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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.

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.

Although half of all patients with pancreatic cancer are diabetic at the time of diagnosis, it remains unclear whether the diabetes associated with pancreatic cancer is a cause or an effect of the malignancy.Epidemiologic studies were reviewed, the geographic prevalence of diabetes and the incidence of pancreatic cancer were examined, and clinical and laboratory studies were reviewed.Long-standing diabetes increases the risk of pancreatic cancer by 40% to 100%, and recent-onset diabetes is associated with a 4- to 7-fold increase in risk, such that 1% to 2% of patients with recent-onset diabetes will develop pancreatic cancer within 3 years. Treatment of diabetes or morbid obesity decreases the risk of pancreatic cancer, and metformin therapy decreases the risk due to both its antidiabetic and antineoplastic effects. Recent-onset diabetes associated with pancreatic cancer likely represents secondary or type 3 diabetes. The discrimination of type 3 diabetes from the more prevalent type 2 diabetes may identify the high-risk subgroup of diabetic patients in whom potentially curable pancreatic cancer may be found.Type 2 and type 1 diabetes mellitus increase the risk of pancreatic cancer with a latency period of more than 5 years. Type 3 diabetes mellitus is an effect, and therefore a harbinger, of pancreatic cancer in at least 30% of patients.

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.

Evidence supports an inverse relationship between serum testosterone (T) and insulin resistance in men. However, data with respect to causality are limited. The aim of this study was to explore the impact of acute biochemical castration on insulin sensitivity in healthy adult men.Ten healthy, adult males (mean age 41.0 +/- 3.9 yr) were studied. Subjects were studied at baseline and after 2 and 4 weeks of biochemical castration. Outpatient hospital research setting. Body composition (dual-energy x-ray absorptiometry), energy expenditure (indirect calorimetry), abdominal and visceral adiposity (MRI), skeletal muscle intramyocellular lipid content ([IMCL] (1)H-MR spectroscopy), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed before and after 2 and 4 weeks of biochemical castration induced by a GnRH antagonist (acyline 300 mug/kg subcutaneous every 10-14 days). Serum T, insulin and glucose levels, body composition, abdominal visceral fat, IMCL, and glucose disposal rate (M) were measured.Acyline administration suppressed serum T to frankly hypogonadal levels in all subjects for the duration of the study (P0.009). No significant changes in body composition, energy expenditure, or M were observed at either 2 or 4 weeks of castration. Acyline is an effective GnRH antagonist inducing acute castration in all subjects. ii) Four weeks of biochemical castration has no impact on insulin sensitivity in healthy men likely due to unchanged body composition variables. iii) Insulin resistance associated with chronic low T levels may be largely driven by decreased fat free mass, increased percent body fat, and/or other metabolic regulatory factors.

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.

Local resection of the pancreatic head with longitudinal pancreaticojejunostomy (or Frey procedure) generally results in excellent pain relief in chronic pancreatitis. We report a patient with chronic pancreatitis who experienced pain recurrence after an uneventful longitudinal pancreaticojejunostomy.This is a single case study of a 58-year-old female with chronic pancreatitis undergoing longitudinal pancreaticojejunostomy for pain relief. Fifteen months after the surgery, the patient experienced pain recurrence. Radiologic evaluation followed by surgical exploration revealed a gastroenteric fistula to the Roux-limb, with obliteration of the anastomosis. After repair of the fistula and re-excavation of the pancreatic head, a two-layer longitudinal pancreaticojejunostomy was reconstructed from the same Roux-limb. An omental flap was interposed between the Roux limb and the repaired stomach. At 6-month follow-up, the patient was pain free and asymptomatic.Late failure of the Frey procedure due to a gastroenteric fistula to the Roux-limb of jejunum has not been previously reported. This finding may explain one of the causes of longitudinal pancreaticojejunostomy late failure.

