Increase In Metabolic Clearance Rate Research Articles

Vegetarian diet-induced increase in linoleic acid in serum phospholipids is associated with improved insulin sensitivity in subjects with type 2 diabetes

BACKGROUND AND AIMS:Fatty acids are important cellular constituents that may affect many metabolic processes relevant for the development of diabetes and its complications. We showed previously that vegetarian diet leads to greater increase in metabolic clearance rate of glucose (MCR) than conventional hypocaloric diet. The aim of this secondary analysis was to explore the role of changes in fatty acid composition of serum phospholipids in diet- and exercise-induced changes in MCR in subjects with type 2 diabetes (T2D).METHODS:Subjects with T2D (n=74) were randomly assigned into a vegetarian group (VG, n=37) following vegetarian diet or a control group (CG, n=37) following a conventional diet. Both diets were calorie restricted (−500 kcal day–1). Participants were examined at baseline, 12 weeks of diet intervention and 24 weeks (subsequent 12 weeks of diet were combined with aerobic exercise). The fatty acid composition of serum phospholipids was measured by gas liquid chromatography. MCR was measured by hyperinsulinemic isoglycemic clamp. Visceral fat (VF) was measured by magnetic resonance imaging.RESULTS:Linoleic acid (LA; 18:2n6) increased in VG (P=0.04), whereas it decreased in CG (P=0.04) in response to dietary interventions. It did not change significantly after the addition of exercise in either group (group × time P<0.001). In VG, changes in 18:2n6 correlated positively with changes in MCR (r=+0.22; P=0.04) and negatively with changes in VF (r=−0.43; P=0.01). After adjustment for changes in body mass index, the association between 18:2n6 and MCR was no longer significant. The addition of exercise resulted in greater changes of phospholipid fatty acids composition in VG than in CG.CONCLUSION:We demonstrated that the insulin-sensitizing effect of a vegetarian diet might be related to the increased proportion of LA in serum phospholipids.

Exercise-Stimulated Glucose Turnover in the Rat Is Impaired by Glucosamine Infusion

The infusion of glucosamine causes insulin resistance, presumably by entering the hexosamine biosynthetic pathway; it has been proposed that this pathway plays a role in hyperglycemia-induced insulin resistance. This study was undertaken to determine if glucosamine infusion could influence exercise-stimulated glucose uptake. Male SD rats were infused with glucosamine at 0.1 mg x kg(-1) x min(-1) (low-GlcN group), 6.5 mg x kg(-1) x min(-1) (high-GlcN group), or saline (control group) for 6.5 h and exercised on a treadmill for 30 min (17 m/min) at the end of the infusion period. Glucosamine infusion caused a modest increase in basal glycemia in both experimental groups, with no change in tracer-determined basal glucose turnover. During exercise, glucose turnover increased approximately 2.2-fold from 46 +/- 2 to 101 +/- 5 pmol x kg(-1) x min(-1) in the control group. Glucose turnover increased to a lesser extent in the glucosamine groups and was limited to 88% of control in the low-GlcN group (47 +/- 2 to 90 +/- 3 pmol x kg(-1) x min(-1); P < 0.01) and 72% of control in the high-GlcN group (43 +/- 1 to 73 +/- 3 pmol kg(-1) 1 min(-1); P < 0.01). Similarly, the metabolic clearance rate (MCR) in the control group increased 72% from 6.1 +/- 0.2 to 10.5 +/- 0.7 ml kg(-1) x min(-1) in response to exercise. However, the increase in MCR was only 83% of control in the low-GlcN group (5.2 +/- 0.5 to 8.7 +/- 0.5 ml x kg(-1) x min(-1); P < 0.01) and 59% of control in the high-GlcN group (4.5 +/- 0.2 to 6.2 +/- 0.3 ml x kg(-1) x min(-1); P < 0.01). Neither glucosamine infusion nor exercise significantly affected plasma insulin or free fatty acid (FFA) concentrations. In conclusion, the infusion of glucosamine, which is known to cause insulin resistance, also impaired exercise-induced glucose uptake. This inhibition was independent of hyperglycemia and FFA levels.

Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs.

