The role of CART in islet function

Diminished insulin secretion and dysregulated glucagon secretion are key features of type 2 diabetes (T2D). The overall aim of this thesis was to study the role of cocaine- and amphetamine-regulated transcript (CART) in islet cell function and how CART regulates glucose homeostasis. We found that CART is expressed in human islet cells and that its expression is increased in patients with T2D, as well as in mouse models of T2D. Rat islet CART expression was regulated by glucose and beta cell CART expression was normalised by insulin treatment in diabetic rats. Furthermore, CART increased insulin secretion from both mouse and human islets in a glucose-dependent fashion. This could partly be explained by increased beta cell exocytosis, altered intracellular Ca²⁺ oscillation pattern as well as improved synchronisation of Ca²⁺ oscillations between islet cells. Importantly, CART increased insulin secretion and glucose elimination in vivo in mice. We also showed that CART decreased glucagon secretion in mouse and human islets, as well as in vivo in mice, and that CART reduced exocytosis in alpha cells. To mimic the situation in patients, with increased beta cell CART expression, we generated transgenic mice with beta cell-specific CART overexpression (CARTtg) and studied the impact of increased beta cell CART expression on glucose homeostasis in vivo. Under basal conditions, CARTtg mice were normoglycaemic and normoinsulinemic, but when challenged by streptozotocin treatment or a high fat diet, and in ageing, CARTtg mice displayed increased insulin secretion compared with wild-type littermates. This was accompanied by improved glucose elimination in streptozotocin-treated and aged mice, but not in high fat diet-fed mice, which instead displayed mild insulin resistance. Moreover, viral overexpression of CART in INS-1 (832/13) cells increased insulin secretion. Finally, we found that adipocytes from CARTtg mice had altered metabolism, suggesting that CART may be a mediator of cross-talk between beta cells and adipose tissue. Collectively, our data imply that CART has an important role in beta cell function and in regulation of glucose homeostasis. Hence, the potential for CART-based therapies in T2D should be evaluated.