Body fat distribution modulates insulin sensitivity in post-menopausal overweight and obese women: a MONET study.

OBJECTIVE: Central fat mass (CFM) correlates with insulin resistance and increases the risk of type 2 diabetes and cardiovascular complications. On the other hand, increased peripheral fat mass (PFM) is associated with higher insulin sensitivity. Thus, we examined the contribution of adipose tissue distribution, as assessed by the PFM/CFM ratio, to insulin sensitivity in overweight and obese postmenopausal women. DESIGN AND METHODS: A total of 124 nondiabetic overweight and obese postmenopausal women underwent an oral glucose tolerance test (OGTT) and a hyperinsulinemic/euglycemic (HI) clamp. Body composition was determined using computed tomography for visceral adipose tissue (VAT) and dual X-ray absorptiometry for fat mass, lean body mass and their respective proportions. Participants were divided by tertiles of the PFM/CFM ratio. RESULTS: Participants with preferential CFM (group 1) had higher fasting insulin levels and insulin area under the curve (AUC) during OGTT, as well as lower glucose infusion rates during the HI clamp, whether it was expressed per kg of body weight (M) or per kg of fat-free mass (Mm), compared with the other two groups. The PFM/CFM ratio also correlated significantly with fasting insulin (r=-0.32, P<0.001), the insulin AUC (r=-0.42 P<0.001), M (r=0.39 P<0.001) and Mm (r=0.37 P<0.001). Using hierarchical regression, we demonstrated that the PFM/CFM ratio was an independent predictor of insulin AUC, M and Mm and that its sequential addition to CFM and VAT improved significantly the predictive value of the model for insulin sensitivity for all variables except fasting insulin. CONCLUSION: The PFM/CFM ratio, which integrates the antagonistic effects of both central and peripheral depots on insulin sensitivity, added substantially to the prediction of insulin sensitivity over VAT and CFM alone.

HOMA or QUICKI: is it useful to test the reproducibility of formulas?

AIM: HOMA and QUICKI are the most widely used indices for assessing insulin sensitivity. Both are based on fasting glucose and insulin measures, and mainly differ by the log transformation of these variables in QUICKI. However, HOMA is less reproducible than QUICKI, and log HOMA does not improve its reproducibility. The aim of this study was to investigate the various mathematical transformations of HOMA and to assess its reproducibility. METHOD: We used data from a clamp study involving 123 non-diabetic overweight and obese postmenopausal women. Fasting insulin and glucose were measured in two visits 15 and 30 days apart. This allowed us to calculate HOMA as (fasting glucose [mmol/L] x fasting insulin [microU/mL])/22.5 and QUICKI as 1/(log fasting glucose [mg/dL]+log fasting insulin [microU/mL]) twice for subjects who were weight-stable between visits. RESULTS: QUICKI had better reproducibility (CV=3.9%) than either HOMA (CV=26.7%) or log HOMA (CV=22.0%). However, log-transforming HOMA using log (glucose x insulin)/log (22.5) and log-transforming HOMA without transforming the constant denominator improved its CV to 6.5% and 5.7%, respectively. CONCLUSION: By modifying the mathematical expression of HOMA, we were able to achieve comparable CVs for QUICKI and HOMA. However, the CV should be used to assess the reproducibility of techniques to measure glucose and insulin, not of mathematical formulas. When evaluating indices for the assessment of insulin sensitivity, the key point is how well they correlate with the 'gold-standard' glucose clamp.

Relationship between the hyperinsulinemic-euglycaemic clamp and a new simple index assessing insulin sensitivity in overweight and obese postmenopausal women.

