Unravelling innervation of pancreatic islets.

The central and peripheral nervous systems play critical roles in regulating pancreatic islet function and glucose metabolism. Over the last century, in vitro and in vivo studies along with examination of human pancreas samples have revealed the structure of islet innervation, investigated the contribution of sympathetic, parasympathetic and sensory neural pathways to glucose control, and begun to determine how the structure and function of pancreatic nerves are disrupted in metabolic disease. Now, state-of-the art techniques such as 3D imaging of pancreatic innervation and targeted in vivo neuromodulation provide further insights into the anatomy and physiological roles of islet innervation. Here, we provide a summary of the published work on the anatomy of pancreatic islet innervation, its roles, and evidence for disordered islet innervation in metabolic disease. Finally, we discuss the possibilities offered by new technologies to increase our knowledge of islet innervation and its contributions to metabolic regulation.

Amygdala-liver signaling orchestrates rapid glycemic responses to stress and drives stress-induced metabolic dysfunction.

Behavioral adaptations to environmental threats are crucial for survival and necessitate rapid deployment of energy reserves. The amygdala coordinates behavioral adaptations to threats, but little is known about its involvement in underpinning metabolic adaptations. Here, we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycemia and hypophagia. The glycemic actions of MeAVMH neurons occur independent of adrenal or pancreatic glucoregulatory hormones. Instead, using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver, which promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose and appetite, resulting in diabetes-like dysregulation of glucose homeostasis and weight gain. Our findings reveal a novel amygdala-liver axis that regulates rapid glycemic adaptations to stress and links recurrent stress to metabolic dysfunction.

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes.

Treatment for type 1 diabetes (T1D) requires stimulation of functional ß cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human ß cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human ß cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected ß cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, ß cell proliferation, and mass in these mice. Serum from T1D subjects induced human ß cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced ß cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.

Lactogens Reduce Endoplasmic Reticulum Stress-Induced Rodent and Human ß-Cell Death and Diabetes Incidence in Akita Mice.

Diabetes occurs due to a loss of functional ß-cells, resulting from ß-cell death and dysfunction. Lactogens protect rodent and human ß-cells in vitro and in vivo against triggers of ß-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway of endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines whether lactogens can protect ß-cells against ER stress and mitigate diabetes incidence in Akita (Ak) mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS-1 cells, primary rodent and human ß-cells in vitro against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of proapoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS-1 cells and rodent islets. Transgenic expression of placental lactogen in ß-cells of Ak mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, ß-cell death, and loss of ß-cell mass observed in Ak littermates. These are the first studies in any cell type demonstrating that lactogens modulate the ER stress pathway, causing enhanced ß-cell survival and reduced diabetes incidence in the face of chronic ER stress.