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D S Weigle

Publications and source records attributed to D S Weigle.

12 recordsLinked to original sources
PubMed1991

Lack of evidence for improvement in long-term glycemic control by pulsatile insulin infusion in streptozocin-induced diabetic baboon.

To assess the potential therapeutic use of pulsatile intravenous insulin delivery, five streptozocin-induced diabetic baboons were treated with alternate 3- to 6-wk periods of pulsatile and continuous insulin infusion. Time-averaged insulin concentrations were matched during two pulsatile administration periods (P1 and P2) and an intervening period of continuous insulin administration (C). There were no significant differences among the overall means of four daily glucose determinations performed during the three periods (P1, 5.7 +/- 1 mM; C, 5.6 +/- 0.9 mM; P2, 5.3 +/- 0.9 mM); the mean M value, a measure of the stability of glycemic control (P1, 4 +/- 1.7; C, 3.9 +/- 1.8; P2, 3.6 +/- 1.5); the percentage of glucose values less than 2.8 mM (P1, 13 +/- 8.5%; C, 14 +/- 12%; P2, 13 +/- 9.1%); or the glycosylated hemoglobin levels determined at the end of the P1 and C (7.5 +/- 3.4 and 6.5 +/- 1.8%, respectively [all values are means +/- SD]). Fasting hepatic glucose production was suppressed to a similar degree during pulsatile and continuous insulin infusion (P1, 23 +/- 3 mumol.kg-1.min-1; C, 24 +/- 8 mumol.kg-1.min-1). Arterial glucagon levels were similar during pulsatile and continuous insulin infusion, both in the fasting state (84 +/- 29 and 84 +/- 31 ng/L, respectively) and postprandially (30 +/- 14 and 27 +/- 12 ng/L, respectively). Pulsatile insulin infusion failed to entrain a corresponding glucagon secretory rhythm. These data suggest that the metabolic consequences of long-term pulsatile and continuous insulin infusion in an animal model of human non-insulin-dependent diabetes are comparable.

Animals↗
PubMed1990

Identification of candidate genes for a factor regulating body weight in primates.

A weight gain of 20-30% above baseline, induced by gastrostomy overfeeding of subhuman primates or gavage overfeeding of rats, was found to completely suppress voluntary food consumption. When overfeeding was discontinued, body weight and oral intake returned in a coordinated fashion to baseline or "set point" values. This regulatory response could have been due to a circulating peptide that was secreted by adipocytes in proportion to the total body energy store and that mediated satiety at the level of the central nervous system. To search for this factor, a subtractive cDNA cloning strategy was developed, permitting the isolation of primate adipocyte genes with augmented expression in the overfed state. A 1.8-kb cDNA clone prepared by subtraction was found to hybridize to a 5-kb message expressed preferentially in the adipose tissue of overfed macaques and rats. This message, which was restricted in distribution among nonadipose tissues, was also detected in human subcutaneous fat. Candidate genes for satiety factors identified by this approach could be used in further studies of body weight regulation and obesity.

Adipose Tissue↗
PubMed1990

Assessment of energy expenditure in ambulatory reduced-obese subjects by the techniques of weight stabilization and exogenous weight replacement.

A technique based on a completely metabolizable liquid diet was developed rapidly to achieve weight stability (+/- 50 g/day) in experimental subjects. Weight-stabilizing caloric intake was then used as an estimate of total daily energy expenditure (24 h EE) in a study of 10 ambulatory obese subjects before and after weight loss. In five control subjects 24 h EE fell by 928 +/- 121 kcal/day (3885 +/- 507 kJ/day) or 29 +/- 3 percent after a 22.6 +/- 1.2 percent weight loss achieved on a three month 700 kcal/day (2930 kJ/day) diet. To determine how much of this decrease was due to the reduced thermic effect of exercise (TEE) at the lower body weight, the remaining five subjects underwent progressive exogenous weight replacement during dieting to compensate exactly for their 21.0 +/- 5.2 percent weight loss. In the latter group 24 h EE fell by only 392 +/- 192 kcal/day (1641 +/- 804 kJ/day) or 12 +/- 5 percent (P less than 0.001). These data, along with indirect calorimetric measurements of resting metabolic rate (RMR), permitted the decrease in 24 h EE with weight loss to be divided into its component parts. Decreases in RMR, TEE and the thermic effect of food accounted for 30 percent, 52 percent and 18 percent respectively of the fall in 24 h EE. A reduction in TEE appears to make a greater contribution to the enhanced energy efficiency of ambulatory reduced-obese subjects than has been suggested by studies based on methods requiring greater subject confinement.

Adult↗
PubMed1990

Human obesity. Exploding the myths.

This discussion was selected from the weekly Grand Rounds in the Department of Medicine, University of Washington School of Medicine, Seattle. Taken from a transcription, it has been edited by Drs Paul G. Ramsey, Associate Professor of Medicine, and Philip J. Fialkow, Professor and Chair of the Department of Medicine.

Body Constitution↗
PubMed1989

Decreased insulin- and glucagon-pulse amplitude accompanying beta-cell deficiency induced by streptozocin in baboons.

