Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort.

BACKGROUND: The contribution of 'environment' has been investigated across diverse and multiple domains related to health. However, in the context of large-scale genomic studies the focus has been on obtaining individual-level endophenotypes with environment left for future decomposition. Geo-social research has indicated that environment-level variables can be reduced, and these composites can then be used with other variables as intuitive, precise representations of environment in research. METHOD: Using a large community sample (N = 9498) from the Philadelphia area, participant addresses were linked to 2010 census and crime data. These were then factor analyzed (exploratory factor analysis; EFA) to arrive at social and criminal dimensions of participants' environments. These were used to calculate environment-level scores, which were merged with individual-level variables. We estimated an exploratory multilevel structural equation model (MSEM) exploring associations among environment- and individual-level variables in diverse communities. RESULTS: The EFAs revealed that census data was best represented by two factors, one socioeconomic status and one household/language. Crime data was best represented by a single crime factor. The MSEM variables had good fit (e.g. comparative fit index = 0.98), and revealed that environment had the largest association with neurocognitive performance (ß = 0.41, p < 0.0005), followed by parent education (ß = 0.23, p < 0.0005). CONCLUSIONS: Environment-level variables can be combined to create factor scores or composites for use in larger statistical models. Our results are consistent with literature indicating that individual-level socio-demographic characteristics (e.g. race and gender) and aspects of familial social capital (e.g. parental education) have statistical relationships with neurocognitive performance.

Weight loss and African-American women: a systematic review of the behavioural weight loss intervention literature.

The excess burden of obesity among African-American women is well documented. However, the behavioural weight loss intervention literature often does not report results by ethnic group or gender. The purpose of this article is to conduct a systematic review of all behavioural weight loss intervention trials published between 1990 and 2010 that included and reported results separately for African-American women. The criteria for inclusion included (i) participants age ≥18 years; (ii) a behavioural weight loss intervention; (iii) weight as an outcome variable; (iv) inclusion of African-American women; and (v) weight loss results reported separately by ethnicity and gender. The literature search identified 25 studies that met inclusion criteria. Our findings suggest that more intensive randomized behavioural weight loss trials with medically at-risk populations yield better results. Well-designed and more intensive multi-site trials with medically at-risk populations currently offer the most promising results for African-American women. Still, African-American women lose less weight than other subgroups in behavioural weight loss interventions. It is now critical to expand on individual-level approaches and incorporate the biological, social and environmental factors that influence obesity. This will help enable the adoption of healthier behaviours for this group of women disproportionately affected by obesity.

3-p-Toluoyl-2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran and 2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran do not act as surfactants or micelles when inhibiting the aggregation of beta-amyloid peptide.

The cmc and IC50 values of the beta-amyloid (Abeta) aggregation inhibitors, 3-p-toluoyl-2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 1, and 2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 2 have been determined. After comparison of the cmc data and biological data (IC50 values), we conclude that these active benzofurans do not act as surfactants or micelles at the concentration required to inhibit beta-amyloid-peptide aggregation.

Muscle glycogen storage following prolonged exercise: effect of timing of ingestion of high glycemic index food.

This study examined the effect of delaying the ingestion of carbohydrate on muscle glycogen storage following prolonged exhaustive exercise. Six endurance trained men cycled on two separate occasions at a workload corresponding to 70% VO2max for 2 h followed by four "all-out" 30-s sprints. Following exercise, subjects were fed five high glycemic index (HGI) meals over a 24-h period, with the first three being fed either at 0-4 h (IT) or 2-6 h (DT) at 2-h intervals. Muscle biopsies were taken immediately after exercise and at 8 and 24 h post-exercise and analyzed for glycogen and glucose-6-phosphate. Blood samples were obtained prior to and at 30, 60, and 90 min after each meal and analyzed for glucose and insulin. No differences were observed in the incremental glucose and insulin areas after each meal when IT and DT were compared. In addition, no differences were observed in muscle glycogen or glucose-6-phosphate any time in the two trials. These data indicate that delayed feeding of a HGI meal by 2 h has no effect on the rate of muscle glycogen resynthesis at 8 and 24 h post-exercise, providing that sufficient carbohydrate is ingested during the recovery period.