Stress-induced hyperglycemia can lead to significant deterioration in glycemic control in individuals with diabetes. Previously, we have shown in normal dogs that, after intracerebroventricular (ICV) administration of carbachol (a model of moderate stress), increases in both the metabolic clearance rate (MCR) of glucose and endogenous glucose production (GP) occur. However, in hyperglycemic diabetic dogs subjected to the same stress, the MCR of glucose does not increase and glycemia therefore markedly deteriorates because of stimulation of GP. Our aims were to determine the following: 1) whether insulin-induced acute normalization of glycemia, with or without beta-blockade, would correct glucose clearance and prevent the hyperglycemic effect of stress, and 2) whether hyperinsulinemia per se could correct these abnormalities. Stress was induced by ICV carbachol in 27 experiments in five alloxan-administered diabetic dogs subjected to the following protocols in random order: 1) basal insulin infusion (BI) to restore normoglycemia; 2) basal insulin infusion with beta-blockade (BI+block); 3) normoglycemic-hyperinsulinemic clamp with threefold elevation of insulin above basal (3x BI); and 4) normoglycemic-hyperinsulinemic clamp with fivefold elevation of insulin above basal (5 x BI). The BI+block protocol fully prevented stress-induced hyperglycemia, both by increasing MCR (deltaMCR at peak: 0.72 +/- 0.25 ml x kg(-1) x min(-1) vs. no change in BI, P < 0.05) and by diminishing the stress-induced increment in GP observed in BI (deltaGP at peak: 3.72 +/- 0.09 micromol x kg(-1) x min(-1) for BI+block vs. 14.10 +/- 0.31 micromol x kg(-1) x min(-1) for BI, P < 0.0001). In contrast, 3x BI and 5x BI treatments with normoglycemic-hyperinsulinemic clamps proportionately increased basal MCR at baseline, but paradoxically were not associated with an increase in MCR in response to stress, which induced a twofold increase in GP. Thus, in alloxan-administered diabetic dogs, stress increased GP but not MCR, despite normalization of glycemia with basal or high insulin. In contrast, beta-adrenergic blockade almost completely restored the metabolic response to stress to normal and prevented marked hyperglycemia, both by limiting the rise in GP and by increasing glucose MCR. We conclude that acute normalization of glycemia with basal insulin or hyperinsulinemia does not prevent hyperglycemic effects of stress unless accompanied by beta-blockade, and we speculate that short-term beta-blockade may be a useful treatment modality under some stress conditions in patients with diabetes.

Glucose uptake during centrally induced stress is insulin independent and enhanced by adrenergic blockade.

Glucose utilization increases markedly in the normal dog during stress induced by the intracerebroventricular (ICV) injection of carbachol. To determine the extent to which insulin, glucagon, and selective (alpha/beta)-adrenergic activation mediate the increment in glucose metabolic clearance rate (MCR) and glucose production (R(a)), we used five groups of normal mongrel dogs: 1) pancreatic clamp (PC; n = 7) with peripheral somatostatin (0.8 microg x kg(-1) x min(-1)) and intraportal replacement of insulin (1,482 +/- 84 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)) infusions; 2) PC plus combined alpha (phentolamine)- and beta (propranolol)-blockade (7 and 5 microg x kg(-1) x min(-1), respectively; alpha+beta; n = 5); 3) PC plus alpha-blockade (alpha; n = 6); 4) PC plus beta-blockade (beta; n = 5); and 5) a carbachol control group without PC (Con; n = 10). During ICV carbachol stress (0-120 min), catecholamines, ACTH, and cortisol increased in all groups. Baseline insulin and glucagon levels were maintained in all groups except Con, where glucagon rose 33%, and alpha, where insulin increased slightly but significantly. Stress increased (P < 0.05) plasma glucose in Con, PC, and alpha but decreased it in beta and alpha+beta. The MCR increment was greater (P < 0.05) in beta and alpha+beta than in Con, PC, and alpha. R(a) increased (P < 0.05) in all groups but was attenuated in alpha+beta. Stress-induced lipolysis was abolished in beta (P < 0.05). The marked rise in lactate in Con, PC, and alpha was abolished in alpha+beta and beta. We conclude that the stress-induced increase in MCR is largely independent of changes in insulin, markedly augmented by beta-blockade, and related, at least in part, to inhibition of lipolysis and glycogenolysis, and that R(a) is augmented by glucagon and alpha- and beta-catecholamine effects.

