Decreased β‐cell insulin secretory function in aged rats due to impaired Ca2+ handling

Abstract

Ageing is associated with an increased impairment in glucose homeostasis and an increased incidence of type2 diabetes. In this study, we evaluated β-cell function and its implications for glucose homeostasis in 24-month-old female Wistar rats. Aged rats showed lower plasma glucose levels in the fed and fasting states compared with control rats. In addition, insulinaemia in the fed state was reduced in the older rats. Insulin receptorβ (IRβ) expression was lower in the livers of the aged animals, whereas IRβ and Akt(1/2/3) protein expressions were higher in the muscles. These effects may contribute to the normal glucose tolerance observed in older rodents. Isolated islets from aged rats secreted less insulin in response to 8.3 and 16.7mm glucose. Accordingly, this group presented a lower [Ca(2+)](i) in the presence of glucose and a depolarizing stimulus (30mm K(+)). In addition, islets from aged rats showed reduced insulin secretion in response to 100μm carbachol (CCh), 10nm phorbol 12-myristate 13-acetate and 10μm forskolin. The expressions of protein kinaseC, protein kinaseA and exocytotic proteins, such as syntaxin1 and synaptosomal-associated protein 25kDa (SNAP-25), were similar in islets from aged and control rats. In conclusion, our evidence suggests that the increased incidence of type2 diabetes with age may be due to a progressive decline in β-cell secretory capacity due to disruption of Ca(2+) handling. Furthermore, the expression of proteins of the insulin transduction cascade showed an adaptive profile, with a compensatory increase in IRβ and Akt(1/2/3) in gastrocnemius muscles, which may maintain normal glucose homeostasis in 24-month-old rats.