Splanchnic and muscle metabolism during exercise in NIDDM patients.

To characterize splanchnic and muscle metabolism during exercise in non-insulin-dependent diabetes mellitus (NIDDM), eight male nonobese patients and seven healthy control subjects (CON) were studied during 40 min of bicycle exercise at 60% of maximal oxygen uptake. Biopsies were obtained from the quadriceps femoris muscle at rest and immediately after exercise. Arterial glucose concentration in NIDDM had declined by 10% (P < 0.01) at the end of exercise, whereas in CON it had risen by 21% (P < 0.05). Leg glucose uptake rose from 0.19 +/- 0.06 mmol/min at rest to 2.25 +/- 0.61 mmol/min at the end of exercise in NIDDM and from 0.13 +/- 0.05 to 1.17 +/- 0.34 mmol/min in CON. Splanchnic glucose output increased from 0.52 +/- 0.06 to 2.37 +/- 0.26 mmol/min in NIDDM and from 0.79 +/- 0.12 to 2.44 +/- 0.38 mmol/min in CON. Leg lactate output during exercise was twofold higher in NIDDM. Muscle contents of lactate and glycogen were similar in both groups at rest, whereas after exercise lactate tended to be higher (19.5 +/- 1.7 vs. 12.7 +/- 5.9 mmol/kg dry wt) and glycogen lower (154 +/- 35 vs. 251 +/- 41 mmol glucosyl units/kg dry wt) in NIDDM. Whole body respiratory exchange ratio during exercise was higher in NIDDM (0.84 +/- 0.02 vs. 0.78 +/- 0.02, P < 0.05). Exercise-induced changes in other muscle metabolites were similar in NIDDM and CON. These data indicate that the decline in blood glucose during exercise in nonobese NIDDM is due to enhanced peripheral glucose utilization rather than to an attenuated increase in splanchnic glucose output.

Development of decreased insulin-induced glucose transport in skeletal muscle of glucose-intolerant hybrids of diabetic GK rats.

1. The effect of glucose intolerance on insulin-stimulated glucose transport in isolated skeletal muscles was investigated in male F1 hybrids of spontaneously diabetic GK (Goto-Kakizaki) and control Wistar rats at 1 and 2 months of age. 2. Hybrid rats are characterized by markedly impaired glucose-induced insulin secretion. The area under the blood glucose curve was significantly higher following an intraperitoneal glucose injection (2 g/kg) in hybrid rats in both age groups than in the control rats (P < 0.001). In 2-month-old hybrid rats the incremental area under the insulin curve during the intraperitoneal glucose tolerance test was not different from that of control rats. Serum cholesterol, triacylglycerol or plasma free fatty acid levels did not differ between the groups. Fasting and post-prandial plasma glucose concentrations were elevated in 2-month-old hybrid rats compared with control rats (54%, P < 0.05, and 27%, P < 0.05, respectively), but were not different in 1-month-old rats. Plasma insulin did not differ between the hybrid and control rats in the fasting or post-prandial state at either age studied. 3. The insulin dose-response curves for 3-O-methylglucose transport did not differ between 1-month-old hybrid and control rats for either the soleus or epitrochlearis muscle. The insulin dose-response curve for the epitrochlearis, but not for the soleus, muscle from 2-month-old hybrid rats was shifted to the right compared with the curve from the control animals (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated free fatty acid levels inhibit glucose phosphorylation in slow-twitch rat skeletal muscle.

