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CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Neuroendocrine tumors (NETs) are difficult to diagnose. Their symptoms may be vague or intermittent, and are frequently associated with much more common diseases; many of the tumors may be asymptomatic. Therefore, diagnosis can be delayed for some years. Because most NETs are secretory, the measurement of circulating biomarkers is helpful not only for diagnosis but also for assessing tumor response to treatment, monitoring disease progression, and use as prognostic indicators., (Copyright © 2010. Published by Elsevier Inc.)

We hypothesized that there is less suppression of whole-body protein breakdown with feeding in patients with cystic fibrosis (CF) who exhibit decreased insulin secretion after a single meal. Using [1-13C]leucine, we measured rates of nonoxidative leucine disappearance (whole-body protein synthesis) and protein breakdown in nine CF patients (6-11 y of age) and five healthy control subjects (8-10 y of age) during feeding and fasting. In the CF patients, synthesis and breakdown (x +/- SD) were 172 +/- 61 and 157 +/- 67 mumol.kg-1.h-1 during feeding and 140 +/- 24 and 178 +/- 26 mumol.kg-1.h-1 during fasting. The respective control values were 129 +/- 27 and 114 +/- 20 mumol.kg-1.h-1 during feeding and 136 +/- 13 and 173 +/- 18 mumol.kg-1.h-1 during fasting. Leucine balance was nearly identical in the two groups. By analysis of variance, there was a significant effect of feeding on protein breakdown but no difference between the groups. However, when each group was analyzed separately, feeding resulted in a 34% decrease in breakdown in the control subjects (P = 0.001) and a 23% increase in synthesis in the CF group (P = 0.058). Plasma insulin concentrations did not differ in the two groups. Thus, feeding may affect protein turnover differently in children with CF than in control children independently of plasma insulin concentration.

Nitric oxide and vasoactive intestinal peptide (VIP) are potent vasodilators and postulated as inducers of hypotension. These mediators activate guanylate cyclase and adenylate cyclase, respectively, with subsequent biosynthesis of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) producing vascular smooth muscle relaxation and vasodilatation. Cyclic nucleotides and VIP were evaluated during Escherichia coli septicemia in two groups of rabbits; 1) sepsis alone and 2) sepsis and a competitive inhibitor of nitric oxide synthase, NG-monomethyl-L-arginine. Arterial blood was obtained for determination of bacteremia, lactic acidemia, nucleotides, nitrites, and VIP levels. Significant bacteremia, endotoxemia, tachycardia, lactic acidosis, and hypotension occurred in all animals (P < 0.005). Circulating blood levels of cGMP, nitrites, cAMP, and VIP (P < 0.005) increased with development of shock. The NG-monomethyl-L-arginine treated animals had less cGMP, nitrites, cAMP, and VIP produced (P < 0.01). Plasma cGMP levels remained stable, suggesting that stimulated phagocytes in whole blood were responsible for increased cGMP levels. Infusion of VIP produced profound hypotension and lactic acidemia. Results of these experiments provide definitive evidence that nitric oxide and VIP are mediators during septic shock and their messengers are cGMP and cAMP, respectively. In addition, phagocytic stimulation with increased production of cGMP may initiate shock, with these mediators acting synergistically to prolong hypotension.

The objective was to evaluate the Semmes-Weinstein monofilament as a potential predictor of foot ulceration. A case-control study was carried out in a teaching hospital clinic specializing in diabetes and hyperlipidemic disorders. Two groups of patients with noninsulin-dependent diabetes mellitus were studied: 168 with no history of foot lesions (No-Ulcer group, aged 58.1 +/- 9.7 years, duration 11.5 +/- 7.8 years) and 14 who had at least one foot ulceration during the last year (foot ulcer group, aged 60.8 +/- 7.8 years', duration 17.1 +/- 10.5 years). The authors defined and measured a "monofilament index" using a size 5.07 Semmes-Weinstein monofilament on three locations on each foot and then measured peroneal nerve current perception thresholds using the Neurometer at three frequencies: 5 Hz, 250 Hz, and 2,000 Hz. The monofilament index score was lower in patients in the foot ulcer group than in patients in the No-Ulcer group (1.71 +/- 2.36 vs 5.21 +/- 1.81, P < 0.001). A cutoff point at an index of 5 out of 6 yielded a sensitivity rate of 85.71% and a false-positive rate of 16.07%. The peroneal nerve current perception threshold was higher (P < 0.005) in patients in the foot ulcer group than in patients in the No-Ulcer group for all frequencies (605.8 +/- 414.6 vs 181.5 +/- 272.3 for 5 Hz; 743.2 +/- 361.7 vs 251.6 +/- 283.7 for 250 Hz; 859.4 +/- 220.2 vs 423.3 +/- 252.6 for 2,000 Hz). (ABSTRACT TRUNCATED AT 250 WORDS)

