An experimental model of intestinal resection and compensated non-hypotensive blood loss.

BACKGROUND: Massive hemorrhage results in hypovolemia and hypotension that activate the sympathetic-adrenal-system, the hypothalamic-pituitary-adrenal axis, and induce metabolic changes such as hyperglycemia. Blood loss during surgery, however, is rapidly compensated by intravenous fluids to minimize negative impact on circulation. The aim of this study was to develop an experimental model for studies of the stress response and metabolic alterations seen after major abdominal surgery by combining intestinal resection with compensated non-hypotensive blood loss. MATERIAL AND METHODS: Intestinal resection in the rat was combined blood loss (7% and 16% of total blood volume) with subsequent fluid replacement (2 x volume of saline + hydroxyethyl starch, 50:50) to investigate the effects on blood pressure, plasma adrenaline, noradrenaline (0-2 h postoperatively), glucose, insulin, corticosterone, and hematocrit (0-24 h postoperatively). RESULTS: Surgical trauma alone or in combination with blood loss and fluid replacement did not decrease mean arterial blood pressure (MAP) compared with anesthetized controls. Plasma levels of catecholamines were unchanged during the period of blood loss. After surgery and blood loss, plasma glucose showed a blood loss volume-dependent increase up to 12 h postoperatively compared to surgery alone (P < 0.001-0.05). Plasma corticosterone increased after surgery alone and in combination with blood loss but the changes were not dependent on the magnitude of blood loss. CONCLUSIONS: Surgical trauma combined with compensated non-hypotensive blood loss induced persistent volume-dependent hyperglycemia that did not depend on changes in plasma corticosterone and, in the early postoperative phase, MAP and catecholamines. Our data indicate that blood loss per se, without causing hypotension or acute elevations in catecholamines, can induce marked postoperative hyperglycemia. The experimental model presented in this report will be a useful tool to further elucidate mechanisms underlying the changes in glucose metabolism seen after surgical injury.

Early impairment of insulin secretion in rats after surgical trauma.

OBJECTIVE: Hyperglycaemia associated with insulin resistance is common after trauma and surgical procedures. Both reduced insulin sensitivity and altered insulin secretion may contribute to the impaired glucose homeostasis. We have demonstrated that skeletal muscle insulin resistance is present 2 h after small intestinal resection in rats. In this study, the aim was to investigate insulin secretion in the same experimental model. DESIGN: Small intestinal resection (5 cm) was performed in adult rats. The control animals underwent anaesthesia only. METHODS: The intravenous glucose tolerance test (IVGTT), the hyperglycaemic clamp and in vitro studies in isolated pancreatic islets were performed after surgery. Concentrations of blood glucose, plasma insulin, corticosterone and interleukin-6 (IL-6) were determined 0-5 h postoperatively. RESULTS: The insulin response in the IVGTT was attenuated 2 h (P<0.05) but not 4 h or during the hyperglycaemic clamp (3.5-4.5 h) postoperatively. Insulin secretion in response to glucose in vitro was decreased 2 h after the surgery (P<0.05), but no change was seen in arginine-stimulated secretion. Plasma levels of corticosterone were increased 3.5-5 h postoperatively (P<0.001-0.05). Increases in IL-6 were also seen postoperatively. CONCLUSION: We demonstrate that glucose-induced, but not arginine-induced, insulin secretion is temporarily impaired after intestinal resection in rats. The later appearance of elevated corticosterone and IL-6 levels, as well as the preservation of the beta-cell inhibition in vitro, argues against the possibility that these two circulating factors are causally responsible for reduced insulin release seen after surgery in this model.

Preoperative glucocorticoid administration attenuates the systemic stress response and hyperglycemia after surgical trauma in the rat.

