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1.
Nutr Diabetes ; 11(1): 3, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33414406

RESUMO

BACKGROUND: The rate of gastric emptying and glucoregulatory hormones are key determinants of postprandial glycaemia. Intragastric administration of L-tryptophan slows gastric emptying and reduces the glycaemic response to a nutrient drink in lean individuals and those with obesity. We investigated whether tryptophan decreases postprandial glycaemia and slows gastric emptying in type 2 diabetes (T2D). METHODS: Twelve men with T2D (age: 63 ± 2 years, HbA1c: 49.7 ± 2.5 mmol/mol, BMI: 30 ± 1 kg/m2) received, on three separate occasions, 3 g ('Trp-3') or 1.5 g ('Trp-1.5') tryptophan, or control (0.9% saline), intragastrically, in randomised, double-blind fashion, 30 min before a mixed-nutrient drink (500 kcal, 74 g carbohydrates), containing 3 g 3-O-methyl-D-glucose (3-OMG) to assess glucose absorption. Venous blood samples were obtained at baseline, after tryptophan, and for 2 h post-drink for measurements of plasma glucose, C-peptide, glucagon and 3-OMG. Gastric emptying of the drink was quantified using two-dimensional ultrasound. RESULTS: Tryptophan alone stimulated C-peptide (P = 0.002) and glucagon (P = 0.04), but did not affect fasting glucose. In response to the drink, Trp-3 lowered plasma glucose from t = 15-30 min and from t = 30-45 min compared with control and Trp-1.5, respectively (both P < 0.05), with no differences in peak glucose between treatments. Gastric emptying tended to be slower after Trp-3, but not Trp-1.5, than control (P = 0.06). Plasma C-peptide, glucagon and 3-OMG increased on all days, with no major differences between treatments. CONCLUSIONS: In people with T2D, intragastric administration of 3 g tryptophan modestly slows gastric emptying, associated with a delayed rise, but not an overall lowering of, postprandial glucose.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esvaziamento Gástrico/efeitos dos fármacos , Triptofano/administração & dosagem , 3-O-Metilglucose/sangue , Idoso , Bebidas , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Vias de Administração de Medicamentos , Glucagon/sangue , Glucose/metabolismo , Humanos , Insulina/sangue , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Nutrientes , Obesidade/tratamento farmacológico , Período Pós-Prandial
2.
Nutrients ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694157

RESUMO

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.


Assuntos
Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Galactanos/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mananas/farmacologia , Gomas Vegetais/farmacologia , Proteínas do Soro do Leite/farmacologia , 3-O-Metilglucose/sangue , Idoso , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Insulina/sangue , Intestino Delgado/metabolismo , Masculino , Período Pós-Prandial/efeitos dos fármacos
3.
Nutrition ; 32(5): 553-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26792024

RESUMO

OBJECTIVE: Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes. METHODS: Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy individuals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was sampled frequently. RESULTS: In healthy individuals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP; P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04). CONCLUSION: In healthy individuals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes.


Assuntos
Citratos/uso terapêutico , Diabetes Mellitus Tipo 2/dietoterapia , Carboidratos da Dieta/metabolismo , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Incretinas/metabolismo , Absorção Intestinal , 3-O-Metilglucose/sangue , 3-O-Metilglucose/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Citratos/administração & dosagem , Citratos/efeitos adversos , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Carboidratos da Dieta/administração & dosagem , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Duodeno/metabolismo , Feminino , Glucose/administração & dosagem , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Incretinas/sangue , Mucosa Intestinal/metabolismo , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade
4.
Brain Dev ; 33(4): 316-20, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20630673

