1515-P: Effect of Aging on Insulin Clearance in Mice Free

Aging is commonly linked with hyperinsulinemia and insulin resistance. Age-related hyperinsulinemia results from increased insulin secretion and/or decreased insulin clearance as compensatory mechanisms to peripheral insulin resistance. Several studies have reported reduced β-cell function in elderly rodents and humans. Earlier reports on decreased insulin clearance due to aging suggest that hyperinsulinemia in elderly could be explained predominantly by a reduction in insulin clearance. Hence, we aim to better understand the role of aging on insulin clearance following fat infusion. To investigate the aging effect, 3 months and 10-14 months old C57BL6 mice were infused with ethylpalmitate for 48h (hydrolyzed to palmitate and ethanol in plasma), to achieve elevated circulating FFA in a non-toxic manner. Mice were then subjected to hyperglycemic clamp, and during the clamp plasma C-peptide and insulin were measured to evaluate insulin clearance. Glucose infusion rate (GINF), insulin sensitivity index (SI) and disposition index (DI) were also assessed during clamp analysis. GINF is a measure of glucose tolerance whereas DI evaluates β-cell function. Whereas insulin secretion did not increase, insulin clearance was reduced in the aging mice, as indicated by the lower C-peptide/insulin molar ratio, observed during hyperglycemic clamp. No significant changes were observed in GINF between old and young mice; however, SI and DI were lower in elderly group. These results collectively suggest that with advancing age, β-cells may lose their ability to maintain a higher insulin secretion and that reduced hepatic insulin clearance plays a more dominant role to compensate for age-related decline in insulin sensitivity.