OBJECTIVE: The purpose of this study was to compare assessment of insulin sensitivity from hyperinsulinemic euglycaemic (HIEG) clamp with indexes derived from fasting and oral glucose tolerance test (OGTT). SUBJECTS AND METHODS: Cross-sectional study with 107 sedentary non-diabetic overweight and obese postmenopausal (BMI=32.4+/-0.4 kg/m(2)) women undergoing both HIEG clamp and OGTT. Pairs of data were analyzed using Pearson correlation and Bland-Altman graphs analysis. Comparison between correlations was made using the method reported by Zar. RESULTS: All the indexes derived from either the OGTT or surrogate indexes were highly correlated with all the clamp-derived formulas (P<0.0001). However, HOMA and QUICKI were generally less correlated than OGTT-derived indexes. Analogically to QUICKI, we calculated a new formula derived from the OGTT measurements of glucose and insulin named simple index assessing insulin sensitivity (SI(is)OGTT)=1/[log(sum glucose t(0-30-90-120)) (mmol/l)+log(sum insulin t(0-30-90-120)) (microUI/ml)]. By using this formula, we found high significant correlations (r's=0.61-0.65; P<0.0001) with the clamp results. Moreover, the correlations of SI(is)OGTT with the clamp data were higher than for other previously published indexes. CONCLUSION: In that large group of non-diabetic overweight and obese postmenopausal women insulin sensitivity index derived from OGTT provided more accurate information than fasting based formula. We propose a new simple index for the assessment of insulin sensitivity from the OGTT data (SI(is)OGTT). The advantage of this new formula over all previously published OGTT-derived indexes of insulin sensitivity is that it is 1) easy to calculate 2) better correlated than other indexes of insulin sensitivity and 3) not affected by the way clamp results are expressed. Further studies are needed to validate SI(is)OGTT index in other populations.

Surrogate indexes vs. euglycaemic-hyperinsulinemic clamp as an indicator of insulin resistance and cardiovascular risk factors in overweight and obese postmenopausal women.

BACKGROUND: There is considerable interest in validating the most convenient method to estimate insulin sensitivity in clinical research protocols that could best indicate cardiovascular risk factors. To address this issue we examined the interrelationships of several cardiovascular risk factors with surrogate indexes such as fasting insulin, the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI) and the revised QUICKI vs the euglycaemic-hyperinsulinemic (EH) clamp in a non-diabetic overweight or obese postmenopausal female population. DESIGN: Cross-sectional study involving 88 obese postmenopausal women (age: 57.5+/-5.0 yrs; body mass index: 32.52+/-4.4 kg/m2; percent body fat: 46.35+/-4.9%). METHODS: Insulin sensitivity was determined by the EH clamp technique as well as by surrogate indexes such as fasting insulin, HOMA, log HOMA, QUICKI and revised QUICKI. Body composition and body fat distribution were measured using dual energy x-ray absorptiometry and computed tomography, respectively. RESULTS: Correlations between insulin resistance indexes (fasting insulin, revised QUICKI, QUICKI, log HOMA, HOMA) vs glucose disposal were similar (range of r's=0.40 to 0.49), suggesting that no index was superior to another with respect to its relationship with the EH clamp. Correlations between the insulin resistance indexes with plasma lipids were comparable among all indexes, however, systolic blood pressure, visceral fat and C-reactive protein were moderately superior with index vs the EH clamp. CONCLUSION: Surrogate measures of insulin resistance, in particular fasting insulin, are simple tools appropriate for epidemiological studies that can be used as substitutes for the EH clamp to estimate glucose disposal and cardiovascular risk factors in overweight and obese postmenopausal women.

Serum bone Gla protein: a marker of bone turnover in hyperthyroidism.

Serum bone Gla protein (BGP) concentrations were measured in 24 hyperthyroid patients before and after treatment. Before treatment, the mean concentration was higher [11.8 +/- 3.4 ( +/- SD) ng/ml] in the patient group than in a group of 12 age-matched normal subjects (6.1 +/- 1.7 ng/ml; P less than 0.001); 16 of the 24 patients had a value above the normal range. Serum BGP concentrations in the patients correlated significantly with serum T3 (r = 0.65; P less than 0.001) and T4 concentrations (r = 0.56; P less than 0.01). Other biochemical markers of bone metabolism (serum alkaline phosphatase, serum and urinary calcium, and urinary hydroxyproline) did not correlate with circulating thyroid hormone levels. Serum BGP also was measured after the patients had become euthyroid; 23 measurements were made on 16 patients at various times after the start of treatment. All values were normal after 16 weeks; before this period, most of the values were still above the normal range despite normal plasma thyroid hormone concentrations in all patients. These results suggest that BGP is a sensitive marker of bone metabolism alterations during hyperthyroidism.

