Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.

BACKGROUND: The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. OBJECTIVE: To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. SUBJECTS AND METHODS: FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. RESULTS: Si was lower in insulinoma patients before, compared with after surgery (3.37 +/- 0.62 vs. 6.24 +/- 1.09 SE [x10(-4)] min(-1)microU(-1) ml, P < 0.05). Sg was similar in patients pre- and post-surgery (3.0 +/- 0.67 vs. 2.4 +/- 0.6 [x10(-2)] min(-1), NS). CONCLUSIONS: Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.

Public Health Follow-up of Suspected Exposure to Echinococcus multilocularis in Southwestern Ontario.

In the 3 years since the first report of canine alveolar echinococcosis (AE) in Ontario, three additional cases have been diagnosed in the province. Of the four cases reported to date, three have had no known history of travel outside the province. It is possible that this development is an indication of previously unrecognized environmental contamination with Echinococcus multilocularis eggs in some areas of the province. If so, there is the potential for an emerging threat to human health. This article describes a local public health department's investigation of the possible exposure to E. multilocularis of a number of individuals who had had contact with the latest of the four cases of canine AE, and summarizes a comprehensive decision process that can be used by public health departments to assist in the follow-up of such exposures.

Challenges in Interpretation of Diagnostic Test Results in a Mumps Outbreak in a Highly Vaccinated Population.

In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccinated population in southwestern Ontario, Canada, and the challenges encountered in interpreting the results of diagnostic tests used in the outbreak. During the outbreak, patients were interviewed and classified according to the outbreak case definition, and specimens were collected for diagnostic testing according to Ontario guidelines. Twenty-seven individuals were classified as confirmed cases (n = 19) or suspect cases (n = 8) according to the case definition, only 9 of which were laboratory-confirmed cases: 7 confirmed by reverse transcriptase PCR (RT-PCR) and 2 by IgM serology. All 19 confirmed cases represented patients who were associated with secondary schools in the local area and had been vaccinated against mumps with one (n = 2) or two (n = 17) doses of the measles-mumps-rubella (MMR) vaccine. This is the first published report of an outbreak of mumps in Ontario in which all confirmed cases had been vaccinated against the disease. It highlights the limitations of and difficulties in interpreting current mumps diagnostic tests when used in vaccinated individuals.

Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity.

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemic effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU.kg-1.min-1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 +/- 5 mU/L (mean +/- SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 +/- 1.4 mumol.kg-1.min-1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Sl) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 +/- 0.1 vs. 1.7 +/- 0.2 min-1 x 10(2), NS; pre- vs. postinfusion Sl 8.4 +/- 2.3 vs. 11.8 +/- 3.7 min-1.mU-1.L x 10(4), P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of epinephrine on glucose-mediated and insulin-mediated glucose disposal in insulin-dependent diabetes.

The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mU/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGTT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 +/- 0.3 SE v 7.7 +/- 0.7 mmol/L, P less than .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 +/- 0.1 v 0.3 +/- 0.1 mmol/L, P less than .05); and (3) profoundly reduced glucose disposal (KG 0.59 +/- 0.1 v 1.91 +/- 0.33 min-1 x 10(2), P less than .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 +/- 0.5 v CTR 7.03 +/- 3.2 min-1.mU-1.L x 10(4), P less than .05) with no significant change in SG (EPI 2.5 +/- 0.2 v CTR 3.1 +/- 0.5 min-1 x 10(2), NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic modeling of the intravenous glucose tolerance test in type 2 diabetes: a new approach to the insulin compartment.

The minimal model of Bergman et al has been used to yield estimates of insulin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by incorporating exogenous insulin protocols into the regular intravenous glucose tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiologic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeutic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/kg) and a "physiologic" insulin infusion throughout the IVGTT in a series of 8 patients, 5 of whom were insulin-requiring. Data from this approach were analyzed using the modelling program CONSAM to apply the Bergman model, either unmodified (BMM), or incorporating an additional delay element between the plasma and "remote" insulin compartments (MMD). Application of the MMD and extension of the IVGTT from 3 to 5 hours improved successful resolution of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subjects (1.86 +/- 0.60 v. 8.65 +/- 2.27 min(-1) x microU(-1) x mL x 10(4) P <.01). The results were validated in the type 2 diabetes group using a 2-stage euglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) x microU(-1) x mL x 10(4) P >.4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v. 1.55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabetic subjects was then analyzed using the MMD, but this approach did not enhance the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality whereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postulated that the physiologic basis for this delayed action may relate to transcapillary endothelial transfer of insulin, this process limiting the rate of onset of insulin action.

