Testosterone metabolic clearance rate and production rate in the male infant rhesus monkey

The male infant rhesus monkey (Macaca mulatta) undergoes a period of testicular activation similar to that seen in the human infant. Plasma testosterone (T) concentrations rise after birth, reaching levels of about 500 ng/dl at 1-3 mo of age and then fall to approximately 50 ng/dl at 60 mo. The plasma T metabolic clearance rates (MCRT) and production rates (PRT) were measured in two rhesus infants at 1 and 6 mo of age to determine the mechanism of the observed increase in plasma T. While there was little change in the MCRT between 1 and 6 mo, PRT was much higher at 1 mo than at 60 mo of age. These observations are consistent with the hypothesis that the increased plasma testosterone levels in infant rhesus monkeys reflect an increased production of testosterone rather than an altered metabolic disposition of the hormone.     

Serum and urine malondialdehyde levels in NIDDM patients with and without hyperlipidemia

Malondialdehyde (MDA), a marker of lipid peroxidation, was measured as thiobarbituric acid reactive substance (TBARS) in 78 noninsulin-dependent diabetic patients, 38 hyperlipidemic patients, and 28 healthy subjects. Diabetic patients were divided into groups and subgroups according to the existence of hyperlipidemia and other complications. Serum and urine MDA concentrations were significantly higher in diabetic and nondiabetic patient groups than in the control group. By contrast to urine MDA level, serum MDA level was significantly higher in hyperlipidemic diabetics than that of normolipidemic diabetics. Serum MDA levels in the hyperlipidemic diabetic group and urine MDA levels in both diabetic groups were significantly higher than those in hyperlipidemic nondiabetic group. In both diabetic groups, the existence of complications didn't affect serum and urine MDA levels. No correlation existed between serum and urine MDA levels in both patient groups and control subjects. This study confirmed the existence of lipid peroxidation disorders in diabetic patients.     

Residual B cell function in patients with long-standing NIDDM and its relation to metabolic control and diabetic complications

We have evaluated the residual pancreatic B cell function by glucagon load test in 28 patients with non-insulin-dependent diabetes mellitus (NIDDM) of a duration of 20 years or more. The increase in serum C-peptide at 6 minutes after glucagon administration (delta C-peptide) was used as an index of residual B cell function. There was much less delta C-peptide in patients treated with insulin than in those treated with sulfonylurea (p less than 0.05), and it was significantly correlated with the body mass index (r = 0.40, p less than 0.05). Long term metabolic control assessed by the average annual mean fasting blood glucose for the observation period (mean, 21 years) was not correlated with delta C-peptide (r = -0.13). The prevalence of retinopathy which needed photocoagulation therapy and of neuropathy in patients with poor residual B cell function (delta C-peptide less than or equal to 0.3 ng/ml) was the same as that in those with good residual B cell function (delta C-peptide greater than or equal to 1.0 ng/ml). The present study shows that the residual B cell function is not correlated with long term glycemic control and the prevalence of diabetic complications in long-standing NIDDM patients.     