Acute effect of glyburide on insulin sensitivity in type I diabetic patients.

Possible extrapancreatic effects of glyburide on insulin action were studied in six patients with insulin-dependent diabetes mellitus. Each patient was studied on two separate occasions with continuous iv infusions of either glyburide (0.3 mg/h after a 1-mg iv bolus dose) or NaCl. During the studies blood glucose concentrations were controlled by a glucose-controlled infusion system (Biostator). The study included the 12-h period after the evening meal, followed by a 4-h period during which euglycemic hyperinsulinemic clamp studies were performed at two rates of insulin infusion: 1 and 10 mU/kg.min. During the glyburide infusion, the Biostator-determined insulin delivery rate was similar to that during the NaCl infusion for the first 6 h after the meal, but it decreased by 32% between the 6th and 12th hours after the meal. During the hyperinsulinemic clamp studies, glucose was delivered at a significantly higher rate when glyburide was infused; this was true for both rates of insulin infusion [5.6 +/- 1.9 (+/- SD) vs. 3.6 +/- 1.4 mg/kg.min and 12.1 +/- 2.4 vs. 9.1 +/- 2.1 mg/kg.min; P less than 0.05, glyburide vs. NaCl, respectively]. Plasma C-peptide was undetectable in all patients during both studies. These results indicate that 1) glyburide has an acute effect on insulin action in insulin-dependent diabetic patients; and 2) this effect occurs at physiological as well as pharmacological insulin concentrations.

Decreased hypoglycemic effect of insulin at night in insulin-dependent diabetes mellitus and healthy subjects.

Diurnal variations in insulin-induced hypoglycemia and in plasma counterregulatory hormone concentrations were explored in eight insulin-dependent diabetic and six healthy subjects during a 100-min iv insulin infusion performed at 0300 h and 1500 h. In healthy subjects, plasma glucose concentrations (mean +/- SD) fell by 35 +/- 2% during the daytime test and by 26.5 +/- 2% during the nocturnal test (P less than 0.01). Plasma cortisol, GH, and epinephrine concentrations increased more during the daytime than during the nocturnal test. In contrast, plasma glucagon concentrations rose more during the nocturnal tests. In insulin-dependent diabetes mellitus patients, insulin infusion had to be interrupted in three subjects because plasma glucose fell below 1.9 mmol/L 80 min after the beginning of the test. In the other five patients plasma glucose fell by 34 +/- 5% during the daytime test while no significant decrease in plasma glucose was observed in any of the eight patients during the nighttime test. Counterregulatory hormone concentrations were consistent with the results of plasma glucose, with no change during the nocturnal test and significant increases in cortisol, GH, and epinephrine during the daytime test. These results show that insulin sensitivity is decreased at night in comparison to midafternoon in healthy subjects and that in insulin-dependent diabetes mellitus patients this phenomenon is exaggerated, even in patients with defective counterregulation to hypoglycemia.

RU 486 prevents the acute effects of cortisol on glucose and leucine metabolism.

