Glucose-induced thermogenesis and insulin resistance in man.
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Adult↗
Biomedical subjects
E Danforth
Publications and source records attributed to E Danforth.
Thyroid hormones and thermogenesis: the metabolic cost of food and exercise.
To mimic plasma T3 levels observed in a previous overfeeding study, six lean healthy men received replacement amounts of L-thyroxine (200 micrograms/d) to block endogenous thyroid hormone production while consuming their habitual diet. After 4 weeks equilibration on T4, L-triiodothyronine (T3) was given (45 micrograms/d) in addition to T4, to produce mild T3-thyrotoxicosis, for another 2 weeks. At the end of this period T3 was discontinued but the subjects continued to receive T4 for another 2 weeks. Resting metabolic rate, exercise efficiency, and the thermic effect of food were measured using a ventilated hood, open circuit indirect calorimeter at the end of each phase of the experiment. There was a significant increase in the resting metabolic rate of 6% (P less than 0.01) while the subjects were mildly T3-thyrotoxic. The increase in energy expenditure however, during exercise on a bicycle ergometer or following a 500 kcal liquid-formula meal remained unaltered in the same situation. Thus, mild T3-toxicosis does not alter the efficiency of exercise or the thermic effect of food. These results suggest that the increased plasma T3 levels, observed in overfeeding, could explain corresponding increases in resting metabolic rate but not changes in the efficiency of exercise or the utilization of food.
Adult↗
Decreased free fraction of serum thyroid hormones during carbohydrate overfeeding.
The impact of the increased T3 production induced by overfeeding is likely to be lessened if overfeeding also decreases the free fraction of thyroid hormones. Therefore, we examined the effect of 17 to 20 days of carbohydrate overfeeding of five men on total serum T4 and T3 concentrations, the free fraction of these hormones, and serum concentrations of thyroid-hormone binding proteins, TBG, TBPA, and albumin. Total serum T4 concentrations were unchanged by overfeeding and total serum T3 concentrations increased 42%. However, the free fraction of both T4 and T3 decreased during the overfeeding period, so that free T3 concentrations increased only 21% and free T4 concentrations decreased 17%. There was an increase in serum concentrations of both TBG (12%) and TBPA (20%), but no change in the concentration of albumin. We conclude that there is an increase in free T3 concentrations during overfeeding, in spite of a decrease in the free fraction of T3. However, the physiological effects of this increase in free T3 concentrations may be diminished by the decrease in free T4 concentrations.
Adult↗
The role of thyroid hormones in the control of energy expenditure.
Thyroid hormones have a direct effect on the basal or resting metabolic rate in man and a permissive effect on the adaptive thermogenesis of small animals, while altering the energy expended in exercise to the extent that patients with thyroid disorders exercise to a greater or lesser degree. The physiological concepts of energy expenditure need to be seen in the context of a new method for measuring 'thyroid thermogenesis'. Thyroid hormones seem, in evolutionary terms, to have developed a thermogenic role during the transition from poikilothermy to homeothermy; they are responsible for the increased heat production required for homeotherms to maintain body temperature above that of the environment. The potential mechanisms responsible for thyroid hormone-controlled energy expenditure are complex. Uncoupled oxidative phosphorylation is probably not responsible for thyroid hormone-controlled thermogenesis except in the special case of brown adipose tissue thermogenesis, where thyroid hormones act permissively. The concept that increased ATP generation must be coupled to ATP utilization needs to be linked with the idea that thyroid hormone-controlled thermogenesis must be through inefficient pathways of metabolism. Several of these potentially important pathways of intermediary metabolism in thyroid hormone-controlled thermogenesis can now be defined and measured, but their role in the regulation of nutritionally induced alterations in thyroid status and thermogenesis remains to be explored.
Body Temperature Regulation↗
Effects of chronic beta-receptor stimulation on sympathetic nervous system activity, energy expenditure, and thyroid hormones.
