RESUMEN
To examine the relative importance of calcium and gastrin in regulation of calcitonin secretion, we administered graded oral doses of calcium to 10 normal men, ages 23-29 yr. Each subject had previously shown an appropriate increase in calcitonin secretion in response to a pharmacologic (0.5 mug/kg) pentagastrin injection. On separate days and in random order, each man drank 250 ml of distilled water containing 0.0, 0.5, 1.5, and 3.0 g of elemental calcium as the gluconate salt. Blood samples were drawn before and at 30, 60, 90, 120, 180, and 240 min after the oral calcium dose. The samples were analyzed for calcium by atomic absorption spectroscopy, and for gastrin and calcitonin by radioimmunoassays of established sensitivity and specificity. Ingestion of water (control) caused no change in any of the three variables. Calcium ingestion resulted in dose-related increases, within the normal range, of all three variables. Immunoreactive gastrin rose promptly, peaking at 30 min, and returning to basal levels or below by 120 min. In contrast, calcium and immunoreactive calcitonin levels rose slowly and in parallel, peaking at 120-240 min. Changes in calcitonin and changes in calcium were strongly and positively correlated, r = 0.73, when all data were pooled. Furthermore, individual linear regressions for changes in calcitonin and calcium levels (calculated separately for the three oral calcium doses in each subject) had positive slopes in 28 out of 30 sets (P < 0.01). The changes in calcitonin concentrations were much more poorly correlated with the corresponding changes in serum gastrin levels; in fact, the regression coefficient was weakly negative, r = -0.20. These results show that, at least in young adult men, changes of ambient calcium concentration within the normal range may be of major importance in physiologic regulation of calcitonin secretion. The findings are consistent with the hypothesis that calcitonin functions to prevent excessive postprandial hypercalcemia.
Asunto(s)
Calcitonina/metabolismo , Calcio/sangre , Gastrinas/sangre , Adulto , Gastrinas/inmunología , Humanos , Inmunoensayo , MasculinoRESUMEN
The ability of products of digestion to stimulate pancreozymin secretion in man was investigated using a bioassay procedure, based on duodenal perfusion, which quantified the total outputs of pancreatic enzymes evoked by intraduodenal stimuli under steady-state conditions. Patterns of response resulting from physiologic intraduodenal concentrations of test material were basal output (with isotonic saline), washout of enzymes (with dextrose, micellar fatty acid, and amino acids), and sustained output of enzymes (with amino acids and micellar fatty acid). The sustained secretion of pancreatic enzymes found during the 2nd hr of perfusion and subsequently was characteristic of pancreozymin-induced secretion. The enzyme output in response to a mixture of essential and nonessential amino acids was significantly higher than that evoked by micellar fatty acid and was comparable with that resulting from the maximally tolerated dose of pancreozymin given by vein. Perfusion with essential amino acids caused enzyme outputs comparable to those induced by perfusion with the original amino acid mixture, whereas perfusion with nonessential amino acids had no effect. When the essential amino acids were tested individually, only phenylalanine, methionine, and valine caused significant increases in pancreatic enzyme output; the effect of tryptophan was indeterminate. However, the pancreatic enzyme output was less in response to these three essential amino acids than to mixtures containing all of them.