Glucocorticoids have deleterious effects on glucose and protein metabolism. RU 486 is an antiprogestin with antiglucocorticoid activity, which could be used to prevent the undesirable metabolic effects of glucocorticoids. A randomized, controlled, double blind study was performed in eight healthy male volunteers who were tested four times: during the iv infusion of cortisol (2 micrograms/kg.min for 5 h) after the oral ingestion of RU 486 (600 mg) or a placebo, and during the infusion of a normal saline solution with placebo or RU 486 ingestion. During each test, a primed continuous iv infusion of D-[6,6-2H]glucose and [1-13C-]leucine was given for the calculation of hepatic glucose production and plasma leucine appearance rate. 13CO2 enrichment in breath was measured for the calculation of leucine oxidation. Plasma concentrations of cortisol, ACTH, insulin, C-peptide, glucagon, and GH were measured at regular intervals. Compared to saline, cortisol infusion increased plasma glucose 5.5 +/- 0.6 vs. 4.7 +/- 0.4 mmol/L; P < 0.01) and leucine (179 +/- 35 vs. 155 +/- 35 mumol/L; P < 0.01) concentrations as well as the leucine appearance rate (2.24 +/- 0.3 vs. 2.0 +/- 0.28 mumol/kg.min; P < 0.05) and oxidation (0.51 +/- 0.22 vs. 0.39 +/- 0.06 mumol/kg.min; P < 0.01), and there was no change in hepatic glucose production. None of the metabolic changes induced by cortisol were seen when cortisol was administered after the ingestion of RU 486. When RU 486 was given before normal saline infusion, plasma glucose concentrations were transiently lower than those after placebo ingestion, as was the hepatic glucose production. No change in insulin, C-peptide, or glucagon was seen between tests. GH concentrations were higher during cortisol infusion, but not when cortisol was administered after the ingestion of RU 486. The following conclusions were reached. 1) RU 486 can suppress the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in man. Long term studies are warranted to explore the potential of antiglucocorticoid molecules as preventive agents of the deleterious effects of chronic glucocorticoid administration. 2) RU 486 is useful molecule for studying the metabolic effects of cortisol in man.

PIP: In Montreal, Quebec, a randomized, double blind study was conducted in eight healthy men at Hotel-Dieu Hospital during administration of cortisol (2 mcg/kg per minute for 5 h) with RU-486 (600 mg), during cortisol administration with a placebo, during 0.9% saline administration with RU-486, and during normal saline administration with a placebo. Clinicians administered a primed continuous infusion of D-[6,6-2H]glucose and [1-13C-]leucine during each test to determine hepatic glucose production and plasma leucine appearance rate. Continuous infusion of labeled bicarbonate in four men was also conducted to calculate the recovery factor of carbon dioxide in their breath. Researchers wanted to examine glucose and protein metabolism during hypercortisolemia with or without RU-486 and the effects of RU-486 on the metabolic effects of acute cortisol deficiency. Among men receiving the placebo, plasma glucose levels were higher during cortisol infusion than saline infusion (5.5 vs. 4.7 mmol/l; p 0.01). The leucine appearance rate was also higher during cortisol infusion than saline infusion (2.24 vs. 2 mcmol/kg per min; p 0.05) as well as leucine oxidation (0.51 vs. 0.31 mcmol/kg; p 0.01). Hepatic glucose production did not change in either placebo group. Cortisol did not induce the same metabolic changes when it was administered after RU-486. Normal saline infusion after RU-486 induced a short-term lower plasma glucose level and hepatic glucose production. Insulin, C-peptide, or glucagon did not change. Cortisol induced increased growth hormone (GH) levels (e.g., at 240 min, 5.9 vs. 1.7 mcg/l; p 0.01) while GH levels did not change when cortisol was administered after RU-486. These findings show that RU-486 suppresses the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in males. Long-term studies could reveal the potential of RU-486 to prevent the adverse effects of chronic glucocorticoid administration. RU-486 allows researchers to study the metabolic effects of cortisol in males.

Intragastric vs oral feeding: effect on the thermogenic response to feeding in lean and obese subjects.