The effect of increased free fatty acid concentrations on glucose metabolism in rat skeletal muscle was investigated at several different steps in glucose metabolism including glucose transport, glucose phosphorylation, glucose oxidation and glycogen synthesis. In isolated soleus (slow-twitch) muscles, insulin-stimulated (100 microU ml-1) glucose phosphorylation, but not glucose transport, was inhibited by 26 and 22% in the presence of 1.0 and 2.0 mM oleate, respectively (P < 0.01). Regardless of oleate concentration (0.3 or 2.0 mM), insulin-stimulated glucose 6-phosphate levels were elevated to the same extent over the non-insulin-stimulated levels in soleus muscles (P < 0.01). Insulin-stimulated glucose oxidation was inhibited by 44% in soleus muscles exposed to 2.0 mM oleate (P < 0.05), whereas the rate of glucose incorporation into glycogen was not altered. In insulin-stimulated epitrochlearis (fast-twitch) muscles, elevated concentrations of oleate had no effect on the rates of glucose transport or glucose phosphorylation, or on the level of glucose 6-phosphate. These data suggest that increased free fatty acid availability decreases glucose utilization by selectively inhibiting glucose phosphorylation and oxidation in slow-twitch, but not fast-twitch skeletal muscle.

Muscle metabolism during exercise and heat stress in trained men: effect of acclimation.

Exercise metabolism was examined in 13 endurance athletes who exercised on three occasions for 40 min at 70% of maximal O2 uptake in an environmental chamber at either 20 degrees C and 20% relative humidity (RTT) or 40 degrees C and 20% relative humidity before (PRE ACC) or after (POST ACC) 7 days of acclimation. Exercise in the heat resulted in a lower (P < 0.05) mean O2 uptake (0.13 l/min) and higher (P < 0.01) heart rate and respiratory exchange ratio. Acclimation resulted in a lower (P < 0.01) mean heart rate and respiratory exchange ratio. Postexercise rectal temperature, muscle temperature, muscle and blood lactate, and blood glucose were higher (P < 0.01) in the PRE ACC than in the RTT trial, but all were reduced (P < 0.01) in the POST ACC compared with the PRE ACC trial. Muscle glycogenolysis and percentage of type I muscle fibers showing glycogen depletion were greater (P < 0.05) in the PRE ACC than in the RTT trial. Muscle glycogenolysis was unaffected by acclimation during exercise in the heat, although the percentage of depleted type I fibers was higher (P < 0.05) in the unacclimated state. Plasma epinephrine was higher (P < 0.01) during exercise in the heat in the unacclimated individual relative to RTT but was lower (P < 0.01) in the POST ACC than in the PRE ACC trial. The greater reliance on carbohydrate as a fuel source during exercise in the heat appears to be partially reduced after acclimation. These alterations are consistent with the observed changes in plasma epinephrine concentrations.

Effects of acute and chronic counterregulatory hormone infusions on glucose tolerance and insulin sensitivity in diabetic dogs.

The effects of elevated EPI and CORT levels on KG, SI, and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng.kg-1.min-1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 micrograms.kg-1.min-1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KG fell acutely from 2.9 +/- 0.4 to 2.0 +/- 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 +/- 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that SI decreased acutely from 4.7 +/- 1.8 to 2.5 +/- 0.6 x 10(-5) min-1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 +/- 2.5 x 10(-5) min-1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and SI, with acute decline from 3.9 +/- 0.4 to 2.1 +/- 0.4 x 10(-2) min-1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 +/- 0.3 x 10(-2) min-1 during long EPI. During CORT infusion, KG tended to fall (SAL 2.9 +/- 0.4 vs. short CORT 2.5 +/- 0.5 vs. long CORT 2.2 +/- 0.5%/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Distinct but nonadditive effects of epinephrine and cortisol on determinants of glucose tolerance in dogs.