The effects of hyper- and hypothyroidism on sympathetic nervous system activity and energy expenditure are well recognized. The impact of altered sympathetic nervous system activity on energy expenditure and thyroid hormone metabolism has not been well studied. We investigated the effects of orally administered terbutaline sulfate, a beta 2-receptor agonist (5 mg, three times per day for 2 weeks), on the activity of the sympathetic nervous system, energy expenditure, and thyroid hormone metabolism in six normal men, aged 21-36 yr. The cardiovascular, metabolic, and thermogenic responses to an infusion of the beta-adrenergic agonist isoproterenol were clearly blunted after 2 weeks of treatment with terbutaline sulfate, indicating down-regulation of beta-receptors and/or development of reduced sensitivity. There were no significant changes in the cardiovascular, metabolic, or thermogenic responses to an infusion of the alpha-adrenergic agonist phenylephrine. Basal metabolic rate was significantly increased by the chronic administration of terbutaline sulfate [5.040 +/- 0.167 (+/- SE) vs. 5.421 +/- 0.234 kJ/min; P less than 0.05]. There was a highly significant change in the serum T3 to T4 ratio (19.4 +/- 1.0 vs. 24.4 +/- 1.0; P less than 0.001). This was a result of increased serum T3 concentrations (136 +/- 9 vs. 160 +/- 14 ng/dl; P less than 0.05) and decreased serum T4 concentrations (7.2 +/- 0.8 vs. 6.7 +/- 0.8 micrograms/dl; P = NS). Chronic beta-receptor stimulation with terbutaline sulfate increases the basal metabolic rate and T3 concentrations. These changes occurred despite down-regulation of beta-receptors and/or decreased sensitivity in response to chronic terbutaline administration.
Adrenergic alpha-Agonists↗
Effects of chronic beta receptor stimulation on glucose metabolism.
The acute administration of a beta receptor-stimulating agent profoundly affects insulin-mediated glucose metabolism; however, little is known about the impact of chronic beta receptor stimulation on glucose metabolism and insulin sensitivity. We therefore investigated the effect of the chronic administration of a beta-2-agonist, terbutaline sulfate (TS), on glucose metabolism in 7 healthy, normal-weight, male volunteers between the ages of 21 and 30 yr. Studies were performed using the euglycemic, hyperinsulinemic (1.0 mU/min X kg) clamp technique before and after the oral administration of 5 mg of TS three times a day for 1 and 2 wk. Basal endogenous glucose production (EGP) (2.54 +/- 0.11 versus 2.64 +/- 0.14 mg/min X kg) and basal glucose oxidation (1.87 +/- 0.16 versus 2.0 +/- 0.2 mg/min X kg) were unchanged by the chronic administration of TS. However, insulin-stimulated total glucose metabolism increased by 29% (7.0 +/- 0.47 versus 9.05 +/- 0.67 mg/min X kg; P less than 0.02). Insulin-stimulated, nonoxidative glucose disposal increased by 45% (3.62 +/- 0.42 versus 5.26 +/- 0.48 mg/min X kg; P less than 0.01), while insulin-stimulated glucose oxidation did not change significantly (3.38 +/- 0.15 versus 3.79 +/- 0.22 mg/min X kg). EGP was completely suppressed under both conditions. Mean basal plasma insulin concentration (41 +/- 9 versus 49 +/- 15 pmol/L) and insulin clearance during the clamp procedure was unchanged (477 +/- 45 versus 474 +/- 37 ml/min X m2). We conclude that chronic beta receptor stimulation with TS improves insulin-stimulated glucose disposal in man, mostly by improving nonoxidative glucose disposal, i.e., "glucose storage."(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Anorectic drugs which stimulate thermogenesis.
Two anorectic drugs commonly prescribed as adjuncts in weight control and a third experimental drug were studied in rats for their anorectic and possible thermogenic activities. Diethylpropion, a congener of amphetamine, mazindol, which is chemically unrelated to amphetamine, and ciclazindol, an experimental drug structurally similar to mazindol, were given in graded doses to determine their effect on food and oxygen consumption (VO2). Anorectic effects exhibited by diethylpropion and mazindol were similar and more potent than ciclazindol. Both resting and anesthetized VO2 measurements were done to assess the thermogenic activity of the drugs. Anesthetized VO2 was performed in an attempt to separate peripheral from centrally-mediated actions of the drugs. Amphetamine was also tested at 1.0 mg/kg in order to correlate relative potencies. Mazindol, but not diethylpropion or ciclazindol, produced a dose response increase in resting VO2. At the 1.0 mg/kg dose, amphetamine produced a greater increase in resting VO2 than mazindol. At this dose, both drugs elicited centrally-induced alertness, although amphetamine elicited greater activity than mazindol. Mazindol and diethylpropion, but not ciclazindol, caused a dose-related increase in anesthetized VO2. The anesthetized VO2 response to amphetamine at 1 mg/kg was greater than the responses of mazindol and diethylpropion at 3.0 mg/kg. These findings confirm the previously recognized anorectic effects of mazindol and diethylpropion and also demonstrate that mazindol and diethylpropion but not ciclazindol (at the doses used) produced dose-related increases in VO2 (energy expenditure) by stimulating directly peripheral mechanisms and in the case of mazindol central mechanisms as well.