The aim of this study was to observe the effects of oropharyngeal stimulation on thermogenic response to feeding (TRF) in obese and healthy individuals. Resting energy expenditure was measured in eight normal-weight (BMI, in kg/m2: 22.9 +/- 1.7) and nine obese subjects (BMI: 36.5 +/- 7.2), once after the ingestion of a standardized meal and once after the intragastric administration of the same, blenderized meal. In control subjects, TRF was lower after intragastric than after oral feeding: 5.6 +/- 1.4% vs 8.0 +/- 1.8% of the ingested energy for intragastric vs oral feeding, respectively (P < 0.01), but in obese subjects no difference occurred (6.5 +/- 3.0% vs 6.1 +/- 2.0%). In obese subjects the response over 6 h after the oral meal was lower than in/control subjects (P < 0.01). Intragastric TRF was not different between the two groups. This study confirms our previous observation that TRF has two components in humans, and suggests that oropharyngeal stimulation elicits a greater TRF in normal-weight than in obese individuals.

Menstrual cycle and voluntary food intake.

The relationship of food intake and the human menstrual cycle has not been well quantified. In this study, voluntary energy and sucrose intake of seven women, aged 24-43 y, were evaluated by the weighed-intake method over one entire menstrual cycle. Portable tape recorders facilitated the recording of food intake. Although daily fluctuations of energy intake were large, analysis of variance showed intake during the luteal phase to be significantly greater than during the periovulatory and follicular phases (p less than 0.05). From 95% simultaneous (Bonferoni) confidence intervals, the estimate of difference was 283 kcal greater during the luteal phase than the periovulatory phase; the estimate of difference was 214 kcal greater during the luteal phase than during the follicular phase. No significant differences in energy intake were found among the menstrual, follicular, and periovulatory phases. No significant relationship was found between sucrose intake and the menstrual cycle.

Effects of marginally negative energy balance on insulin binding to erythrocytes of normal men.

Six healthy male volunteers were confined to a metabolic unit for 105 days. Energy intake (EI) and energy expenditure (EE) were varied in order to achieve either a marginally negative (-15%) or an equilibrated energy balance (EB), in different metabolic periods (MP) as follows: MP I: EE = 1, EI = 1, EB = 0; MP II: EE = 1, EI = 0.85, EB = -15%; MP III: EE = 0.85, EI = 0.85, EB = 0; MP IV: EE = 0.85, EI = 0.70, EB = -15%; MP VI: EE = 1.15, EI = 1.15, EB = 0; MP VII: EE = 1.15, EI = 1, EB = -15%. An egg protein formula diet was fed throughout the study. The amount given in MP I was sufficient to maintain body weight constant. Assigned physical activity consisted of regulated walking and cycling. During MP I, this physical activity accounted for 15% of the energy intake. Serum insulin, insulin binding to erythrocytes and body fat content were determined at the end of each MP. No significant changes were found in serum insulin level throughout the study, but specific insulin binding did change significantly. Binding increased with increased physical activity by 23% at the end of MP VI and an additional 35% at the end of MP VII. The maximum percentage of insulin binding to erythrocytes correlated inversely with the percentage of body fat in each MP. These data suggest that insulin binding to erythrocytes, in normal men, is sensitive to a small change in energy balance, and especially to physical activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Milk- and soy-protein ingestion: acute effect on serum uric acid concentration.

Acute effect of the ingestion of 80 g each of casein, lactalbumin, and soybean isolate on serum and urinary uric acid concentrations was investigated in 10 healthy subjects. Serum and urinary uric acid concentrations were measured before and after the ingestion of proteins. Serum uric acid decreased significantly 3 h after ingestion of lactalbumin and casein but increased after soybean consumption. Urate clearance was significantly increased after ingestion of each of the three proteins. Multivariate analysis of urate clearance during lactalbumin and casein loads showed that independent correlation was obtained for serum alanine and urea concentration. These results demonstrate that, in addition to their known uricosuric effect, milk proteins acutely decrease serum uric acid concentration. Analysis of the effects of lactalbumin and casein on urinary uric acid elimination suggests that the uricosuric effect of proteins is a multifactorial phenomenon.

Hormonal changes in normal men under marginally negative energy balance.