Severe burn causes a catabolic response with profound effects on glucose and muscle protein metabolism. This response is characterized by hyperglycemia and loss of muscle mass, both of which have been associated with significantly increased morbidity and mortality. In critically ill surgical patients, obtaining tight glycemic control with intensive insulin therapy was shown to reduce morbidity and mortality and has increasingly become the standard of care. In addition to its well-known anti-hyperglycemic action and reduction in infections, insulin promotes muscle anabolism and regulates the systemic inflammatory response. Despite a demonstrated benefit of insulin administration on the maintenance of skeletal muscle mass, it is unknown if this effect translates to improved clinical outcomes in the thermally injured. Further, insulin therapy has the potential to cause hypoglycemia and requires frequent monitoring of blood glucose levels. A better understanding of the clinical benefit associated with tight glycemic control in the burned patient, as well as newer strategies to achieve and maintain that control, may provide improved methods to reduce the clinical morbidity and mortality in the thermally injured patient.

Objective: Glucagon-like peptide-1 (GLP-1) (7–36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP-1 are mediated through its principal metabolite, GLP-1 (9–36) amide (GLP-1m). Methods and Procedures: Glucose turnover during two, 2-h, euglycemic clamps was measured in 12 lean and 12 obese (BMI 30 kg/m2) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP-1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP-1 receptor (GLP-1R) antagonist, exendin (9–39) amide was infused from −60 to 60 min with GLP-1m from 0 to 60 min. Results: No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP-1m infusions. However, in obese subjects glucose infusion was necessary during GLP-1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP-1R blockade, infusion of glucose was immediately required upon starting GLP-1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response. Discussion: We conclude that GLP-1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP-1 (7–36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP-1m may have therapeutic usefulness.

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.

Exocrine and endocrine abnormalities in chronic pancreatitis contribute to the morbidity and mortality risks of the disease. Complications of exocrine insufficiency include malabsorption, vitamin deficiency syndromes, and weight loss. Oral enzyme replacement therapy is usually effective if attention is paid to factors that affect the bioavailability of enzyme preparations. Complications of endocrine insufficiency can be more difficult to treat due in part to an incomplete knowledge of their etiology.This review focuses on the endocrine aspects of chronic pancreatitis and highlights the observations of our laboratory on the pathogenesis of the metabolic complications of the disease.In addition to decreased insulin secretory capacity, pancreatogenic (or apancreatic) diabetes is characterized by decreased or absent glucagon and pancreatic polypeptide (PP) secretion, a loss of hepatic insulin receptor (IR) expression/availability, and an impairment in hepatic IR function (phosphorylation and endocytosis). Diminished hepatic IR expression in chronic pancreatitis appears to be because of PP deficiency; laboratory animals and patients with PP deficiency demonstrate decreased hepatic IR availability that is reversed by prolonged (8-hour) PP administration. The impairment in hepatic IR function appears independent of PP deficiency but is reversed by prolonged (28-day) treatment with the insulinotropic/insulinomimetic hormone glucagon-like peptide 1. The endocytosis of hepatic IR is linked to the endocytosis of the glucose transporter 2 from the hepatocyte plasma membrane, and studies suggest that the 2 plasma membrane-bound proteins are complexed noncovalently to function and translocate as a unit after insulin binding to the hepatic IR. The process appears vigorous and sensitive enough to account for a significant reduction in hepatic glucose output and may represent a major mechanism for insulin regulation of hepatic glucose production.The regulatory mechanisms of PP-mediated hepatic IR expression and combined IR and GLUT2 endocytosis after insulin binding are defective in chronic pancreatitis and contribute to the apancreatic diabetes, which characterizes this disease.

Goals: To assess outcomes following 6 months of endoscopic stenting for dominant pancreatic duct strictures in painful chronic pancreatitis. Background: Pancreatic stent placement may improve pain in chronic pancreatitis. Long-term outcomes after a 6-month period of stenting are unknown. Study: We identified all patients with chronic pancreatitis who underwent stenting of a dominant pancreatic duct stricture at one hospital. Stents were left in place for 6 months. Changes in weight, hospital visits, and narcotic use were analyzed. Results: Mean follow-up for the 15 subjects was 36 months; 87% improved following stent placement, and 11 (73%) completed 6 months of stent therapy. Hospital visits per subject decreased from 3.6 in the year prior to stent placement to 0.1 in the year after stent removal (P < 0.01). Oral narcotic use decreased from 33 mg MSO 4 /day in the month prior to stenting to 2 mg MSO 4 /day in the 12 months after stent removal (P = 0.01 ). Mean weight change was - 5 kg in the year prior to stenting and +3.2 kg in the year after stent insertion (P < 0.01); 36% required endoscopic reintervention during the follow-up period. Conclusions: Six months of stenting resulted in sustained clinical improvement in most patients with chronic pancreatitis and a dominant pancreatic duct stricture. Stenting was associated with subsequent weight gain, fewer hospital visits, and less narcotic use.