The stress response to surgery is characterized by activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, and by an inflammatory response and hyperglycemia. The aim of the present study was to investigate if preoperative corticosterone could reduce the postoperative systemic stress response, without aggravating hyperglycemia or interfering with activation of the hypothalamic-pituitary-adrenal axis, in a standardized rat model of surgical trauma. We used a standardized experimental model of intestinal resection in the rat. Exogenous corticosterone (8 mg/kg body weight) or vehicle was administered 2 hours before surgery; and postoperative plasma concentrations of interleukin-6, interleukin-10, adrenaline, noradrenaline, glucose, and insulin were determined. Exogenous corticosterone decreased preoperative plasma adrenaline but did not change plasma glucose or insulin levels. Moreover, corticosterone reduced postoperative plasma interleukin-6, catecholamines, and glucose (all P < .001-.05) without any effect on the plasma corticosterone concentration compared with vehicle-treated controls. A preoperative 2-hour exposure of physiologic poststress corticosterone concentrations not only suppressed plasma IL-6 levels but also inhibited surgery-induced adrenaline release and suppressed plasma glucose levels. We hypothesize that glucocorticoids attenuated the inflammatory response in injured tissues that reduced afferent input into brain areas regulating the neuroendocrine response.

Hypoxia inducible factor-1 mediates effects of insulin on pancreatic cancer cells and disturbs host energy homeostasis.

Intratumoral hypoxia and paracrine insulin stimulate the expression of hypoxia inducible factor-1alpha (HIF-1alpha) in pancreatic cancer cells. In the present studies, we investigated whether insulin-induced HIF-1alpha expression is a prerequisite for insulin to induce other trophic effects in MiaPaCa2 human pancreatic cancer cells and whether inhibition of HIF-1alpha expression would decrease tumor glycolysis and improve host energy homeostasis. We found that hypoxia was a prerequisite for induction of HIF-1alpha mRNA expression by insulin in MiaPaCa2 cells. Under hypoxic conditions, insulin stimulated glycolysis, cell proliferation, and the secretion of vascular endothelial growth factor in regular MiaPaCa2 cells but not in a MiaPaCa2 variant (si-MiaPaCa2) that expressed specific short interfering RNA for HIF-1alpha and therefore lacked HIF-1alpha protein. This suggests that HIF-1alpha expression is required for insulin to induce other trophic effects. When si-MiaPaCa2 cells were transplanted into the pancreas of athymic mice, they were less tumorigenic and expressed less hexokinase than regular MiaPaCa2 cells. Body weight gain was attenuated in mice hosting tumors composed of regular MiaPaCa2 but not si-MiaPaCa2 cells. These results suggest that an interaction between insulin and HIF-1alpha helps sustain pancreatic cancer cells and disturbs host energy homeostasis.

Delayed gastric emptying and intestinal hormones following pancreatoduodenectomy.

BACKGROUND/AIMS: Delayed gastric emptying (DGE) is frequently reported in patients following pancreatoduodenectomy (PD). The present study tested the hypothesis that gastrointestinal hormones known to effect gastric emptying contribute to DGE in patients after PD. METHODS: Patients with (delayed, n = 9) or without clinical signs of DGE (non-delayed, n = 22) after PD were investigated. Plasma concentrations of motilin, glucagon-like peptide-1 (GLP-1), neurotensin, and peptide YY (PYY) and the gastric emptying rate (GER), assessed by the paracetamol absorption method were measured after a liquid meal on postoperative day 11. RESULTS: Days with a nasogastric tube (p < 0.01), days until solid food was tolerated (p < 0.05), and hospital stay (p < 0.001) were increased in delayed compared to non-delayed patients. The total and incremental integrated peptide responses of motilin and GLP-1 were similar, but the responses of neurotensin and PYY were reduced, in delayed compared to non-delayed patients, whether considered on clinical grounds or by measured GER (p < 0.05-0.005). CONCLUSION: Neurotensin and PYY slow the rate of gastric emptying in humans. Therefore, our findings suggest that reduced hormone responses were the consequence of DGE arising from delayed delivery of nutrients to the distal intestine where the endocrine cells secrete neurotensin and PYY reside.