Six men were confined to a metabolic unit for 105 days. Their assigned work and energy intake were varied throughout six metabolic periods in order to create either a marginally negative (-15%) or an equilibrated energy balance. They were fed a defined diet providing a constant amount of protein. At each metabolic period, T4, T3, reverse T3(rT3), free T3, free reverse T3, thyroid-stimulating hormone, cortisol, cortisol-binding globulin, testosterone, and testosterone/estradiol-binding globulin were measured. Free urinary cortisol was measured daily. Results show that serum thyroid hormones are sensitive to marginal changes in energy intake, expenditure, and balance. The ratio T4/T3 appears to be more sensitive to the balance itself, with the ratio T3/rT3 being more sensitive to the intake and expenditure level at which this balance is established. Regulations of T3 and rT3 production are probably distinct. Urinary cortisol did not show any variation that could be related to the energy balance. However, daily urinary cortisol was correlated to daily urinary nitrogen excretion. No change in serum testosterone was found.

Increased serum-soluble interleukin-2 receptor in burn patients: characterization and effects on the immune system.

The consequences of high serum concentrations of the interleukin (IL)-2 receptor alpha chain (sIL-2Ralpha) in several diseases are poorly understood. The objective of this study was to determine the form of sIL-2Ralpha in burn patients and its biological role. sIL-2Ralpha was measured in 18 severely burned individuals who received nutritional support with a normal or low fat content. sIL-2Ralpha was elevated throughout the study and it was notably lower in patients fed a low fat diet. Serum IL-6 and sIL-2Ralpha significantly correlated (r = 0.74, p < 0.05) in burn patients. The presence of sIL-2Ralpha was associated with a decrease in DR molecules in the CD2(-) and CD11b(+) cells of these patients. Western blot analysis of serum protein with N-terminal or C-terminal specific antibodies indicated that sIL-2Ralpha represents the extracellular domain of this molecule. Patient serum inhibited specifically murine, but not human IL-2-dependent T-cell proliferation. To determine the significance of sIL-2Ralpha, recombinant sIL-2Ralpha was used in different cellular model involving IL-2. sIL-2Ralpha inhibited natural killer cell activity by 50% in the presence of IL-2. The basal proliferation of peripheral blood mononuclear cells was inhibited by sIL-2Ralpha, but phytohemagglutinin-induced proliferation was unaffected by this form of receptor. Interferon (INF)-gamma production induced by OKT-3 on peripheral blood mononuclear cells was not altered by sIL-2Ralpha, but IL-2 induced increase in INF-gamma production was suppressed. The decreasing production of INF-gamma in the presence of IL-4 was significantly increased in the presence of sIL-2Ralpha in media. These results show that the large amount of sIL2-Ralpha circulating in burn patients is related to the inflammatory response. The amount of dietary fat modulates sIL2Ralpha concentration in burn patients, confirming the beneficial effect of low fat administration after burn trauma. Inhibition of T-cell activation in burn patients is not directly related to sIL-2Ralpha, although the presence of sIL-2Ralpha in serum can inhibit some IL-2 mediated response, such as the emergence of TH1 and TH2 cells.

Sex steroid-binding protein in nonendocrine diseases.

In humans, sex steroid-binding protein (SBP) is a protein from the liver which binds with high affinity sex steroid hormones. The plasma concentration of SBP is regulated in part by hormonal factors. It has been shown that estrogens and/or thyroid hormones increase the production of SBP by hepatoma cell lines. It is therefore assumed that the increase in SBP levels in patients given oral estrogens or thyroid hormones is the consequence of a direct stimulation of the liver production of SBP by these hormones. The effects of androgen, progestagen and glucocorticoid hormones are unclear or still a matter of controversy. Moreover, the regulation of the metabolic clearance rate of SBP and the influence of nonhormonal factors on the production of SBP are still speculative. Changes in SBP have been described in a few nonendocrine diseases. A slight hormonal dysfunction may be either the primary or the sole cause of the changes in SBP occurring in these diseases. As an example, elevated SBP levels have been reported in men with liver cirrhosis together with testicular hypofunction and increased estrogen levels. It is therefore difficult to demonstrate that the increase in SBP is due to the liver dysfunction rather than to the endocrinological side effects of cirrhosis. The aim of this review is to present some aspects of the nonhormonal regulation of SBP. There is accumulating evidence in the literature for a relation between SBP levels and body weight and fat distribution, energy balance, diet and physical activity, and lipid metabolism. Therefore, it is tempting to propose that SBP is an index which reflects the status of endocrine, metabolic and nutritional functions. Measurement of SBP may be considered of interest in the light of previous epidemiological studies and the preventive approach to diseases such as hormone dependent tumors, cardiovascular diseases and osteoporosis.