Asunto(s)
Aminoácidos/farmacología , Amilasas/análisis , Colecistoquinina/farmacología , Lipasa/análisis , Jugo Pancreático/metabolismo , Tripsina/análisis , Adulto , Bioensayo , Duodeno , Femenino , Glucosa/farmacología , Humanos , Inyecciones Intravenosas , Intubación Gastrointestinal , Masculino , Persona de Mediana Edad , Jugo Pancreático/enzimología , Peptonas/farmacología , Perfusión , Proteínas/farmacología , Triglicéridos/farmacologíaRESUMEN
The effects of intraduodenal glycerol, fatty acid (FA) chain length and FA loads, and bile acid (BA) concentrations on pancreatic and gallbladder function were investigated in 31 healthy volunteers by a perfusion method. FA absorption rates in the duodenum and proximal jejunum were measured simultaneously. Pancreatic and gallbladder responses were augmented by increasing FA chain length and FA loads until the "maximal" secretory capacity of the pancreas and gallbladder emptying was attained. Glycerol had no effect. Raising BA concentrations above the critical micellar concentration accelerated FA absorption rates but decreased the magnitude of pancreatic and gallbladder responses to FA. Higher BA concentrations exerted an opposite effect, slowing FA absorption and increasing pancreatic and gallbladder responses. Indeed, a significant, inverse correlation was found between FA absorption and pancreatic and gallbladder responses to FA, suggesting a relationship between the length of intestine exposed to FA and the amount of cholecystokinin (and/or other neurohormonal factors) released, which stimulates pancreatic secretion and gallbladder contraction.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Ácidos Grasos/metabolismo , Vesícula Biliar/fisiología , Páncreas/fisiología , Adulto , Ácidos y Sales Biliares/farmacología , Bilirrubina/metabolismo , Relación Dosis-Respuesta a Droga , Duodeno , Ácidos Grasos/farmacología , Glicerol/farmacología , Humanos , Yeyuno , Lipasa/metabolismo , Masculino , Sistemas Neurosecretores/fisiología , Páncreas/enzimología , Perfusión , Tripsina/metabolismoRESUMEN
Interactions between bile acids (taurocholate, TC; taurochenodeoxycholate, TCDC; or taurodeoxycholate, TDC) and digestive products (essential amino acids, EAA or monoolein, MO) in the lumen of the proximal small bowel, affecting pancreatic enzyme secretion and gallbladder contraction, were studied in 77 healthy volunteers by a perfusion method. Perfusion of EAA or MO caused significant increases in pancreatic enzyme output together with gallbladder contraction; MO was more potent and induced enzyme outputs comparable to the maximal response attained with intravenous cholecystokinin-pancreozymin (CCK-PZ). Perfusion of TC alone had no effect, but addition of 10 mM of either TC, TCDC, or TDC to perfusates containing EAA, or 10 mM TC to MO, or both significantly reduced pancreatic enzyme output and prevented gallbladder contraction. A lower concentration of TC (5 mM) added to EAA also produced a significant inhibitory effect. Inhibition of the stimulatory action of digestive products occurred in the jejunum as well as in the duodenum. The inhibitory action of bile acid was considered to be intraluminal since (a) bile acid did not modify the effects of CCK-PZ given intravenously; and (b) the stimulatory effect of digestive products perfused in the duodenum on pancreatic and gallbladder function was not influenced by simultaneous perfusion of bile acid in the jejunum. It is proposed that this inhibitory effect of bile acid is mediated through inhibition of CCK-PZ secretion by high intraluminal concentrations of bile acid. Inhibition of CCK-PZ secretion by bile acid may contribute to the regulation of pancreatic and gallbladder function during digestion by reducing pancreatic enzyme secretion and permitting the gallbladder to refill after evacuation of its contents.