RESUMO

PURPOSE: Glucose transporter type 1 (Glut1) is expressed in vascular endothelial cells comprising blood-brain barrier. Glut1 deficiency syndrome is characterized by low cerebrospinal fluid (CSF) concentration of glucose with normoglycemia, infantile seizure, acquired microcephaly, developmental delay and ataxia. As Glut1 is also expressed in erythrocytes, the diagnosis is confirmed by a decreased uptake of 3-O-methylglucose (3-OMG) into erythrocytes. However, patients with T295M mutation in the Glut1 gene show normal 3-OMG uptake. An in vitro study has proved that the T295M affects efflux rather than influx of glucose, explaining the discrepancy. However, the normal 3-OMG uptake in erythrocytes still indicates a possibility that the phenotype associated with this particular mutation may be milder. We compared the phenotype of three T295M-associated patients with that of other Glut1-deficient patients. PATIENTS AND METHODS: Two patients are from our clinic and one is a patient reported elsewhere. The phenotype and biochemical data of patients with mutations other than T295M were obtained from a review and our previous report. RESULTS: Despite the normal 3-OMG uptake into erythrocytes, all patients with T295M showed decreased glucose levels in CSF (33, 31 and 38mg/dl, respectively). The levels were comparable to those in patients with mutations other than T295M (31±4.3mg/dl (n=45)). All patients had convulsion, ataxia, speech delay, microcephaly and spasticity. CONCLUSION: Despite the normal 3-OMG uptake in erythrocytes, phenotype of T295M-associated Glut1 deficiency was not significantly different from that of patients with a deficient 3-OMG uptake, indicating that T295M affects the glucose transport at the blood-brain barrier as much as other mutations.


Assuntos
3-O-Metilglucose/sangue , Eritrócitos/metabolismo , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/genética , Mutação , Adolescente , Criança , Feminino , Humanos , Masculino , Fenótipo , Síndrome
5.
Br J Nutr ; 104(6): 803-6, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20420761

RESUMO

It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0.9% saline) or control (0.9% saline) at 4 ml/min for 150 min (T = - 30 to 120 min). After 30 min (T = 0), glucose (25 %) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2.5 %), were co-infused intraduodenally (T = 0-120 min; 4.2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagon-like peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P < 0.005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects.


Assuntos
3-O-Metilglucose/sangue , Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/metabolismo , Intestino Delgado/efeitos dos fármacos , Sacarose/análogos & derivados , Edulcorantes/farmacologia , Adulto , Feminino , Glucose/administração & dosagem , Humanos , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Masculino , Valores de Referência , Método Simples-Cego , Sacarose/farmacologia
6.
Crit Care Med ; 38(5): 1261-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20228679

RESUMO

OBJECTIVE: To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients. DESIGN: Randomized, double-blind, crossover study. SETTING: Intensive care unit. SUBJECTS: Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days. INTERVENTIONS: Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between -30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 microg of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered. MEASUREMENTS AND MAIN RESULTS: Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve(0-330), 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, -15 [15] vs. -3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve(-30-330), 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve(0-330), 2071 [353] vs. 2419 [594] mmol/L/min; p = .001). CONCLUSIONS: Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.


Assuntos
Estado Terminal , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/metabolismo , 3-O-Metilglucose/sangue , Glicemia/análise , Testes Respiratórios , Estudos Cross-Over , Método Duplo-Cego , Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/sangue , Humanos , Insulina/sangue , Unidades de Terapia Intensiva , Respiração Artificial
7.
J Chem Ecol ; 36(2): 236-43, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20145981

RESUMO

Mounting evidence suggests that small birds rely largely on non-mediated intestinal absorption of glucose through the paracellular pathway, while non-flying mammals rely on mediated absorption across the enterocyte membranes by using glucose transporters SGLT-1 and GLUT-2. Relying on non-mediated transport of glucose may decrease its absorption rate at low glucose concentrations but may release small birds from the effects of glucose transport inhibitors. We evaluated transport by using flavonoids known to inhibit glucose transport in vitro. Quercetin, isoquercetrin, and phloridzin were tested in rats (Rattus norvegicus) and robins (Turdis migratirius), and naringenin, naringenin-7-glucoside, genistein, epigallocatechin gallate (EGCG), and phloretin were used only in rats. By using a pharmacokinetic approach that involves serial blood collection and area under the curve calculations, we determined the bioavailability of 3-0-methyl D-glucose, the non-metabolized analogue of D-glucose. Six of the eight flavonoids tested in rats significantly decreased the absorption of 3-0-methyl D-glucose, while none of the flavonoids tested in robins significantly decreased the bioavailability of 3-0-methyl D-glucose. We conclude that flavonoids effectively decrease glucose absorption in rats, which rely on mediated absorption of glucose, but that flavonoids do not have an effect in robins, which rely on non-mediated absorption of glucose.