No change in glucose tolerance and substrate oxidation after a high-carbohydrate, low-fat diet.

Possible changes in glucose tolerance and substrate oxidation after a high-carbohydrate, low-fat diet were studied in seven healthy volunteers. Each subject consumed two experimental diets for 1 week after 1 week on a stabilization diet; diet no. 1 11% fat and 64% carbohydrates, and diet no. 2 30% fat and 45% carbohydrates. At the end of each experimental week, plasma levels of glucose, insulin, and free fatty acids were measured before and every 30 minutes for 6 hours after a 75-g oral glucose challenge. At the same time, energy expenditure and substrate oxidation were measured by indirect calorimetry. Plasma lipid and lipoprotein levels were measured at the end of one stabilization period and at the end of each diet. Plasma glucose concentrations and areas under the curve of glucose concentrations were identical after the two experimental periods; the means +/- standard deviation for the values at 120 minutes were 6.4 +/- 0.3 and 6.4 +/- 0.6 mmol/L after diets no. 1 and 2, respectively, and areas under the curve were 1,853 +/- 115 and 1,862 +/- 211 mmol.min/L after diets no. 1 and 2, respectively. Similarly, plasma concentrations of insulin and free fatty acids after glucose ingestion were unaffected by the dietary changes. Energy expenditure increased after glucose administration, and this thermic effect of glucose was identical after the two experimental diets at 4.2% +/- 1.4%, and 3.9% +/- 1.4% of ingested energy for diets no. 1 and 2, respectively. Substrate oxidation rates were also identical for both the fasted and post-glucose periods after the two diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of moderate physical training on prednisone-induced protein wasting: a study of whole-body and bone protein metabolism.

This study investigated the possibility of preventing prednisone-induced protein wasting by regular physical activity. Eight healthy untrained volunteers took prednisone (30 mg/d for nine days), once after a 4-week exercise program that consisted of jogging 2.5 miles four times a week, and once without exercise. Whole body protein turnover was measured from the 15N enrichment plateau of urinary ammonia during ingestion of 15N glycine at hourly intervals. Whole-body protein synthesis and breakdown were derived from nitrogen flux, nitrogen intake, and urinary nitrogen elimination. Muscle myofibrillar protein breakdown was explored by measuring urinary 3-methylhistidine excretion. Bone protein metabolism was studied by measuring serum bone GLA protein (BGP), a specific marker of bone protein synthesis, and urinary elimination of hydroxyproline, an index of bone resorption. Whole-body protein turnover was significantly increased by exercise and prednisone (+19% and +17%, respectively); this effect was related to increased protein synthesis during exercise training (+27%, P less than .01) and to increased protein breakdown during prednisone administration without exercise (+21%, P less than .05). In contrast, values of protein turnover, synthesis, and breakdown were not different from control when the subjects took prednisone after training. Urinary excretion of 3-methylhistidine was decreased (-15%, P less than .05) at the end of the prednisone administration period but was identical to the control value when the subjects took prednisone in association with exercise. In contrast, serum BGP was significantly decreased by prednisone, with or without exercise (-35%, P less than .001). These data suggest that moderate exercise training can prevent, at least in part, the protein loss induced by prednisone.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved clinical status and length of care with low-fat nutrition support in burn patients.

