This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This protocol investigates the role of increased free fatty acids on endogenous insulin secretion and insulin and C-peptide clearance in normal subjects when fatty acid levels are manipulated by co-infusion of intralipid/heparin during hyperglycemic clamp. We confirm that increases in free fatty acids results in hyperinsulinemia in these normal volunteers. Contrary to established dogma, we have found that the hyperinsulinemia is entirely due to decreases in total clearance rate of insulin; there is no change in insulin secretory rates. This result may or may not be restricted to highly unsaturated fats since intralipid is a highly unsaturated source of fat.Somewhat surprisingly, and in contrast to the RIA results noted above, in subjects undergoing intralipid/heparin infusion to raise plasma FFA, suggests that in fact C-peptide clearance is increasing by ~20% (107.6 4.7 vs 87.3 7.8 ml/m2/m2/min; IDA vs RIA methods, p<.05) We believe this disparity is likely due to matrix affects of hyperlipidemia on antigen/antibody binding in the RIA. Small decreases in antibody/antigen binding affinity due to fatty acid/lipid detergent effects could easily result in 20-30% higher C-peptide concentrations due to the logarithmic nature of RIA methods. This emphasizes the usefulness of isotope dilution assays to avoid artifactual changes in analyte measurements by immunoassay methods. The net result is that the isotope dilution assay appears to be intrinsically less prone to artifacts of measurement.
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