Reduction of metabolic rate and thermoregulation during daily torpor

Physiological mechanisms causing reduction of metabolic rate during torpor in heterothermic endotherms are controversial. The original view that metabolic rate is reduced below the basal metabolic rate because the lowered body temperature reduces tissue metabolism has been challenged by a recent hypothesis which claims that metabolic rate during torpor is actively downregulated and is a function of the differential between body temperature and ambient temperature, rather than body temperature per se. In the present study, both the steady-state metabolic rate and body temperature of torpid stripe-faced dunnarts, Sminthopsis macroura (Dasyuridae: Marsupialia), showed two clearly different phases in response to change of air temperature. At air temperatures between 14 and 30°C, metabolic rate and body temperature decreased with air temperature, and metabolic rate showed an exponential relationship with body temperature (r ²=0.74). The Q ₁₀ for metabolic rate was between 2 and 3 over the body temperature range of 16 to 32°C. The difference between body temperature and air temperature over this temperature range did not change significantly, and the metabolic rate was not related to the difference between body temperature and air temperature (P=0.35). However, the apparent conductance decreased with air temperature. At air temperatures below 14°C, metabolic rate increased linearly with the decrease of air temperature (r ²=0.58) and body temperature was maintained above 16°C, largely independent of air temperature. Over this air temperature range, metabolic rate was positively correlated with the difference between body temperature and air temperature (r ²=0.61). Nevertheless, the Q ₁₀ for metabolic rate between normothermic and torpid thermoregulating animals at the same air temperature was also in the range of 2–3. These results suggest that over the air temperature range in which body temperature of S. macroura was not metabolically defended, metabolic rate during daily torpor was largely a function of body temperature. At air temperatures below 14°C, at which the torpid animals showed an increase of metabolic rate to regulate body temperature, the negative relationship between metabolic rate and air temperature was a function of the differential between body temperature and air temperature as during normothermia. However, even in thermoregulating animals, the reduction of metabolic rate from normothermia to torpor at a given air temperature can also be explained by temperature effects.Abbreviations BM body mass - BMR basal metabolic rate - C apparent conductance - MR metabolic rate - RMR resting metabolic rate - RQ respiratory quotient - T _a air temperature - T _b body temperature - T _lc lower critical temperature - T _tc critical air temperature during torpor - TMR metabolic rate during torpor - TNZ thermoneutral zone - T difference between body temperature and air temperature - VO₂ rate of oxygen consumption     

Reduction of C-peptide secretion in noninsulin-dependent diabetic patients with long duration of insulin treatment

We examined the responses of serum free C-peptide immunoreactivity (CPR) during a 100 g oral glucose tolerance test (OGTT) on diabetic patients undergoing different kinds and durations of treatment. None of the patients were ketosis-prone or had any history of nephropathy and they all developed diabetes when over the age of 30. The sigma serum free CPR (the sum of serum free CPR values during OGTT) of group A (duration of insulin treatment was less than 5 years, N = 10) was found to be higher than that of group B (duration of insulin treatment was 5 years or more, N = 10) (p less than 0.005). On the other hand, the sigma serum free CPR of group C (treatment with an oral hypoglycemic agent for less than 5 years, N = 9) was not statistically different from that of group D (treatment with an oral hypoglycemic agent for 5 years or more, N = 11). There were no statistical differences between group A and group B in age at onset, duration of diabetes, daily insulin dose, relative body weight index, serum creatinine or sigma BG (the sum of blood glucose values during OGTT). Just before the start of insulin treatment, there were no significant differences between the two groups in the following: 1. fasting blood glucose values (all 10 patients measured in group A and 9 patients in group B) 2. blood glucose and plasma immunoreactive insulin (IRI) responses (7 patients measured in group A and 6 in group B). Among those with plasma IRI measured on the previous occasion, sigma serum free CPR was found to be higher in group A than in group B (p less than 0.025) at the time of the present study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patterns of control of maximum metabolic rate in humans

In this analysis, four performance phenotypes were used to compare mechanisms of control of aerobic maximum metabolic rate (MMR): (i) untrained sedentary (US) subjects, as a reference group against which to compare (ii) power trained (PT), (iii) endurance trained (ET) and (iv) high altitude adapted native (HA) subject groups. Sprinters represented the PT group; long distance runners illustrated the ET group; and Quechuas represented the HA group. Numerous recent studies have identified contributors to control on both the adenosine triphosphate (ATP) supply side and the ATP demand side of ATP turnover. Control coefficients or c(i) values were defined as fractional change in MMR/fractional change in the capacity of any given step in ATP turnover. From the best available evidence it appears that at MMR all five of the major steps in energy delivery (namely, ventilation, pulmonary diffusion, cardiac output, tissue capillary - mitochondrial O(2) transfer, and aerobic cell metabolism per se) approach an upper functional ceiling, with control strength being distributed amongst the various O(2) flux steps. On the energy demand side, the situation is somewhat simplified since at MMR approximately 90% of O(2)-based ATP synthesis is used for actomyosin (AM) and Ca(2+) ATPases; at MMR these two ATP demand rates also appear to be near an upper functional ceiling. In consequence, at MMR the control contributions or c(i) values are rather evenly divided amongst all seven major steps in ATP supply and ATP demand pathways right to the point of fatigue. Relative to US (the reference group), in PT subjects at MMR control strength shifts towards O(2) delivery steps (ventilation, pulmonary diffusion and cardiac output). In contrast in ET and HA subjects at MMR control shifts towards the energy demand steps (AM and Ca(2+) ATPases), and more control strength is focussed on tissue level ATP supply and ATP demand. One obvious advantage of the ET and HA control pattern is improved metabolite homeostasis. Another possibility is that, with some reserve capacity in the O(2) delivery steps and control focussed on ATP turnover at the tissue level, nature has designed the ideal 'endurance machine'.     