The effect of fasting and vitamin E on insulin action in obese type 2 diabetes mellitus.

The influence of either short-term fasting or vitamin E administration on insulin action was studied in two groups of obese Type 2 diabetic patients. Twelve patients underwent 7 days of fasting (group A), whereas 600 mg of vitamin E was administered daily during 3 months in 9 diabetic patients (group B). Insulin action was examined by using hyperinsulinemic isoglycemic clamps (insulin infusion rate, 1.0 mU/kg/min) and insulin receptors on erythrocytes before and after respective regimens. An increase of glucose disposal rate (29.5 +/- 8.9 vs. 24.0 +/- 7.5 mumol/kg/min, p < 0.01) and an increase of metabolic clearance rate of glucose (4.0 +/- 2.5 vs. 2.3 +/- 0.9 mL/kg/min, p < 0.01) were observed in group A after fasting. On the contrary, decreases of glucose disposal rate (21.3 +/- 8.5 vs. 26.6 +/- 9.8 mumol/kg/min, p < 0.02), metabolic clearance rate of glucose (2.9 +/- 0.8 vs. 3.7 +/- 1.7 mL/kg/min, p < 0.05), and insulin receptor number (p < 0.01) were found after vitamin E administration as compared with pretreated values. A worsening of diabetes control as observed by an increase of HbA1C (p < 0.01) was present in the latter group. In summary, we found an improvement of insulin action after short-term fasting in contrast with the worsening of metabolic parameters after vitamin E administration in obese Type 2 diabetic patients.

Prolactin Kinetics during Freshwater Adaptation of Mature Chum Salmon, Oncorhynchus keta

Abstract When mature chum salmon (Oncorhynchus keta) caught in Otsuchi Bay (salinity 34 ppt), northern Honshu Island, Japan, were transferred directly to fresh water, they attained normal plasma ion levels within 24 hr. Plasma prolactin remained low in the fish kept in seawater. On transfer to fresh water, a significant increase in plasma prolactin concentration was seen only in females, but not in males. Metabolic clearance rate (MCR) and secretion rate of prolactin were calculated from its plasma levels after intra-arterial injection of chum salmon prolactin into chronically-cannulated fish. In both males and females, a significant increase in MCR was seen after transfer to fresh water, indicating that prolactin is involved in freshwater adaptation in both sexes. In females, the secretion rate increased significantly after 6 days in fresh water. No such change in the secretion rate was seen in males. It seems likely that prolactin secretion is affected by reproduction-related changes occurring in mature...

Contribution of excitatory amino acids to morphine-induced metabolic alterations

Previous studies have indicated that excitatory amino acids are involved in the analgesic and addictive properties of morphine. However, their role in the morphine-induced alterations in glucose metabolism is not known. This study assessed the contribution of NMDA receptor activation to the morphine-induced hormonal and metabolic alterations in conscious unrestrained chronically catheterized rats. Whole body glucose flux was assessed with a primed constant intravenous infusion of [3- 3H]glucose in rats pretreated with the NMDA-receptor antagonist MK-801 (0.25 mg/kg, intraarterial) or an equal volume (1.5 ml) of sterile saline (0.9% ) administered 15 min prior to i.c.v. injection of H 2O (Con; 5 μl) or morphine sulfate (80 μg). No significant alterations were noted in metabolic and hormonal parameters of H 2O injected rats. i.c.v. morphine increased the plasma glucose concentration (60%), hepatic glucose production ( R a ; 60%) and whole body glucose utilization ( R d ; 53%), but did not alter the glucose metabolic clearance rate (MCR). MK-801 alone resulted in transient hyperglycemia (25%), stimulation of glucose R a (60%) and glucose R d (53%), and a significant (30%) increase in MCR. MK-801 pretreatment blunted the morphine-induced hyperglycemia and the increased glucose R a and R d . Morphine increased the plasma concentration of epinephrine (4-fold), norepinephrine (2-fold) and corticosterone (67%); however, no alterations in plasma insulin and glucagon were detected. MK-801 pretreatment, blunted the morphine-induced increase in corticosterone and norepinephrine, and elicited a significant rise in insulin concentrations. These results indicate that activation of the NMDA receptors contributes to the morphine-induced hyperglycemia and hormonal alterations. Furthermore, this response appears partially mediated by activation of sympathetic outflow and suppression of insulin release, which is blunted by inhibition of NMDA receptors.