Assuntos
Flavonoides/farmacologia , Glucose/metabolismo , Absorção Intestinal/efeitos dos fármacos , Aves Canoras/metabolismo , 3-O-Metilglucose/administração & dosagem , 3-O-Metilglucose/sangue , 3-O-Metilglucose/metabolismo , 3-O-Metilglucose/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Glucose/administração & dosagem , Glucose/farmacocinética , Injeções , Masculino , Ratos , Ratos Sprague-Dawley
8.
Physiol Biochem Zool ; 83(2): 376-84, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19320596

RESUMO

3-O-methyl-D-glucose has been extensively used as a proxy for d-glucose uptake. This nonmetabolizable analog has lower affinity for transporters, potentially leading to underestimates of glucose absorption rates as well as overestimates of the nutritional significance of passive uptake. Here we sought to precisely quantify the bias, if any, incurred when using 3-O-methyl-D-glucose by comparing relative absorption rates with D-glucose in vivo in a seasonally frugivorous bird, the American robin. By simultaneously administering these D-glucose probes with L-glucose--the latter absorbed only via nonmediated mechanisms and the former absorbed by both mediated and nonmediated mechanisms--using common pharmacokinetic procedures, we were able to estimate the nutritional significance of paracellular uptake in this species. The relative absorption rate of 3-O-methyl-D-glucose calculated over the initial absorptive phase was not significantly different from that of D-glucose, indicating that the former provides reasonable estimates of glucose absorption rates in vivo. The ratio of L-glucose to D-glucose cumulative fractional absorption indicates that around 60% of total glucose absorption in American robins is paracellular and showed no apparent bias in using 3-O-methyl-D-glucose when averaged over the entire initial absorptive phase. Although the absorption and elimination kinetics of radiolabeled D-glucose were appropriate for pharmacokinetic analysis in this study, because of the potential for interspecific differences in loss to catabolism, it should be used in vivo with caution and with independent verification of absorption efficiency.


Assuntos
3-O-Metilglucose/farmacocinética , Glucose/farmacocinética , 3-O-Metilglucose/sangue , Animais , Glicemia/análise , Radioisótopos de Carbono , Glucose/metabolismo , Absorção Intestinal , Aves Canoras/metabolismo , Trítio
9.
Am J Physiol Gastrointest Liver Physiol ; 296(2): G226-34, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19056760

RESUMO

The route of absorption of ingested compounds is a determinant of their distribution and metabolism. Portal vein absorption results in direct transport to the liver, where metabolism may take place before extrahepatic delivery. Lymphatic absorption can result in delivery of parent compound to nonhepatic tissues. Understanding the fate of an ingested compound requires determination of the importance of each of these routes. Portal vein absorption can be estimated from the difference in concentrations of an ingested compound between the portal vein and peripheral vessel blood. To make these estimations, one must make assumptions on the basis of estimates of flow rate and dilution. We report here methodology that allows a direct measurement of portal vein absorption that is independent of these assumptions. Mesenteric lymph was diverted from rats by cannulation. Portal blood was sampled after duodenal infusion of a bolus of compound of interest along with a portal absorption marker, 3-O-methylglucose. Since lymph was diverted, the appearance in portal blood was solely the result of portal absorption. Absorption was quantified by the areas under the curve for the compound and marker. Portal absorption was a function of the octanol/water partition coefficients for four organochlorine compounds: hexachlorobenzene, pentachlorophenol, DDT, and its metabolite 1,1,1-trichloro-2,2-bischlorophenylethylene.


Assuntos
Hidrocarbonetos Clorados/farmacocinética , Técnicas de Diluição do Indicador , Circulação Hepática , Linfa/metabolismo , Veia Porta/metabolismo , 3-O-Metilglucose/sangue , Absorção , Animais , DDT/farmacocinética , Duodeno/metabolismo , Mucosa Gástrica/metabolismo , Hexaclorobenzeno/farmacocinética , Hidrocarbonetos Clorados/administração & dosagem , Hidrocarbonetos Clorados/sangue , Absorção Intestinal , Intubação Gastrointestinal , Masculino , Pentaclorofenol/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
10.
Placenta ; 29(4): 347-55, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18339421

