It is currently envisioned that future treatments for diabetes will include harnessing the body's own mechanisms of b-cell growth, survival and proliferation. Thus it is important to understand the processes through which ?-cell mass (BCM) is maintained and amplified. Our lab has characterized the short-term effects of celiac vagotomy (Cvx) in Sprague-Dawley rats (SD) and the growth and proliferation of b-cells in Zucker fatty (ZF) rats, in response to increasing insulin demands and resistance to insulin. Contributing factors to BCM are hypertrophy of existing cells, proliferation, augmented longevity and the neogenesis of new ss-cells from existing progenitor populations. The ZF rat utilizes all of these mechanisms in an age-dependent fashion that allows them to increase their BCM proportionally to body mass, and allows them to maintain euglycemia in the face of increasing insulin resistance. Our lab has also identified key signaling intermediates involved in b-cell growth mechanisms, including significant correlation of growth with the expression of the b-cell transcription factor Pdx-1. The complexity of signaling mechanisms, growth factors and hormones make parsing the contributions to steady-state and compensatory growth complex. We will focus on known activated signaling intermediates involved in survival (p-Akt), proliferation (Pdx1), neural signaling (p-CREB) as well as apoptosis (TUNEL). The parasympathetic branch of the ANS is a central regulator of gastrointestinal (GI) function and metabolic activity which integrates sensory information from the GI tract, the hepatic portal circulation, the pancreas, and the energy needs of the organism to appropriately modulate the activities of metabolically active tissues. Since it has been shown that both afferent hepatic vagus transection and hypothalamic ablation can both lead to changes in BCM, it is reasonable to assume that the vagus nerve provides not only functional control of insulin needs, but of compensatory growth mechanisms needed to maintain glucose homeostasis. Prior to weaning, both ZF and ZLC animals have the same BCM, glucose and insulin levels. At the peri-weaning period, ZF rats exhibit increased BCM, b-cell proliferation and increasing insulin levels. Interruption of vagal signaling during this time will likely have greater relative effects on downstream compensation and may provide insight into the propogation of metabolism during development and maturity in metabolic syndrome. This study seeks to examine the role of parasympathetic innervation in BCM maintenance in both steady-state and compensatory growth, and the effector pathways by which the vagus accomplishes this end. By use of morphometric analysis, molecular techniques and subcellular growth factor activation, we hope to identify mechanisms through which BCM and compensation is controlled by parasympathetic signaling to maintain metabolic homeostasis in adult and developing animals.
We envision future strategies for the treatment of diabetes to include augmenting the ability of patients to maintain physiologically appropriate b-cell mass through a combination of increased proliferation, hypertrophy, increased longevity and through recruitment of new b-cell mass. It is likely parasympathetic innervation plays a central role in these processes, despite the absence of direct evidence for that currently. Ultimately, further understanding of neurally influenced growth of b-cells may even lead to improvements in islet transplantation and, conceivably, through enhanced functional mass through pharmacological means.