Amphetamine↗
The role of thyroid hormones and insulin in the regulation of energy metabolism.
Strong support has been gathered for a defect in insulin-glucose-mediated thermogenesis in obese and particularly obese insulin-resistant and/or diabetic subjects compared to lean subjects. This defect appears to be reversible with weight loss and improved insulin sensitivity. The mechanism for this blunted thermogic response is directly related to the decreased glucose storage in the obese and obese diabetic subjects.
Diet↗
Thermic effect of infused glucose and insulin in man. Decreased response with increased insulin resistance in obesity and noninsulin-dependent diabetes mellitus.
The thermic effect of infused glucose and insulin was measured by combining the hyperinsulinemic euglycemic clamp technique with indirect calorimetry, in 10 normal weight volunteers (group I), 7 obese subjects with normal glucose tolerance (group II), and 13 obese subjects with abnormal glucose tolerance or noninsulin-dependent diabetes mellitus before (group IIIa) and after weight loss of 10.8 +/- 0.4 kg (group IIIb). During hyperinsulinemia (760-1,100 pmol/liter), total glucose disposal from combined endogenous production and glucose infusion was 545 +/- 49, 441 +/- 70, 233 +/- 35, 231 +/- 31 mg/min and energy expenditure changed by + 0.476 +/- 0.080, +0.293 +/- 0.095, -0.114 +/- 0.063, and +0.135 +/- 0.082 kJ/min in group I, II, IIIa, and IIIb, respectively. The increased energy expenditure correlated with glucose storage (measured cost of processing the glucose: 1.33 kJ/g). In group IIIa there was no increase in energy expenditure in response to glucose and insulin infusions. After therapy (group IIIb) there was a significant recovery (P less than 0.05) of the thermic effect of infused glucose although total glucose disposal was unchanged. It is proposed that the recovered thermic effect of infused insulin/glucose is due to the different contributions of gluconeogenesis in the fasting state and during the glucose clamp before and after weight loss. In addition we hypothesize that some of the lower thermic effect of food reported in obese noninsulin-dependent diabetics may be explained by decreased energy expenditure due to a greater suppression of hepatic gluconeogenesis as well as by lower storage rate.
Blood Glucose↗
Characteristics of diet-induced brown adipose tissue growth and thermogenesis in rats.
The characteristics of regional brown (BAT) and white adipose tissue (WAT) growth and of thermogenesis following experimental overfeeding were studied in groups of male Sprague-Dawley rats fed lab chow or cafeteria diets for 8 weeks postweaning. Regional BAT and WAT growth was determined by dissection and weighing, and thermogenesis was characterized by measurements of resting and norepinephrine (NE)-stimulated oxygen consumption, of serum thyroid hormone concentrations, and of 24-hour urinary NE excretion levels. Cafeteria feeding resulted in a 113% increase in total BAT, with the most prominent increases in the interscapular, thoracic, and perirenal regions. Retroperitoneal, epididymal, and omental WAT were significantly greater in cafeteria than in chow-fed rats. Resting oxygen consumption of cafeteria-fed rads increased by 10% and NE excretion by 64% compared to chow-fed controls, while serum T3 concentrations were nearly doubled in the cafeteria-fed rats. The thermogenic response to NE injection in cafeteria-fed rats was 102% of their resting levels, compared to a 51% increase in the chow-fed controls. The results indicate that increased BAT growth occurs in all primary BAT depots following cafeteria-feeding in rats, and that the greater BAT mass is qualitatively proportional to their greater capacity for non-shivering thermogenesis. Also, the increased NE excretion and greater serum T3 concentration are consistent with increased sympathetic and thyroidal activity and may in part explain the thermogenic response to diet in the rat.
Adipose Tissue↗
Effect of cafeteria feeding on brown and white adipose tissue cellularity, thermogenesis, and body composition in rats.