Beta cell hypersecretion is associated with the syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans. It is unknown whether concomitant alpha cell secretory dysfunction occurs in patients with this syndrome. The authors evaluated the gastroenteropancreatic hormones in four family members with varying degrees of the hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome. Gastroenteropancreatic hormones were measured during oral glucose tolerance test with and without subcutaneous octreotide injection. The study revealed that the administration of subcutaneous octreotide resulted in suppression of beta cell function (insulin and c-peptide) but had no effect or a delayed effect on alpha cell secretion (glucagon). Furthermore, the severity of glucagon abnormalities paralleled that of beta cell hypersecretion and the clinical and phenotypic manifestations of acanthosis nigricans in our four patients. We speculate that this alpha cell aberration could potentially be involved in the altered glucose homeostasis and perhaps the skin manifestations of this syndrome. Therefore, glucagon levels should be evaluated in the hormonal studies in patients with hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome.

The GI tract is one of nature's great pharmacies. Most, if not all, biologically active peptides can be found there, and it is quite likely that others remain to be discovered. Our ability to exploit this resource has expanded considerably over the past two decades. Advances in analytical techniques have allowed investigators to rapidly isolate and purify new compounds from tissue extracts. Sequencing and de novo synthesis of newly discovered peptides are now routine, and the structural modifications required to alter activity and tailor a compound to a particular use are easily made. A number of gastrointestinal peptides or their analogues for use in clinical studies are available from commercial sources (see Table 7). Somatostatin is the first gut peptide to successfully complete development and yield a pharmaceutical compound with a broad range of action. Several of the peptides discussed in this article have similar potential. TRH stands out as a candidate because of its effectiveness in the treatment of experimental spinal cord injury and a variety of shock states. Such a broad range of action in critical fields may justify the intensive development required to yield potent, long-acting, and highly specific analogues. Similarly, the antimetastatic and immunostimulant properties of the enkephalins offer promise for new therapies in the treatment of AIDS, ARC, and cancer. Studies with amylin may lead to new and more precise regimens of blood sugar control in insulin-dependent diabetics and could in turn, prevent some of the worst long-term effects of the disease. The development of effective intranasal forms of GHRH could spare children with GH-GHRH deficiency the distress of repeated injections and help to prevent excessive GH blood levels. Secretin, glucagon, or CGRP might be used one day in cardiovascular emergencies, and VIP or its analogues could prove effective in the treatment of asthma. Although preliminary results with many of these peptides are encouraging, further progress will require the development of standardized experimental models and a more rigorous approach to experimental design. Many of the studies reported here suffered from small patient numbers, a narrow or nonexistent range of doses, or the use of only one or two dosing regimens. Lack of objective criteria for determining the level of response, e.g., in studies of mental illness or degenerative diseases, and the ethical problems of withholding treatment from some patients to establish proper controls further hamper research in this area. If the questions of efficacy and safety are to be resolved, thorough, well-planned trials will be required.

Objective: Our objective was to elucidate the pathophysiologic effects and potential reversibility of terbutaline-induced changes in carbohydrate metabolism., Study Design: We prospectively evaluated serum glucose, insulin, glucagon, C-peptide, and pancreatic polypeptide levels in response to a 100 gm glucose challenge (oral 3-hour glucose tolerance test) in 17 obstetric patients without complications who were given terbutaline (5 mg orally every 4 hours) for 5 consecutive days between 24 and 32 weeks' gestation. Each patient served as her own control, with day 1 representing pretreatment, day 7 the treatment phase, and day 14 the posttreatment evaluation. Body mass index and posttreatment serum terbutaline levels were also measured., Results: A significant initial treatment effect (day 1 versus 7) was observed for glucose (elevated), insulin (elevated), insulin/glucose ratio (elevated), and pancreatic polypeptide (elevated). A significant delayed treatment effect (day 1 versus 14) was also observed for insulin (elevated), insulin/glucose ratio (elevated), and pancreatic polypeptide (elevated). Body mass index directly correlated with postchallenge measures of insulin, insulin/glucose ratio, pancreatic polypeptide, and C-peptide. Posttreatment serum terbutaline levels directly correlated with pancreatic polypeptide, but not with other parameters., Conclusions: Our data support a dose-independent, terbutaline-induced glucose intolerance mediated by glucagon and caused by diminished insulin sensitivity.