Asunto(s)
Aminoácidos/farmacología , Ácidos y Sales Biliares/farmacología , Vesícula Biliar/fisiología , Glicerol/farmacología , Páncreas/metabolismo , Adulto , Bilirrubina/análisis , Ácido Quenodesoxicólico/farmacología , Colecistoquinina/administración & dosificación , Ácido Desoxicólico/farmacología , Duodeno/efectos de los fármacos , Vesícula Biliar/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Yeyuno/efectos de los fármacos , Lipasa/análisis , Masculino , Persona de Mediana Edad , Contracción Muscular , Ácidos Oléicos/farmacología , Páncreas/efectos de los fármacos , Páncreas/enzimología , Perfusión , Ácido Taurocólico/farmacología , Tripsina/análisisRESUMEN
Gastric inhibitory polypeptide (GIP) is considered to be the principal mediator of the enteroinsular axis. A glucose-insulin clamp technique was used to study the effects of differing blood glucose levels on the insulinotropic and glucagonotropic actions of fat-stimulated GIP in seven healthy subjects, as well as the effect of physiologic hyperinsulinemia on GIP secretion. Blood glucose levels were clamped for 4 h at 43+/-2 mg/dl (hypoglycemic clamp), 88+/-1 mg/dl (euglycemic clamp), and 141+/-2 mg/dl (hyperglycemic clamp) in the presence of a constant insulin infusion (100 m U/kg per h). Under hypoglycemic clamp conditions there was no increase in C-peptide nor glucagon after Lipomul ingestion, despite an increase of GIP of 51.7+/-8.7 ng/ml per 120 min. Under euglycemic clamp conditions, small and inconsistent increases in C-peptide and glucagon were observed after fat ingestion and a concomitant increase of GIP of 35.2+/-9.4 ng/ml per 120 min. Under hyperglycemic clamp conditions after fat ingestion and a GIP increase of 24.0+/-5.7 ng/ml per 120 min, C-peptide increased from 6.4+/-5 ng/ml to 11.0+/-1.1 ng/ml (P < 0.01) but glucagon did not change. These findings confirm that in healthy man GIP exerts its insulinotropic properties only under hyperglycemic conditions and indicate that GIP is not glucagonotropic. Under euglycemic clamp conditions (plasma glucose, 89+/-1 mg/dl) and physiologic hyperinsulinemia (serum immunoreactive insulin, 137+/-3 muU/ml) GIP responses to fat ingestion (39.7+/-9.8 ng/ml per 120 min) were not different from the GIP responses to fat ingestion in the absence of hyperinsulinemia (39.7+/-11.1 ng/ml per 120 min). Therefore, insulin under normoglycemic conditions does not exert an inhibitory effect on fat-stimulated GIP secretion. The higher GIP response to oral fat in the hypoglycemic clamp, and the lower GIP response in the hyperglycemic clamp compared to the response in the euglycemic clamp suggests an effect of glycemia itself on GIP secretion in the presence of hyperinsulinemia.
Asunto(s)
Grasas de la Dieta/farmacología , Polipéptido Inhibidor Gástrico/fisiología , Hormonas Gastrointestinales/fisiología , Islotes Pancreáticos/metabolismo , Adulto , Glucemia/metabolismo , Péptido C/sangre , Péptido C/metabolismo , Femenino , Polipéptido Inhibidor Gástrico/sangre , Polipéptido Inhibidor Gástrico/metabolismo , Glucagón/sangre , Glucagón/metabolismo , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , MasculinoRESUMEN
A bank of serum specimens from women at varying risks of breast cancer has been established. Panels of test specimens can be secured by qualified investigators to evaluate newly discovered biological markers for breast cancer, to verify preliminary data, and to compare performance of established assays among different laboratories. Panels consisting of coded 1-ml vials of sera will be sent upon request to approved investigators. The procedure for application for serum panels is described.
Asunto(s)
Bancos de Sangre , Recolección de Muestras de Sangre/normas , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/prevención & control , Femenino , Humanos , Tamizaje Masivo/métodos , Estándares de ReferenciaRESUMEN
Determinations of carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), and alpha-fetoprotein (AFP) were done by use of frozen serum samples antedating the diagnosis of cancer for 9 pancreatic and 8 gastric carcinoma patients from the Framingham Heart Study. The longest intervals for elevated antigens before cancer diagnosis were 10 months for CEA and 26 months for HCG. (The single elevated AFP was found in a sample 10 days before clinical diagnosis.) Samples from 31 controls matched with the cancer subjects by age, sex, vital capacity, and smoking status showed over 20% "false" positive CEA elevations (all smokers with low vital capacities) and over 20% borderline false positive HCG elevations in postmenopausal females. Although 10-26 months' lead time could infer some potential for use of these tumor-associated antigens to help detect malignant neoplasms at an earlier stage, a serious problem of frequent false positives prevents CEA and HCG levels from being useful as cancer-screening tests at this time.