RESUMO

In guinea pigs, maternal insulin-like growth factor (IGF) infusion in early-pregnancy enhances placental transport near-term, increasing fetal growth and survival. The effects of IGF-II, but not IGF-I, appear due to enhanced placental labyrinthine (exchange) development. To determine if the type-2 IGF receptor (IGF2R) mediates these distinct actions of exogenous IGF-II in the mother, we compared the impact of IGF-II with an IGF-II analogue, Leu(27)-IGF-II, which only binds the IGF2R. IGF-II, Leu(27)-IGF-II (1mg/kg per day.sc) or vehicle were infused from days 20-38 of pregnancy (term = 67 days) and placental structure and uptake and transfer of [(3)H]-methyl-D-glucose (MG) and [(14)C]-amino-isobutyric acid (AIB) and fetal growth and plasma metabolites, were measured on day 62. Both IGF-II and Leu(27)-IGF-II increased the volume of placental labyrinth, trophoblast and maternal blood space within the labyrinth and total surface area of trophoblast for exchange, compared to vehicle. Leu(27)-IGF-II also reduced the barrier to diffusion (trophoblast thickness) compared to vehicle and IGF-II. Both IGF-II and Leu(27)-IGF-II increased fetal plasma amino acid concentrations and placental transfer of MG to the fetus compared to vehicle, with Leu(27)-IGF-II also increasing AIB transport compared with vehicle and IGF-II. In addition, Leu(27)-IGF-II increased fetal weight compared to vehicle. In conclusion, maternal treatment with IGF-II or Leu(27)-IGF-II in early gestation, induce similar placental and fetal outcomes near term. This suggests that maternal IGF-II in early gestation acts in part via the IGF2R to persistently enhance placental functional development and nutrient delivery and promote fetal growth.


Assuntos
Fator de Crescimento Insulin-Like II/farmacologia , Placentação , Receptor IGF Tipo 2/fisiologia , 3-O-Metilglucose/sangue , 3-O-Metilglucose/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Aminoácidos/sangue , Ácidos Aminoisobutíricos/sangue , Ácidos Aminoisobutíricos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Peso Fetal/efeitos dos fármacos , Feto/irrigação sanguínea , Feto/efeitos dos fármacos , Feto/metabolismo , Cobaias , Fator de Crescimento Insulin-Like II/análogos & derivados , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Placenta/anatomia & histologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Trofoblastos/efeitos dos fármacos
11.
Am J Physiol Gastrointest Liver Physiol ; 292(4): G1099-104, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17204542

RESUMO

Upper gastrointestinal motor function and incretin hormone secretion are major determinants of postprandial glycemia and insulinemia. However, the impact of small intestinal flow events on glucose absorption and incretin release is poorly defined. Intraluminal impedance monitoring is a novel technique that allows flow events to be quantified. Eight healthy volunteers were studied twice, in random order. A catheter incorporating six pairs of electrodes at 3-cm intervals, and six corresponding manometry sideholes, was positioned in the duodenum. Hyoscine butylbromide (20 mg) or saline was given as an intravenous bolus, followed by a continuous intravenous infusion of either hyoscine (20 mg/h) or saline over 60 min. Concurrently, glucose and 3-O-methylglucose (3-OMG) were infused into the proximal duodenum (3 kcal/min), with frequent blood sampling to measure glucose, 3-OMG, insulin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The frequency of duodenal pressure waves and propagated pressure wave sequences was reduced by hyoscine in the first 10 min (P<0.01 for both), but not after that time. In contrast, there were markedly fewer duodenal flow events throughout 60 min with hyoscine (P<0.005). Overall, blood glucose (P<0.01) and plasma 3-OMG concentrations (P<0.05) were lower during hyoscine than saline, whereas plasma insulin, GLP-1, and GIP concentrations were initially (t=20 min) lower during hyoscine (P<0.05). In conclusion, intraluminal impedance measurement may be more sensitive than manometry in demonstrating alterations in duodenal motor function. A reduction in the frequency of duodenal flow events is associated with a decreased rate of glucose absorption and incretin release in healthy subjects.


