Vagal control of pancreatic β-cell proliferation

Abstract

The physiological mechanisms that preserve pancreatic ␤-cell mass (BCM) are not fully understood. Although the regulation of islet function by the autonomic nervous system (ANS) is well established, its potential roles in BCM homeostasis and compensatory growth have not been adequately explored. The parasympathetic vagal branch of the ANS serves to facilitate gastrointestinal function, metabolism, and pancreatic islet regulation of glucose homeostasis, including insulin secretion. Given the functional importance of the vagus nerve and its branches to the liver, gut, and pancreas in control of digestion, motility, feeding behavior, and glucose metabolism, it may also play a role in BCM regulation. We have begun to examine the potential roles of the parasympathetic nervous system in short-term BCM maintenance by performing a selective bilateral celiac branch-vagus nerve transection (CVX) in normal Sprague-Dawley rats. CVX resulted in no detectable effects on basic metabolic parameters or food intake through 1 wk postsurgery. Although there were no differences in BCM or apoptosis in this 1-wk time frame, ␤-cell proliferation was reduced 50% in the CVX rats, correlating with a marked reduction in activated protein kinase B/Akt. Unexpectedly, acinar proliferation was increased 50% in these rats. These data suggest that the ANS, via the vagus nerve, contributes to the regulation of BCM maintenance at the level of cell proliferation and may also mediate the drive for enhanced growth under physiological conditions when insulin requirements have increased. Furthermore, the disparate effects of CVX on ␤-cell and acinar cells suggest that the endocrine and exocrine pancreas respond to different neural signals in regard to mass homeostasis.␤-cell mass; celiac vagotomy THE PANCREATIC ␤-CELL HAS A TREMENDOUS CAPACITY to functionally compensate in response to physiological and pathophysiological changes in tissue insulin demands. A key feature of this adaptive response is the ability of the ␤-cell mass (BCM) to be dynamically regulated. For instance, BCM is normally maintained proportionally to body size. It increases during obesity and pregnancy (5,14,20) and regresses postpartum (42) to adjust to physiological insulin requirements. The steady-state BCM is determined by new cell recruitment by hyperplasia of existing cells and neogenesis from pancreatic epithelial progenitors, apoptotic death and clearance, and hypertrophy (5). The relative importance of each of these different processes is largely unknown and depends on the model under study; nonetheless, several recent reports suggest that proliferation from preexisting ␤-cells predominates in mice (10,11,29,30).The interplay of nutrients, growth factors, and hormones is known to impact ␤-cell growth; however, the influence of the nervous system on ␤-cell growth processes has been understudied. There are a handful of reports highlighting the importance of the vagus efferents in ␤-cell proliferation. A transient decrease in ␤-cell proliferation was observed in ob/ob mice, bu...

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…Parasympathetic signaling through the vagus nerve also regulates β-cell mass (43)(44)(45)(46) and has been implicated in the regulation of β-cell mass by the liver (47), although liver-specific secreted factors (48, 49) also may regulate β-cell proliferation directly (49).…”

GDNF is required for neural colonization of the pancreas

“…More recently, a role of the nervous system in embryonic and adult β-cell formation has been described. Ablation of NC cells leads to an increase in embryonic β-cell proliferation, while in adult mice parasympathetic denervation via vagotomy reduces islet proliferation (Nekrep et al, 2008;Lausier et al, 2010;Plank et al, 2011). How β-cell proliferation is regulated by neural input is far from being 3677 RESEARCH ARTICLE GDNF in developing pancreas understood and further studies are needed to clarify the underlying mechanisms.…”

“…The importance of both sympathetic and parasympathetic innervation in the physiology of the endocrine and exocrine pancreas is well established (Brunicardi et al, 1995;Ahrén, 2000;Gilon and Henquin, 2001). The study of pancreatic innervation has gained renewed interest due to reports indicating that the proliferation of adult endocrine β-cells is controlled by neural stimuli (Imai et al, 2008;Lausier et al, 2010;Grouwels et al, 2012). Moreover, it has been suggested that embryonic β-cell formation is regulated by signals provided by the neural crest (NC) cells that populate the pancreas during development (Nekrep et al, 2008;Plank et al, 2011).…”

Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding

“…Intra-islet capillaries are thicker, denser and more tortuous than capillaries of the exocrine pancreas, and are highly fenestrated (Brissova et al, 2006;Lammert et al, 2003b), allowing for the rapid exchange of nutrients and hormones between the islet and bloodstream. Input from the nervous system fine-tunes islet hormone secretion (Ahrén, 2000), regulates islet blood flow (Atef et al, 1992;Jansson and Hellerström, 1986), and influences β cell mass (Imai et al, 2008;Lausier et al, 2010;Nekrep et al, 2008;Plank et al, 2011). To acquire their specialized vasculature, islet endocrine cells produce angiogenic factors, such as vascular endothelial growth factor A (VEGF), which is crucial for islet vascularization, revascularization and function (Brissova et al, 2006;Cai et al, 2012;Lammert et al, 2003a;Magenheim et al, 2011).…”