Total parenteral nutrition (TPN) provides an experimental situation where adequate nutrition is provided intravenously, bypassing the gastrointestinal tract. Under these conditions the importance of orally ingested nutrients in the control of gastric and pancreatic endocrine secretion can be assessed. The objectives of this thesis were two-fold. First, to examine the effects of TPN on the enteroinsular axis component of insulin secretion. Second, to study the importance of orally ingested nutrients in the regulation of gastric hormone secretion using the TPN rat model. In order to carry out these objectives, techniques for TPN and enteral feeding (TEN) of the rat were first developed. A dietary regimen for use in TPN and TEN rats was formulated from commercially-available, human TPN components. Under most circumstances, the TPN/TEN regimen met or exceeded the nutritional requirements for growing rats, as determined by the National Research Council (1978). Hematological analysis revealed few side effects of — intravenous or intragastric feeding. Parenterally and enterally-fed animals demonstrated comparable weight gain to that of a control group (ORAL) fed a rat chow (#5012, Ralston Purina) diet ad libitum. In addition, both TPN and TEN animals appeared healthy after the 7-day infusion period. These studies indicated that the infusion formulation was suitable for chronic intravenous and intragastric feeding. In the first series of experiments, the effects of TPN and TEN on the hormonal component of the enteroinsular axis were studied. TPN animals exhibited hyperinsulinemia and mild hyperglycemia. Conversely, TEN animals exhibited normal plasma glucose and immunoreactive insulin (IRI) concentrations. These data suggested that enterally delivered nutrients were assimilated with greater efficiency than intravenously administered nutrients. It was hypothesized that gut factors normally released by oral food intake facilitated the disposal of nutrients by hepatic and/or peripheral tissues. During the infusion period, TPN animals exhibited chronically depressed circulating IR-gastric inhibitory polypeptide (GIP) levels, in contrast to TEN animals where IR-GIP was elevated. Seven days of TPN or TEN resulted in no change in fasting plasma IRI or IR-GIP levels. However, an exaggerated insulin response to an oral glucose challenge (OGC) occurred after TPN, while the glucose response was reduced. The insulin response from the perfused pancreata of TPN animals to a GIP gradient was 20% and 40% greater than from ORAL and TEN pancreata respectively. Shorter periods of TPN (3 and 5-day periods) indicated that the hypersensitivity of the pancreas to GIP was a progressive condition, increasing with longer periods of infusion. Immunocytochemical and morphometric analysis revealed no differences in the jejunal GLP-cell population after chronic (7-day) intravenous or intragastric feeding. In addition, these routes of feeding had no effect on pancreatic islet area or endocrine cell composition of the islets. Based on these results, it was hypothesized that the increased B-cell sensitivity to GIP may have been causally related to the exposure of the pancreas to chronically low plasma GIP levels during the infusion period. To further test this hypothesis, chronically depressed plasma GIP levels, observed during TPN, were elevated by exogenous GIP infusion to levels seen in TEN rats. Chronic GIP —treatment in TPN animals (TPN-GIP) resulted in normalization of the insulin response to an OGC and in the in vitro insulin response of the isolated pancreas to GIP. These data were taken as further evidence that B-cell sensitivity to GIP was affected by ambient plasma GIP levels, and it was hypothesized that changes in sensitivity may be mediated by alteration at the receptor or post-receptor level. The effect of TPN on nutrient and neuronally mediated insulin release was also investigated. During TPN, metabolites and neuronal elements provided the main stimulus for insulin release, since hormonal components of the enteroinsular axis remained inactive. The present experiments indicated that the B-cell was hypersensitive to glucose, vagal stimulation and the cholinergic agonist methacholine, but normally sensitive to vasoactive intestinal polypeptide (VIP) and the insulinotropic amino acid arginine. These results indicated that TPN was associated with an increased B-cell sensitivity to specific hormonal, nutritive and neuronal stimuli. It was hypothesized that an increased B-cell sensitivity to these specific stimuli contributed to hyperinsulinemia observed in TPN animals during the infusion period, and to the exaggerated insulin response observed after an oral glucose challenge. Total parenteral nutrition also provided an experimental situation in which to study the importance of gastric nutrients in the regulation of Gl-hormone secretion. TPN resulted in a rapid and progressive depletion of circulating gastrin levels. G-cell secretory activity in vivo under basal and stimulatory conditions was also reduced by TPN. This condition persisted in vitro in the isolated stomach. The antral G-cell population was shown to decrease progressively with longer TPN periods, but G-cell hypoplasia and reductions in antral gastrin content were less dramatic than reductions in G-cell secretory activity. It was hypothesized that reductions in G-cell secretory activity were in part causally related to antral G-cell hypoplasia. The present data further suggested, however, that mechanisms which control synthesis and/or secretion within G-cells may have also been impaired, since various stimulants of gastrin release could not reverse gastrin hyposecretion observed during basal periods. Gastrin hyposecretion also could not be reversed by chronic bombesin administration, but was reversed by a 6-day period of oral — refeeding, indicating that the presence of nutrients in the gastric lumen was the primary regulator of tissue gastrin levels and G-cell secretory activity. The gastric D-cell was much less affected by the absence of nutrients in the gastric lumen than was the G-cell, and antral somatostatin hypersecretion may have contributed to G-cell hyposecretion. The experiments presented in this thesis indicated that total parenteral nutrition had marked effects on both B- and G-cell secretory activity. These studies clearly demonstrated the importance of enteral feeding in the maintenance of normal pancreatic and gastrointestinal endocrine secretion. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.