Assuntos
Brometo de Butilescopolamônio/farmacologia , Duodeno/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/metabolismo , Absorção Intestinal/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , 3-O-Metilglucose/sangue , 3-O-Metilglucose/metabolismo , Adulto , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , Duodeno/inervação , Duodeno/metabolismo , Impedância Elétrica , Polipeptídeo Inibidor Gástrico , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Insulina/sangue , Masculino , Manometria/métodos , Peristaltismo/efeitos dos fármacos , Valores de Referência , Sensibilidade e Especificidade , Método Simples-Cego , Fatores de Tempo
12.
Biochemistry ; 44(7): 2650-60, 2005 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-15709778

RESUMO

Standard models for carrier-mediated nonelectrolyte transport across cell membranes do not explain sugar uptake by human red blood cells. This means that either (1) the models for sugar transport are incorrect or (2) measurements of sugar transport are flawed. Most measurements of red cell sugar transport have been made over intervals of 10 s or greater, a range which may be too long to measure transport accurately. In the present study, we examine the time course of sugar uptake over intervals as short as 5 ms to periods as long as 8 h. Using conditions where transport by a uniform population of cells is expected to be monophasic (use of subsaturating concentrations of a nonmetabolizable but transported sugar, 3-O-methylglucose), our studies demonstrate that red cell sugar uptake is comprised of three sequential, protein-mediated events (rapid, fast, and slow). The rapid phase is more strongly temperature-dependent than the fast and slow phases. All three phases are inhibited by extracellular (maltose or phloretin) or intracellular (cytochalasin B) sugar-transport inhibitors. The rate constant for the rapid phase of uptake is independent of the 3-O-methylglucose concentration. The magnitude (moles of sugar associated with cells) of the rapid phase increases in a saturable manner with [3-O-methylglucose] and is similar to (1) the amount of sugar that is retained by red cell membrane proteins upon addition of cytochalasin B and phloretin and (2) the d-glucose inhibitable cytochalasin B binding capacity of red cell membranes. These results are consistent with the hypothesis that previous studies have both under- and overestimated the rate of erythrocyte sugar transport. These data support a transport mechanism in which newly bound sugars are transiently sequestered within the translocation pathway where they become inaccessible to extra- and intracellular water.


Assuntos
Membrana Eritrocítica/química , Membrana Eritrocítica/metabolismo , Proteínas de Transporte de Monossacarídeos/química , 3-O-Metilglucose/antagonistas & inibidores , 3-O-Metilglucose/sangue , Sítios de Ligação , Transporte Biológico Ativo/fisiologia , Citocalasina B/sangue , Citocalasina B/química , Membrana Eritrocítica/fisiologia , Líquido Extracelular/química , Líquido Extracelular/metabolismo , Transportador de Glucose Tipo 1 , Hemólise/fisiologia , Humanos , Soluções Hipotônicas , Líquido Intracelular/química , Líquido Intracelular/metabolismo , Maltose/sangue , Maltose/química , Modelos Biológicos , Modelos Químicos , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Proteínas de Transporte de Monossacarídeos/sangue , Floretina/sangue , Floretina/química , Temperatura , Fatores de Tempo , Trítio
13.
Ann Neurol ; 57(1): 111-8, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15622525

RESUMO

Impaired glucose transport across the blood-brain barrier results in Glut-1 deficiency syndrome (Glut-1 DS, OMIM 606777), characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. We studied 16 new Glut-1 deficiency syndrome patients focusing on clinical and laboratory features, molecular genetics, genotype-phenotype correlation, and treatment. These patients were classified phenotypically into three groups. The mean cerebrospinal fluid glucose concentration was 33.1 +/- 4.9mg/dl equal to 37% of the simultaneous blood glucose concentration. The mean cerebrospinal fluid lactate concentration was 1.0 +/- 0.3mM, which was less than the normal mean value of 1.63mM. The mean V(max) for the 3-O-methyl-D-glucose uptake into erythrocytes was 996 fmol/10(6) red blood cells per second, significantly less (54 +/- 11%; t test, p < 0.05) than the mean control value of 1,847. The mean Km value for the patient group (1.4 +/- 0.5mM) was similar to the control group (1.7 +/- 0.5mM; t test, p > 0.05). We identified 16 rearrangements, including seven missense, one nonsense, one insertion, and seven deletion mutations. Fourteen were novel mutations. There were no obvious correlations between phenotype, genotype, or biochemical measures. The ketogenic diet produced good seizure control.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/tratamento farmacológico , Erros Inatos do Metabolismo dos Carboidratos/genética , Cetoses/uso terapêutico , Proteínas de Transporte de Monossacarídeos/deficiência , Mutação/genética , 3-O-Metilglucose/sangue , Adolescente , Glicemia/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Dietoterapia/métodos , Eletroencefalografia/métodos , Éxons , Feminino , Glucose/líquido cefalorraquidiano , Transportador de Glucose Tipo 1 , Humanos , Lactente , Ácido Láctico/líquido cefalorraquidiano , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Fenótipo , Polimorfismo Genético
15.
Am J Gastroenterol ; 97(12): 3123-30, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12492199