Effects of physiological increments of epinephrine (Epi) and cortisol (F) on glucose metabolism were assessed in dogs just before and during an intravenous glucose tolerance test performed in the last 3 h of an acute (short F + Epi, 4 h F and 3.5 h Epi) or prolonged (long F + Epi, 75 h F and Epi) infusion period. Comparison of the F + Epi effects with those of F and Epi alone enabled us to describe interactions between these hormones. The increase in plasma glucose after long F + Epi [from control (saline, Sal) of 5.2 +/- 0.1 to 5.8 +/- 0.1 mmol/l; n = 8; P less than 0.01] was not greater than the sum of the glucose increments after long F and long Epi individually. Long Epi and long F both reduced glucose tolerance (KGlc) significantly, but the decline during long F + Epi (from Sal 3.6 +/- 0.7 to 2.9 +/- 0.5%/min; P greater than 0.1) was less than during either individual infusion. Minimal model analysis showed that F attenuated the inhibitory effects of long Epi on glucose-mediated glucose disposal (SGlc), so that it was not reduced from 3.8 +/- 0.8 (Sal) during long F + Epi compared with the fall to 1.3 +/- 0.7 x 10(-2) min-1 (n = 6; P less than 0.05) during long Epi alone. F had the dominant influence on insulin sensitivity (SI) during infusion of F + Epi. The reduction of SI from 8.4 +/- 1.1 (Sal) to 6.6 +/- 1.2 (short F + Epi) and 5.1 +/- 1.1 x 10(-4) min-1 per mU/l (long F + Epi; P less than 0.05) paralleled that seen with F alone but contrasted with the acute reduction of SI during short Epi (4.8 +/- 1.5; P less than 0.02 vs. Sal) and its restoration to control values of 9.0 +/- 2.1 x 10(-4) min-1 per mU/l during long Epi. We conclude that Epi and F have distinct but nonadditive effects on determinants of glucose tolerance.

Application of the SAAM modeling program to minimal model analysis of intravenous glucose tolerance test data.

The minimal model approach to analysis of intravenous glucose tolerance tests (IVGTT) yields estimates of parameters representing insulin sensitivity, glucose-mediated glucose disposal and pancreatic responsiveness. The precision of these estimates can deteriorate if the glucose and insulin data lack well-defined structure or freedom from data noise (random error). The precision of parameter estimates can be enhanced if data sets from two or more IVGTTs, obtained under different experimental conditions in the same subject, are analysed together in one data file. Following initial fitting using CONSAM, the conversational version of the modeling program SAAM, those parameters whose estimates remain at the same value under the different experimental conditions are constrained. This effectively reduces the number of adjustable parameters, and their estimates can then be fine-tuned with enhanced precision using the batch version of SAAM.

Practical application of methods for in vivo assessment of insulin secretion and action.

In vivo measurement of insulin sensitivity can be made using the glucose clamp technique or the intravenous glucose tolerance test (IVGTT) with minimal model analysis. The glucose clamp provides a direct, readily understandable measure of insulin action but is more demanding for investigators and subjects. Assessment of insulin secretion must be made by a separate test. The IVGTT is easier to perform but the data are more difficult to analyse and the value for insulin sensitivity is a derived rather than direct measure. As well as insulin sensitivity, glucose mediated glucose disposal and insulin secretion are measured by the IVGTT. In fact the IVGTT technique relies on adequate endogenous insulin secretion whereas the glucose clamp does not. The choice between these two techniques depends on the study to be performed and the available laboratory facilities.

Alternative method for minimal model analysis of intravenous glucose tolerance data.

The minimal models of glucose-insulin kinetics were used to analyze sets of data obtained from human subjects and dogs during frequently sampled intravenous glucose tolerance tests (FSIGTs). Analysis of some data sets from both species resulted in poor identification of parameters. To improve the parameter resolution, the information base on which the parameters are estimated was enlarged. This was accomplished by incorporating into the analysis 1) glucose data obtained between 0 and 8 min of the FSIGT and some of the insulin data obtained prior to the insulin peak and 2) a second set of FSIGT data for each individual obtained during a physiological perturbation. As a result, data analysis was considerably enhanced, with parameter fractional standard deviation being routinely reduced to less than 0.5. Analysis of stimulated data with noise levels for glucose and insulin set between 0.05 and 0.15 confirmed the improvement in parameter estimates. This modified approach to analysis of FSIGTs therefore consistently leads to well-defined kinetic descriptions of experimental data in various situations and supports the usefulness of the minimal model in examining the complex interplay between the parameters that influence overall glucose tolerance.

Effects of epinephrine infusion on determinants of intravenous glucose tolerance in dogs.

