Adaptations in pulsatile insulin secretion, hepatic insulin clearance, and β-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.

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

“…Insulin clearance and IDE expression are reduced in type 2 diabetic individuals (Butterfield 1970, Groves et al 2003, Karamohamed et al 2003, Kotronen et al 2007, Kwak et al 2008, Slominskiȋ et al 2009) and in obese and diabetic rodents (McCarroll & Buchanan 1973, Rabkin et al 1986, Strömblad & Björntorp 1986, Kotronen et al 2008, Matveyenko et al 2008, Rezende et al 2012. Also, as previously mentioned, changes in insulin clearance are probably more relevant than the increase in insulin secretion to the higher insulinemia observed in obese individuals ( Erdmann et al 2008Erdmann et al , 2009 and are highly heritable (Guo et al 2012) with the highest correlation with insulinemia (Goodarzi et al 2011).…”

Islet inflammation and ductal proliferation may be linked to increased pancreatitis risk in type 2 diabetes

“…In 16-week-old WT rats (n = 9) chronic indwelling right internal jugular vein and left carotid artery catheters were implanted as previously described (42). Glucose was infused (n = 5) to maintain arterial glucose at ~250 mg/dl for 72 hours versus saline infused in controls (n = 4) (Supplemental Figure 3A).…”

Pancreatic β-cells are generated by neogenesis from non-β-cells after birth

“…The number of pancreatic β-cells increases in response to systemic insulin demand in obesity (18) and pregnancy (29), as well as in the neonatal period (17). It has been thought that β-cells are constantly replenished even under normal conditions (turnover) (9,19). In general, adult tissues and organs are thought to be maintained by the stem cell system.…”

“…The mass of the β-cells is not static but rather dynamic throughout lifetime (9,19). The number of pancreatic β-cells increases in response to systemic insulin demand in obesity (18) and pregnancy (29), as well as in the neonatal period (17).…”