Dietary macronutrients and glucostatic control of feeding.
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Appetite↗
Biomedical subjects
R J Stubbs
Publications and source records attributed to R J Stubbs.
Covert manipulation of the ratio of medium- to long-chain triglycerides in isoenergetically dense diets: effect on food intake in ad libitum feeding men.
OBJECTIVE: This study examined whether isoenergetic substitution of MCT for LCT in HF, HE diets (639 kJ/100 g) limits the excess energy intakes frequently observed on high-fat diets of high energy density (HF, HE). SUBJECTS: Six healthy male volunteers [mean age (SD) = 27.17 (4.17 y) mean weight = 63.33 (7.33 kg), mean height = 1.72 (0.05 m)]. DESIGN: The subjects were each studied three times during 14 d throughout which they had ad libitum access to one of three covertly-manipulated diets, which were randomly assigned in a counter-balanced design. The fat, carbohydrate (CHO) and protein in each diet (as percent energy) were identical at 62:28:10, with 2 day maintenance (1.5 x BMR, MF) beforehand. The ratio of MCT to LCT was 1:2, 1:1 and 2:1 on the low-, (LMCT) medium- (MMCT) and high-MCT (HMCT) diets, respectively. Within each diet every item was of the same composition and offered as a 3 day rotating menu. RESULTS: Energy intakes were significantly lower on the HMCT diet [F (2,240) = 7.52; p < 0.001] giving mean values of 13.50, 13.67, and 12.43 MJ/d on the LMCT, MMCT and HMCT diets, respectively. Food intake followed a parallel trend. By day 14 body weight changes amounted to +0.45, +0.41 and -0.03 kg, respectively. CONCLUSION: These data suggest that substitution of a readily metabolised fat for a less readily metabolised fat, in very high fat diets can limit the excess energy intakes and weight gain that is usually produced by HF, energy-dense diets.
Adult↗
Covert manipulation of the dietary fat to carbohydrate ratio of isoenergetically dense diets: effect on food intake in feeding men ad libitum.
OBJECTIVE: High-fat, high energy-density (HF, HED) diets promote an increase in energy intakes relative to low-fat lower-energy density diets (LF, LED). This study examined whether HF diets promote higher levels of energy intake when isoenergetically dense (IE) relative to LF (high carbohydrate) diets, as predicted by glucostatic and glycogenostatic models for energy intake regulation. SUBJECTS: Six normal-weight healthy men [mean age (SD) = 37.33 (13.32 y) mean weight = 73.03 (5.14 kg), mean height = 1.80 (0.05 m)]. DESIGN: Six men were each studied three times (factorial design) during 14-d throughout which they had ad libitum access to one of three covertly-manipulated diets. The fat, carbohydrate (CHO) and protein in each diet (as % energy) were 20:68:12, [low-fat (LF)]; 40:48:12, [medium-fat (MF)]; 60:28:12 [high-fat (HF)], with 2-d maintenance (1.4 x BMR, MF) beforehand. Within each diet every item was of the same composition and offered as a 3-d rotating menu. MEASUREMENTS: Energy and nutrient intakes, body weight, subjective pleasantness and satisfaction of the food. RESULTS: Energy intakes were 10.69, 11.02 and 10.90 MJ/d on the LF, MF and HF diets respectively. The increase in energy intake that occurred in previous studies when the energy density of the diet was increased by addition of fat was not apparent when LF, MF and HF diets were of the same energy density. CONCLUSION: Neither carbohydrate nor fat intake were tightly regulated. These data do not support an entirely glucostatic or glucogenostatic model of food intake regulation.
Adult↗
Breakfasts high in protein, fat or carbohydrate: effect on within-day appetite and energy balance.
