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

Abstract

In health insulin is secreted in discrete insulin secretory bursts from pancreatic beta-cells, collectively referred to as beta-cell mass. We sought to establish the relationship between beta-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 beta-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 beta-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 beta-cell mass vs. insulin sensitivity. These data support a central role of adaptive changes in beta-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 beta-cells and the liver in regulating the secretion and delivery of insulin to the systemic circulation.

Fig. 1.

The mean arterial glucose (top), arterial insulin (middle), and portal vein insulin concentrations (bottom) at fasting (−30 to 0 min) and during a hyperglycemic clamp (0–75 min) in rats at 2, 7, and 12 mo of age.

Fig. 2.

Fasting state. Insulin concentration (top) and deconvolved corresponding insulin secretion rates (bottom) (measured at 1-min intervals) at the portal vein in representative rats at 2, 7, and 12 mo of age in the fasting state.

Fig. 3.

Glucose-stimulated state. Insulin concentration (top) and deconvolved corresponding insulin secretion rates (bottom) (measured at 1-min intervals) at the portal vein in representative rats at 2, 7, and 12 mo of age during the hyperglycemic clamp.

Fig. 4.

Mean insulin secretion rate (left), insulin pulse mass (middle), and interpulse interval (right) at fasting and during the hyperglycemic clamp in rats at 2, 7, and 12 mo of age. Data are expressed as means ± SE. Statistical analysis was restricted to effects of aging. P < 0.05 for 7 vs. 2 mo (*), for 12 vs. 2 mo (†), and for 12 vs. 7 mo (‡).

Fig. 5.

Relationship between the clearance of endogenously secreted insulin and the mean insulin pulse amplitude in each rat at fasting (left) and during the hyperglycemic clamp at 2, 7, and 12 mo of age.

Fig. 6.

Relationship between the individual β-cell mass (mg) and deconvolved total insulin secretion rate in each rat at 2, 7, and 12 mo of age at fasting (A) and during the hyperglycemic clamp (B). The mean fasting (C) and glucose-stimulated (D) β-cell workload calculated as the ratio of insulin secretion to mg of β-cell mass. Data are expressed as means ± SE. P < 0.05 for 7 vs. 2 mo (*) and for 12 vs. 2 mo (†).

Fig. 7.

Hyperbolic relationship between insulin sensitivity vs. the β-cell mass (left), pulse mass (middle), and deconvolved total insulin secretion (right) in each rat at 2, 7, and 12 mo of age.