Asunto(s)
Antígenos de Neoplasias/análisis , Antígeno Carcinoembrionario/análisis , Gonadotropina Coriónica/análisis , Neoplasias/diagnóstico , alfa-Fetoproteínas/análisis , Adulto , Anciano , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Massachusetts , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/inmunología , Lesiones Precancerosas/inmunología , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/inmunología , Factores de TiempoRESUMEN
Material with carcinoembryonic antigen (CEA)-like activity, isolated from colon lavages of healthy individuals, has been chemically characterized. The CEA-like activity in these lavages was purified by gel filtration on Sepharose 6B and Sephadex G-200 and by affinity chromatography on concanavalin A linked to Sepharose. The purified material migrated in polyacrylamide-sodium dodecyl sulfate electrophoresis as a single diffuse band with mobility identical with that of tumor CEA. The material with CEA activity from tumor tissue and from normal colon lavages gave lines of identity in double diffusion experiments and had similar inhibition curves with esssentially the same specific activities in a radioimmune assay for tumor CEA. The amino acid and carbohydrate compositions were similar to that observed for CEA tumor preparations. Lysine was the single amino terminus. Methylation analysis demonstrated that the monosaccharide linkages were similar to those in CEA isolated from tumor tissue.
Asunto(s)
Antígeno Carcinoembrionario/análisis , Colon/inmunología , Adulto , Aminoácidos/análisis , Carbohidratos/análisis , Antígeno Carcinoembrionario/aislamiento & purificación , Cromatografía , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Inmunoquímica , Masculino , Metilación , Persona de Mediana Edad , Irrigación TerapéuticaRESUMEN
Serum alpha-fetoprotein levels were measured by a sensitive double-antibody radioimmunoassay in 580 patients with a variety of malignant and nonmalignant gastrointestinal diseases to determine the incidence of levels elevated above 40 ng/ml. Over 200 normal control subjects have all had levels below 40 ng/ml. Fifteen % of 95 patients with gastric carcinoma, 3 percent of 191 patients with colorectal carcinoma, 24 percent of 45 patients with pancreatic carcinoma, 25 percent of 8 patients with biliary tract carcinoma, and 70 percent of 73 patients with hepatocellular carcinoma had elevated serum alpha-fetoprotein. None of 14 patients with esophageal or small bowel carcinoma had elevated levels. In contrast, 1 percent of 154 patients with nonmalignant, nonhepatic gastrointestinal disease had elevations of serum alpha-fetoprotein. Alpha-Fetoprotein appears to be a potential marker for tumor activity in some patients with certain gastrointestinal cancers.
Asunto(s)
alfa-Globulinas/metabolismo , Proteínas Fetales/metabolismo , Neoplasias Gastrointestinales/metabolismo , Adulto , Anciano , Neoplasias de los Conductos Biliares/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias Esofágicas/metabolismo , Femenino , Enfermedades Gastrointestinales/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias del Recto/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
A glycoprotein has been isolated from the colonic lavages of healthy individuals that is immunologically equivalent to carcinoembryonic antigen purified from tumor tissue. The NH2-terminal sequence of the glycoprotein from normal colon lavages is Lys-Leu-Thr-lle-Glu-Ser-Thr-Pro-Phe-(Asn)-Val-Ala-Glu-Gly-Lys-Glu-Val-(Leu,lle)-(Leu,lle)-(Leu,lle)-Val-(His,Arg?)-?-(Leu,lle). This is homologous to the NH2-terminal sequence of 23 of the first 24 amino acids of carcinoembryonic antigen isolated from tumor tissue.
