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Adaptations in pulsatile insulin secretion, hepatic insulin clearance, and β-cell mass to age-related insulin resistance in rats

¹Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and ²Endocrine Division, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota

Submitted 20 May 2008 ; accepted in final form 21 July 2008

In health insulin is secreted in discrete insulin secretory bursts from pancreatic β-cells, collectively referred to as β-cell mass. We sought to establish the relationship between β-cell mass, insulin secretory-burst mass, and hepatic insulin clearance over a range of age-related insulin sensitivity in adult rats. To address this, we used a novel rat model with chronically implanted portal vein catheters in which we recently established the parameters to permit deconvolution of portal vein insulin concentration profiles to measure insulin secretion and resolve its pulsatile components. In the present study, we examined total and pulsatile insulin secretion, insulin sensitivity, hepatic insulin clearance, and β-cell mass in 35 rats aged 2–12 mo. With aging, insulin sensitivity declined, but euglycemia was sustained by an adaptive increase in fasting and glucose-stimulated insulin secretion through the mechanism of a selective augmentation of insulin pulse mass. The latter was attributable to a closely related increase in β-cell mass (r = 0.8, P < 0.001). Hepatic insulin clearance increased with increasing portal vein insulin pulse amplitude, damping the delivery of insulin in the systemic circulation. In consequence, the curvilinear relationship previously reported between insulin secretion and insulin sensitivity was extended to both insulin pulse mass and β-cell mass vs. insulin sensitivity. These data support a central role of adaptive changes in β-cell mass to permit appropriate insulin secretion in the setting of decreasing insulin sensitivity in the aging animal. They emphasize the cooperative role of pancreatic β-cells and the liver in regulating the secretion and delivery of insulin to the systemic circulation.

pulse mass; deconvolution analysis; insulin sensitivity; aging; rat

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