Octreotide (Sandostatin), a potent and long-acting octapeptide analogue of somatostatin, exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end, we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose, 200 micrograms; high dose, 400 micrograms) in nine female, C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose, free insulin, glucagon, GH, and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control, despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%, glucagon by 50%, and PP by 80%. Steady-state octreotide levels varied considerably among patients (low, mean +/- SEM), 1000 +/- 101, range 638 to 1375 pg/ml; high, mean 1940 +/- 147, range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses, we observed greater interindividual variability (low, mean 2.45 +/- 0.30, range 1.31 to 3.78 ml/kg/min; high, mean 2.36 +/- 0.19, range 1.68 to 3.48 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

An integral transmembrane glycoprotein of the Human Immunodeficiency Virus (HIV) is gp 41. Five peptides (P1, P2, P3, P4, and P5) containing a conserved region of the gp 41 molecule have been synthesized. We tested P3, P4 and P5 for their effects on short-circuit current (Isc) across rat colonic mucosa. All three peptides increased the Isc; P5 was the most potent agonist. Serosal pretreatment of tissues with the chloride transport inhibitor, bumetanide (0.1 mM) or chloride replacement with gluconate, inhibited the response, suggesting that the increase in Isc was due to stimulation of active chloride secretion. The synthetic somatostatin analog octreotide (0.1 mM) also inhibited (P less than .05) the response to P5 (1 microM). The data provide a possible rationale for one aspect of the efficacy of octreotide in treating secretory diarrhea in patients with Acquired Immunodeficiency Syndrome (AIDS).

Ten children with Prader-Willi syndrome (PWS) were given two 90-min infusions of pancreatic polypeptide (PP) (100 pmol.kg-1.h-1) counterbalanced with two saline infusions. Thirty minutes into each infusion, a 60-min appetite test was given. Tests were done after an overnight fast and 1 h after a 275-kcal breakfast meal. Serum assays for biochemistry, glucose, insulin, C peptide, glucagon, cortisol, and PP were performed at the beginning and end of the infusion. Although infusion of PP increased PP concentrations 10-fold, it did not cause physical signs or symptoms, changes in vital signs, or changes in serum biochemistry. Although the test design was sufficiently sensitive to reveal an effect of the pretest meal on subsequent food intake, there was no difference in eating behavior with the saline and PP infusions. This suggests that a short-term normalization of blood PP concentrations does not correct the excessive food intake.

Eight patients with postprandial hypotension and orthostatic hypotension were treated with the somatostatin analogue SMS-201-995. Low doses of this drug (0.2-0.4 microgram/kg) raised the blood pressure after breakfast in all six patients with postprandial hypotension. 60 min after breakfast the mean sitting blood pressure was 35 +/- 10 (SEM) mm Hg higher after administration of SMS-201-995 0.4 microgram/kg than after placebo (p less than 0.001). Larger doses (up to 1.6 micrograms/kg) raised upright blood pressure during the postprandial period in five of seven patients. Before therapy three patients were unable to stand after eating; after an injection of SMS-201-995 0.8 microgram/kg at the beginning of breakfast they were able to walk for 35-100 min. The duration of therapeutic effect of each injection was 3-6 h. Treatment was followed by abdominal cramps and nausea in two patients with gastroparesis diabeticorum. SMS-201-995 holds promise as a treatment for postprandial hypotension and orthostatic hypotension.