OBJECTIVE: To compare the effect of isoenergetically-dense, high-protein (HP), high-fat (HF) or high-carbohydrate (HC) breakfasts (at 08.30) on subjective hunger, fullness and appetite (measured hourly on a 100 mm visual analogue scale), macronutrient balance and ad libitum energy intake (EI), at a test meal (13.30) and throughout the rest of the day (until 23.00). DESIGN: Six men each spent 24 h in a whole-body indirect calorimeter on three separate occasions during which they received breakfasts designed to match 75% of BMR and that comprised, on average 3.1 MJ of protein (HP), carbohydrate (HC) or fat (HF), respectively, the remainder being split between the other two macronutrients. Every item of the ad libitum diet comprised 13% protein, 40% fat and 47% carbohydrate by energy, with an energy density of 550 kJ/100 g. RESULTS: Subjectively-rated pleasantness did not differ between the breakfasts, or any of the subsequent ad libitum meals. Subjective hunger was significantly greater during the hours between breakfast and lunch after the HF (26) treatment relative to the HP (18) or HC (18 mm) meals (P < 0.001), although the HP treatment suppressed hunger to a greater extent than the other two treatments over 24 h. However, mean ad libitum lunch intakes were similar at 5.38, 5.30 and 5.18 MJ (NS) on the HP, HC and HF treatments, respectively. After-lunch intakes were also very similar at 6.14, 6.18 and 5.83 MJ (NS). Mean 24-h energy expenditure amounted to 11.12, 11.14 and 10.93 MJ, respectively, producing energy balances of 5.71, 5.83 and 5.04 MJ (NS), respectively. The HP, HF and HC breakfasts led to enhanced P, F and C oxidation, respectively (P < 0.003). CONCLUSIONS: Large HP, HC or HF breakfasts led to detectable changes in hunger that were not of sufficient magnitude to influence lunch-time intake 5 h later, or EI for the rest of the day. A single positive balance of each macronutrient can be buffered by oxidation and storage capacity, without leading to changes in meal-to-meal EI, when subjects feed ad libitum on unfamiliar diets of fixed composition.
Adult↗
Effect of overfeeding macronutrients on day-to-day food intake in man.
OBJECTIVE: To test whether overfeeding isoenergetic doses protein, carbohydrate and fat would differentially influence appetite on the same day, and the subsequent day's food intake. DESIGN: Six men were each studied three times on a 5-day protocol. On days 1 and 2 they were fed a medium fat (MF) maintenance diet (comprising 40:47:13% fat, CHO and protein by energy) calculated at 1.6 x RMR. Subjects entered the calorimeter at 08.00 on day 3 for 48 h. On day 3 (manipulation day), they ate a MF diet at 1.5 x RMR with an additional 0.6 x RMR as protein (HP), carbohydrate (HC) or fat (HF). On days 4 and 5, (outcome days), subjects had ad libitum access to isoenergetically dense MF (40:47:13) foods (550kJ/100 g). Subjective hunger and satiety were tracked hourly during waking hours throughout days 1-5. RESULTS: Throughout day 3 subjects felt significantly more full and less hungry on the high protein diet relative to the other two diets (P = 0.002). Also by the end of day 3 each overfed nutrient led to a significant increase in its own balance of the other two diets (P < 0.01). These effects did not influence the subsequent day's energy intake. The alterations in nutrient balance by the end of day 3 were partially buffered by increases in the oxidative disposal of each overfed macronutrient throughout day 4 (which was proportionately greater for protein (P < 0.001) than carbohydrate (P = 0.07) or fat (P = 0.1)). CONCLUSIONS: HP diets were more satiating that isoenergetically-dense HC or HF diets on the day they are eaten. The HC diet was transiently more satiating than the HF diet after each meal. This study supports previous work which suggests that relatively large changes in nutrient balance produced on one day appear to be poorly compensated by changes in energy intake on a subsequent day in men.
Adult↗
Automated high-performance liquid chromatographic method for the determination of a neuraminidase inhibitor (GG167) in human serum by pre-column fluorescence derivatisation using benzoin.
A pre-column fluorescence derivatisation high-performance liquid chromatographic method for the analysis of a neuraminidase inhibitor, GG167, in human serum is described. GG167 was extracted from serum samples using Bond Elut SCX solid-phase extraction cartridges, followed by derivatisation with benzoin prior to reversed-phase chromatography with fluorescence detection. This method has been automated using a Zymark robot and used in the analysis of human serum samples from clinical studies. The method has been shown to be valid over a concentration range of 10-800 ng/ml using a 1-ml sample volume.
Autoanalysis↗
Covert manipulation of dietary fat and energy density: effect on substrate flux and food intake in men eating ad libitum.