Effects of four- to fivefold elevations of epinephrine (EPI) on glucose (Glc) metabolism were assessed in eight dogs before and after an intravenous Glc tolerance test, performed 30 min (short EPI) and 72 h (long EPI) after start of EPI infusion. Short EPI increased plasma nonesterified fatty acids (NEFA; 0.46 +/- 0.08 to 0.78 +/- 0.12 mmol/l, P less than 0.05), but Glc and insulin were unchanged. After long EPI, NEFA returned to control but Glc increased from 5.1 +/- 0.1 to 5.7 +/- 0.2 mmol/l (P less than 0.05). EPI reduced overall Glc tolerance (KG) from 3.5 +/- 0.7 to 2.5 +/- 0.2 (short EPI, P less than 0.05) and 2.3 +/- 0.3%/min (long EPI, P less than 0.02). Minimal model analysis showed that short EPI decreased insulin sensitivity (SI) from 7.9 +/- 1.1 to 4.2 +/- 1.2 min-1 per mU/l X 10(-4) (P less than 0.005) and increased pancreatic responsiveness (phi 1 from 3.7 +/- 0.3 to 7.4 +/- 2.9 mU/l.min-1 per mg/dl, P less than 0.025; phi 2 from 2.6 +/- 0.7 to 4.9 +/- 1.2 mU/l.min-2 per mg/dl). After long EPI SI, phi 1, and phi 2 returned to control. In contrast, Glc-mediated Glc disposal (SG) was decreased from 3.5 +/- 0.5 X 10(-2) to 2.8 +/- 0.6 X 10(-2) (short EPI) and 1.3 +/- 0.6 X 10(-2) min-1 (long EPI, P less than 0.02). We conclude that prolonged infusion of EPI leads to adaptation to its acute effects on NEFA, SI, phi 1, and phi 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic actions of cortisol in a macropodid marsupial Thylogale billardierii.

In undisturbed pademelon wallabies (Thylogale billardierii) with indwelling jugular venous catheters, an increase in the plasma cortisol concentration from 0.25 +/- 0.05 to 1.35 +/- 0.15 (S.E.M.) mumol/l in 2 h, during i.v. infusion of cortisol at 1.0 mg/kg per h, caused no significant change in the plasma glucose concentration from the control value of 4.26 +/- 0.25 mmol/l. The rates of appearance (Ra) and metabolic clearance (MCR) of glucose, measured by steady-state isotope dilution, also did not change significantly from the control values of 14.9 +/- 0.7 mumol/kg per min and 3.52 +/- 0.19 ml/kg per min respectively. Twice-daily i.m. injections of 7 mg cortisol/kg for 7 days caused increases in plasma concentrations of cortisol, from 0.26 +/- 0.02 to 0.66 +/- 0.04 mumol/l on day 7, and glucose, from 5.1 +/- 0.1 to 7.2 +/- 0.6 mmol/l by day 5. The concentration of glycogen in the liver of wallabies fasted for 24 h increased from the control level of 1.17 +/- 0.56 to 5.92 +/- 1.14 g/100 g on day 7 (P less than 0.01), but mean glucose Ra and MCR did not change significantly. Plasma concentrations of alpha-amino nitrogen rose from 2.73 +/- 0.13 to 3.22 +/- 0.12 mmol/l on day 1 and remained at this level. Plasma concentrations of urea rose from 8.59 +/- 0.62 to 9.70 +/- 0.32 mmol/l on day 1, but then declined below the control level. Food intake and urinary excretion of nitrogen did not change in undisturbed animals. However, fasting followed by liver biopsy was accompanied by urinary excretion of nitrogen in excess of food intake, persisting until day 2 of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal and metabolic changes during hypothermic coronary artery bypass surgery in diabetic and non-diabetic subjects.