VIP-secreting tumors are rare, but they produce a dramatic clinical picture, the most prominent feature of which is profuse, watery diarrhea and hypokalemia. A definitive diagnosis is aided by the determination of plasma VIP concentrations through the use of the sensitive radioimmunoassays that are now available. Intestinal secretion resulting from the direct action of VIP on the intestinal epithelial cell receptors accounts for the loss of fluid and electrolytes in patients with VIPoma. The hypokalemia is the result of passive and VIP-induced active secretion of potassium by colonic epithelial cells. Surgery is the most definitive treatment of VIPoma; pharmacotherapy is extremely important in controlling symptoms and stabilizing the patient prior to surgery. Sandostatin and glucocorticoids are well established agents in the management of the secretory diarrhea; other pharmacologic agents, including clonidine, indomethacin, phenothiazines, lithium carbonate, and propranolol, may be helpful in selected patients but require further study. The most potent and promising drug for the treatment of VIPoma is a new peptidomimetic agent--Sandostatin. This metabolically stable synthetic analogue of somatostatin appears, in part, to inhibit the release of VIP from the tumor and the secretion of chloride by the intestine. In addition to controlling the diarrhea, it may have a direct effect on the tumor in reducing its size.

We present a case of histoplasmosis with skin manifestations occurring 17 years after initial diagnosis. The clinical manifestations of disseminated disease are discussed. Amphotericin B administered through an A-V shunt resulted in prompt resolution of the skin lesions.

Twelve men with abnormally high insulin responses to a sucrose load and 12 normal men were fed diets containing 0, 7.5, or 15% of the calories as fructose for 5 weeks each. The diets contained approximately 43% of the calories as total carbohydrate, 42% as fat and 15% as protein. Mean insulin responses of the hyperinsulinemic men were initially 235% of control responses. Plasma glucose concentrations 1 hour after the sucrose load were significantly higher in hyperinsulinemic men than in controls. There were no initial differences between the two groups in glucagon or gastric inhibitory polypeptide (GIP) responses. Consumption of 7.5 and 15% Fructose diets increased fasting plasma glucose and GIP responses in both groups. Consumption of the 15% fructose diet resulted in significantly higher insulin and glucose responses than consumption of the other two diets. These results indicate that moderate levels of dietary fructose can produce undesirable changes in glucose metabolism of both normal and hyperinsulinemic men.

Ten men and nine women aged 35 to 55 consumed two diets for 6 weeks each in a cross-over design. The diets were composed of identical natural foods and 30% of the calories as either sucrose or wheat starch. Carbohydrate, fat and protein supplied 43, 42, and 15% of the calories, respectively. The dietary pattern consisted of two meals divided so as to provide 10% of the calories at breakfast (7:00 to 8:30 AM) and 90% of the calories at dinner (4:30 to 6:30 PM). Initial body weights were essentially maintained. The gastric inhibitory polypeptide response after a sucrose load (2 g/kg body weight) was significantly greater (P < 0.01) after th subjects consumed the sucrose rather than the starch diet. The gastric inhibitory polypeptide response was significantly greater (P < 0.01) after 6 weeks on diet than during pretest. These results suggest that the increases in insulin levels observed after sucrose feeding may be mediated by an effect on the enteric hormone gastric inhibitory polypeptide.

Pancreatic polypeptide (PP), neurotensin, substance P, and vasoactive intestinal polypeptide (VIP) are peptides that modify various autonomic and neural functions. These substances are secreted into the blood in response to physiologic stimuli affecting the gastrointestinal tract. To determine the effect of adrenal hormones on gastrointestinal peptide release we measured blood levels of PP, VIP, substance P, and neurotensin in adrenalectomized and intact dogs undergoing cardiac arrest and cardiopulmonary resuscitation (CPR), a condition associated with maximal adrenal stimulation. One hour after completion of abdominal surgery consisting of bilateral adrenalectomy or exposure of the adrenal glands (sham operation), ventricular fibrillation was induced in 19 dogs by direct ventricular discharge. Despite marked elevations of plasma epinephrine and norepinephrine, CPR was associated with minimal endocrine gastrointestinal involvement, restricted to increased VIP levels in sham-operated dogs. No specific gastrointestinal peptide response to cardiac arrest was seen in adrenalectomized animals, but their plasma PP and VIP levels were higher than those of sham-operated dogs. Therefore, acute maximal adrenal stimulation is associated with selective VIP release. In addition, the higher level of the vagally controlled plasma PP in adrenalectomized animals suggests a tonic inhibitory effect of adrenal secretions on the release of this peptide.