KOC (K homology domain containing protein overexpressed in cancer) is a novel oncofetal RNA-binding protein highly expressed in pancreatic carcinomas. Recently, Corixa Corporation developed a monoclonal antibody specific for KOC that can be used with standard immunohistochemical techniques. The purposes of this study were 1) to assess KOC mRNA expression in pancreatic carcinoma, 2) to determine the pattern of KOC immunoexpression among benign, borderline, and malignant pancreatic epithelial lesions, and 3) to evaluate the utility of the KOC antibody in distinguishing between these entities. mRNA was isolated from fresh pancreatic tissues (19 carcinomas, 2 normal pancreas, 1 chronic pancreatitis) and amplified using standard RT-PCR techniques. Fifteen of 19 (79%) carcinomas overexpressed KOC mRNA relative to non-neoplastic tissue samples and expression increased progressively with tumor stage: the mean copy number of KOC mRNA transcripts was 1.5, 11.1, 31, and 28 for stage I, II, III, and IV carcinomas, respectively, compared with 0.9 and 1 for normal pancreatic tissue and chronic pancreatitis, respectively. Immunostains using the KOC antibody were performed on 50 surgical resection specimens (38 invasive adenocarcinomas, 3 intraductal papillary-mucinous neoplasms, 2 mucinous cystic neoplasms, 7 chronic pancreatitis). KOC staining was present in 37 of 38 (97%) carcinomas: the staining reaction was moderate or strong in 36 of 38 (94%) and present in >50% of the tumor cells in 35 of 38 (92%) cases. Severe dysplasia of the ductal epithelium, present in 19 foci of intraductal papillary mucinous carcinoma, mucinous cystadenocarcinoma, and grade 3 pancreatic intraepithelial neoplasia (PanIN3) showed strong or moderate staining in 15 (79%) cases, whereas foci of mild and moderate dysplasia (intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms with adenoma and/or moderate dysplasia, PanIN1, and PanIN2) were uniformly negative for this marker in 25 and 22 cases, respectively. In the normal pancreas, weak background staining of acini was present in 12 of 50 (24%) cases but was easily distinguishable from the type of staining identified in neoplastic epithelium, and benign ducts and ductules were negative in all cases. Four of 38 (11%) foci of chronic pancreatitis, present in the 7 resections performed for chronic pancreatitis as well as 31 foci of peritumoral chronic pancreatitis, showed weak staining in

The hepatic glucose transporter, GLUT2, facilitates bidirectional glucose transport across the hepatocyte plasma membrane under insulin regulation. We studied the interactions of IR and GLUT2 proteins to determine whether they are physically coupled in a receptor-transporter complex. By comparing endosome and plasma membrane IR and GLUT2 ratios before and after feeding, it was determined that IR and GLUT2 are internalized in a fixed ratio. When solubilized hepatocytes were immunoprecipitated with antibodies against either IR or GLUT2, both proteins co-precipitated. The association of IR and GLUT2 was further assessed by confocal microscopy. Sections of fed liver were incubated with fluorescein-tagged anti-GLUT2 or Texas Red-tagged anti-IR. Colocalization was observed both at the plasma membrane and in the cytosol. Fluorescence-resonance energy transfer studies further confirmed this association. We conclude that IR and GLUT2 form a receptor-transporter complex in hepatocytes, which forms a mechanism of insulin-mediated hepatic glucose regulation.