CRF-receptor 1 blockade attenuates acute posttraumatic hyperglycemia in rats.

BACKGROUND: Hyperglycemia and insulin resistance after surgical stress are mediated by a complex neuroendocrine response. The present studies were undertaken to determine whether a corticotropin releasing factor (CRF)-receptor 1 (R1) antagonist, CP-154,526 (CP) could alter trauma-induced effects on blood glucose levels, insulin action on skeletal muscle, and dexamethasone-induced suppression of endogenous glucocorticoid secretion. MATERIALS AND METHODS: We used a standardized experimental model of small intestinal resection in the rat. Studies were performed 2 hours after surgery in four groups of rats (n = 24-48) given vehicle or 40 mg of CP i.p. 1 hour before surgical trauma or only anesthesia (controls). Measurements of (I) b-glucose and p-insulin, corticosterone, and ACTH; (II) glucose transport; (III) phosphatidylinositol 3-kinase (PI 3-K) activity in skeletal muscle; and (IV) the dexamethasone-suppression test were performed. RESULTS: Surgery resulted in hyperglycemia, reduced insulin-stimulated glucose transport, and a pathological dexamethasone-suppression test. B-glucose levels were attenuated in traumatized rats given CP compared to vehicle (P < 0.05). After surgery, p-corticosterone levels were moderately reduced by CP (P < 0.05) and p-ACTH unchanged by the drug. Glucose transport and PI 3-kinase activity as well as the dexamethasone-suppression test were unaffected by administration of CP. CONCLUSIONS: Hyperglycemia in response to small intestinal resection in the rat could be reduced but not inhibited by CRF-R1 blockade. We hypothesize that CRF action within the central nervous system can regulate the hyperglycemic response to surgical stress via mechanisms other than the pituitary-adrenal axis. Our results also indicate that the hypothalamic stress response after surgical stress is dependent on other factors apart from CRF.

Diagnosis and treatment of hemosuccus pancreaticus during a nonbleeding episode: A case report of a patient with obscure intermittent gastrointestinal bleeding and silent chronic pancreatitis.

BACKGROUND: Hemorrhage from the pancreatic duct, i.e. hemosuccus pancreaticus (HP), is a rare cause of gastrointestinal bleeding. This potentially life-threatening complication of chronic pancreatitis may pose a significant diagnostic and therapeutic dilemma, especially in patients with silent forms of the disease. METHODS: We report a case of a 64-year-old man with no history or symptoms but positive findings of chronic calcifying pancreatitis at computed tomography (CT) scan. RESULTS: The patient presented with repeated episodes of gastrointestinal bleeding requiring transfusion and did not, until later in the disease, develop hyperamylasemia and epigastric pain. Repeated endoscopies could not reveal the source of bleeding. The radiological diagnosis and successful transcatheter embolization of a small splenic pseudoaneurysm were performed during an interval when the patient was asymptomatic and showed no signs of bleeding. CONCLUSION: We suggest that when HP is suspected, a contrast-enhanced CT angiography with reconstruction of the arteries should be performed regardless of whether the patient shows signs of active bleeding or not.

Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients.

INTRODUCTION: Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined. AIM: To characterize basal and insulin-stimulated glucose transport, phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in skeletal muscles of PC patients. METHODOLOGY: Skeletal muscle samples were obtained from the abdominal wall of 17 PC patients during surgery. Control muscles were sampled in the same way from 11 donors undergoing abdominal surgery for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were assessed in vitro in these muscles. RESULTS: In the presence of physiologic concentrations of insulin, glucose transport and PI 3-kinase activity were significantly decreased in the PC group compared with controls. At supraphysiologic insulin concentrations, glucose transport was significantly decreased but PI 3-kinase activity was normalized. In the absence of insulin, these parameters were not significantly different between PC and control groups. Muscle GLUT4 contents were similar between PC and control groups. CONCLUSION: Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute to the insulin resistance in patients with PC.