RESUMO

OBJECTIVE: Small intestinal glucose absorption is increased in animal models of diabetes mellitus, but little data are available in humans. Small intestinal motility is reported to be frequently abnormal in patients with diabetes and could potentially affect glucose absorption. Our aim was to evaluate small intestinal glucose absorption and duodenal motor responses to intraduodenal nutrients, in patients with type 1 diabetes and controls. METHODS: Eight type 1 patients (two with autonomic neuropathy) and nine controls were studied during euglycemia. A manometric catheter was positioned across the pylorus, and nutrient infused intraduodenally (90 kcal over 30 min), followed by a bolus of 3-O-methylglucose (3-OMG). Blood was sampled to measure glucose and 3-OMG concentrations. RESULTS: During nutrient infusion, the number of duodenal waves did not differ between patients and controls. After the infusion, patients with diabetes had more propagated duodenal wave sequences (p < 0.05). The area under the plasma 3-OMG curve did not differ between the groups but correlated with both the blood glucose concentration at the time of 3-OMG administration (r = 0.64, p < 0.005) and the number of duodenal waves (r = 0.52, p < 0.05) and antegrade propagated duodenal sequences (r = 0.51, p < 0.05) preceding the 3-OMG bolus. CONCLUSIONS: During euglycemia, duodenal motor responses to small intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and healthy subjects, but duodenal motility after nutrient infusion is increased in patients. Small intestinal glucose absorption is similar in patients and controls, but may be dependent on the blood glucose concentration and duodenal motor activity.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Duodeno/fisiopatologia , Motilidade Gastrointestinal , Glucose/metabolismo , Absorção Intestinal , Intestino Delgado/metabolismo , 3-O-Metilglucose/sangue , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Glicemia/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Período Pós-Prandial , Pressão , Fatores de Tempo
16.
Biochemistry ; 41(25): 8075-81, 2002 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-12069599

RESUMO

It has been proposed that GLUT1, a membrane protein that transports hexoses and the oxidized form of vitamin C, dehydroascorbic acid, is also a transporter of nicotinamide (Sofue, M., Yoshimura, Y., Nishida, M., and Kawada, J. (1992) Biochem. J. 288, 669-674). To ascertain this, we studied the transport of 2-deoxy-D-glucose, 3-O-methyl-D-glucose, and nicotinamide in human erythrocytes and right-side-out and inside-out erythrocyte membrane vesicles. The transport of nicotinamide was saturable, with a K(M) for influx and efflux of 6.1 and 6.2 mM, respectively. We found that transport of the hexoses was not competed by nicotinamide in both the erythrocytes and the erythrocyte vesicles. Likewise, the transport of nicotinamide was not affected by hexoses or by inhibitors of glucose transport such as cytochalasin B, genistein, and myricetin. On the other hand, nicotinamide blocked the binding of cytochalasin B to human erythrocyte membranes but did so in a noncompetitive manner. Using GLUT1-transfected CHO cells, we demonstrated that increased expression of GLUT1 was paralleled by a corresponding increase in hexose transport but that there were no changes in nicotinamide transport. Moreover, nicotinamide failed to affect the transport of hexoses in both control and GLUT1-transfected CHO cells. Therefore, our results indicates that GLUT1 does not transport nicotinamide, and we propose instead the existence of other systems for the translocation of nicotinamide across cell membranes.