Asunto(s)
Antígeno Carcinoembrionario , Colon/inmunología , Glicoproteínas/inmunología , Secuencia de Aminoácidos , Epítopos , Glicoproteínas/aislamiento & purificación , Humanos , Irrigación TerapéuticaRESUMEN
To assess the contribution of changes in insulin secretion and clearance to the incretin effect (greater insulinemia after oral than after intravenous glucose), 10 healthy subjects were studied after oral glucose (1 g/kg body wt) and again when glucose was infused intravenously at rates to match arterialized plasma glucose concentrations after oral glucose. Although basal and integrated plasma glucose did not differ between oral and intravenous glucose, integrated responses of insulin (3.3 +/- 0.5 vs. 1.8 +/- 0.4 mU ml-1.240 min-1, P less than .001), C-peptide (456.5 +/- 58.5 vs. 327.9 +/- 46.3 ng.ml-1.240 min-1, P = .002), gastric inhibitory polypeptide, (16.8 +/- 3.5 vs. -2.8 +/- 1.0 micrograms.ml-1.240 min-1, P less than .001), and insulin secretion (6.6 +/- 1.1 vs. 4.7 +/- 0.7 U.240 min-1, P = .003) were greater with oral than intravenous glucose. However, insulin clearance, whether calculated as the molar ratio of integrated C-peptide to integrated insulin responses (6.9 +/- 0.7 vs. 14.2 +/- 3.8, P = .005) or from the formula insulin clearance equals insulin secretion divided by integrated insulin responses (1.1 +/- 0.2 vs. 2.5 +/- 0.7 L.min-1.m-2, respectively, P = .002), was less for oral than for intravenous glucose. Therefore, the incretin effect is mediated both by increased secretion and decreased clearance of insulin.
Asunto(s)
Glucosa/administración & dosificación , Insulina/sangre , Administración Oral , Adulto , Glucemia/análisis , Péptido C/sangre , Femenino , Polipéptido Inhibidor Gástrico/sangre , Glucosa/farmacología , Humanos , Inyecciones Intravenosas , Insulina/metabolismo , Secreción de Insulina , Masculino , Valores de Referencia , Caracteres SexualesRESUMEN
Vasoactive intestinal polypeptide, a neurotransmitter peptide detected in animal and human hearts, has been found in nerves of coronary arteries. To determine the amount and distribution of vasoactive intestinal polypeptide in the large coronary vessels and its possible participation in coronary vasoregulation, two groups of animals were studied. In the first group, 11 anesthetized dogs were sacrificed to collect three (1 cm) segments along the circumflex and left anterior descending coronary arteries. These segments represented proximal (I), middle (II) and distal (III) portions of the two arteries. Concentrations (ng/g) of vasoactive intestinal polypeptide-like immunoreactive substance were determined by radioimmunoassay. Vasoactive intestinal polypeptide-like immunoreactivity was present in the left anterior descending (I = 7.28 +/- 1.65, II = 3.74 +/- 0.57, III = 2.29 +/- 0.53) and circumflex (I = 4.16 +/- 1.52, II = 4.58 +/- 1.13, III = 4.00 +/- 0.81) coronary arteries. The difference in vasoactive intestinal polypeptide-like immunoreactivity among epicardial segments of the anterior descending artery was significant, but there was no significant difference among segments of the circumflex coronary artery. In the second group (eight closed chest anesthetized dogs), the effects of vasoactive intestinal polypeptide intracoronary infusion on epicardial coronary constriction were examined at rest and with the artery constricted by serotonin. Left anterior descending (segments I, II and III) artery responses (% area change) to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide plus serotonin were examined using quantitative coronary angiography. Vasoactive intestinal polypeptide infusion resulted in significant vasodilation in all the segments (I, II and III) of the left anterior descending artery.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Vasos Coronarios/análisis , Péptido Intestinal Vasoactivo/análisis , Animales , Aorta/análisis , Cateterismo Cardíaco , Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/fisiopatología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/inervación , Perros , Hemodinámica/efectos de los fármacos , Infusiones Intraarteriales , Miocardio/análisis , Radioinmunoensayo , Serotonina/farmacología , Péptido Intestinal Vasoactivo/farmacología , Péptido Intestinal Vasoactivo/fisiologíaRESUMEN
Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.