The effect of beta-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of beta-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate. Highly regular pulses were less prevalent in baboons compared with rhesus monkeys and humans, but the mean frequency was similar and was not affected by treatment. The principal effect of beta-cell destruction was to proportionately reduce the pulse amplitude of insulin (-39%, P less than .003) without detectable change in pulse frequency, interhormonal phase relationship, or the regularity of pulses. Glucagon-pulse amplitude also fell (-19%, P less than .09), but not significantly. However, glucagon-pulse amplitude was strongly correlated with insulin-pulse amplitude (r = -.59, P less than .002), whereas mean fasting plasma concentrations of insulin and glucagon were not significantly changed after treatment. Because streptozocin affects only the beta-cell, the data indicate a major influence of the insulin pulse on the alpha-cell secretory pulse. The data do not support the presence of a separate pacemaker for the alpha-cell but do not eliminate this possibility. The strong correlation of reduction in insulin-pulse amplitude with increasing fasting glucose and decreasing glucose disappearance lends support to growing evidence that the pattern of insulin secretion is an important determinant of normal glucose homeostasis.

Animals↗
PubMed1989

Preliminary assessment of very low calorie diets by conventional and signal-averaged electrocardiography.

Fatalities accompanying the use of very low calorie diets have been attributed to cardiac arrhythmias, which may have been associated with myocardial catabolism and hypokalemia. Delayed activation of damaged regions of myocardium may result in low amplitude potentials late in the QRS complex which have been associated with sustained ventricular tachycardia. We used the techniques of routine electrocardiography, signal averaging of the surface electrocardiogram and ambulatory electrocardiographic (Holter) monitoring to evaluate a group of 11 obese men (116 +/- 14 kg) who consumed a potassium-supplemented 660 kcal/day (2763 kJ/day) milk-based liquid diet for 95 +/- 14 days. Electrocardiographic measurements were made before beginning the diet, during the final week on the diet, and after refeeding. Corrected QT interval, QRS voltage and duration, absence of signal-averaged late potentials and ventricular ectopy during 24 h Holter monitoring during the diet and refeeding did not differ from baseline determinations at any point in the obese subjects. In this study, which involved only 11 subjects, neither standard electrocardiographic techniques nor a newer signal-averaging technique revealed any electrocardiographic changes from the diet. A very large population would have to be studied to evaluate the usefulness of these techniques in predicting myocardial damage serious enough to cause arrhythmias. Until such studies are available, the safety of such diets remains unknown.

Arrhythmias, Cardiac↗
PubMed1988

Weight loss leads to a marked decrease in nonresting energy expenditure in ambulatory human subjects.

The extent to which the resting and nonresting components of 24-hour energy expenditure decrease after weight reduction has not been prospectively assessed in ambulatory, weight-stable, reduced-obese humans. Accordingly, 24-hour energy expenditure was estimated as the weight-stabilizing (+/- 50 g/d) daily caloric intake of a defined liquid diet in a cross-sectional study of ten reduced-obese subjects after a 23.2% +/- 9.4% weight loss and 18 obese subjects at baseline weight. A regression analysis demonstrated an 18% decrease in the mean daily energy requirement of the reduced-obese subjects compared with that of subjects of the same relative body weight who had never dieted. Strong linear relationships were noted between estimated 24-hour energy expenditure and fat-free mass (FFM), and between resting metabolic rate (RMR) and FFM in the subjects at baseline weight. In six reduced-obese men, the 24-hour energy expenditure was only 75.7% +/- 5.6% of the value predicted by regression analysis for the decreased FFM. In these six subjects the RMR was 97.4% +/- 7.5% of that predicted for the decreased FFM, suggesting that essentially all the energy savings relative to FFM in the reduced-obese state occurred in nonresting energy expenditure. In a subsequent group of seven subjects studied longitudinally before and after a 21.5% +/- 2.3% weight loss, the decrease in nonresting energy expenditure accounted for 582 +/- 276 kcal/d or 71% of the decrease in estimated 24-hour energy expenditure. These data suggest a decrease in the nonresting energy expenditure of ambulatory reduced-obese individuals, which is greater than previously appreciated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Contribution of decreased body mass to diminished thermic effect of exercise in reduced-obese men.

Reduced energy expenditure after weight loss contributes to the difficulty which obese individuals face in maintaining a lower body weight. To evaluate the contribution of decreased energy cost of physical activity at a lower body weight to diminished total energy expenditure, two groups of unconfined obese men were studied before and after a 22 percent weight loss. A control group received a 700-cal diet alone whereas the experimental group, while consuming an identical diet, wore a vest into which weights were inserted twice weekly to exactly compensate for body weight loss. In the control group the total daily caloric requirement for weight maintenance fell by 916 +/- 121 kcal/day (3834 +/- 507 kJ/day) in contrast to only a 404 +/- 192 kcal/day (1691 +/- 804 kJ/day) fall in the experimental group at full exogenous weight replacement (P less than 0.001). Body composition, maximal exercise performance, and resting metabolic rate were unaffected by weight replacement. Activity levels decreased at the same rate in both subject groups with progressive weight loss. In conclusion, loss of body weight reduces the energy cost of physical activity sufficiently to account for more than half of the major fall in energy expenditure noted in free-living men after weight loss.