The effect of norepinephrine on insulin secretion and glucose effectiveness in non-insulin-dependent diabetes.

It has previously been shown that in normal subjects, physiological elevation of norepinephrine (NE) impairs insulin sensitivity (Si) but does not influence insulin secretion. The aim of this study was to determine the effect of short-term physiological elevation of NE on insulin secretion, Si, and glucose-mediated glucose disposal, or the glucose effectiveness index (Sg), in non-insulin-dependent diabetes mellitus (NIDDM). Two intravenous glucose tolerance tests (IVGTTs) were performed in eight well-controlled NIDDM patients, using a supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. The IVGTTs were performed in random order after 30 minutes of either the saline (SAL) or NE (25 ng/kg/min) infusions, which were continued throughout the 3-hour IVGTT. Sg and Si were estimated by minimal model analysis of the IVGTT data as previously described. Plasma C-peptide was used to estimate insulin secretion rate using the ISEC program. NE infusion produced approximately a threefold increase in plasma NE, associated with (1) a significant reduction in glucose disposal ([KG] SAL v NE, 0.73 +/- 0.06 v 0.61 +/- 0.06 x 10(-2).min-1, P < .05), (2) no reduction in Si (2.33 +/- 0.8 v 2.62 +/- 0.9 x 10(-4).min-1/mU/L, NS), (3) a reduced mean second-phase insulin secretion rate (1.21 +/- 0.19 v 1.01 +/- 0.16 x 10(-3) pmol/kg/min per mmol/L glucose, P < .05), (4) a significant increase in Sg (0.89 +/- 0.08 v 1.63 +/- 0.2 x 10(-2).min-1, P < .05), and (5) a corresponding increase in glucose effectiveness at zero insulin ([GEZI] 0.55 +/- 0.13 v 1.30 +/- 0.33 x 10(-2).min-1, P < .05). These results show that in contrast to normal subjects, physiological elevation of NE in NIDDM does not result in a reduction in Si, but causes a reduction in glucose disposal related to inhibition of insulin secretion that is only partially compensated for by increased Sg.

Evaluation of a methodology for the use of preparations from rat small intestine in the Salmonella/microsome assay.

A methodology is evaluated for the use in the Ames assay of a microsomal metabolising system derived from villous tip cells of rat small intestine. The procedure involved high frequency vibration of everted gut segments followed by gentle lysis and homogenisation. This technique, which has previously been shown to result routinely in high levels of cytochrome P450 and linked enzymes, has now been investigated for its ability to yield preparations capable of activating several promutagens in the Salmonella/plate incorporation test. The data obtained have been compared with results observed with standard rat liver metabolising fractions. In the presence of intestinal microsomes, 2-aminoanthracene, 2-aminofluorene, 2-acetylaminofluorene, aflatoxin B1, benzo[a]pyrene and cyclophosphamide all caused dose-related increases in revertants, the maximum yields of which were lower than those detected with liver microsomes or S9 mix. These and other differences in dose-responses have been discussed in relation to the levels of microsomal protein and cytochrome P450 plated and with respect to the activities of relevant enzymes in the tissue extracts.

The effect of collection and extension on tarsal flexion and fetlock extension at trot.

A recent epidemiological study indicated that various factors may be related to injury in dressage horses, but the mechanism by which these injuries occur has yet to be determined. The suspensory ligament (SL) is a frequent site of injury, and it is assumed that greatest strain is placed on this structure in collected trot; this has yet to be proved conclusively. The study aimed to investigate the effect of collected and extended trot on the hindlimb movement pattern. Four dressage horses were fitted with markers and inertial motion sensors (IMS). High-speed video was obtained for 2 strides on each rein in collected and extended trot on 3 different surfaces: waxed outdoor; sand/plastic granules; and waxed indoor. Maximal tarsal flexion during stance and distal metatarsal coronary band ratio (MTCR), representing fetlock extension, were determined. Inertial motion sensor data determined stride duration, speed and stride length. Data were compared between collection and extension within horses on each surface, and compared between surfaces. Collected trot had significantly lower speed and stride length but longer stride duration than extended trot on all surfaces. All horses had less tarsal flexion and fetlock extension in collected compared with extended trot (P<0.05), which is likely to increase SL loading. The study findings indicate that extended trot may increase SL strain, providing a possible explanation for the high incidence of SL injury in horses trained for extravagant movement. It is possible that substantial use of extended trot could be a risk factor for development of suspensory desmitis, which might be one contributory factor in the prevalence of suspensory desmitis in young horses repeatedly undertaking extravagant movement.