Hormonal and metabolic responses to hypothermic coronary artery bypass grafting (CABG) were studied in three groups: 8 non-diabetic patients, 8 patients with non-insulin-dependent diabetes mellitus (NIDDM) given a glucose pump priming solution and 8 NIDDM patients given a non-glucose infusion. There were no significant differences in stress hormone responses between NIDDM and non-diabetic patients, with adrenaline concentrations rising 10-fold, noradrenaline 4-fold and cortisol 2 to 3-fold. Glucagon rose significantly during bypass only in the NIDDM patients who did not receive a glucose prime. Comparable marked hyperglycaemia was seen in both glucose primed groups during bypass and exclusion of glucose from the prime in NIDDM patients prevented this major rise. Postoperatively, the rise in insulin in the glucose primed NIDDM patients contrasted with the slower rise in the non-glucose primed NIDDM patients who were also hyperglycaemic by this stage. Perioperative hyperglycaemia in NIDDM patients undergoing CABG can be prevented by using a non-glucose priming solution and by giving insulin infusion, particularly postoperatively.

Adrenocortical functions in a macropodid marsupial Thylogale billardierii.

In a study of adrenocortical functions in macropodid marsupials, measurements were made of the effects of ACTH infusion, ether stress and adrenaline infusion on plasma corticosteroid and glucose concentrations in wallabies (Thylogale billardierii) provided with indwelling venous catheters. The mean plasma total glucocorticoid concentration in undisturbed males and females was 80 +/- 5 (S.E.M.) micrograms/l, of which more than 90% was cortisol. This fraction declined to 68% of the total at the highest ACTH-stimulated concentration of 225 micrograms/l, due to an increase in the contribution by 11-deoxycortisol. Although maximal ACTH stimulation (4.5 i.u./kg per h) caused a five- to sixfold increase in cortisol secretion rate, as measured by isotope dilution during constant-rate tracer infusion, plasma cortisol concentration rose only two- to threefold, due to a marked increase in metabolic clearance. Plasma glucose concentration did not change significantly during either short-term (1 h) i.v. infusion or long-term (8 days) i.m. injection of ACTH, even though plasma cortisol concentration was significantly increased. Ether anaesthesia caused a marked hyperglycaemia that preceded an increase in plasma cortisol concentration and was not sustained while plasma cortisol concentration continued to increase. Infusion of adrenaline i.v. at rates sufficient to cause a similar hyperglycaemia had no significant effect on plasma cortisol concentration. A marked hyperglycaemia during xylazine anaesthesia was not associated with an increase in plasma cortisol concentration and was attributable to suppression of insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of pancreatectomy, tolbutamide and insulin on glucose fluxes in chickens.

The effects of pancreatectomy and of injection of insulin or Tolbutamide on glucose fluxes in chickens were examined. This was prompted by earlier observations that Tolbutamide seems not to require the presence of pancreatic insulin for its acute hypoglycaemic action in this species. Rates of appearance (Ra) and disappearance (Rd) of glucose were estimated by isotope dilution using [14C]glucose in single-injection experiments and [14C]glucose and [6-3H]glucose in priming-injection + constant-infusion experiments. Six hours after sub-total pancreatectomy (splenic lobe remained in situ), chickens were hyperglycaemic (16.7 v. 10-4 mmol glucose/1 in controls), had a larger sampled glucose pool (4.41 v. 3.10 mmol) and a higher average rate of glucose utilization (41.7 v. 33.3 micron mol/kg per min) than sham-operated controls as estimated in single-injection experiments. Tolbutamide (50 mg/kg injected i.v.) reduced Ra in intact chickens from 33.9 to 1.1 micro mol/kg per min and reduced Ra in pancreatectomized chickens from 42.2 to 10.2 micro mol/kg per min. in priming-injection + constant-infusion experiments tolbutamide again reduced Ra significantly. In all case Rd tended to fall, apparently as a result of the developing hypoglycaemia. tolbutamide did not affect the volume of extracellular fluid (sucrose space). In single-injection experiments , insulin (1 unit/kg injected i.v.) reduced Ra by 56% and transiently increased Rd by 39%. It was concluded that pancreatectomy and injection of insulin or tolbutamide produce responses in glucose movements in chickens that are qualitatively similar to those in mammals. In chickens the hypoglcaemic action of tolbutamide, which persists in the absence of the pancreas, depends on an inhibition of glucose release by the liver.