Asunto(s)
Neoplasias de la Mama/fisiopatología , Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/fisiología , Fitoestrógenos/farmacología , Adenocarcinoma , Línea Celular Tumoral , Estradiol/farmacología , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/genética , Femenino , Humanos , Mutagénesis Sitio-Dirigida , Plásmidos , Mutación Puntual , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Activación Transcripcional , TransfecciónRESUMEN
Both basal and postprandial pancreatic polypeptide (PP) concentrations were exaggerated twofold in lean NIDDM patients, whereas they were normal in lean IDDM and obese NIDDM patients who were hyperglycemic as a result of partial insulin withdrawal. Insulin infusion from an artificial endocrine pancreas, which resulted in fasting euglycemia and near-normoglycemia postprandially, had no effect on PP responses in any of the diabetic patients. No postprandial PP responses were observed in totally pancreatectomized (TPX) patients. Excessive basal and postprandial concentrations of PP in diabetes appear to be related to both leanness and residual beta cell function and, therefore, potential markers for lean NIDDM.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Polipéptido Pancreático/sangre , Adulto , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ingestión de Alimentos , Femenino , Humanos , Sistemas de Infusión de Insulina , Masculino , Persona de Mediana Edad , Obesidad , PancreatectomíaRESUMEN
Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.
RESUMEN
The gastrointestinal contribution to carbohydrate metabolism includes carbohydrate absorption and the release of gastrointestinal hormones that interact with the endocrine pancreas. To learn the contributions to the enteroinsular axis from different levels of the gastrointestinal tract and different nutrients in chyme, we determined serum concentrations of glucose, gastric inhibitory peptide (GIP), insulin, and glucagon postprandially in six normal subjects who underwent diversion of chyme just proximal to an occlusive balloon at the ligament of Treitz and jejunal infusion of saline or chyme carbohydrate, protein, and lipid, separately or in combination. Postprandial elevations of serum glucose, GIP, and insulin and decrease of serum glucagon were elicited predominantly from the bowel and its contents distal to the ligament of Treitz. In this segment, each chyme nutrient (but especially carbohydrate) significantly stimulated factors affecting carbohydrate metabolism. Protein and lipid were able to block carbohydrate-induced glucagon inhibition. The gastroduodenal segment, although containing several proposed insulinotropic hormones (gastrin, secretin, and cholecystokinin), had no effect on serum glucose of glucagon and stimulated only small insulin and GIP responses.
Asunto(s)
Digestión , Fenómenos Fisiológicos del Sistema Digestivo , Alimentos , Islotes Pancreáticos/fisiología , Adulto , Glucemia/metabolismo , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Proteínas en la Dieta/farmacología , Sistema Digestivo/efectos de los fármacos , Femenino , Polipéptido Inhibidor Gástrico/sangre , Glucagón/sangre , Humanos , Insulina/sangre , Yeyuno/fisiología , Masculino , Persona de Mediana EdadRESUMEN
To assess the influence of enteric factors on insulin action, seven lean healthy subjects were studied under conditions of hyperinsulinemic euglycemic glucose clamp, double isotope administration, and enteral vs. parenteral glucose infusion. In random order, glucose and mannitol radiolabeled with [2-3H]glucose were infused intraduodenally for 4 h while the systemic rate of glucose turnover was assessed by [6-14C]glucose. During the final hour of the study, plasma glucose, insulin, C-peptide, glucagon, cholecystokinin, and neurotensin were similar under both experimental conditions. Despite an increase in gastric inhibitory polypeptide concentration during combined enteral and iv glucose infusion to levels that mimicked meal ingestion, total glucose infusion rate, insulin-induced stimulation of glucose uptake, and insulin-induced suppression of hepatic glucose release were comparable to those observed during iv glucose administration. These data indicate that under conditions of modest hyperinsulinemia and euglycemia, gastric inhibitory polypeptide did not influence hepatic or extrahepatic insulin action.