Increased clearance of lactate after short-term training in men.

A short-term training model previously shown to result in a tighter metabolic control in working muscle in the absence of an increase in mitochondrial potential was used to examine changes in lactate turnover. Lactate flux was studied before and after 10 days of cycle training [2 h/day at 59% maximal oxygen consumption (VO2max)] in untrained men [VO2max = 45.5 +/- 2.4 (SE) ml.kg-1.min-1). A primed constant infusion of L-[1-13C]lactate was used to examine lactate kinetics during a prolonged exercise protocol (90 min at 59% VO2max). Rate of appearance of lactate increased with exercise (P < 0.01), both pretraining (rest = 30.3 +/- 4.9 ml.kg-1.min-1, exercise = 115 +/- 14 ml.kg-1.min-1) and posttraining (rest = 28.4 +/- 4.7 ml.kg-1.min-1, exercise = 112 +/- 13 ml.kg-1.min-1). Despite a lower blood lactate concentration (P < 0.05) during exercise after training, there was no difference in the rate of appearance of lactate. Training increased (P < 0.05) the metabolic clearance rate of lactate during exercise from 36.8 +/- 4.8 to 51.4 +/- 6.8 ml.kg-1.min-1. These findings indicate that at least part of the lower exercising blood lactate observed after training is due to an increase in metabolic clearance rate. In addition, the lower intramuscular lactate levels suggest a decreased recruitment of glycolysis particularly early in exercise.

Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance.

The aim of this study was to determine whether angiotensin receptor subtypes play a role in angiotensin clearance from plasma. Angiotensin metabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes, and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearance rate by > 50% at low-dose infusion, suggesting that type 1 angiotensin II receptors are involved in angiotensin II clearance from plasma. At higher angiotensin infusion rates, the-metabolic clearance rate of angiotensin was unaffected. To dissect the contribution of renin-generated angiotensin, additional experiments were performed in nephrectomized rats. In anephric rats, angiotensin clearance was unaffected by type 1 angiotensin II receptor inhibition. In contrast, the type 2 angiotensin II receptor ligand PD123319 in intact rats caused a > 50% increase in metabolic clearance rate of angiotensin at higher infusion rates (P < .05). In anephric rats, the type 2 angiotensin II receptor ligand alone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T1/2 for angiotensin disappearance. These data argue against a role for type 1 or 2 angiotensin II receptors as clearance receptors. Increased clearance of angiotensin by type 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 ligands may alter angiotensin effects.

Role of IL-1α in central nervous system immunomodulation of glucoregulation

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3- 3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1α (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a propertional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1α, or i.c.v. injection of IL-1β, or heat-inactivated IL-1α. Indomethacin (5 mg/kg, i.v.) blocked the hyperglycemia and increased HGO induced by i.c.v. injection of prostaglandin E 2 (100 ng) produced comparable increases in glucose flux. These results indicate that IL-1α can act centrally to enhance whole body glucose metabolism, and that this response is probably mediated by prostaglandins.

Effects of subbasal insulin infusion on resting and exercise-induced glucose turnover in depancreatized dogs