Adipose Tissue↗
PubMed1987

A kinetic analysis of hepatocyte responses to a glucagon pulse: mechanism and metabolic consequences of differences in response decay times.

Pulsatile administration of glucagon to perifused rat hepatocytes stimulates hepatocyte glucose production (HGP) more effectively than continuous administration. Having established that this effect was due to delayed relaxation of glucagon-stimulated HGP (t1/2 for decay = 3.54 +/- 0.60 min) we wished to examine the mechanism of response termination. Delayed dissociation of glucagon from its receptor was excluded by the brisk washout of [125I]glucagon from perifusion columns (t1/2 = 1.00 +/- 0.13) and the rapid decay in glucagon-stimulated cAMP released into the perifusion medium (t1/2 = 1.14 +/- 0.12). The relaxation of the HGP response to a pulse of administered cAMP was comparable to the decay in glucagon-stimulated HGP (t1/2 = 3.28 +/- 0.22). Furthermore, the phosphodiesterase inhibitor isobutyl-methylxanthine did not alter the decay of the HGP response to glucagon despite increasing the amplitude of the response (t1/2 = 3.04 +/- 0.36). These data place the rate-limiting step for HGP relaxation distal to cAMP generation and degradation. The decay of the beta-hydroxybutyrate response to a glucagon pulse was not different from the cAMP response (t1/2 = 1.14 +/- 0.23), whereas the decay of gluconeogenesis from lactate was not significantly different from HGP relaxation (t1/2 = 1.94 +/- 0.08). We conclude that rate-limiting events for HGP relaxation occur distal to the second messenger cascade; however, ketogenesis is more closely coupled to the kinetics of cAMP. These results may help to explain the absence of excessive ketosis during fasting in normal humans, who secrete glucagon episodically at 10- to 14-min intervals.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Evidence that the physiological pulse frequency of glucagon secretion optimizes glucose production by perifused rat hepatocytes.

We have reported that glucagon administered to perifused rat hepatocytes as a series of pulses at 15-min intervals is a more effective stimulus for hepatocyte glucose production (HGP) than is continuous glucagon infusion. To test whether the efficiency of HGP depends upon the frequency of pulsatile glucagon delivery, we administered glucagon to perifused rat hepatocytes as a series of pulses of fixed amplitude [922 +/- 30 (+/- SE) pg/ml] at eight separate pulse intervals ranging from 3-45 min. Compared to continuous infusion of the same total amount of hormone, pulsatile glucagon administration clearly enhanced HGP in a frequency-dependent fashion. At pulse intervals between 10 and 20 min, pulsatile HGP exceeded continuous HGP by a factor of 1.5-2. This range of optimal intervals compared favorably with the glucagon secretory period of 10 min observed in nonhuman primates and that of 13-20 min observed in humans. We noted a desensitization of the hepatocyte response to glucagon that was directly proportional to the log of the time-averaged hormone concentration. Since the magnitude of the desensitization elicited by pulsatile glucagon delivery exceeded the desensitization elicited by continuous hormone delivery regardless of pulse frequency, differential desensitization could not explain the frequency dependency of the pulse enhancement effect. A mathematical simulation of our data demonstrated that the asymmetry of the HGP waveform elicited by a brief glucagon pulse could account for the observed frequency dependency of HGP. Pulse to pulse summation and the desensitization phenomenon modulated both the magnitude of the pulse enhancement effect and the frequency range over which the effect was manifest. We conclude that the enhancement of HGP by glucagon pulses is a frequency-dependent phenomenon and that the physiological glucagon secretory period optimizes HGP.

Animals↗
PubMed1985

A model for augmentation of hepatocyte response to pulsatile glucagon stimuli.

We have reported that in the physiological concentration range pulsatile glucagon delivery (6 pulses in 90 min) is a more effective stimulus of rat hepatocyte glucose production than is continuous infusion of the same amount of hormone (pulsatile EC50 = 186 +/- 41 pg/ml, continuous EC50 = 884 +/- 190 pg/ml). At supraphysiological glucagon concentrations, however, the maximal response to continuous glucagon infusion exceeds the response to pulses (241 +/- 14 vs. 140 +/- 11 mumol X G-1 X 90 min-1). In an effort to explain these observations we derived a model for the 90-min hepatocyte responses to pulsatile and continuous glucagon delivery based on the waveform of the hepatocyte response to a transient glucagon stimulus. The model demonstrated that the time constant for response decay was an important determinant of the relative efficacy of the two patterns of hormone delivery. For the observed decay constant value of 0.132 +/- 0.02 min-1 the model predicted the following dose-response parameters: pulsatile EC50 = 131 pg/ml, Rmax = 119 mumol X G-1 X 90 min-1, continuous EC50 = 656 pg/ml, Rmax = 272 mumol X G-1 X 90 min-1. The ability of a model based only on the kinetics of a single pulse to simulate the observed dose-response relationship suggests that pulsatile stimulation is intrinsically more effective than continuous hormonal stimulation.

Animals↗