Division of Endocrinology, Diabetes & Metabolic Diseases
Dr. Klein’s research efforts have focused unwaveringly on gaining a better understanding of lipoprotein metabolism using in vivo based investigations in animal models of atherosclerosis, and later, in vitro, using human cells maintained in culture. More recently these studies have focused on the modifications to lipoprotein composition and metabolism which result from diabetes mellitus. Critical to this work, his lab was the first to develop methodology to separate and isolate the subfraction of LDL which had been modified in vivo in patients with diabetes through the non-enzymatic glycation of the apolipoprotein B moiety of the lipoprotein to enable this lipoprotein subfraction to be studied distinct from the non-glycated subfraction of LDL isolated from the same patient.
More recently his lab has focused investigations on HDL and determined that incubation of human adipocytes with increasing concentrations of HDL3, but not HDL2, stimulated PAI-1 secretion in a concentration dependent manner. More importantly, the Klein lab demonstrated additionally that sphingosine-1-phosphate (S1P), and especially the HDL3 subfraction which contains higher amounts of S1P than the HDL2 subfraction, significantly increased PAI-1 secretion from adipocytes. This series of studies provided the foundation for much of the current work being conducted in his laboratory in which the role of lipoprotein sphingolipids in the modification of cell metabolism is investigated. These investigations resulted in the seminal publication which reported not only the composition of sphingolipids in plasma from type 1 diabetic patients, but also demonstrated the potential of the plasma concentrations of select ceramide species to predict the future development of nephropathy in type 1 diabetes patients.
Lipids in plasma, including sphingolipids, require transport vehicles for their movement in plasma and these vehicles are the lipoproteins. The underlying belief in the Klein lab is that a shift to the emphasis of the study of plasma lipid metabolism from that of simple determinations of plasma concentrations of lipids to precise measures of lipids, including sphingolipids, in the lipoproteins themselves, will offer distinct advantages to support efforts to better understand the changes in sphingolipid metabolism that contribute to diabetes complications and ultimately, to assist in the management of these disorders.