Local overexpression of the myostatin propeptide increases glucose transporter expression and enhances skeletal muscle glucose disposal.

Insulin resistance (IR) in skeletal muscle is a prerequisite for type 2 diabetes and is often associated with obesity. IR also develops alongside muscle atrophy in older individuals in sarcopenic obesity. The molecular defects that underpin this syndrome are not well characterized, and there is no licensed treatment. Deletion of the transforming growth factor-ß family member myostatin, or sequestration of the active peptide by overexpression of the myostatin propeptide/latency-associated peptide (ProMyo) results in both muscle hypertrophy and reduced obesity and IR. We aimed to establish whether local myostatin inhibition would have a paracrine/autocrine effect to enhance glucose disposal beyond that simply generated by increased muscle mass, and the mechanisms involved. We directly injected adeno-associated virus expressing ProMyo in right tibialis cranialis/extensor digitorum longus muscles of rats and saline in left muscles and compared the effects after 17 days. Both test muscles were increased in size (by 7 and 11%) and showed increased radiolabeled 2-deoxyglucose uptake (26 and 47%) and glycogen storage (28 and 41%) per unit mass during an intraperitoneal glucose tolerance test. This was likely mediated through increased membrane protein levels of GLUT1 (19% higher) and GLUT4 (63% higher). Interestingly, phosphorylation of phosphoinositol 3-kinase signaling intermediates and AMP-activated kinase was slightly decreased, possibly because of reduced expression of insulin-like growth factor-I in these muscles. Thus, myostatin inhibition has direct effects to enhance glucose disposal in muscle beyond that expected of hypertrophy alone, and this approach may offer potential for the therapy of IR syndromes.

Analysis of errors in laparoscopic surgical procedures.

BACKGROUND: The determination of laparoscopic surgeon ability is essential to training error avoidance. The present study describes a practical method of surgical error analysis. METHODS: After review of practice videotapes of the excisional phase of laparoscopic cholecystectomy, consensus on the identification of eight errors was achieved. Interrater agreement at the end of this phase was 84-96%. Fourteen study videotapes of gallbladder excision were then observed independently by expert reviewers blinded to surgical team identity. Procedures were assessed using a scoring matrix of 1-min segments with each error reported each minute. RESULTS: Interrater agreement was 84-100% for all error categories. CONCLUSIONS: The present study demonstrates that excellent interrater agreement of procedural errors can be achieved by carefully defining and training recognition of targeted events. Extension of this simple and reliable analysis tool to other procedures should be feasible to define behaviors leading to adverse clinical outcomes.

Pancreatic resection: effects on glucose metabolism.

Pancreatic resection results in hormonal abnormalities that are dependent on the extent and location (proximal versus distal) of the resected portion of the gland. The form of glucose intolerance which results from pancreatic resection is termed pancreatogenic diabetes. It is associated with features distinct from both type I (insulin-dependent) and type II (insulin-independent, or adult-onset) diabetes. Hepatic insulin resistance with persistent endogenous glucose production and enhanced peripheral insulin sensitivity result in a brittle form of diabetes which can be difficult to manage. In addition to insulin deficiency, the endocrine abnormalities that accompany pancreatic resection can include glucagon deficiency or pancreatic polypeptide (PP) deficiency if the resection is distal or proximal, respectively. Glucagon deficiency can contribute to iatrogenic hypoglycemia, and PP deficiency can contribute to persistent hyperglycemia due to impaired hepatic insulin action. Pancreatic resections that spare the duodenum, such as distal pancreatectomy, duodenum-preserving pancreatic head resection (Beger procedure), or extended lateral pancreaticojejunostomy with excavation of the pancreatic head (Frey procedure), are associated with a lower incidence of new or worsened diabetes than the standard or pylorus-preserving pancreaticoduodenectomy (Whipple procedure) or total pancreatectomy. Operative considerations for the treatment of pancreatic disease should include strategies to minimize the hormonal impairment of pancreatic resection.

Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.