beta-Adrenergic blockade suppressed lipolysis and normalized the exercise-induced increments in glucose uptake (GlcU) and metabolic clearance rate (MCR) in alloxan-diabetic dogs with residual insulin, but not in insulin-deprived depancreatized dogs even when combined with methylpalmoxirate (MP), which suppresses fatty acid oxidation. The effects of a minimal amount of insulin (as in the alloxan-diabetic dog), were studied in depancreatized, 24-h insulin-deprived dogs during rest and treadmill exercise (6 km/h, 10% slope) using a 1/4 basal insulin infusion (50 microU.kg-1.min-1, insulin, n = 6) alone, or with MP (20 mg.kg-1.day orally, 2.5 days, MP+insulin, n = 6). At rest, insulin decreased circulating fatty acids (31%) and Glc (13%) and increased GlcU and MCR (86 and 72%). Glc production was unaffected. MP plus insulin markedly suppressed hepatic fatty acid oxidation, decreased Glc (44%) and Glc production (50%), and markedly increased MCR (128%). The exercise-induced increments in MCR were markedly improved only by MP plus insulin but were still lower than in the propranolol-treated alloxan-diabetic dogs. Plasma Glc inversely correlated with the exercise-induced increase in MCR (r = -0.86). We conclude that 1) acute infusion of subbasal insulin improved GlcU in depancreatized dogs at rest but not during exercise; 2) inhibition of fatty acid oxidation combined with subbasal insulin improved the exercise-induced increase in MCR; and 3) the difference in GlcU and MCR between the MP plus insulin-treated depancreatized dogs and the beta-blockade-treated alloxan-diabetic dogs suggests a difference between acute and chronic effects of insulin.

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Chronic metabolic acidosis results in metabolic bone disease, calcium nephrolithiasis, and growth retardation. The pathogenesis of each of these sequelae is poorly understood in humans. We therefore investigated the effects of chronic extrarenal metabolic acidosis on the regulation of 1,25-(OH)2D, parathyroid hormone, calcium, and phosphate metabolism in normal humans. Chronic extrarenal metabolic acidosis was induced by administering two different doses of NH4Cl [2.1 (low dose) and 4.2 (high dose) mmol/kg body wt per d, respectively] to four male volunteers each during metabolic balance conditions. Plasma [HCO3-] decreased by 4.5 +/- 0.4 mmol/liter in the low dose and by 9.1 +/- 0.3 mmol/liter (P < 0.001) in the high dose group. Metabolic acidosis induced renal hypophosphatemia, which strongly correlated with the severity of acidosis (Plasma [PO4] on plasma [HCO3-]; r = 0.721, P < 0.001). Both metabolic clearance and production rates of 1,25-(OH)2D increased in both groups. In the high dose group, the percentage increase in production rate was much greater than the percentage increase in metabolic clearance rate, resulting in a significantly increased serum 1,25-(OH)2D concentration. A strong inverse correlation was observed for serum 1,25-(OH)2D concentration on both plasma [PO4] (r = -0.711, P < 0.001) and plasma [HCO3-] (r = -0.725, P < 0.001). Plasma ionized calcium concentration did not change in either group whereas intact serum parathyroid hormone concentration decreased significantly in the high dose group. In conclusion, metabolic acidosis results in graded increases in serum 1,25-(OH)2D concentration by stimulating its production rate in humans. The increased production rate is explained by acidosis-induced hypophosphatemia/cellular phosphate depletion resulting at least in part from decreased renal tubular phosphate reabsorption. The decreased serum intact parathyroid hormone levels in more severe acidosis may be the consequence of hypophosphatemia and/or increased serum 1,25-(OH)2D concentrations.

Estradiol and progesterone during exercise in healthy untrained women

Ten eumenorrheic nonathletic women, aged 21-25, were studied on the 8th day following the LH peak in three consecutive cycles. Plasma level and metabolic clearance rate (MCR) of estradiol (E2) and progesterone (P) were measured before and during a 2-h continuous treadmill test at a speed corresponding to 70% of their running speed at anaerobic threshold on three separate occasions. A significant decrease of plasma level of the hormones (-30% and -40%, respectively, P less than 0.01; mean) from resting values was found, while their metabolic clearance rate increased significantly [E2-MCR from 1017 l.d-1 to 1312 l.d-1 (+29%), P less than 0.001; mean; P-MCR from of 2061 l.d-1 to 2988 l.d-1 (+45%), P less than 0.003; mean]. The increase in MCR of the two hormones was significantly correlated with the increase in heart rate and systolic blood pressure accompanying the beginning of the exercise test.