This study assessed whether human food intake is regulated by negative feedback, directly or indirectly, from carbohydrate stores (glycogenostatic model). Six men were studied on three occasions during 7 d of whole-body indirect calorimetry, throughout which they had ad libitum access to one of three covertly manipulated diets: low fat (20% of energy as fat, 67% of energy as carbohydrate, and 13% of energy as protein; 4.80 kJ/g; LF), medium fat (40% of energy as fat, 47% of energy as carbohydrate, and 13% of energy as protein; 5.59 kJ/g; MF), or high fat (60% of energy as fat, 27% of energy as carbohydrate, and 13% of energy as protein; 7.04 kJ/g; HF). Energy intakes increased with percent fat (F[92,60] = 36.7; P < 0.001), producing average daily balances of -0.27, 0.77, and 2.58 MJ/d during the LF, MF, and HF diets, respectively. Changes in carbohydrate stores were attenuated by autoregulatory changes in carbohydrate oxidation. Carbohydrate balance showed a negative relation to the subsequent day's energy balance (t = 2.696; P = 0.0082) but explained only 5.5% of the variance. The relation for fat was positive (t = 5.245; P < 0.0001), accounting for 19.9% of the variance (stepwise regression). LF, lower-energy diets are more satiating than are HF-higher-energy diets, but carbohydrate stores per se did not entirely account for the change that diet composition had on energy intake. This study suggests that protein and carbohydrate have potential to reduce subsequent energy intake whereas there was no apparent reductive effect due to fat.
Adult↗
Covert manipulation of the ratio of dietary fat to carbohydrate and energy density: effect on food intake and energy balance in free-living men eating ad libitum.
We previously increased the energy density and fat content across three diets (factorial design), which led to a marked increase in energy intake in six men over 7 d while continuously resident in a whole-body indirect calorimeter. In the present study we fed the same diets to seven men who were resident in, but not confined to, a metabolic suite for 2 wk/diet. This added a component of increased physical activity. The fat, carbohydrate, and protein contents, respectively, of each diet (as a percent of energy) were as follows: low-fat (LF), 20:67:13; medium-fat (MF), 40:47:13; and high-fat (HF), 60:27:13. Energy density increased as the percent of fat in the diet increased. Energy intakes from the LF, MF, and HF diets (9.11, 10.32, and 12.78 MJ/d, respectively) were almost identical to those in our calorimeter study (9.02, 10.2, and 12.35 MJ/d, respectively) whereas energy expenditures (estimated by the doubly labeled water method) were 12.45, 12.10, and 11.97 MJ/d on the LF, MF and HF diets, respectively, compared with 9.48, 9.53, and 9.78 MJ/d, respectively, in our calorimeter study. This finding suggests that diet composition and energy expenditure combined influence energy balance in humans.
Adult↗
Macronutrient effects on appetite.
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Appetite↗
Alterations in fuel selection and voluntary food intake in response to isoenergetic manipulation of glycogen stores in humans.
This study investigated the relative importance of alterations in carbohydrate intake or oxidation as mechanisms for rectifying extreme perturbations of glycogen stores. Six lean men were studied on three occasions in which a stabilization period (days 1 and 2) was immediately followed by whole-body indirect calorimetry (days 3-5). Glycogen stores were manipulated on days 3 and 4 by using isoenergetic diets providing carbohydrate at 79% (HC), 48% (MC), or 9% (LC) of energy. Free access to MC meals and snacks was allowed on days 5 and 6 outside the calorimeter. The manipulations caused large alterations in glycogen stores (HC, +206 g; MC, +132 g; LC, -121 g; HC vs LC, 327 g), but subsequent voluntary food intake was very similar across treatments (HC, 18.2 MJ/36 h; MC, 17.7 MJ/36 h; LC, 18.1 MJ/36 h, NS). Over days 3-5 the average difference in carbohydrate intake (HC vs LC) was 16.1 MJ (1010 g), but balances differed by only 1.7 MJ (110 g) because of autoregulatory changes in carbohydrate oxidation. These were the only significant mechanisms for reestablishing carbohydrate balance.
Adult↗
Carbohydrate balance and the regulation of day-to-day food intake in humans.
The hypothesis that carbohydrate stores are an important determinant of voluntary food intake was tested by covert dietary manipulation of carbohydrate stores in nine men during 2 d of continuous whole-body calorimetry that provided half-hourly monitoring of energy and fuel balance. On day 1 subjects were fed diets intended to maintain energy balance but containing carbohydrate at either 3% (depletion) or 47% (control) energy. Average carbohydrate balance changed by 153 +/- 42 g (mean +/- SD). Subsequent (day 2) ad libitum food intake from a normal diet of fixed macronutrient composition was identical on the control and depletion protocols: 12.73 +/- 2.24 and 12.72 +/- 2.01 MJ, respectively. The carbohydrate-depletion protocol caused a suppression of carbohydrate oxidation (174 +/- 41 vs 256 +/- 39 g, P < 0.001) and a reciprocal elevation in fat oxidation (120 +/- 11 vs 89 +/- 12 g, P < 0.001). These readjustments in fuel utilization were the primary mechanism for re-establishing carbohydrate balance. This study does not support the hypothesis that the need to maintain specific carbohydrate stores is a determinant of food intake in the short term.