We aimed to determine whether early trends in the serum pancreatic enzymes and liver tests of patients with gallstone pancreatitis predict persistent common bile duct (CBD) stones and complications.Medical records of patients with gallstone pancreatitis were reviewed retrospectively. Serial serum pancreatic enzymes and liver tests were recorded until the time of cholangiography. Laboratory trends were analyzed by comparing initial results obtained in the emergency department to subsequent results obtained 8-24 h, 24-48 h, and 48-72 h after presentation.Of 154 patients with gallstone pancreatitis, 28 (18%) had persistent CBD stones at cholangiography. Complications and death were more frequent in patients with persistent CBD stones than in those without CBD stones (29% and 11% vs 12% and 1%, respectively; p0.05). Laboratory trends predicted both persistent CBD stones and complications of pancreatitis. When any laboratory value rose between admission and 24-48 h of hospitalization, persistent CBD stones were present in 31% of cases, versus 8% of those in whom all laboratory values remained constant or fell (p = 0.001). Likewise, complications occurred in 21% of those with any rising laboratory value, versus 8% of those in whom all values remained constant or fell (p0.05).Patients with gallstone pancreatitis and rising serum chemistries had a 4-fold risk of persistent CBD stones and a nearly 3-fold risk of complications compared to patients in whom all chemistry values remained constant or fell. This simple prediction rule may identify patients with biliary pancreatitis who are most likely to benefit from early interventions to diagnose and remove persistent CBD stones.

Chronic pancreatitis (CP) is associated with impaired glucose tolerance and with reduced hepatic sensitivity to insulin. We have previously shown that in normal and sham-operated rats, insulin suppresses hepatic glucose production, and this suppression is associated with a decrease in the hepatocyte plasma membrane-bound quantity of the facilitative glucose transport protein GLUT2. The insulin-mediated reduction in membrane-bound GLUT2 is impaired in CP, and may play a role in the glucose intolerance associated with CP. To determine whether GLUT2 is actively internalized and whether this mechanism is disordered in CP, livers from fed and fasting rats in whom CP had been induced 2-3 months earlier by pancreatic duct oleic acid infusion, and in sham-operated (sham) rats, were fractionated to yield endosome (E)- and plasma membrane (PM)-enriched fractions. Forty-five minutes after duodenal intubation alone (fasting) or intubation plus duodenal feeding, livers were removed, homogenized and ultracentrifuged, and microsomal pellets were separated by sucrose density gradient ultracentrifugation. GLUT2 content of fractions was determined by Western blotting and scanning densitometry. The E:PM ratio of GLUT2 increased from 0.68 +/- 0.11 (mean +/- SEM) in fasting sham livers (n = 8) to 1.04 +/- 0.09 in fed sham livers (n = 8; p < 0.05). However, there was no change in the E:PM ratio of GLUT2 in CP livers after duodenal feeding (0.90 +/- 0.12 vs. 0.86 +/- 0.10; n = 8,8; p = NS). To test our findings using confocal laser scanning microscopy, liver specimens from fed and fasting CP and sham rats were minced, fixed in 4% paraformaldehyde, sectioned, and stained with rabbit antirat GLUT2 antibody followed by rhodamine-labeled secondary antibody. GLUT2 was quantified by mean pixel intensity in an 8 x 16-pixel area of PM and a 16 x 16-pixel area of cytosol (CYT) in each of 30 random cells/field (400x) in each of three rats per group. As in the fractionation study, duodenal feeding increased the CYT:PM ratio of GLUT2 from 0.75 +/- 0.01 in fasting sham liver to 0.86 +/- 0.01 in fed sham liver (p < 0.0001), while the CYT:PM ratio in CP remained unchanged. We conclude that feeding induces a shift in GLUT2 from the plasma membrane to the endosomal pool. The feeding-induced internalization of GLUT2 is absent in livers from rats with CP and may play a role in the glucose intolerance associated with CP.

The anatomy of the pancreas changes with normal aging. Atrophy of the pancreas occurs with age, and its weight may fall from a normal 60–100 g to 40 g or less by 85 years of age.1 This may actually facilitate detection of a small or subtle pancreatic mass, which may appear more prominent on imaging studies relative to the atrophied gland. The head of the pancreas and duodenal C loop may be displaced interiorly, with the ampulla of Vater found as low as the third or fourth lumbar vertebra; and in one case it was reported at the level of the second sacral vertebra.2 This inferior displacement of the pancreas can potentially cause difficulty interpreting radiographic studies.