Assuntos
Proteínas de Transporte de Monossacarídeos/metabolismo , Niacinamida/metabolismo , 3-O-Metilglucose/sangue , Animais , Células CHO/metabolismo , Cricetinae , Citocalasina B/antagonistas & inibidores , Citocalasina B/metabolismo , Citocalasina B/farmacologia , Desoxiglucose/sangue , Membrana Eritrocítica/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Flavonoides/farmacologia , Genisteína/farmacologia , Transportador de Glucose Tipo 1 , Humanos , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Proteínas de Transporte de Monossacarídeos/biossíntese , Proteínas de Transporte de Monossacarídeos/sangue , Niacinamida/sangue , Ligação Proteica/efeitos dos fármacos , Transfecção , Vesículas Transportadoras/metabolismo
17.
Pediatr Res ; 50(2): 254-60, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11477212

RESUMO

Methylxanthines such as caffeine and theophylline are known to inhibit glucose transport. We have studied such inhibition in the glucose transporter type 1 deficiency syndrome (Glut1DS) by erythrocyte glucose transport assays. Data from four patients with individual mutations in the GLUT1 gene are discussed: patient 1 (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 (R333W). Zero-trans influx of (14)C-labeled 3-O-methyl glucose (3-OMG) into erythrocytes of patients is reduced (patient 1, 51%; 3, 45%; 15, 31%; 17, 52%) compared with maternal controls. Inhibition studies on patients 1, 3, 17, and maternal controls show an IC(50) for caffeine of approximately 1.5 mM both in controls (n = 3) and patients (n = 3) at 5 mM 3-OMG concentration. In the same two groups, kinetic studies show that 3 mM caffeine significantly decreases V(max) (p < 0.005), whereas the decrease in K(m) is significant (p < 0.01) only in the three controls and one patient (patient 3). Kinetic data from individual patients permit us to speculate that the interactions between caffeine and Glut1 are influenced by the mutation. Three mM caffeine also inhibits the transport of dehydroascorbic acid (DHA), another substrate for Glut1. The combined effects of caffeine (3 mM) and phenobarbital (10 mM) on glucose transport, as determined in patient 15 and the maternal control, show no additive or synergistic inhibition. These data indicate that caffeine and phenobarbital have similar Glut1 inhibitory properties in these two subjects. Our study suggests that Glut1DS patients may have a reduced safety margin for methylxanthines. Consumption of methylxanthine-containing products may aggravate the neurologic symptoms associated with the Glut1DS.


Assuntos
Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , 3-O-Metilglucose/sangue , Adolescente , Cafeína/farmacologia , Estudos de Casos e Controles , Criança , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Humanos , Técnicas In Vitro , Cinética , Masculino , Mutação , Fenobarbital/farmacologia , Síndrome , Teofilina/farmacologia
18.
J Nucl Med ; 42(5): 795-801, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11337579

RESUMO

UNLABELLED: Metabolic processes studied by PET are quantified traditionally using compartmental models, which relate the time course of the tracer concentration in tissue to that in arterial blood. For liver studies, the use of arterial input may, however, cause systematic errors to the estimated kinetic parameters, because of ignorance of the dual blood supply from the hepatic artery and the portal vein to the liver. METHODS: Six pigs underwent PET after [15O]carbon monoxide inhalation, 3-O-[11C]methylglucose (MG) injection, and [18F]FDG injection. For the glucose scans, PET data were acquired for 90 min. Hepatic arterial and portal venous blood samples and flows were measured during the scan. The dual-input function was calculated as the flow-weighted input. RESULTS: For both MG and FDG, the compartmental analysis using arterial input led to systematic underestimation of the rate constants for rapid blood-tissue exchange. Furthermore, the arterial input led to absurdly low estimates for the extracellular volume compared with the independently measured hepatic blood volume of 0.25 +/- 0.01 mL/mL (milliliter blood per milliliter liver tissue). In contrast, the use of a dual-input function provided parameter estimates that were in agreement with liver physiology. Using the dual-input function, the clearances into the liver cells (K1 = 1.11 +/- 0.11 mL/min/mL for MG; K1 = 1.07 +/- 0.19 mL/min/mL for FDG) were comparable with the liver blood flow (F = 1.02 +/- 0.05 mL/min/mL). As required physiologically, the extracellular volumes estimated using the dual-input function were larger than the hepatic blood volume. The linear Gjedde-Patlak analysis produced parameter estimates that were unaffected by the choice of input function, because this analysis was confined to time scales for which the arterial-input and dual-input functions were very similar. CONCLUSION: Compartmental analysis of MG and FDG kinetics using dynamic PET data requires measurements of dual-input activity concentrations. Using the dual-input function, physiologically reasonable parameter estimates of K1, k2, and Vp were obtained, whereas the use of conventional arterial sampling underestimated these parameters compared with independent measurements of hepatic flow and hepatic blood volume. In contrast, the linear Gjedde-Patlak analysis, being less informative but more robust, gave similar parameter estimates (K, V) with both input functions.