To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%-60% lower following the lipid infusion compared with the glycerol infusion and were associated with a approximately 90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated PI 3-kinase activity.

Overexpression of hepatic pancreatic polypeptide receptors in chronic pancreatitis.

Pancreatic polypeptide (PP) receptors have recently been demonstrated on liver microsomal membranes although the mechanisms of PP action on hepatocytes remain uncertain. The binding characteristics of these high affinity receptors under pathophysiologic conditions were studied in rats with oleic acid-induced chronic pancreatitis (CP), a state associated with diminished pancreatic PP content. Sixteen pancreatitic and 11 sham-operated control animals either were 16-h fasted or were given free access to food prior to organ removal. Competitive binding studies were performed by incubating hepatocyte microsomal preparation with 125I-labeled PP (20-40 pM) and increasing concentrations of nonlabeled PP (1 x 10(-10) to 1 x 10(-6) M). After total and nonspecific binding was quantified by gamma counting, coefficients of dissociation (Kd) and maximal binding sites (Bmax) were determined by Scatchard analysis of specifically bound radioactivity. Binding data were normalized to membrane protein content and expressed as means +/- standard error. Bmax was significantly greater in tissue from fed control animals than from fasted controls (4.46 +/- 0.36 versus 2.83 +/- 0.25, P < 0.05). Bmax was significantly greater under fasted conditions in tissue from CP animals than from controls (5.25 +/- 0.94 versus 2.83 +/- 0.25, P < 0.01). Under fed conditions, this differences was abolished by the increase in maximal binding in the control group. The fasting-associated decrease in maximal binding sites observed in controls did not occur in CP specimens. Increased Bmax in fed versus fasted control, as well as fasted CP versus fasted control, were associated with slight reciprocal decreases in receptor affinity. These data indicate that hepatic PP receptor concentration is upregulated in this model of chronic pancreatitis, most likely due to diminished exposure to ligand. Furthermore, normal PP receptor responses to the fed/fasted state are blunted in this condition. Regulatable PP receptor changes may play a role in altered hepatic metabolism previously observed in chronic pancreatitis.

Pancreatic polypeptide administration improves abnormal glucose metabolism in patients with chronic pancreatitis.

Chronic pancreatitis (CP) is associated with lowered plasma levels and a blunted nutrient-induced release of pancreatic polypeptide (PP). To investigate the possible role of PP on glucose metabolism, we studied male patients with documented CP (n = 5) and obesity-matched control subjects (NL) (n = 6). Hepatic glucose production (HGP) and overall glucose disposal rates were determined by [3-3H]glucose infusion during a hyperinsulinemic-euglycemic clamp during three separate admissions. Basal rates of HGP were higher in CP patients. In response to an infusion of insulin (60 pmol.m-2.min-1), HGP fell 91 +/- 5% in NL subjects but only 68 +/- 8% in CP subjects (P < 0.05). One month later, the clamp was repeated during the final 2 h of an 8-h infusion of bovine PP (2 pmol.kg-1.min-1). HGP before the insulin infusion and its subsequent suppression (NL: 83 +/- 5%; CP: 86 +/- 15%) were nearly identical between groups. In follow-up studies 1 month after the PP infusion, HGP both basally and in response to insulin alone were similar to the first study. During oral glucose tolerance tests (OGTT) performed 18 h after the PP infusion, subjects with normal (n = 7) baseline OGTT responses showed no effect. All patients with diabetic (n = 3) or nondiagnostic (n = 1) OGTT responses, however, demonstrated lowered mean plasma glucose levels (approximately -2.3 mmol/L; range: -0.6 to -7.2 mmol/L). OGTTs repeated 1 month after the PP treatment showed a return to pretreatment responses. We conclude that chronic pancreatitis accompanied by PP deficiency is associated with partial hepatic resistance both in the basal state and in response to hyperinsulinemia. This impairment is reversed after iv PP administration. PP deficiency may therefore play a role in the development of pancreatogenic diabetes caused by pancreatic injury.

Regulation of hepatic insulin receptors by pancreatic polypeptide in fasting and feeding.