To determine the effects of cafeteria feeding on brown (BAT) and white (WAT) adipose tissue cellularity, thermogenesis and body composition, male Sprague-Dawley rats were fed a cafeteria or a Purina chow diet for 52 days postweaning. Interscapular BAT (IBAT) was removed from subgroups of rats on each diet, and the animals continued on the same regimens. The IBAT weight of rats fed cafeteria diets was 160% of controls after 3 days and 220% after 52 days of the dietary regimens, and brown adipocyte numbers were 130 and 300% those of stock diet-fed rats, respectively, during the same period. Brown adipocyte diameters were initially greater in rats fed cafeteria diet than in rats fed stock diet but were similar after 52 days. Norepinephrine-stimulated thermogenesis was greater in rats fed cafeteria diets than in rats fed stock diet and was intermediate between the two in the IBAT-lipectomized group fed cafeteria diet. Surgical reduction of IBAT resulted in hypertrophy of WAT and an improved efficiency of weight gain, whereas body composition, WAT cellularity, and the efficiency of weight gain of similarly operated rats fed stock diet were unaltered from those of unoperated animals fed stock diet. These results are consistent with the development of a nutritionally induced hyperplasia and/or differentiation of BAT similar to that which follows cold acclimatization. BAT may play an active role in the expenditure of excess energy during periods of overnutrition, and thereby influence an animal's propensity for fatness.
Adipose Tissue↗
Impact of hydrogen ion on fasting ketogenesis: feedback regulation of acid production.
To determine whether acid-base balance regulates hydrogen ion production, seven obese volunteers were given NaHCO3 and NH4Cl (2 mmol.kg-1.day-1) during two separate 7-day fasts. On days 5-7 plasma bicarbonate was lower in the NH4Cl fasts (14.0 +/- 1.4 mM) than in the NaHCO3 fasts (18.3 +/- 1.1 mM), while urine pH and net acid excretion did not differ. Acid production (acid excretion minus intake) was greater by 204 mmol/day in the NaHCO3 fasts (274 +/- 16 mmol/day) than in the NH4Cl fasts (70 +/- 19 mmol/day). Ketoacid excretion, which reflected net ketoacid production, paralleled acid production, decreasing from 213 +/- 24 mmol/day in the NaHCO3 fasts to 67 +/- 18 mmol/day in the NH4Cl fasts. Thus, during starvation, alterations in hydrogen ion intake and the associated changes in acid-base balance modify the net production of endogenous acid by influencing the synthesis or utilization of ketoacids. Although the specific site of this metabolic regulation is undefined, these results indicate that systemic acid-base status can exert feedback control over hydrogen ion production.
Acid-Base Equilibrium↗
The interaction of free fatty acids in radioimmunoassays for reverse triiodothyronine.
We have investigated the effect of FFA on the RIA of rT3 because of our previous findings of a correlation between serum rT3 values and increased FFA concentrations during prolonged exercise and reports of interference by FFA in other thyroid hormone assays. Apparent rT3 values increased by 19% and 34% in in vivo studies of acute lipolysis in subjects 5 min post exercise or 10 min post heparin, respectively, while T3 and T4 concentrations were unchanged. Varying concentrations of palmitic acid were added in vitro to four normal sera, and the increase in FFA concentration correlated significantly with the increase in apparent rT3 values. The mean +/- SE of the regression slope was 9.3 +/- 1.8 ng/dl rT3/mM FFA (r = 0.96 +/- 0.02). The addition of linoleic acid produced a similar effect. T3 and T4 concentrations were unchanged. The interaction of FFA in the rT3 RIA was unrelated to the procedure used to separate the assay, to the concentration of 8-anilino-1-napthalene-sulfonic acid in the assay buffer, to FFA binding directly to the antisera or to use of a particular antisera. The magnitude of the effect was similar in charcoal-treated sera, and the addition of 2 mM palmitic acid to the assay standard curve decreased the y intercept but did not alter the slope, suggesting an interaction of rT3 with FFA, rather than change in affinity of the antisera.
Energy Intake↗
Influence of diet composition on serum triiodothyronine (T3) concentration, hepatic mitochondrial metabolism and shuttle system activity in rats.
