Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol x kg(-1) x min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.

Peripheral insulin release after pancreatic resection: the effect of decreased beta-cell mass with systemic or portal drainage.

Surgical alteration of the pancreas can result in several anatomic alterations which may affect insulin release. We evaluated the effects of resection, systemic drainage, and autotransplantation of the canine pancreas on peripheral insulin levels and glucose disposal as measured by iv glucose tolerance tests (IVGTT) and a steady state hyperglycemic challenge (clamp). Proximal pancreatectomy (PPx) with reduced beta-cell mass and intact portal drainage resulted in a modestly elevated fasting glucose level and increased integrated glucose response to IVGTT. Compared to preoperative normals, basal insulin was unchanged from preoperative controls; however, peak insulin and integrated insulin response to IVGTT were decreased in PPx animals. Splenocaval drainage or autotransplantation of the distal pancreas resulted in normalization of the severely altered insulin response and fasting glucose levels. K values were significantly reduced after all three procedures. Clamp studies confirmed the basal glucose and insulin findings of the IVGTT. During the clamp, PPx animals had peripheral insulin values approximately 50% of normal controls, while autotransplantation and splenocaval drainage animals had insulin values that approximate normal controls. All three postsurgical groups had blunted insulin levels during stable hyperglycemia. Glucose utilization rates were severely decreased in all three groups. Reduction of beta-cell mass with intact portal drainage resulted in reduced insulin response to glucose challenge by either IVGTT or clamp. Systemic drainage of this same reduced beta-cell mass resulted in peripheral insulin levels comparable to normal controls. Denervation (autotransplantation) had little additive effect. All three groups demonstrated severely decreased rates of glucose disappearance as measured by both IVGTT and clamp studies. Therefore, reduction in beta-cell mass, drained systemically or portally, results in altered glucose disposal regardless of the peripheral insulin levels.

The hepatic extraction of gastric inhibitory polypeptide and insulin.

The hepatic extractions of gastric inhibitory polypeptide (GIP) and insulin were determined using in vitro and in vivo methods to assess the role of the liver in GIP metabolism and the possible effect of GIP on the hepatic extraction of insulin. During in vitro studies using the isolated perfused rat liver, infusion of GIP (2000 pg/ml) alone and in combination with porcine insulin (200 microU/ml) resulted in negligible hepatic extraction of immunoreactive GIP (IR-GIP) in both fed and fasted animals during either physiologically euglycemic or hyperglycemic perfusions. Hepatic extraction of insulin, however, ranged from 26-36% in fasted animals and from 7-25% in fed animals. Hepatic extraction of insulin and net hepatic glucose appearance were minimally affected by GIP. In vivo studies in awake dogs were then performed, in which simultaneous portal and peripheral venous levels of IR-GIP, immunoreactive insulin (IRI), and glucose were assessed after intraduodenal glucose administration. The portal to peripheral (PORT/PERI) venous ratio of endogenous IRI and IR-GIP reflected the findings of the in vitro studies; the PORT/PERI ratio of IRI levels rose from a basal value of 1.9 +/- 0.3 to a peak of 3.7 +/- 0.9, while the PORT/PERI ratio of IR-GIP levels rose from a basal value of 1.0 +/- 0.1 to a peak of 1.4 +/- 0.2, then rapidly returned to 1.0. The in vivo data are consistent with a continuous hepatic extraction of 40-50% of the insulin entering the liver and a negligible hepatic extraction of IR-GIP. We conclude that hepatic extraction of GIP in vitro or in vivo is minimal. In addition, while the fed state of the animal before infusion can result in changes in the in vitro hepatic extraction of insulin, GIP does not mediate these changes.

Circulating dihydroxyphenylglycol and norepinephrine concentrations during sympathetic nervous system activation in patients with pheochromocytoma.