Pancreatic polypeptide (PP) increases hepatic insulin receptor (IR) binding activity in fasted PP-deficient rats, but not fasted normal animals. PP-induced alteration of hepatic IR levels in normal animals may be detectable in the fed state when IR concentrations are lower than during fasting. In the current study, the effect of exogenous PP on IR concentrations in the fed and fasted states was determined in healthy 300- to 350-g male Sprague-Dawley rats. Ten animals were administered PP 100 microgram/kg/day for 3 days by intraperitoneal injection and 10 weight-matched control animals received saline vehicle. Five PP- and five saline-administered rats were fasted for 12 hr prior to organ procurement, while 5 PP- and 5 saline-treated rats were given free access to food for this period. Livers were removed and snap-frozen. IRs were isolated from solubilized hepatocyte membranes by affinity chromatography with agarose-bound wheat germ agglutinin. Western blots were performed using a specific antibody to the beta subunit of the IR, which was detected by a chemiluminescence technique after 45-min exposure to X-ray film. Exposed films were examined by scanning densitometry and IR concentration was expressed as absorbance units per milligram of hepatic protein (mean +/- SE). Statistical comparisons were by Student's t test with significance taken at P < 0.05. Feeding was associated with a significantly lower IR concentration in saline-administered animals compared with the fasted state (24.2 +/- 4.0 vs 53.3 +/- 11.1). PP administration in fed rats resulted in significantly increased IR concentration as compared with that seen in saline-administered fed animals (43.8 +/- 8.9 vs 24.2 +/- 4.0). This difference may be due to increased IR synthesis with long-term PP administration, and supports the role of PP as a regulatory factor in hepatic carbohydrate metabolism.

Production of a rat pancreatic polypeptide-specific monoclonal antibody and its influence on glucose homeostasis by in vivo immunoneutralization.

To test the effect of endogenous pancreatic polypeptide (PP) on rat hepatic glucose homeostasis by immunoneutralization, a rat PP-specific monoclonal antibody (MAb) was produced. Binding of this IgG1 monoclonal antibody was inhibited 50% by 350 pM rat PP. Immunohistochemistry showed that the antibody produced the expected pattern of endocrine cell staining in rat pancreas. Groups of six adult male Sprague-Dawley rats were given 5 mg of Protein-A-purified anti-PP MAb or anti-KLH MAb (control) ip every 48 hr for 5 dosing intervals. The rate of hepatic glucose output during isolated liver perfusion was 0.25 +/- 0.03 mg/g/min for the PP MAb-treated rats and 0.17 +/- 0.02 mg/g/min for the control group (p < 0.05). Liver glycogen content was 21.8 +/- 2.9 mg/g for the PP MAb-treated rats and 14.7 +/- 2.4 mg/g for the control group (N = 5). Chronic in vivo immunoneutralization of PP with this new monoclonal antibody suggests that PP influences glucose homeostasis in the rat by affecting hepatic glucose output.

Alterations in hepatocyte insulin binding in chronic pancreatitis: effects of pancreatic polypeptide.