Two experiments were conducted to determine if variations in diet composition sufficient to alter circulating triiodothyronine (T3) concentration would influence hepatic mitochondrial metabolism. In experiment 1, mitochondrial respiration and the activity of succinate dehydrogenase (SDH), cytochrome oxidase (CO) and alpha glycerophosphate dehydrogenase (m alpha-GPD) were measured in 42-day-old male rats fed diets containing casein/carbohydrate/fat: 8/73/10% (low protein), 22/59/10% (control protein), and 45/36/10% (high protein) for 3 weeks. When compared to control, serum T3 was increased 2-3 times in the low and decreased 19% in the high protein-fed groups. Mitochondria isolated from low protein-fed rats consumed less oxygen in both state 4 and state 3 with succinate as substrate when compared to control or high protein fed rats. However, ADP/O and respiratory control (RC) ratios were similar in all groups. Activity of SDH and CO was decreased only in low protein-fed rats. M alpha-GPD activity was increased in the low and decreased in the high protein fed-rats. In experiment 2, alpha-glycerophosphate shuttle activity was increased 2-3 fold and malate-aspartate shuttle activity decreased 60% in intact mitochondria isolated from low protein-fed rats when compared to rats pair-fed control diet. These results suggest a role for diet composition as a regulator of hepatic intermediary metabolism mediated by thyroid hormones.
Adenosine Diphosphate↗
Capacity for moderate exercise in obese subjects after adaptation to a hypocaloric, ketogenic diet.
To study the capacity for moderate endurance exercise and change in metabolic fuel utilization during adaptation to a ketogenic diet, six moderately obese, untrained subjects were fed a eucaloric, balanced diet (base line) for 2 wk, followed by 6 wk of a protein-supplemented fast (PSF), which provided 1.2 g of protein/kg ideal body wt, supplemented with minerals and vitamins. The mean weight loss was 10.6 kg. The duration of treadmill exercise to subjective exhaustion was 80% of base line after 1 wk of the PSF, but increased to 155% after 6 wk. Despite adjusting up to base line, with a backpack, the subjects' exercise weight after 6 wk of dieting, the final exercise test was performed at a mean of 60% of maximum aerobic capacity, whereas the base-line level was 76%. Resting vastus lateralis glycogen content fell to 57% of base line after 1 wk of the PSF, but rose to 69% after 6 wk, at which time no decrement in muscle glycogen was measured after >4 h of uphill walking. The respiratory quotient (RQ) during steady-state exercise was 0.76 during base line, and fell progressively to 0.66 after 6 wk of the PSF. Blood glucose was well maintained during exercise in ketosis. The sum of acetoacetate and beta hydroxybutyrate rose from 3.28 to 5.03 mM during exercise after 6 wk of the PSF, explaining in part the low exercise RQ. The low RQ and the fact that blood glucose and muscle glycogen were maintained during exhausting exercise after 6 wk of a PSF suggest that prolonged ketosis results in an adaptation, after which lipid becomes the major metabolic fuel, and net carbohydrate utilization is markedly reduced during moderate but ultimately exhausting exercise.
Adult↗
Interrelationships between energy metabolism and thyroid hormone metabolism during starvation in the rat.
Thyroid hormone metabolism and plasma concentrations of TSH were studied after short-term hypocaloric refeeding of rats starved for 2-6 days. Carbohydrate and protein (10 kcal) refeeding after 4 days of starvation resulted in a rapid increase in serum T3 (P less than 0.01) and, less consistently of T4. Plasma TSH did not change. These findings were not due to changes in the metabolic clearance rates or in thyroid hormone binding proteins, as the disappearance of injected labelled T3 and T4, and the free fractions of T3 and T4, were unchanged. Increased thyroidal secretion, and for T3, increased peripheral conversion from T4 were therefore responsible for these changes. Fat refeeding had no immediate effect on plasma T4, T3 or TSH. After 6 days of starvation, refeeding of any nutrient was ineffective in altering the plasma concentrations of T3 and T4. The intraperitoneal administration of nicotinamide (100 mg/100 g body weight) to starving animals caused an increase in blood glucose and a decrease in blood beta-hydroxybutyrate similar to that which followed carbohydrate refeeding; T3, however, did not increase. In spite of producing a profile of substrates in the serum similar to that found following carbohydrate refeeding, nicotinamide administration had no effect on the blood lactate/pyruvate ratio which was increased following carbohydrate refeeding. Therefore, the cytoplasmic redox state, as reflected by the lactate/pyruvate ratio, may be closely related to the control of peripheral thyroid hormone metabolism.
Animals↗
Starvation-induced decreased sensitivity of resting metabolic rate to triiodothyronine.
The decrease in resting oxygen consumption induced by starvation was found to occur not only in euthyroid rats but also in hypothyroid and even in hypothyroid animals treated with triiodothyronine. Furthermore, the effectiveness of triiodothyronine was decreased when given to hypothyroid animals.
Animals↗
The effect of diet on thermogenesis in acquired lipodystrophy.
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Adolescent↗