Why does intensive insulin treatment reduce the incidence of microvascular complications but not the frequency or severity of macrovascular disease in IDDM? We believe that this paradox in part results from several adverse effects of conventional subcutaneous insulin therapy (CIT) on lipoprotein transport. We have shown in IDDM patients that CIT leads to peripheral hyperinsulinism and stimulation of lipoprotein lipase (LpL) which alters the surface properties of larger VLDL and enhances their affinity for cholesterol ester transfer protein (CETP). These interactions augment neutral lipid exchange between VLDL and HDL leading to the production of atherogenic CE-enriched apoB- containing lipoproteins that, like remnant particles, may be taken up by arterial wall macrophages rather than by receptor-mediated pathways in the liver. To demonstrate this influence of CIT, we have found that when 7 IDDM patients were first treated intensively for 3 months with CIT: 1) their basal LpL activity and 24 hr integrated free insulin levels were both increased; 2) the transfer of cholesterol ester (CET) was accelerated; and 3) the core lipid composition of VLDL and HDL was altered in a manner consistent with increased CET occurring in vivo. When they were then treated with insulin delivered into the portal circulation via an intraperitoneal pump (IP), their insulin levels fell by one-half, and LpL, CET, and lipoprotein composition returned to normal. We have sought to identify a suitable insulin-treated diabetic animal model in which to study the mechanisms that underlie these disturbances. As part of this effort, we have found in pilot studies with colleagues at the Bowman Gray Department of Comparative Medicine that a group of cynomolgus monkeys (Macaca fascicularis) with insulin-dependent diabetes mellitus have abnormalities in CET and core lipid composition that resemble those we have observed in humans. These diabetic animals offer an extraordinary opportunity to systematically examine at the molecular level the impact of hyperinsulinism and its amelioration on the major lipoprotein remodeling systems in IDDM. We intend to demonstrate the differing effects of CIT and IP in these monkeys on: 1) CET and CETP mass in plasma and CETP mRNA abundance and mass in liver, omental fat, and skeletal muscle; 2) basal LpL activity and mass in plasma and LpL mRNA abundance and mass in omental fat and skeletal muscle; 3) basal hepatic lipase activity in plasma and its mRNA abundance in liver; 4) apoprotein and lipoprotein surface and core lipid composition. These parameters and insulin levels estimated during CIT and IP will we compared and correlated. Since studies of this type cannot be performed in humans, the proposed experiments in this unique non-human primate model should provide the most detailed body of evidence so far assembled regarding the pathogenetic role of CIT in the inappropriate activation of LpL and CET that likely contribute to accelerated atherogenesis in IDDM humans.
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