BACKGROUND: Hepatic insulin resistance has previously been demonstrated in chronic pancreatitis, and has been shown to be ameliorated by pancreatic polypeptide administration. Insulin binding was investigated in chronic pancreatitis induced by infusion of oleic acid into the pancreatic duct of rats. METHODS: Acute pancreatitis was induced in 12 200 to 225 g 8-week-old male Sprague-Dawley rats by intubation of the main bile duct at its junction with the duodenum through a small midline abdominal incision, and infusion of 99% oleic acid 0.015 mL/min for 4 minutes, with an additional 4 minutes dwell-time after infusion. Sham-operated animals served as controls. After 6 weeks, chronic pancreatitic and sham-operated animals received either intraperitoneal bovine pancreatic polypeptide or saline vehicle for 5 days. Intraduodenal glucose tolerance tests (GTT) were performed in fasted animals, after which tissues were procured. Insulin receptors were isolated from solubilized hepatocyte and rectus abdominus membranes and competitive-binding studies were performed by incubation with 125I-insulin. Dissociation coefficients (Kd) and maximum binding capacities (Bmax) for high-affinity receptors were derived from Scatchard analyses. RESULTS: Bmax and Kd in muscle were not altered in animals with chronic pancreatitis. In liver, Bmax was significantly less in rats with chronic pancreatitis given saline than in sham-operated rats given saline (17.0 +/- 6.3 versus 47.6 +/- 13.1 fmol/mg protein; data are mean +/- SEM). Pancreatic polypeptide administration increased hepatic Bmax in rats with chronic pancreatitis (to 47.2 +/- 9.8 fmol/mg protein), but had no significant effect in sham-operated rats. Receptor affinity was not significantly different in rats with chronic pancreatitis or rats who underwent sham operations and was unaltered by the administration of pancreatic polypeptide. The integrated plasma glucose response during the GTT was reduced by pancreatic polypeptide administration in rats with chronic pancreatitis (29.5 +/- 15.0 mg/dL per minute versus 69.0 +/- 21.8 in chronic pancreatitis without pancreatic polypeptide), but was not significantly altered in sham-operated animals. CONCLUSION: Diminished expression of high-affinity receptors on the hepatocyte membrane may contribute to hepatic insulin resistance in chronic pancreatitis. In this model, pancreatic polypeptide improved glucose tolerance and increased receptor capacity to the level observed in livers from nonpancreatitic animals.

Insulin regulation of hepatic glucose transporter protein is impaired in chronic pancreatitis.

OBJECTIVE: The effect of chronic pancreatitis and insulin on the expression of the hepatic facilitative glucose transporter protein (GLUT-2) was determined in rats. SUMMARY BACKGROUND DATA: Chronic pancreatitis is associated with diabetes mellitus or impaired glucose tolerance. Suppression of hepatic glucose production (HGP) by insulin is impaired, although the mechanism is unknown. METHODS: Normal rats, rats with chronic pancreatitis induced 12 to 16 weeks earlier by oleic acid injection into the pancreatic ducts, and sham-operated rats were studied. Isolated, single-pass liver perfusion was performed, during which glucagon (1.2 pM) was infused, with or without insulin (0.6 or 1.2 nM). The suppression of HGP production by insulin was compared with changes in GLUT-2 in the membrane fraction of liver biopsies obtained before and after hormone perfusion. RESULTS: Glycogen-rich (fed) livers of normal rats (n = 16) demonstrated a dose-dependent suppression of hepatic glucose production by insulin (50 +/- 5% HGP induced by glucagon alone during 1.2-nM insulin perfusion) and a dose-dependent decrease in GLUT-2 (30 +/- 13% of basal level during 1.2-nM insulin perfusion). Sham-operated rats (n = 6) also showed reductions in HGP (51 +/- 4%) and GLUT-2 (14 +/- 10%) during 1.2-nM insulin perfusion. In contrast, rats with chronic pancreatitis (n = 6) showed no suppression of HGP during 1.2-nM insulin perfusion, and an increase in GLUT-2 (+20 +/- 6%) after insulin perfusion (p < 0.02 vs. sham). CONCLUSIONS: Insulin suppresses glucagon-stimulated HGP in normal and sham-operated rats, and this reduction in HGP is associated with a decrease in the membrane-bound quantity of GLUT-2. In chronic pancreatitis, insulin suppression of HGP is absent, and this is accompanied by an increase in GLUT-2 in the hepatocyte membrane. The authors conclude that the insulin-mediated change in the level of hepatocyte GLUT-2 is impaired in chronic pancreatitis, and may contribute to the altered glucose metabolism observed commonly in this disease.

The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects.

Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.

Splanchnic neural regulation of somatostatin secretion in the isolated perfused human pancreas.