Activation of benzo[a]pyrene and aflatoxin B1 to mutagenic chemical species by microsomal preparations from rat liver and small intestine in relation to microsomal epoxide hydrolase.

Rat small intestinal microsomes have been compared with liver preparations for their ability to activate promutagens using the Salmonella mutagenicity assay. Induced levels of arylhydrocarbon hydroxylase and cytochrome P-450 in intestinal microsomes are significantly lower than the corresponding amounts in liver microsomes. Greater activation of benzo[a]pyrene (BP) by liver extracts would thus be expected. Although this was observed at greater than 1 microgram BP/plate, at lower doses comparatively high levels of activation were obtained with intestinal microsomes. This could be due to preferential formation of the mutagenic 4,5-oxide with intestinal microsomes, as opposed to the putative major active metabolite, the 7,8-diol-9,10-epoxide. Microsomal epoxide hydrolase inactivates the K-region epoxide by forming the corresponding dihydro-diol. Differences in the levels of these metabolites may thus be a result of higher activity of the enzyme in liver extracts. This hypothesis has been studied using the epoxide hydrolase inhibitor, 1,2-epoxy-3,3,3-trichloropropylene oxide (TCPO). Enzyme activity has been measured using [3H]-BP-4,5-oxide as substrate. Since aflatoxin B1 (AFB) may also be activated via analogous epoxide intermediates, the effects of TCPO on activation of AFB were also investigated. Intestinal microsomal epoxide hydrolase activities were significantly lower than those in liver preparations obtained from animals pre-treated with enzyme inducers. Enzyme activity and promutagen activation ability of intestinal microsomes, respectively, were less susceptible to and not inhibited by TCPO. However, TCPO strongly inhibited microsomal epoxide hydrolase activity and activation of BP and AFB due to liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of a microsomal fraction from rat small intestine for metabolic activation of some promutagens.

Rat small intestine possesses cytochrome P-450 mixed function oxidase activity and is thus potentially capable of activating procarcinogens during absorption. The low spontaneous tumour incidence at this site may be due partially to the detoxification activity of the intestinal mucosa. To study the contribution of the intestine to the metabolism of foreign chemicals, microsomes have been obtained from rat small intestine by a procedure facilitating recovery of preparations with consistently high enzyme activities and abilities to activate some selected promutagens in the Salmonella mutagenicity assay. Intestinal microsomes from animals with and without pretreatment with inducers have been used for investigations of biochemical properties and ability to activate several mutagens in the Salmonella plate incorporation assay. The effects of microsomal protein concentration and inhibitors were also studied. The results are compared with data obtained using liver microsomes from the same animals. Despite the induction of lower numbers of revertants, intestinal microsomes were at least as efficient as liver preparations for the activation of all the promutagens used when the data were corrected for cytochrome P-450 contents. Differences in dose-response curves for certain mutagens using liver and intestinal microsomes are discussed in relation to variation in metabolism of promutagens. Activation was linearly dependent on microsomal protein concentration, for both liver and small intestinal microsomes. The intestine was generally less susceptible to the effects of cytochrome P-450 and P-448 inducers, although sensitivity to orally administered phenobarbitone was increased by extending treatment times. SKF525A and beta-naphthoflavone inhibited microsomes from both sources, equal inhibition being observed for each type following incorporation of the inhibitor, although they differed in their ability to activate 2-acetylaminofluorene in the presence of the deacylase inhibitor, NaF. The data are discussed in relation to the possible role of the small intestine in metabolic activation in vivo and the utility of microsomes therefrom for the in vitro detection of putative dietary carcinogens.

Atrial natriuretic factor increases the magnitude of duodenal spontaneous phasic contractions.