Although increased plasma norepinephrine (NE) concentrations mediate vasoconstriction during episodic hypertension and hypertensive crises in patients with pheochromocytoma (Pheo), the precise origin of this circulating NE (tumor or sympathetic nerves) is not known. Dihydroxyphenylglycol (DHPG), a deaminated metabolite of NE, is formed principally in sympathetic nerve endings. Under basal conditions, plasma NE and DHPG concentrations correlate closely, and during sympathetic nervous system activation, both plasma NE and DHPG concentrations increase. This observation suggests that plasma DHPG concentrations may reflect the source of circulating NE (tumor or sympathetic nerves) during hypertensive episodes in patients with Pheo. Plasma NE and DHPG concentrations were measured simultaneously, and the NE/DHPG ratio was calculated in seven patients with Pheo during 20 min of sympathetic nervous system activation (treadmill exercise) before and after surgical resection of the tumor. Age- and sex-matched normal subjects were also studied. Exercise resulted in a significant increase in plasma NE and DHPG concentrations in patients with Pheo and in normal subjects (Pheo: basal NE, 1827 +/- 639; peak NE, 3016 +/- 769 pg/mL (P = 0.02); normal subjects: basal NE, 266 +/- 27; peak NE, 1166 +/- 197 pg/mL (P = 0.01); Pheo: basal DHPG, 1521 +/- 280; peak DHPG, 2313 +/- 252 pg/mL (P = 0.007); normal subjects: basal DHPG, 870 +/- 50; peak DHPG, 1630 +/- 180 pg/mL (P = 0.01)]. The NE/DHPG ratio increased with exercise in normal subjects (basal, 0.30 +/- 0.02; peak, 0.83 +/- 12; P = 0.005), but did not change in patients with Pheo (basal, 1.22 +/- 0.32; peak, 1.54 +/- 0.27). Exercise also increased plasma NE and DHPG concentrations and the NE/DHPG ratio in five patients studied after surgical resection of the tumor. Systolic blood pressure and heart rate increased significantly during exercise in all three study groups. The increase in plasma NE and HDPG concentrations during exercise-induced sympathetic nervous system stimulation in patients with Pheo is similar to that in normal subjects and may indicate that the sympathetic nervous system plays an important role in the pathogenesis of hypertension and hypertensive crises in patients with Pheo.

Inhibition of basal and meal-stimulated choleresis by somatostatin.

The effect of somatostatin, an inhibitor of release of a number of gastrointestinal and other hormones, on choleresis was investigated in chronic, bile fistula dogs with taurocholate-stabilized bile flow. Somatostatin inhibited both fasting and meal-stimulated choleresis, and bile flows during somatostatin inhibition of both fasting and fed dogs were similar, suggesting a complete suppression of factors causing feeding choleresis. Although a transient decrease in bile salt output was observed, bile salt output was unaffected during most of the period of bile flow inhibition. Hormone suppression by somatostatin, indicated by measurement of serum insulin, occurred over a similar time course as inhibition of choleresis. These observations provide further evidence for physiological humoral regulation of choleresis.

Selective biliary secretion of basal and glucagon-inhibited neutral sterol after triparanol administration.

Biliary cholesterol secretion was studied in dogs with chronic bile fistulas, using glucagon, an inhibitor of biliary cholesterol secretion, and triparanol, an inhibitor of cholesterol synthesis. Glucagon inhibited neutral sterol secretion before and after triparanol administration. Triparanol caused a significant accumulation in bile of the cholesterol precursor desmosterol which comprised a significant portion of the neutral sterol in bile but not in blood. Glucagon inhibited both biliary desmosterol and cholesterol secretions to a similar degree. These findings suggest that biliary cholesterol is derived from newly synthesized hepatic sterol as well as from equilibrated sources. Furthermore, glucagon suppressed biliary secretion of both equilibrated as well as newly synthesized neutral sterol, suggesting that glucagon inhibits the movement of neutral sterol to or through the canalicular membrane.

Insulin-dependent and insulin-independent effects after surgical alterations of the pancreas.

