UBC Theses and Dissertations
On the role of the enteroinsular axis in obesity Chan, Catherine Barbara
The enteroinsular axis refers to the effects of nutrient, hormonal and nervous inputs from the gut on pancreatic endocrine secretion. The objective of these studies was to examine the role of the enteroinsular axis in the development and maintenance of obesity, using the Zucker fatty rat as an animal model. Onset of glucose-stimulated hyperinsulinemia at 21 days in fa/fa rats was preceded by the appearance of enlarged pancreatic islets at 7 days of age. -The metabolic events triggering insulin hypersecretion could not be replicated in vitro and did not appear to involve GIP (glucose-dependent insulinotropic polypeptide; gastric inhibitory polypeptide) or cholinergic agonists. Fasting hyperinsulinemia was measurable by 5 weeks of age, developing concomitantly with a loss of the glucose threshold for the insulinotropic activity of GIP. A causal relationship was postulated. This condition persisted in adult rats and was hypothesized to contribute to the maintenance of fasting hyperinsulinemia in obese rats. In a second study, adult rats were treated with jejunoileal bypass (JIB) surgery and the effects on the enteroinsular axis were examined. Hyperinsulinemia of obese rats was reduced by JIB, but not to levels of lean controls. However, this did not appear to be an effect of alterations in the nutrient or known hormonal components of the enteroinsular axis. JIB did not alter in vitro pancreatic sensitivity to glucose or GIP, nor was the glucose threshold for the insulinotropic action of GIP restored by this treatment. The reduced hyperinsulinemia observed in obese JIB rats could not be accounted for by weight loss, as insulin levels of obese rats subjected to prolonged fasting were normal both in vivo and in vitro. Changes in endocrine cell population of the continuous and bypassed small bowel were observed and may contribute to alterations in appetite, weight loss and hormone secretion observed in obese rats. In particular, a strong correlation between enteroglucagon-cell number and plasma glucagon-like immunoreactivity was noted. JIB studies also demonstrated that daily perfusion of the bypassed loop of JIB rats with a nutrient solution could stimulate the release of GIP and possibly other hormones, resulting in a reduction of pancreatic sensitivity to GIP. The involvement of neural aspects of the enteroinsular axis in the hyperinsulinemia in Zucker rats was also investigated. No evidence was shown to support a hypothesis of hyperactivity of the vagus nerves. The pancreata of obese Zucker rats responded to the cholinergic antagonists, hexamethonium and atropine, in a manner identical to that of the pancreata of lean animals. A second hormonal system influenced by vagal innervation is gastrin secretion from the stomach. Adult obese Zucker rats were shown to be hypergastrinemic, but in vitro gastrin secretion responded normally to atropine administration both basally and when stimulated by vagal excitation. Antral hyperplasia of G-cells was noted and may cause hypergastrinemia in obese rats. D-cell population and somatostatin secretion appeared normal. The physiologic significance of hypergastrinemia in obesity remains unknown. From these studies of the hormonal, nutrient and nervous components of the enteroinsular axis, it was not possible to deduce the cause of the onset of hyperinsulinemia in obese Zucker rats. However, nutrients and the hormone GIP may make important contributions to the maintenance of fasting hyperinsulinemia of these animals due to the notable absence of a minimum glucose concentration required for GIP to stimulate insulin release. Unlike obese VMH-lesioned rats, the cholinergic nervous system did not appear to be important in the development or maintenance of hyperinsulinemia in Zucker fatty rats. A second objective of these studies was to investigate the possible presence in plasma of incretins other than GIP. Plasma collected from rats was extracted using immunoadsorbent chromatography and resultant fractions were assayed for incretin activity employing the perfused rat pancreas bioassay. The data provided evidence that plasma of lean rats contained more incretins than plasma of obese rats, but no data was shown for an increase in incretin activity with aging in normal Wistar rats. Improved methodology is required for clarification of these studies.