Asunto(s)
Duodeno/efectos de los fármacos , Polipéptido Inhibidor Gástrico/fisiología , Hígado/efectos de los fármacos , Bazo/efectos de los fármacos , Adulto , Glucemia/análisis , Péptido C/metabolismo , Colecistoquinina/metabolismo , Colecistoquinina/fisiología , Duodeno/metabolismo , Femenino , Polipéptido Inhibidor Gástrico/metabolismo , Glucosa/administración & dosificación , Glucosa/metabolismo , Humanos , Hiperglucemia/metabolismo , Hiperinsulinismo/metabolismo , Infusiones Parenterales , Insulina/administración & dosificación , Insulina/metabolismo , Hígado/metabolismo , Masculino , Manitol/administración & dosificación , Bazo/metabolismoRESUMEN
The impaired epinephrine and glucagon responses to hypoglycemia often found in patients with insulin-dependent diabetes mellitus (IDDM) may be due to autonomic neuropathy. Since the pancreatic polypeptide response to hypoglycemia is mediated by cholinergic mechanisms, we used this response as an indicator of autonomic neuropathy to determine whether deficient epinephrine and glucagon responses in IDDM could be ascribed to an autonomic defect. The relationships between pancreatic polypeptide, epinephrine, and glucagon responses during insulin-induced hypoglycemia were assessed in 18 patients with IDDM who had no overt evidence of autonomic neuropathy, including normal standard cardiovascular reflex tests, and 11 age-matched nondiabetic subjects. All of the diabetic patients had impaired glucagon responses [19 +/- 3 (SEM) vs. 96 +/- 11 pg/ml, peak increment, P less than 0.001]. Ten of the 18 diabetic patients had either impairment of plasma epinephrine or plasma pancreatic polypeptide responses or both to hypoglycemia. Moreover, pancreatic polypeptide responses were significantly correlated with epinephrine responses (r = 0.53, P less than 0.003). There was no association between the plasma glucagon response and the epinephrine (r = 0.02, NS), norepinephrine (r = 0.03, NS), or pancreatic polypeptide (r = 0.35, NS) response. Last, there was no correlation between the plasma hormone responses and the cardiovascular reflex test results. Therefore, the association of impaired plasma pancreatic polypeptide responses with impaired plasma epinephrine responses suggests that the impaired epinephrine responses are due to autonomic neuropathy, whereas the dissociation of plasma glucagon responses with both plasma pancreatic polypeptide and epinephrine responses suggests that the impaired pancreatic alpha-cell response to hypoglycemia is not due to autonomic neuropathy. In addition, the plasma pancreatic polypeptide and epinephrine responses to hypoglycemia appear to be an earlier indicator of underlying autonomic dysfunction than standard cardiovascular reflex tests. Thus, the responses of plasma pancreatic polypeptide and epinephrine to insulin-induced hypoglycemia may be a useful test for the identification of early autonomic neuropathy in IDDM.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Neuropatías Diabéticas/fisiopatología , Epinefrina/metabolismo , Hipoglucemia/fisiopatología , Polipéptido Pancreático/metabolismo , Adolescente , Adulto , Sistema Nervioso Autónomo/fisiopatología , Sistema Cardiovascular/fisiopatología , Niño , Preescolar , Glucagón , Humanos , Hipoglucemia/etiología , Reflejo Anormal/fisiopatologíaRESUMEN