Assuntos
Glucose/farmacocinética , Fígado/metabolismo , Radioisótopos de Oxigênio , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão , 3-O-Metilglucose/sangue , 3-O-Metilglucose/farmacocinética , Animais , Volume Sanguíneo , Monóxido de Carbono/sangue , Fluordesoxiglucose F18/sangue , Fluordesoxiglucose F18/farmacocinética , Glucose/análogos & derivados , Artéria Hepática , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Circulação Hepática , Veia Porta , Suínos
19.
Res Commun Mol Pathol Pharmacol ; 107(5-6): 349-60, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11589362

RESUMO

All-trans retinyl palmitate (RP) (1000 IU/kg body weight) was orally administered to rats for three days. The absorption of 3-O-methyl-D-glucose (3-OMG), which is actively transported by Na+-dependent D-glucose co-transporter (SGLT1), in the small intestine of the control and RP-treated rats was investigated by the in vito everted sac and in situ closed loop of intestine techniques. The absorption of [3H]3-OMG in both experiments of the in vito everted sac and in situ closed loop of intestine significantly increased in the RP-treated rats. AUC(0-120min) obtained from the [3H]3-OMG plasma concentration vs. time curve in the RP-treated rats was significantly larger than that in the control rats. On the other hand, the activity of Na+-K+-adenosinetriphosphatase (ATPase) and the transport rate of D-glucose mediated by Na+-independent facilitative glucose transporter (GLUT2) on the basolateral membrane (BLM) were similar between the control and RP-treated rats. Thus it is suggested that RP treatment of rats enhance the small intestinal absorption of glucose mediated by SGLT1.


Assuntos
3-O-Metilglucose/farmacocinética , Antioxidantes/farmacologia , Absorção Intestinal/efeitos dos fármacos , Vitamina A/análogos & derivados , Vitamina A/farmacologia , 3-O-Metilglucose/sangue , Administração Oral , Animais , Área Sob a Curva , Peso Corporal/efeitos dos fármacos , Diterpenos , Masculino , Glicoproteínas de Membrana/fisiologia , Proteínas de Transporte de Monossacarídeos/fisiologia , Ratos , Ratos Wistar , Ésteres de Retinil , Transportador 1 de Glucose-Sódio
20.
Biochemistry ; 38(51): 16974-83, 1999 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-10606533

RESUMO

The human erythrocyte sugar transporter presents sugar import (e2) and sugar export (e1) sites simultaneously. This study asks whether the sugar transporter exposes only one or multiple import sites. We approached this question by analysis of cytochalasin B binding to the human erythrocyte sugar export site in the presence of sugars that bind to the sugar import site. Extracellular maltose does not enter human erythrocytes. High concentrations of maltose (1-100 mM) inhibit cytochalasin B binding to human red cells. Low concentrations (25-500 microM) increase the level of erythrocyte cytochalasin B binding. Maltose modulation of cytochalasin B binding is mediated by altered affinity of sugar export sites for cytochalasin B. Similar results are obtained with other cell-impermeant inhibitors of sugar uptake. Extracellular D-glucose (a transported sugar) stimulates cytochalasin B binding at low D-glucose concentrations (10-250 microM), but this effect is lost at higher concentrations. Intracellular D-glucose inhibits cytochalasin B binding. Low concentrations of extracellular maltose and other nontransported inhibitors stimulate 3-O-methylglucose uptake in erythrocytes. Higher sugar concentrations (1-100 mM) inhibit transport. These data support the hypothesis that the erythrocyte sugar transporter presents two sugar import sites and at least one sugar export site. This conclusion is consistent with the proposed oligomeric structure of the sugar transporter, a complex of four GluT1 proteins in which each subunit presents a translocation pathway.


Assuntos
Carboidratos/sangue , Eritrócitos/metabolismo , Proteínas de Transporte de Monossacarídeos/sangue , Proteínas de Transporte de Monossacarídeos/química , 3-O-Metilglucose/sangue , Sítios de Ligação/efeitos dos fármacos , Carboidratos/farmacologia , Citocalasina B/sangue , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Glucose/farmacologia , Transportador de Glucose Tipo 1 , Humanos , Maltose/farmacologia , Modelos Biológicos , Trissacarídeos/farmacologia
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