Anatomic alterations of the pancreas result in physiologic alterations that have not been completely analyzed. Insulin plays a major role in carbohydrate metabolism; nevertheless, as much as 50% of a hyperglycemic load may be metabolized independent of insulin. We analyzed the effects of surgical alterations of the pancreas on postoperative glucose metabolism, including insulin-independent effects. Mongrel female dogs underwent one of three procedures: proximal partial pancreatectomy (PPx), PPx plus diversion of pancreatic venous effluent to the systemic circulation (SC), or PPx plus segmental pancreatic autotransplantation (PAT). Intravenous glucose tolerance tests, with or without a background infusion of somatostatin (SST; 400 ng/kg/min) were performed on all animals preoperatively and postoperatively. SST completely suppressed secretion of assayable peripheral insulin. The rate of glucose disposal during SST suppression approximates the rate of insulin-independent glucose disposal (IIGD). Although there was a significant decrease in the rate of glucose disposal during SST infusion when compared with the rate without SST, no differences in IIGD were found between postoperative groups. IIGD was calculated at 50% to 55% for control, PPx, and SC groups and at 67% for PAT. Peripheral sensitivity to an exogenous insulin infusion (euglycemic clamp) was unchanged by any of the procedures. We conclude that surgical alteration of the pancreas, including pancreas transplantation, results in altered glucose handling in the face of "normal" peripheral levels of insulin. Changes in IIGD and analysis of peripheral sensitivity to insulin do not explain these alterations completely.

Gastrointestinal complications after cardiopulmonary bypass.

Gastrointestinal (GI) complications after surgery requiring cardiopulmonary bypass (CPB) can be serious, often lethal events. In our study, from 1970 through 1981 there were 43 such complications after 5080 CPB cases (0.85%). We noted on annual persistent occurrence of approximately 1%. The overall mortality rate was 63%. The most frequent complication was hemorrhage (usually gastroduodenal). Other complications encountered were pancreatitis, cholecystitis, hyperbilirubinemia, bowel perforations or infarcts, and gastroduodenal alterations. We concluded that GI complications after CPB are associated with a high mortality rate and often occur with other complications. Careful judgment is needed for appropriate diagnosis and therapy.

Chronic primary intestinal pseudo-obstruction.

Chronic primary intestinal pseudo-obstruction (CPIP) has received attention despite of its unclear etiology and infrequent occurrence. Recently a patient with this disorder had evidence of a primary visceral neuropathy. Reviewing the literature, we found 30 case reports of CPIP and evaluated their clinicopathologic findings. Presenting symptoms and radiologic findings were nonspecific. Esophageal motility was abnormal in 12 of 14 reports. Intestinal histopathology revealed normal muscle wall, mucosa, and ganglion cells in over 50% of reports. Only 48% of cases demonstrated clinical improvement. Thirty percent (8 of 30) ultimately died. We conclude that CPIP is a perplexing, often fatal entity that can mimic mechanical obstruction in the absence of definite etiology. Primary neurologic or muscular disease may be a possible explanation, but, as yet, definite documentation does not exist.

Preoperative evaluation and predictive value of fine-needle aspiration and frozen section of thyroid nodules.

BACKGROUND: We sought to evaluate the predictive value of preoperative fine-needle aspiration (FNA) on surgical decision making by evaluating the final pathologic diagnosis and comparing it to the preoperative diagnosis. Further, we wished to calculate the predictive accuracy of each of several types of preoperative FNA diagnosis. STUDY DESIGN: A retrospective chart review of 151 thyroid resections between July 1990 and April 1996 at the University of Virginia was undertaken. The mean age was 45 years (range, 11 to 85 years). Preoperative laboratory values, presenting symptoms, imaging studies, and predictive values of preoperative FNA and intraoperative frozen section were analyzed. RESULTS: Symptomatology was poorly predictive of a benign versus malignant postoperative final pathologic diagnosis. Sensitivity, specificity, and accuracy of frozen section versus FNA was 86% versus 86%; 99% versus 93%, and 96% versus 92%, respectively, if the reading "cancer" or "suspicious" were predicted as positive for malignancy and "benign" or "follicular" were predicted as negative for malignancy. If only the reading "cancer" was predicted as positive for malignancy and only "benign" was predicted as negative for malignancy, sensitivity and specificity for FNA were 100% and 96%, respectively, and 100% and 99%, respectively, for frozen section. Forty-nine "follicular" lesions obtained by preoperative FNA resulted in 46 benign diagnoses after surgical resection. CONCLUSIONS: The use of preoperative FNA is a powerful diagnostic tool in the hands of skilled pathologists. There is increasing evidence that intraoperative frozen section adds little to intraoperative decision making in patients diagnosed with thyroid cancer by preoperative FNA. Less definitive interpretations decrease the sensitivity, specificity, and accuracy of the FNA diagnosis.