VIP is a 28 amino acid peptide found in highest concentration in central and peripheral nervous tissue. This study measured VIP in pure populations of peripheral blood cells to determine the presence or absence of VIP in noninnervated tissues. Cell populations were purified by Ficoll-hypaque gradient centrifugation followed by dextran sedimentation or differential adherence to culture plates. Platelets were purified by differential centrifugation. VIP was isolated by acid-ethanol extraction and quantified by radioimmunoassay. A mean value of 1.1 +/- 0.6 ng of VIP per 10(8) cells was extracted from PMNs. This peptide appears to be a specific marker for PMNs, since it was not measurable in pure populations of lymphocytes, monocytes, erythrocytes, or platelets. Mononuclear cells obtained from five patients with AML and seven patients with CML contained measurable VIP, whereas mononuclear cells from nine of 10 patients with AMML and from five patients with ALL contained very low or unmeasurable levels of VIP. Thus, although the role of VIP in normal PMN function is unknown, measurement of VIP in leukemic cells may aid in the differential diagnosis of acute leukemias.

Vasoactive intestinal peptide (VIP) is a known potent hypotensive and vasodilatory agent. Studies were performed to determine the possible role of VIP in the human menstrual cycle in 44 patients in the reproductive age group, some of whom were using oral contraceptives, three pregnant patients, and four postmenopausal patients. No significant relationship between VIP and menstrual cycle phase was found.

Ten Type I insulin-dependent diabetics who were receiving single daily injections of intermediate acting insulin were studied to assess time-response characteristics of this therapy on 24-hour profiles of both glucose and free insulin. Nine of ten patients had undetectable postprandial levels of C-peptide. All patients had insulin antibodies typical of chronically treated Type I diabetes. Mean peak free insulin levels occurred four hours post injection with free insulin rising from 12.3 +/- 1.6 microU/ml to 26.5 +/- 1.4 microU/ml; p less than 0.01. The glucose nadir for the 24-hour profile also occurred at four hours after injection with glucose declining from 199 +/- 29 mg/dl fasting to 155 +/- 5 mg/dl; p less than 0.05. There was significant negative correlation between mean glucose and free insulin throughout the first six hours after insulin injection (r = -0.74; p less than 0.02); no correlation occurred 8 to 12 hours post injection. Two of the ten patients had hypoglycemic symptoms within four hours after their morning insulin. Although free insulin levels remained above basal for 20 hours, single dose intermediate insulin therapy never really controlled postprandial glucose levels after breakfast or lunch. These data suggest there may be limitations in managing Type I diabetics with single dose intermediate insulin. Furthermore, some patients on intermediate acting insulin may have a more rapid than anticipated maximal hypoglycemic response, often within four hours.

Our purpose was to determine the effect of vasoactive intestinal polypeptide (VIP) on the cardiovascular system with special emphasis on coronary vascular effects. In section I, VIP was infused into six healthy and six cobalt-cardiomyopathic dogs at two infusion rates (0.02 and 0.05 micrograms/kg/min). Left ventricular end diastolic pressure and mean systemic pressure fell significantly in both groups. Heart rate rose in both, and maximum systolic dP/dt increased in the myopathic group. Cardiac output and regional blood flows were determined by serial left atrial injections of radioactive 15 +/- 3 mum (mean +/- SD) microspheres. In both groups, blood flow increased significantly to the esophagus, pancreas, atria, and ventricles and to the endocardial and epicardial regions of the left ventricular free wall. Blood flow to the brain decreased. In section II, VIP was infused intravenously at 0.1 micrograms/kg/min into six anesthetized dogs with coronary sinus flow, pulmonary artery, and systemic artery catheters inserted. Cardiac index rose from baseline (3.1 +/- 0.5 to 4.8 +/- 1.3 L/min/m2, P less than 0.005), as did coronary blood flow (90 +/- 25 to 159 +/- 54 ml/min, P less than 0.005) during the VIP infusion. Myocardial oxygen consumption rose from 14.1 +/- 3.9 to 19.8 +/- 5.4 ml/min (P less than 0.001), but the aorta-to-coronary sinus O2 difference decreased from 157 +/- 19 ml/L to 132 +/- 42 ml/L (P less than 0.05), and the percent O2 extracted from coronary blood also decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparable groups of type I diabetic patients (n = 19) were matched for age, duration of diabetes, mean HbA1 values, insulin requirements, degree of neuropathy, and the mean of nerve conduction velocities (CV) in median, ulnar, and peroneal motor and median, ulnar, and sural sensory nerves. One group (n = 9) was managed with continuous subcutaneous infusion of (regular) insulin (CSII); the other (n = 10) with split-mixed injections of (intermediate and regular) insulin (SMII). After 12 months, glucose regulation was equally and significantly improved in both groups (P less than 0.005), although it was not sufficiently intense to normalize mean total glycosylated hemoglobin values in either group. Furthermore treatment produced no difference between groups in the values for mean amplitude of glycemic excursions, 12 month average of consecutive M-values or in clinical evaluation. However, in the CSII group, mean CV had increased 6.4% (2.75 + 0.56 m/s; mean +/- SEM) versus 1.3% (0.57 +/- 0.54 m/s) in the SMII group (P less than 0.005). Multivariate analysis on a nerve-by-nerve basis found significantly improved conduction in 2/6 nerves (median motor; ulnar sensory) in the CSII group compared to the SMII group. These results suggest that CSII may provide a more favorable microenvironment for nerve repair.

