknown. In addition, both local tissue inflammation and changes in the biology of circulating white blood cells (WBCs) could lead to pathological changes in organs and vascular tissues. In this regard, we have recently found that loss of WBCs from atherosclerotic mouse lesions is defective in the presence of streptozotocin diabetes. Moreover, we provide Preliminary Results showing that changes in circulating WBCs that occur with diabetes are corrected by glucose reduction using inhibitors to the sodium glucose co-transporter 2 (SGLT2). Thus, the studies proposed will allow us to “understand the possible in vivo efficacy of a promising new therapy for diabetes”, glucose reduction via inhibition of SGLT2. This Pilot application has two aims: Aim 1. To determine if hyperglycemia reduction leads to an alteration in the inflammatory state of circulating monocytes and neutrophils. Aim 2. To determine whether glucose reduction in STZ-treated LDL receptor knockout mice with atherosclerosis will reduce the inflammatory profile of lesional CD68+ cells. Techniques to lower glucose in diabetic mice, isolate circulating monocytes subsets (Lys6-C hi and lo) and granulocytes by FACS, and vascular wall CD68+ cells by laser capture microdissection are in hand. We expect that our studies will clarify the importance of hyperglycemia alone in altering the inflammatory status of circulating and vascular WBCs.

Glucose Regulation of Hypertriglyceridemia
Patients with metabolic syndrome (MetS), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) are at increased risk of cardiovascular disease (CVD), but the underlying mechanisms remain poorly understood. Many lines of evidence indicate that elevated levels of plasma triglyceride (TG) are causal, especially in T2DM. Moreover, hypertriglyceridemia (hyperTG) is a likely cause of changes in circulating levels of HDL cholesterol (HDL-C), a negative risk factor for CVD. We propose to determine the pathophysiology responsible for hyperTG in humans with diabetes and how hyperglycemia affects levels of plasma TG and other lipoproteins. Moreover, we will assess whether hyperTG and diabetes alter HDL function. This Pilot and Feasibility application has two specific aims. Aim 1 is to determine why glucose reduction reduces TG levels in diabetic mice. We will determine whether this is due to a reduction in TG production or greater TG clearance. Aim 2 will determine the effects of acute hyperTG and insulin-deficient diabetes on HDL composition and function. We will determine the structural and lipid changes that occur in HDL from LpL-deleted mice and whether these HDL are defective in promoting cholesterol efflux from macrophages. The studies will lay the foundation for future investigations of how altering circulating lipids in the setting of diabetes impact atherosclerosis.

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