Laparoscopic versus traditional appendectomy for suspected appendicitis.

We compared the results of concurrently performed laparoscopic versus open appendectomy as treatments for suspected acute appendicitis. The 68 laparoscopic procedures resulted in 62 appendectomies, 47 by the laparoscopic (LA) technique and 15 by the open (LO) technique. Another 54 patients underwent open appendectomy (OA). Significantly more females underwent laparoscopy (LA and LO: 52% versus OA: 33%, p = 0.047). Operative duration was shortest for OA (81 +/- 3 minutes), which was shorter than for LO (108 +/- 7 minutes), but not different than LA (86 +/- 6 minutes). The postoperative length of stay was not different for LA (3.5 +/- 0.5 days) compared with OA (5.9 +/- 1.6 days) or LO (4.8 +/- 1.3 days). One death occurred in the OA group. Wound complication rates were not significantly different for LA (4.3%) compared with OA (9.4%) and LO (13.3%). Overall complication rates were lower for LA (10.6%) and OA (18.9%) compared with LO (46.7%, p < 0.01). Median hospital cost for LO ($10,425) was higher (p < 0.02) than for either LA ($5,899) or OA ($5,220). When appendicitis was not present, definitive confirmation of pathology was achieved in 9 of 18 patients undergoing LA versus 4 of 14 patients having OA (p = not significant). We conclude that when laparoscopy and laparoscopic appendectomy can be performed, the procedure is safe and produces results comparable with those of open appendectomy without significant overall cost differences.

Effect of glipizide on the surgically altered pancreas.

Surgical alterations of the pancreas affect peripheral glucose, insulin, and glucagon levels with accompanying changes in carbohydrate metabolism. The sulfonylurea glipizide has been used to treat insulin-deficient states; however, its mechanism is not completely known. We hypothesized that glipizide would correct postoperative changes in glucose handling in a way that would allow more complete understanding of the drug's action. Two surgical groups (Group 1:80 percent proximal pancreatectomy; Group 2: proximal pancreatectomy plus splenocaval diversion) were compared with a healthy control group (Group 3). We have concluded that glipizide may have affected basal insulin sensitivity in the control group and Group 2 animals without affecting insulin secretion in response to oral or intravenous glucose stimulation. Glipizide does not correct the alterations in glucose handling or insulin secretion after reduction in beta-cell mass.

The effect of clinical pathway implementation on total hospital costs for thyroidectomy and parathyroidectomy patients.

Clinical pathways have long been used to guide the delivery of patient care in varied practice settings. There is little information in the literature to document the effectiveness of pathway implementation in general surgical populations. This study reports the effect of clinical pathway implementation in two general surgical patient groups, thyroidectomy and parathyroidectomy. Clinical pathways were implemented to serve patients undergoing thyroidectomy and parathyroidectomy surgery. The effects of both clinical pathways on total hospital costs, length of hospitalization, variances, and outcomes were collected and evaluated from July 1998 through July 1999. These data were compared to data from the previous year. The average length of stay for parathyroidectomy patients decreased from 2.4 to 1.5 days (P = 0.26) for pathway patients as compared to prepathway patients. The average cost per case decreased from $5071 to $4291 (P = 0.50) for parathyroidectomy pathway versus prepathway patients. The average length of stay decrease for thyroidectomy patients was 1.4 to 1.2 (P = 0.16) for the pathway to prepathway comparison. The average cost per case decrease was minor at $4117 to $4111. Pharmacy costs and laboratory utilization were effectively reduced. Perioperative costs rose dramatically during this period, operating room/central sterile supply cost per case rose 12 per cent, anesthesia supply cost per case rose 15 per cent, and surgical pathology costs increased 110 per cent overall for both patient groups. Clinical pathway implementation has allowed us to reduce or maintain total hospital costs in the face of rising perioperative costs. We conclude that implementation of these clinical pathways has allowed us to improve consistency with which we deliver care while maintaining the quality of patient outcomes and reducing the costs of care and length of hospital stay.

Primary small bowel malignancies.