Effect of plane of nutrition on insulin sensitivity during lactation in the ewe

The hyperinsulinaemic euglycaemic insulin clamp technique was used to compare insulin sensitivity in lactating ewes at two levels of feeding. Clamps were performed at two (restricted intake) or three (ad libitum intake) stages of lactation and also 30 d after drying off. Dose response curves for insulin were constructed using the glucose metabolic clearance rate (MCR) as the measure of glucose metabolism and these were statistically compared between stages of lactation within the feeding levels, and also between feeding regimes. Animals on a restricted feed intake showed a weight loss throughout lactation, coupled with a lower insulin sensitivity as measured by the ED50 (concentration of insulin required to produce a half maximal increase in MCR), while those on ad libitum feeding showed a weight gain and a decreased insulin sensitivity in the dry period. Endogenous glucose production was less sensitive to inhibition by insulin in the animals subjected to restricted food intake, compared with those on the ad libitum regime, which suggested a major role for the plane of nutrition in adjusting the homeorhetic control of metabolism during lactation.

The effect of a diet rich in brussels sprouts on warfarin pharmacokinetics.

Ten healthy subjects were given 20 mg of warfarin orally before, and after a daily intake of 400 g of brussels sprouts for 2 weeks. The brussels sprouts diet stimulated warfarin disposal as evidenced by a 29% increase in mean elimination rate constant, accompanied by a 27% increase in metabolic clearance rate and a 16% decrease in plasma AUC. It is concluded that a high intake of brussels sprouts, a cruciferous vegetable, accelerates warfarin disposal, and thereby might contribute to less anticoagulation.

The metabolic clearance rate of estradiol-17β in rainbow trout, Salmo gairdneri R., estimated by both single injection and constant infusion methods: Increase during oocyte maturation

A dual cannulation of free-swimming rainbow trout is used to estimate the metabolic clearance rate (MCR) of Estradiol-17β (E 2-17β) by both single injection and constant infusion methods. It is shown that E 2-17β MCR changes significantly during the progress of oogenesis, mainly at the end of the sexual cycle. The same changes in MCR and very similar values are found with both single injection and constant infusion methods: MCR is stable (28.8 ml/hr/kg) from the postovulation period (throughout endogenous vitellogenesis) to early exogenous vitellogenesis. It decreases significantly during advanced exogenous vitellogenesis (18.7 ml/hr/kg) and increases clearly at the onset of oocyte maturation (40.9 ml/hr/ kg). A direct relationship between MCR and plasma E 2-17β occurs: Plasma E 2-17β levels increase (advanced exogenous vitellogenesis) when MCR decreases. Then estradiol decline takes place at the same time that MCR reaches its highest values (oocyte maturation). An increase in MCR is probably one event required to allow the establishment of an appropriate hormonal environment for oocyte maturation.

Chronic 1,25-dihydroxyvitamin D3 administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate.

Administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can lower the serum concentration of 25-hydroxyvitamin (25-OH-D). To determine if 1,25(OH)2D3 lowers serum 25-OH-D by increasing clearance or reducing production, we directly measured the metabolic clearance rate (MCR) of 25-OH-D in rats chronically infused with 1,25(OH)2D3. Chronic 1,25(OH)2D3 administration (0 to 75 pmol/d) reduced, in a time- and dose-dependent fashion, the serum concentrations of 25-OH-D3 and 24,25(OH)2D3 from 18 +/- 2 to 9 +/- 1 ng/ml and from 4.8 +/- 0.7 to 1.3 +/- 0.3 ng/ml, respectively, and increased sevenfold the in vitro conversion of 25-OH-D to 24,25(OH)2D3 by kidney homogenates. The reduction in serum 25-OH-D3 was completely accounted for by an increase in MCR. No change in production occurred. The influence of 1,25(OH)2D3 on serum 25-OH-D3 and 24,25(OH)2D3 was shown not to be dependent on induction of hypercalcemia. These data suggest that chronic 1,25(OH)2D3 administration lowers serum 25-OH-D by increasing the metabolic clearance of 25-OH-D3 and not by decreasing its production.

Effect of hematocrit reduction on hormonal and metabolic responses to exercise.