Gastric inhibitory polypeptide (GIP) is the leading candidate for gut hormonal augmentation of insulin release. The release of its subspecies (mol wt, 5000 and 7500) and the physiological action of total immunoreactive GIP (IR-GIP) were investigated during isotonic glucose infusions at 75, 225, and 465 mg/min in nine volunteers. Each dose was infused intraduodenally and iv in the same volunteer. Intestinal augmentation of insulin release occurred during the high dose intraduodenal glucose infusion (P less than 0.001) but not during the lower doses. An elevation of 17-20 mg/dl in plasma glucose was required before this insulinotropic effect occurred (P less than 0.001). At increments of plasma glucose above 17 mg/dl, the augmentation of gut-mediated insulin release was dependent on the degree of hyperglycemia (r = 0.81; P less than 0.01). At each dose of intraduodenally administered glucose, IR-GIP was elevated within 20-40 min (P less than 0.01), remaining at a steady level until the infusion was stopped. The release of IR-GIP was elevated within 20-40 min (P less than 0.01), remaining at a steady level until the infusion was stopped. The release of IR-GIP was proportional to the intestinal glucose load but was unchanged from the basal level during iv glucose studies. The attained IR-GIP levels remained constant in each study despite large variations over time in plasma glucose and insulin concentrations. During intestinal glucose infusion, 58.7 +/- 4.1% of IR-GIP was accounted for by the 5000 mol wt subspecies and 17.3 +/- 3.5% was accounted for by the 7500 mol wt subspecies, with the remaining immunoreactivity found in the void volume of a Sephadex G-50 column. Relative proportions remained constant throughout the 4-h study. Thus, during glucose stimulation, the total IR-GIP released 1) is proportional to the absorbable luminal stimulus, 2) is independent of ambient plasma insulin and glucose levels, 3) is composed predominantly of the 5000 mol wt form, and 4) requires an elevation in plasma glucose of 17-20 mg/dl before it augments insulin release, but then stimulates insulin release in a fashion linearly dependent upon the increment in plasma glucose.
Asunto(s)
Polipéptido Inhibidor Gástrico/sangre , Hormonas Gastrointestinales/sangre , Glucosa , Adulto , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Duodeno , Glucosa/administración & dosificación , Humanos , Insulina/sangre , Cinética , MasculinoRESUMEN
To clarify further the etiology of the carbohydrate intolerance in idiopathic hemochromatosis, we investigated the glucose, insulin, C-peptide, and glucagon responses to arginine (0.5 g/kg) infused during 30 min in lean normal subjects; in insulin-requiring subjects with hemochromatosis, genetic diabetes, and total pancreatectomy; and in nondiabetic cirrhotic subjects without portosystemic shunting. Serum insulin, C-peptide, and glucagon responses (30K antibody) were determined by RIA, and glucose level was determined by a glucose oxidase technique. Hemochromatotic and genetic diabetic subjects had similar basal glucose (157 +/- 25 vs. 168 +/- 40 mg/dl) and C-peptide (0.73 +/- 0.42 vs. 0.65 +/- 0.22 ng/ml) values, with subnormal C-peptide peak responses to stimulation (1.05 +/- 0.38 and 1.40 +/- 0.83 vs. 3.95 +/- 0.4 ng/ml in normals; P less than 0.05). No glucagon or C-peptide response to arginine was seen in any pancreatectomized subject. Similar but excessive glucagon levels were present in hemochromatosis, diabetes, and cirrhosis under basal conditions (166 +/- 24, 232 +/- 111, and 263 +/- 116 vs. 76 +/- 15 pg/ml; P less than 0.05) and after arginine stimulation (782 +/- 80, 834 +/- 123, and 902 +/- 275 vs. 489 +/- 81 pg/ml; P less than 0.05) when compared with normals. The excessive glucagon levels found in hemochromatosis, diabetes mellitus, and cirrhosis contrast to the absent response in pancreatectomized subjects and indicate that generalized islet cell destruction is not the major factor in diabetic hemochromatotic subjects.