OBJECTIVE: The somatostatin-secreting delta cells in the islets of Langerhans appear to be regulated by neural mechanisms that have not been defined clearly. In this study, the celiac neural bundle of the human pancreas was electrically stimulated in the presence and absence of selective neural antagonists. SUMMARY BACKGROUND DATA: The authors previously reported on studies of the splanchnic neural regulation of insulin, glucagon, and pancreatic polypeptide secretion. In these studies, alpha-adrenergic fibers appeared to have a predominant effect, strongly inhibiting the secretion of insulin, glucagon, and pancreatic polypeptide secretion. Cholinergic fibers appeared to stimulate strongly, although beta-adrenergic fibers weakly stimulated, the secretion of these hormones. Investigations of neural regulatory mechanisms governing human somatostatin release in vitro have not been previously reported. METHODS: Pancreata were obtained from eight cadaveric organ donors. The isolated perfused human pancreas technique was used to assess the regulation of somatostatin secretion by the various neural fibers contained within the celiac plexus. The secretory response of somatostatin was examined in the presence of 16.7 mmol/L glucose, with and without neural stimulation, and specific neural antagonists. RESULTS: The basal somatostatin secretion was 88 +/- 26 fmol/g/min and increased 131 +/- 23% (n = 8, p < 0.01) in response to 16.7 mmol/L glucose. The augmentation seen with glucose was inhibited 66 +/- 22% (n = 8, p < 0.05) during celiac neural bundle stimulation. Alpha-adrenergic blockade resulted in a 90 +/- 30% (n = 6, p < 0.01) augmentation of somatostatin release. Beta-adrenergic blockade caused a 13 +/- 2% (n = 6, p < 0.05) suppression of somatostatin release. Complete adrenergic blockade resulted in a 25 +/- 23% (n = 5, p = not significant) inhibition of somatostatin release. Cholinergic blockade resulted in a 40 +/- 10% (n = 6, p < 0.02) suppression of somatostatin release. CONCLUSIONS: The predominant effect of celiac neural bundle stimulation was inhibition of somatostatin secretion through an alpha-adrenergic effect. Beta-adrenergic fibers stimulate somatostatin secretion; cholinergic fibers have a negligible effect on somatostatin secretion. These data suggest that the splanchnic innervation of the pancreas has a potent regulatory role in somatostatin release in this in vitro human model.

Surgery in the elderly: observations on the pathophysiology and treatment of cholelithiasis.

Biliary tract disease is particularly prevalent in older persons, and is the leading indication for acute abdominal surgery in the elderly. The complications of biliary stone disease are more insidious in the elderly, and the recognition of "symptomatic" disease is often delayed. The unreliable manifestations of biliary tract pathology result in a higher morbidity and mortality of the disease, and a large number of emergency operations. Recent studies suggest that the pathophysiology of cholelithiasis is specifically altered in the elderly. Pigmented gallstones, which are more common in the elderly, are thought to result from the action of bacterial enzymes that deconjugate bilirubin and form insoluble bile salts; bacterial contamination of the extrahepatic biliary system is more frequent in elderly patients. Gallbladder stasis may be due to age-related changes in the response of gallbladder musculature to the kinetic action of cholecystokin (CCK), possibly through a decrease in CCK receptor affinity or availability. Other hormonal factors which inhibit choleresis, such as pancreatic polypeptide, are increased with aging as well. Current efforts are being directed toward closer surveillance and discovery of cholelithiasis, and improved outcomes of therapy have been aided by the development of "minimally invasive" approaches to the treatment of cholelithiasis in the elderly.

The effect of pancreatic polypeptide on glucose disposal after surgical alterations of the pancreas.