Twelve carbohydrate-sensitive and 12 normal men were selected for the study. Carbohydrate-sensitivity was based on an abnormal insulin response to a sucrose load. The subjects were fed a diet consisting of 45% of the calories as carbohydrate, 40% fat and 15% protein for 5 days prior to a sucrose or invert sugar tolerance test. In a crossover design, subjects were given 2 g/kg body weight of sucrose or invert sugar, and responses of insulin, glucose, fructose and gastric inhibitory polypeptide (GIP) were determined. Blood samples were taken at 0, 0.5, 1, 2 and 3 hours after being given the test loads. Insulin and glucose levels were significantly higher in carbohydrate-sensitive as compared to normal men. Glucose and GIP did not show any significant differences between the two carbohydrate loads. At 1 hour, the carbohydrate-sensitive men given sucrose had significantly higher insulin levels than carbohydrate-sensitive men given invert sugar (disaccharide effect). At 1, 2 and 3 hours, the disaccharide effect was shown in the fructose levels of the carbohydrate-sensitive men. In normal men, the disaccharide effect with levels of fructose was seen at 0.5 and 3 hours. This study indicates that the disaccharide effect on blood insulin cannot be explained by differences in gastric inhibitory polypeptide in unadapted human subjects.

Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Xanthan gum (12 g/day) was fed in muffins during either the first or second half of a 12-wk period of muffin feeding, to free-living subjects. Nine subjects were diabetic, having moderately elevated serum glucose but managing without insulin or hypoglycemic drugs, and four were nondiabetic controls. Before the study and at the end of the xanthan and xanthan-free periods, bloods were taken before and 2 h after an oral glucose load. The feeding of xanthan gum lowered fasting and postload serum glucose and reduced fasting levels of total plasma cholesterol in diabetic subjects. Xanthan gum also tended to lower fasting and postload levels of gastrin and gastric inhibitory polypeptide (GIP) and fasting levels of total and VLDL triglyceride and cholesterol in VLDL and LDL fractions. Subjects reported a sense of fullness after consuming xanthan muffins but no severe digestive symptoms.

Platelets from patients with type 1 diabetes have exhibited more sensitivity to aggregation when compared with platelets from controls without diabetes after challenge with platelet-activating factor (PAF). The production of thromboxane B2 (TxB2) and 12-hydroxyeicosatetraenoic acid (12-HETE) and the release of 5-hydroxytryptamine (5HT) were increased when the platelets were challenged by PAF (5.0 X 10(-6) mol/L and 1.0 X 10(-6) mol/L). The production of TxB2 and 12-HETE and the release of 5HT were related to the irreversible biphasic aggregation profiles observed in the patients with diabetes. Inhibition of thromboxane A2 (TxA2) production by acetylsalicylic acid abolished the secondary wave of aggregation of platelets from patients with diabetes, changing an irreversible aggregation to a reversible one. Inhibition of both TxA2 and 12-HETE production by eicosatetraynoic acid did not contribute further to the inhibition caused by acetylsalicylic acid alone, indicating that 12-HETE was not involved in the secondary wave of aggregation. These data show that the increased aggregation observed in the platelets from the group with diabetes in response to PAF results in part from their higher production of TxA2 and release of 5HT.