Adult↗
Myopathy associated with HMG-CoA reductase inhibitors (HMGRIs) and cyclosporin A: evaluation in a rat model.
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Animals↗
Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy through administration of a controlled-porosity osmotic pump dosage form.
An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the beta-hydroxyacid form of simvastatin, a potent HMG-CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.
Animals↗
Single-dose pharmacokinetics of 14C-lovastatin in chronic renal failure.
An open study on the pharmacokinetics of lovastatin was conducted in six patients with chronic renal failure (mean creatinine clearance, 0.40 ml/sec; range, 0.20 to 0.65 ml/sec) and seven healthy subjects. Plasma levels of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitory activity (total and active) and total radioactivity were determined over 168 hours after a single dose of 80 mg 14C-lovastatin. The mean area under the plasma concentration-time curve for active inhibitors were 606 +/- 346 and 282 +/- 138 ngEq.hr/ml (p = 0.04) in patients and control subjects, respectively. Total inhibitors in plasma and total radioactivity were similarly elevated in patients with chronic renal failure. Results indicate that patients with severe renal dysfunction have altered elimination kinetics of lovastatin. Current ongoing clinical studies in patients with renal dysfunction will allow better assessment of the pharmacodynamic meaning of our observations.
Adult↗
Effects of signal-to-noise ratio, signal periodicity, and degree of hearing impairment on the performance of voice-separation algorithms.
Procedures for enhancing the intelligibility of a target talker in the presence of a co-channel competing talker were evaluated in tests involving (i) continuously voiced sentences spoken on a monotone, (ii) continuously voiced sentences with time-varying intonation, and (iii) noncontinuously voiced sentences produced with natural intonation. The procedures were based on the methods of harmonic selection and cepstral filtering [R.J. Stubbs and Q. Summerfield, J. Acoust. Soc. Am. 87, 359-372 (1990)]. Target and competing voices were combined at signal-to-noise ratios (SNRs) between -10 dB and +10 dB. Subjects were a group with normal hearing and a heterogeneous group with mild-moderate cochlear hearing impairments. Processing enhanced the target voice over a range of SNRs for each type of sentence and for most listeners. Enhancement was greatest at negative SNRs. Among the impaired listeners, benefit was generally greater for those with milder losses. These results consolidate and extend previous demonstrations that voice-separation algorithms that exploit the harmonic structure of the voiced portions of speech can enhance intelligibility. However, practical application of such algorithms depends on a solution to the problem of tracking the fundamental-frequency contour of one voice in the presence of a competing voice.
Algorithms↗
HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies.
Recent clinical evidence indicates a potential for skeletal muscle toxicity after therapy with HMG-CoA reductase inhibitors (HMGRIs) in man. Although the incidence of drug-induced skeletal muscle toxicity is very low (0.1-0.2%) with monotherapy, it may increase following concomitant drug therapy with the immunosuppressant, cyclosporine A (CsA), and possibly with certain other hypolipidemic agents. In the Sprague-Dawley rat, very high, pharmacologically comparable dosages (150-1200 mg/kg/day) of structurally similar HMGRIs (lovastatin, simvastatin, pravastatin and L-647, 318) produced dose-related increases in the incidence and severity of skeletal muscle degeneration. Physical signs included inappetence, decreased activity, loss of body weight, localized alopecia and mortality. To evaluate the interaction between HMGRIs and CsA, a rat model of CsA-induced cholestasis was developed. In this 2-week model, the skeletal muscle toxicity of the HMGRIs was clearly potentiated by CsA (10 mg/kg/day). Doses of HMGRIs which did not produce skeletal muscle toxicity when given alone caused between 75 and 100% incidence of myopathy (very slight to marked skeletal muscle degeneration) when CsA was coadministered. Typical light microscopic changes included myofiber necrosis with interstitial edema and inflammatory infiltration in areas of acute injury. Histochemical characterization of the muscle lesion indicated that type 2B fibers (primarily glycolytic white fibers) were most sensitive to this toxicity but that, with prolonged administration, all fiber types were ultimately affected. Results of pharmacokinetic studies in rats treated with various HMGRIs +/- CsA indicated that coadministration of CsA alters the disposition of these compounds, resulting in increased systemic exposure (e.g., increased area under the plasma drug concentration vs. time curve-AUC) and consequent (up to 13-fold) increases in skeletal muscle drug levels. Evaluation of the potential interaction between the HMGRI, lovastatin and CsA at the level of hepatic microsomal metabolism indicated that CsA did not inhibit the metabolism of lovastatin in isolated microsomes from female rats. In light of the above findings, it appears that HMGRI-induced myopathy is a class effect in the rat, which is potentiated by CsA as the result of altered clearance and resultant increased tissue exposure. Cholestasis associated with CsA and HMGRIs may form the basis for decreased elimination and the resultant elevated systemic exposure. Furthermore, this toxicity is muscle fiber-selective and may be associated with impaired skeletal muscle energy metabolism.