We wished to determine the effect of a 25% hematocrit reduction on glucoregulatory hormone release and glucose fluxes during exercise. In five anemic dogs, plasma glucose fell by 21 mg/dl and in five controls by 7 mg/dl by the end of the 90-min exercise period. After 50 min of exercise, hepatic glucose production (Ra) and glucose metabolic clearance rate (MCR) began to rise disproportionately in anemics compared with controls. By the end of exercise, the increase in Ra was almost threefold higher (delta 15.1 +/- 3.4 vs. delta 5.2 +/- 1.3 mg X kg-1 X min-1) and MCR nearly fourfold (delta 24.6 +/- 8.8 vs. delta 6.5 +/- 1.3 ml X kg-1 X min-1). Exercise with anemia, in relation to controls resulted in elevated levels of glucagon [immunoreactive glucagon (IRG) delta 1,283 +/- 507 vs delta 514 +/- 99 pg/ml], norepinephrine (delta 1,592 +/- 280 vs. delta 590 +/- 155 pg/ml), epinephrine (delta 2,293 +/- 994 vs. delta 385 +/- 186 pg/ml), cortisol (delta 6.7 +/- 2.2 vs. delta 2.1 +/- 1.0 micrograms/dl) and lactate (delta 12.1 +/- 2.2 vs. delta 4.2 +/- 1.8 mg/dl) after 90 min. Immunoreactive insulin and free fatty acids were similar in both groups. In conclusion, exercise with a 25% hematocrit reduction results in 1) elevated lactate, norepinephrine, epinephrine, cortisol, and IRG levels, 2) an increased Ra which is likely related to the increased counterregulatory response, and 3) we speculate that a near fourfold increase in MCR is related to metabolic changes due to hypoxia in working muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of ketamine HC1 and barbiturate anaesthesia on the metabolic clearance and production rates of testosterone in the male rhesus monkey, Macaca mulatta

The study compares metabolic clearance rates, production rates and serum levels of testosterone in conscious and ketamine and barbiturate anaesthetized adult male rhesus monkeys. Using the single injection technique for the determination of metabolic clearance rate, a significant increase in metabolic clearance rate from 430 ± 71 1/day in conscious animals to 908 ± 46 1/day for ketamine and 1224 ± 174 1/day for barbiturate anaesthetized animals was observed. Serum testosterone was increased from 106 ± 9 ng 100 ml to 450 ± 186 ng/100 ml in barbiturate anaesthetized animals, and this marked increase in serum testosterone was accompanied by a 13-fold increase in the production rate of testosterone from 0.44 ± 0.04 mg/day to 6.0 ± 3.3 mg/day. Serum testosterone levels and production rates were not significantly different in conscious and ketamine anaesthetized animals. Barbiturate anaesthesia caused continual changes in serum LH and testosterone levels over an observation period of 3.5 h. Serum LH gradually increased from 4.8 ± 2.1 mlU/ml to 19.0 ± 4.1 mIU/ml within 1 h, while serum testosterone rose from 214 ± 62 ng 100 ml to 836 ± 53 ng/100 ml within 2 h. In the light of these findings it may be concluded that barbiturate anaesthesia is not suitable for such prolonged studies of endocrine function. Effects exerted by ketamine anaesthesia are less pronounced.

Effect of food restriction (undernutrition) on pharmacokinetics of levonorgestrel in rabbits

Twelve female rabbits aged about 3–4 months were randomly divided into two groups (group A and group B) and were individually matched for their initial body weights. Animals of group A received a stock diet ad libitum while each of the animals in group B were fed 50% of the diet consumed by the corresponding matched control from group A. Pharmacokinetics of levonorgestrel were determined in all animals between 1 1 2 –2 months after these diets were started, using an intravenous dose of 8–20 μC i of 3H-levonorgestrel and 15–20 μg of levonorgestrel per kg body weight. Urinary excretion of radioactivity was also measured in all the animals for a period of 5 days following the dose. The body weights of animals on the restricted diet were 17% lower than those of the ad lib fed animals. Haemoglobin levels and plasma albumin concentration were found to be in the normal range in both groups. There was a significant increase in Metabolic Clearance Rate (MCR) and t 1 2 π and a decrease in elimination half-life in animals of group B as compared to those seen in animals of group A. The urinary excretion of label was found to be slightly increased in group B animals as compared to that in group A controls.