Fifty-five patients with primary small bowel malignancies were evaluated from 1955 to 1983. Twenty-seven patients (49%) had carcinoid tumors, 16 (29%) had adenocarcinomas, and 12 (22%) had leiomyosarcomas. The average age at presentation was 68 years (range: carcinoids, 27-82; leiomyosarcomas, 36-75; adenocarcinomas, 40-83). Carcinoids and leiomyosarcomas were 1.7 and 2.0 times, respectively, more common in men; adenocarcinomas showed no sex predominance. Eighty-nine per cent of all patients had symptoms: abdominal pain in 65 per cent, obstruction in 23 per cent, bleeding in 8 per cent, and palpable mass in 5 per cent. Although 27 per cent of carcinoid patients were asymptomatic, 40 per cent exhibited the carcinoid syndrome. Symptoms were longstanding in the majority of cases, and, at the time of diagnosis, 49 per cent of the carcinomas were metastatic. Fifty-five per cent of the tumors were in the ileum, 24 per cent in the jejunum, and 21 per cent in the duodenum. Fifty-five patients (89%) underwent resection for palliation or cure. Five adenocarcinoma patients (32%) survived 1 year, and one (6%) lived 10 years. Twenty-five per cent of leiomyosarcoma patients survived for 10 years. Eighty-seven per cent of patients with carcinoids survived for 1 year, 39 per cent for 5 years, and 22 per cent for 10 years. Previous reports have documented the difficulty of diagnosing these lesions, as does the present study. A higher degree of physician awareness and a more aggressive investigation of referable symptoms should lead to earlier treatment and better long-term results.

Effect of total laryngectomy on esophageal motility.

Total laryngectomy for cancer can result in dysphagia and altered esophageal motility. Manometric changes in the upper esophageal sphincter (UES), and in proximal and distal esophageal function have been reported. However, most studies have failed to take into account radiation therapy and appropriate controls. We selected ten male patients (54.3 +/- 1.9 yr) for longitudinal manometric evaluation prior to laryngectomy then at two weeks and again six months later. No patient received preoperative radiation therapy, had a previous history of esophageal surgery, or developed a postoperative wound infection or fistula. Seven of ten patients had positive nodes and received 6,000-6,600 rads postoperative radiation therapy. Preoperatively 4 of 10 patients complained of dysphagia which did not significantly change following surgery and radiation. Two of three patients who did not complain of dysphagia preoperatively and received radiation postoperatively developed dysphagia. No patient without dysphagia preoperatively who received no radiation therapy developed symptoms. Our studies show that laryngectomy causes alterations in the UES resting and peak pressures but not in the proximal or distal esophagus, or the lower esophageal sphincter. These data also imply radiation therapy may be associated with progressive alterations in motility and symptomatology. Further study regarding the effects of radiation on esophageal motility and function are urged.

Dynamic CT for parathyroid disease: are multiple phases necessary?

BACKGROUND AND PURPOSE: A 4D CT protocol for detection of parathyroid lesions involves obtaining unenhanced, arterial, early, and delayed venous phase images. The aim of the study was to determine the ideal combination of phases that would minimize radiation dose without sacrificing diagnostic accuracy. MATERIALS AND METHODS: With institutional review board approval, the records of 29 patients with primary hyperparathyroidism who had undergone surgical exploration were reviewed. Four neuroradiologists who were blinded to the surgical outcome reviewed the imaging studies in 5 combinations (unenhanced and arterial phase; unenhanced, arterial, and early venous; all 4 phases; arterial alone; arterial and early venous phases) with an interval of at least 7 days between each review. The accuracy of interpretation in lateralizing an abnormality to the side of the neck (right, left, ectopic) and localizing it to a quadrant in the neck (right or left upper, right or left lower) was evaluated. RESULTS: The lateralization and localization accuracy (90.5% and 91.5%, respectively) of the arterial phase alone was comparable with the other combinations of phases. There was no statistically significant difference among the different combinations of phases in their ability to lateralize or localize adenomas to a quadrant (P = .976 and .996, respectively). CONCLUSIONS: Assessment of a small group of patients shows that adequate diagnostic accuracy for parathyroid adenoma localization may be achievable by obtaining arterial phase images alone. If this outcome can be validated prospectively in a larger group of patients, then the radiation dose can potentially be reduced to one-fourth of what would otherwise be administered.