BACKGROUND: The optimal amount and type of fat in the nutrition support of burned patients have not been determined. The aim of this study was to test low-fat nutritional solutions, with or without fish oil, on protein metabolism, morbidity, and length of care in severely burned adults. METHODS: In a prospective randomized clinical trial, 43 patients were assigned to one of the following groups: control (35% fat), low-fat solution (ie, 15% of total calories as fat), low-fat with fish oil, given for 30 days. Nitrogen balance, urinary 3-methylhistidine excretion, urinary cortisol, and clinical status were measured daily. Corticosteroid-binding globulin and total and free serum cortisol were measured every 3 days. RESULTS: Compared with controls, patients on low-fat support had fewer cases of pneumonia: 3/24 vs 7/13 (p = .02), better respiratory and nutrition status, and shorter time to healing: 1.2 vs 1.8 days/% burned area (p = 0.01). There was no difference in nitrogen balance between groups, and 3-methylhistidine excretion was higher and serum free cortisol was lower in log-fat--fed patients than in controls. There was no difference between the two low-fat groups in any of the parameters measured. CONCLUSIONS: This study showed that low-fat nutrition support decreases infectious morbidity and shortens length of stay in burn patients. Fish oil does not seem to add clinical benefit to low-fat solutions. In addition, this study provides the first evidence that nutrition intervention modulates cortisol-binding globulin and the concentration of free circulating cortisol after a severe stress.

Thermogenic response to feeding in severely burned patients: relation to resting metabolic rate.

Energy expenditure (EE) was measured one to five times by indirect calorimetry for 1 h after an overnight fast, and for 2 h after starting feeding in 19 severely burned patients (TBSA > 20 per cent) for a total of 36 tests. Twelve tube-fed volunteers served as controls. Thermogenic response to feeding (TRF) was calculated as the percentage of energy intake and hypermetabolism as the percentage of values obtained with the Harris-Benedict formula (%HB). Measured energy expenditure values were compared with values given by three predicting formulae. TRF was present in 10 out of the 33 measurements. Fasting EE was not different between the tests with and without TRF, but %HB was different between the two groups: 121.1 +/- 25.8 vs 157.8 +/- 32.0 per cent (tests with and without TRF, respectively (P < 0.01)). TRF was always absent when %HB was higher than 50. When TRF was present it was not statistically different from the control values. None of the three predicting formulae gave values within 10 per cent of the measured values in more than 25 per cent of the patients. We conclude that TRF is suppressed in burned patients with marked hypermetabolism, and that EE measured in the fed state reflects resting expenditure accurately in these patients. In addition, EE cannot be predicted from existing formulae.

Role of wound healing myofibroblasts on re-epithelialization of human skin.

In human skin, large burned surfaces heal using two concomitant phenomena: re-epithelialization and dermal neoformation. Numerous studies report the role of interactions between keratinocytes and fibroblasts, but the relationship between wound healing myofibroblasts and keratinocytes is not clear, even though these two cell types coexist during healing. We investigated the influence of myofibroblasts on keratinocyte growth and differentiation using an in vitro skin model. A histological study was performed to determine the speed and quality of epithelialization. When the dermis was populated with fibroblasts, a continuous epidermis was formed in 7-10 days. In contrast, with wound healing myofibroblasts or without cell in dermis, the complete reepithelialization never occurred over the 10-day period studied. After 7 further days of epidermal differentiation, histology showed an epidermis more disorganized and expression of basement membrane constituents was reduced when wound healing myofibroblasts or no cells were added in the dermis instead of fibroblasts. These results suggest that wound healing myofibroblasts are not efficient to stimulate keratinocyte growth and differentiation. Treatment of fibroblasts with TGFbeta1 induced an increase of epidermal cell differentiation as seen when myofibroblasts were present. However, this cytokine did not change re-epithelialization rate and induced an increase of basement membrane matrix deposition in opposition to myofibroblasts. Thus, TGFbeta1 action is not sufficient to explain all the different keratinocyte reactions towards fibroblasts and wound healing myofibroblasts. Our conclusion is that myofibroblasts seem to have a limited role in the re-epithelialization process and might be more associated with the increased extracellular matrix secretion.