Surgical alterations of the pancreas result in anatomic changes that can affect postoperative glucose metabolism. Pancreas transplantation results in reduction of beta-cell mass, systemic release of insulin, and denervation. The authors hypothesized that such alterations affect peripheral glucose disposal to induce an "insensitivity" to endogenously (systemically) released insulin. Additionally, they hypothesized that surgically induced deficiency of the postprandial hormone, pancreatic polypeptide, might contribute to altered glucose disposal. The authors studied two surgical models in dogs known to be devoid of pancreatic polypeptide--70% proximal pancreatectomy (PPx) and PPx plus distal pancreas autotransplantation (PAT/B). Oral glucose challenge and euglycemic hyperinsulinemic clamp studies were performed before and after a 16-day "pulsed" infusion of pancreatic polypeptide. Both surgical procedures resulted in elevations in the integrated glucose response after oral glucose, which was not affected by pancreatic polypeptide infusion. Euglycemic clamp studies showed decreased hepatic glucose output (Ra) and overall glucose disposal (Rd) in the fasted state for both surgical groups. The transplant animals demonstrated significant decreases in Rd during the hyperinsulinemic challenge (3.2 +/- 0.01 versus 5.7 +/- 0.01 mg/kg/minute at 60 to 120 minutes for PAT/B versus control). After 16 days of pancreatic polypeptide infusion, however, basal Ra, as well as basal and 60- to 120-minute Rd values, were returned to control values in the transplant group. The authors conclude that pancreas transplantation results in altered glucose disposal, possibly due to an altered effectiveness of systemically released insulin. They conclude that pancreatic polypeptide is an important modulator of peripheral insulin action. Therefore, the role of pancreatic polypeptide must be taken into account when evaluating postoperative glucose metabolism in canine models of pancreas transplantation.

Recurrent abdominal pain due to chronic appendiceal disease.

Recurrent appendicitis and chronic appendicitis are the subjects of much controversy, but long-standing inflammation of the appendix and surrounding tissues has been reported in rare instances. We have described two patients, both with recurrent episodes of abdominal pain, who subsequently were shown to have chronic appendiceal disease. Appendiceal disease should be considered in the differential diagnosis in patients with recurrent abdominal pain.

Taking the lead: challenges of supply and demand in academic surgery.

I have tried to forecast some of the real challenges which we will all face within our departments over the next few years. If we are to be successful in attracting the best and the brightest young people to join us in the pursuit of an academic surgical career, we must serve as role models, genuine role models, for what may be a decreasing pool of medical students entering our institutions. Second, we must reward those individuals in our departments who truly inspire and motivate our young trainees, whether this inspiration is at the bedside, in the operating rooms, or in the laboratories. Third, we must begin to explore new initiatives where professional organizations and associations such as the AAS can reach out to these young trainees and help them realize early on the advantages and gratification of a career in academic surgery. Fourth, we must realize that academic and research training, like charity, begins at home. Through workshops, local seminars, and training programs modeled after the one which seems to have been so successfully done by the AAS, our departments and institutions can begin to teach solid research skills and demonstrate a genuine commitment for the future success of our young trainees. Finally, we have to rethink our notion of the model academic surgical department. The time has passed where every surgical faculty member should be at the beck and call of the operating room. If we take our obligations to recruiting and training young academic surgeons seriously, we will realize that it is not enough for use to simply sit back and wait for them to come.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pancreatic polypeptide infusion on glucose tolerance and insulin response in longitudinally studied pancreatitis-induced diabetes.

Glucose intolerance is often associated with pancreatitis. Pancreatitis-induced diabetes represents a different clinical syndrome than type I and type II diabetes mellitus. Patients with pancreatitis-induced diabetes may be extremely sensitive to exogenous insulin, rarely develop ketoacidosis, and rarely exhibit classic diabetic complications, such as retinopathy, nephropathy, or accelerated vasculopathy. Pancreatic polypeptide (PP) deficiency has been implicated in the defect of glucose homeostasis found after pancreatitis. This study evaluated intravenous and oral glucose tolerance and insulin response to glucose loading, in the setting of pancreatitis, with and without short-term PP replacement. Dogs (n = 7) underwent pancreatic duct ligation (PDL) and were studied with and without PP infusion (2 micrograms/kg/hr) before PDL and at 1 week, 6 weeks, and 4 months after PDL by means of intravenous and oral glucose tolerance tests. Basal and bombesin-stimulated PP levels at 4 months after PDL were subnormal, verifying PP deficiency in these animals with pancreatitis. PP levels during PP infusion reproduced normal postcibal levels, averaging 897 +/- 40 pg/ml. Glucose tolerance, expressed as the glucose decay constant for the intravenous glucose tolerance tests and as the integrated glucose response for the oral glucose tolerance tests, deteriorated over time and was not improved by acute PP replacement. The integrated insulin response to glucose was not affected by PP. The acute infusion of PP at a dose that reproduces normal postprandial PP levels fails to improve glucose tolerance or augment insulin release in this model of pancreatitis-induced diabetes.

Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas.

To investigate the effects of stimulant interactions on alpha- and beta-cell secretions, the differential effects of gastric inhibitory polypeptide (GIP) and cholinergic stimulation (CS) on insulin (IRI) and glucagon (IRG) release were examined during euglycemic, single-pass perfusion in the isolated human pancreas. Pancreata obtained from 12 cadaver organ donors were perfused for 15-min test periods with (a) 1 nM GIP (b) intrinsic CS via bipolar electrical stimulation (10 V, 5 msec, 10 Hz) of the splanchnic neural fibers during simultaneous perfusion with 4 microM phentolamine and 6 microM propranolol, or (c) GIP and CS. The integrated response of IRI and IRG demonstrated that IRI release was stimulated 308 +/- 52 microU/g-min by GIP, 366 +/- 73 microU/g-min by CS, and 560 +/- 50 microU/g-min by GIP and CS (P less than 0.05). IRG release was stimulated 111 +/- 33 pg/g-min by GIP, 34 +/- 12 pg/g-min by CS, and 90 +/- 36 pg/g-min by GIP and CS. Combined hormonal and cholinergic stimulation was additive for IRI release, but not for IRG release. We conclude that the interaction of neural and hormonal islet cell stimuli is cell-type specific. This may result in selective impairment of hormone release after pancreatic denervation.

Reversal of in vitro hepatic insulin resistance in chronic pancreatitis by pancreatic polypeptide in the rat.

In vitro isolated liver perfusion in a rat model of chronic pancreatitis (CP) has been shown to demonstrate hepatic resistance to insulin. The ability of pancreatic polypeptide (PP) to reverse the resistance to insulin on glucagon-stimulated hepatic glucose production was therefore investigated in this model. CP was induced in 250 to 300 gm Sprague-Dawley rats by infusion of 50 microliters of 99% oleic acid into the pancreas via the common bile duct. After 6 to 8 weeks, isolated liver perfusion was performed on livers from both CP rats and sham-operated control animals (n = 12, 14), both with and without PP administration. Glucagon infusion (100 pg/ml for 30 minutes) produced a five- to sixfold increase in hepatic glucose production. The integrated hepatic glucose output (IHGO) response to glucagon alone was comparable in pancreatic and sham-operated animals; during period 1 (0 to 10 minutes) IHGO was 7.1 +/- 0.5 mg/gm-min for sham-operated controls (n = 8) and 7.1 +/- 0.4 mg/gm-min for pancreatitic animals (n = 6) without PP treatment. Animals that received PP (100 ng intraperitoneally 5 hours before liver harvest and perfusion with 4.2 ng/ml from 10 to 30 minutes) demonstrated an IHGO for period 1 for the sham (n = 6) and pancreatitic animals (n = 6) of 5.6 +/- 0.6 and 4.8 +/- 0.8 mg/gm-min, respectively. Insulin infusion (100 microU/ml added to perfusate from 10 to 30 minutes) in CP livers without PP revealed impaired responsiveness to insulin; the ratio of period 3 (20 to 30 minutes)/period 1 IHGO was 110% +/- 5% in CP livers compared with 77% +/- 5% in sham controls (p less than 0.01). In contrast, PP treatment restored hepatic responsiveness to insulin to control levels; the period 3/period 1 IHGO was 75% +/- 13% in CP livers treated with PP, which was indistinguishable from the 67% +/- 9% response seen in sham-operated control animals. These data provide the first in vitro evidence of a primary hepatic glucoregulatory role of PP. Therefore PP deficiency may contribute to altered glucose metabolism through the induction of a reversible hepatic resistance to insulin.