The present investigation was designed to determine if atrial natriuretic factor relaxes non-vascular smooth muscle. Rather than cause a relaxation, atrial natriuretic factor induced a two-to-four fold enhancement in the amplitude of the spontaneous phasic contractions of duodenal longitudinal muscle. Dose-response curves revealed that ANF enhanced these contractions over a concentration range of 10 picomoles to 100 nanomoles with the ED50 at 1 nanomolar. The increased amplitude of contraction began within 30 seconds and was calcium-dependent. The increased force of contraction was associated with a three-fold increase in cyclic GMP levels and activation of particulate guanylate cyclase [E.C.4.5.1.2.]. Atrial natriuretic factor had its half-maximal [ED50] activation of guanylate cyclase at its 1 nM concentration while maximal enhancement was at its 100 nM concentration in duodenum, jejunum, and ileum. Atrial natriuretic factor did not stimulate adenylate cyclase [E.C.4.6.1.1.]. Thus, atrial natriuretic factor increases the force of the spontaneous phasic contractions of the small intestine which are calcium-dependent and associated with activation of the guanylate cyclase-cyclic GMP system.

The effect of cimetidine on cyclic nucleotides in human gastric mucosa.

1 Pre-drug concentrations of both nucleotides were similar in patients with or without peptic ulceration. 2 The effect of a singly infusion or repeated oral administration of cimetidine on human gastric mucosal content of cyclic AMP and cyclic GMP was studied. 3 Biopsies from the body of the stomach were taken at endoscopy from patients who were participating in a clinical trial of the value of cimetidine in the treatment of duodenal ulcer. Cyclic nucleotide determinations and histological examinations were performed on biopsies taken before and after cimetidine treatment. 4 Gastric mucosal content of cyclic AMP was significantly increased (P less than 0.01) 20 min after intravenous infusion of 200 mg cimetidine. There was also a significant increase (P less than 0.01) in gastric mucosal cyclic AMP following administration of the drug orally for 28 days. No alterations in gastric mucosal histology were observed following cimetidine treatment. 5 Gastric mucosal content of cyclic GMP was not altered by intravenous drug infusion, or by chronic treatment.

Atrial natriuretic prohormone peptides 1-30, 31-67, and 79-98 vasodilate the aorta.

Human prohormone atrial natriuretic peptides 1-30, 31-67, and 79-98 caused vasodilation of porcine aortas which began in 30 seconds and was maximal at 10 minutes. These three peptides were found to be equally potent to atrial natriuretic factor in their vasodilatory activity which was found with or without endothelium present. This vasodilation was associated with a 4 to 5 fold increase in cyclic GMP in the aorta secondary to activation of particulate guanylate cyclase [E.C. 4.6.12]. These data demonstrate that three N-terminal peptide segments of the atrial natriuretic factor prohormone cause vasodilation.

Gastric neoplasm in the West of Ireland: an endoscopic survey.

The results of endoscopic examination, biopsy taken at endoscopy and cytology of brush smears and/or gastric lavage specimens in 100 patients with proven malignant gastric lesions are described. Overall, a correct pre-operative diagnosis was achieved in 98 cases. Endoscopic appearance was a more accurate criterion in cases of exophytic advanced carcinoma, malignant ulcer and lymphoma than in diffuse infiltrative carcinoma or in early carcinoma, where biopsy and cytology were more accurate. Nine per cent of neoplasms were malignant lymphomas, which is much higher than the usual reported incidence. Early carcinoma was found in 5% of cases. In spite of readily available facilities for endoscopic diagnosis, most cases of gastric neoplasm were already advanced at the time of examination.

Mucosal enzyme patterns in gastric epithelial disease.

A correlation was sought between changes in enzymes involved in gastric acid secretion (Mg-, NaK-, K- and HCO3-stimulated ATPases) and histological changes in gastric biopsies. Alkaline phosphatase was also studied. Mg- and NaK-stimulated ATPase activities increased significantly in biopsies from the pylorus and antrum which showed moderate or severe gastritis. NaK ATPase levels increased and HCO3 ATPase decreased in incisural, body and fundic mucosa which had intestinal metaplasia and atrophic gastritis. No K+ ATPase was found in normal mucosa. The total activity of alkaline phosphatase did not vary with histological changes in the gastric mucosa. Results indicate that the ATPase enzyme systems are sensitive indicators of gastric mucosal disease.