The majority of the injuries of the biliary tract is iatrogenic. They are usually associated with operations in the upper abdomen. More than 80% of the injuries occur during cholecystectomy, which is the most common operation of the digestive system. Langenbuch performed the first cholecystectomy in 1882, after which the number of cholecystectomies increased rapidly, inevitably increasing the number of complications. Iatrogenic bile duct injuries are unfortunately not rare and may have disastrous consequences and very significant long-term morbidity and mortality.1,2 With adherence to well-established technical principles for open cholecystectomy, the incidence of bile duct injuries remained less 0.5% in most of the published retrospective series.3–5

Pancreatic polypeptide (PP) has been scrutinized as a potential metabolic regulatory substance since its discovery. Data are now emerging that indicates PP has effects on insulin action and carbohydrate metabolism, which may be of great physiologic importance. The demonstration of such effects has been difficult despite characteristics that have invited the belief that this peptide might be a glucoregulator, namely its presence in pancreatic islets along with other substances with well-known glucoregulatory effects, and its postprandial pattern of release. Despite these characteristics, the physiologic role of PP was initially thought to involve actions such as inhibition of choleresis and exocrine pancreatic secretion through indirect effects on central and peripheral nerve fibers (1,2).

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 125 I-labeled PP (20-40 pM) and increasing concentrations of nonlabeled PP (1 × 10 -10 to 1 × 10 -6 M). After total and nonspecific binding was quantified by gamma counting, coefficients of dissociation (K d ) and maximal binding sites (B max ) were determined by Scatchard analysis of specifically bound radioactivity. Binding data were normalized to membrane protein content and expressed as means ± standard error. B max 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). B max 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 difference 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 B max 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.

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-weeek-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 pancreathic and sham-operated animals received either intraperitoneal bovine pancreatic polypeptide or saline vehicle for 5 days. Intraduodenal glucose tolerance tests (GIT) 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 125 I-insulin. Dissociation coefficients (K d ) and maximum binding capacities (B max ) for high-affinity receptors were derived from Scatchard analyses. Results B max and K d in muscle were not altered in animals with chronic pancreatitis. In liver, B max was significantly less in rate 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 B max 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 highaffinity 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.

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.

To examine the effect of previous-day excessive alcohol consumption on laparoscopic surgical performance.Study 1 was a randomized controlled trial. Study 2 was a cohort study.Surgical skills laboratory.Sixteen science students (laparoscopic novices) participated in study 1. Eight laparoscopic experts participated in study 2.All participants were trained on the Minimally Invasive Surgical Trainer Virtual Reality (MIST-VR). The participants in study 1 were randomized to either abstain from alcohol or consume alcohol until intoxicated. All study 2 subjects freely consumed alcohol until intoxicated. Subjects were assessed the following day at 9 am, 1 pm, and 4 pm on MIST-VR tasks.Assessment measures included time, economy of diathermy use, and error scores.In study 1, both groups performed similarly at baseline, but the alcohol group showed deterioration on all performance measures after alcohol consumption. Overall, although the time score differences between the 2 groups were not statistically significant (P = .29), there was a significant difference between the 2 groups' diathermy (P.03) and error (P.003) scores. There was also a significant effect for time of testing (P.003), diathermy (P.001), and errors (P.001). In study 2, experts demonstrated a similar postalcohol performance decrement for time (P.02), diathermy (P.001), and error scores (P.001).Excessive consumption of alcohol appeared to degrade surgical performance the following day even at 4 pm, suggesting the need to define recommendations regarding alcohol consumption the night before assuming clinical surgical responsibilities.

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

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)

Hypothesis: Widespread use of computed tomography and ultrasound has led to the identification of increasing numbers of patients with asymptomatic cystic lesions of the pancreas. Design: Retrospective case series of patients with pancreatic cystic lesions. Setting: University-affiliated tertiary care referral center. Patients: Two hundred twelve patients with pancreatic cystic lesions seen in our surgical practice during 5 years (April 1997-March 2002). Main Outcome Measures: Presence or absence of symptoms, cyst size and location, cytologic or pathologic diagnosis, surgical treatment, and outcome. Results: Seventy-eight (36.7%) of 212 patients were asymptomatic. Incidental cysts were smaller (3.3 3 ±1.9 vs 4.6 ±2.7 cm; P