Animals↗
Algorithms for separating the speech of interfering talkers: evaluations with voiced sentences, and normal-hearing and hearing-impaired listeners.
Two signal-processing algorithms, derived from those described by Stubbs and Summerfield [R.J. Stubbs and Q. Summerfield, J. Acoust. Soc. Am. 84, 1236-1249 (1988)], were used to separate the voiced speech of two talkers speaking simultaneously, at similar intensities, in a single channel. Both algorithms use fundamental frequency (FO) as the basis for segregation. One attenuates the interfering voice by filtering the cepstrum of the signal. The other is a hybrid algorithm that combines cepstral filtering with the technique of harmonic selection [T.W. Parsons, J. Acoust. Soc. Am. 60, 911-918 (1976)]. The algorithms were evaluated and compared in perceptual experiments involving listeners with normal hearing and listeners with cochlear hearing impairments. In experiment 1 the processing was used to separate voiced sentences spoken on a monotone. Both algorithms gave significant increases in intelligibility to both groups of listeners. The improvements were equivalent to an increase of 3-4 dB in the effective signal-to-noise ratio (SNR). In experiment 2 the processing was used to separate voiced sentences spoken with time-varying intonation. For normal-hearing listeners, cepstral filtering gave a significant increase in intelligibility, while the hybrid algorithm gave an increase that was on the margins of significance (p = 0.06). The improvements were equivalent to an increase of 2-3 dB in the effective SNR. For impaired listeners, no intelligibility improvements were demonstrated with intoned sentences. The decrease in performance for intoned material is attributed to limitations of the algorithms when FO is nonstationary.
Algorithms↗
Bedside and field methods for assessing body composition: comparison with the deuterium dilution technique.
Estimates of body composition by the deuterium dilution technique were made in 55 healthy subjects (38 men and 17 women) with a mean age of 28.4 years, weight 65.5 kg and height 173.7 cm (body mass index 16.9-29.4 kg/m2). The results were compared with estimates obtained in the same subjects by 5 bedside techniques (skinfold thickness, impedance, resistance and 2 equations predicting body composition from weight and height). The results of all the bedside predictive methods were found to differ significantly from those of the deuterium dilution method (P less than 0.001). The Holtain impedance method underestimated the fat-free mass (FFM) obtained by deuterium dilution (50.8 +/- 7.9 kg) by a mean difference (mean bias) of 4.1 kg while the other methods overestimated FFM (mean bias or mean difference of -1.3 to -2.4 kg). The resistance (Valhalla equations) and skinfold methods showed the narrowest 95 per cent limits of agreement, when compared with the deuterium dilution technique, while the weight and height equations showed the widest limits of agreement. It is concluded that in this population, the resistance (Valhalla equations) and the skinfold thickness methods were the best predictors of body composition as measured by deuterium dilution. Discrepancies between the bedside methods and deuterium dilution method may be due to (a) methodological or biological differences between the test population used in this study and the original population used to validate the method, (b) differences in the structure of the equations used to interpret the measured biological variables, such as impedance and resistance, and (c) the use of predictive equations that are based on different 'reference' methods, such as deuterium dilution or densitometry, and on different assumptions. Predictive equations based on a combination of these reference methods are preferable to those based on single methods.
Adolescent↗