Serum cortisol levels affect the metabolic clearance rate of progesterone in female baboons.

Since interactions between progesterone (P₄), Cortisol (F), cortisone (E) and corticosteroid binding globulin (CBG) may influence the metabolic clearance rates (MCR) of these steroids, the effect of altering circulating F concentrations on clearance of the steroids was determined. MCR of P₄, F and E were determined by the iv constant infusion method in 6 pregnant and 6 nonpregnant baboons (Papio papio). Serum F concentrations were altered by iv infusion of 5 mg F/90 min or im injection of betamethasone (3 mg bi-daily for 2 days). Mean MCR-P₄ (1/d/kg ± SE) was greater (P < 0.01) in pregnant (92.8 ± 8.5) than in nonpregnant (53.9 ± 4.4) animals while mean MCR-F was similar in both groups ($\text{10.8 ± 1.2}\text{vs}\text{13.0 ± 1.5}$, respectively). Mean MCR-E was also similar in pregnant (30.8 ± 4.9) and nonpregnant (34.1 ± 4.5) baboons. Mean serum F concentrations (/gmg/100 ml ± SE) in 4 nonpregnant (42.0 ± 8.6) and 4 pregnant (52.2 ± 10.0) baboons were increased (P < 0.05) 60% by F administration but MCR-P₄, -F and -E were unaltered. Betamethasone treatment reduced (P < 0.05) serum F 75% in both groups. In nonpregnant baboons, betamethasone treatment reduced (P < 0.01) MCR-P₄ (37.3 ± 3.9), MCR-F (7.4 ± 1.6) and MCR-E (18.5 ± 3.7). Betamethasone treatment of pregnant animals reduced (P < 0.01) MCR-P₄ (56.5 ± 7.4), MCR-F (6.3 ± 0.8) and MCR-E (14.6 ± 2.6). Infusion of F into betamethasone-treated animals increased serum F levels and increased MCR-P4, -F and -E. It is concluded that variations in serum F levels affect the clearance of F, E and P₄ presumably because of the mutual interactions of these steroids with CBG.     

Noradrenaline clearance in human urine]

The urinary clearance for DL-[3H] noradrenaline has been measured in four human subjects. The mean ratio of noradrenaline clearance over glomerular filtration rate was 0.93, the confidence limit for the mean at the 5% level being 0.81-1.06. These results are in perfect agreement with those obtained in dogs with the same experimental procedure. It is concluded that the urinary excretion of noradrenaline is strictly proportional to the glomerular filtration rate.     

Effect of plasma calcium concentration on the metabolic clearance rate of calcitonin in the dog

Plasma immunoreactive calcitonin (iCT) levels generally are not elevated in chronic, nonmalignant, hypercalcemic states. Normocalcitoninemia might occur despite increased CT secretion if hypercalcemia itself accelerated the clearance of CT from the circulation. Therefore, we have measured the metabolic clearance rate (MCR) of human CT (hCT), infused to constant plasma levels in thyroparathyroidectomized dogs, under conditions of acute and chronic hypo- and hypercalcemia. Acute increases of plasma calcium were without significant effect on the MCR of hCT, but chronic hypercalcemia, induced by dihydrotachysterol treatment, reduced the MCR of hCT by 30% (P less than 0.05) and glomerular filtration rate (GFR) by 40% (P less than 0.02). There was a significant, positive correlation (r = 0.60, P less than 0.02) between GFR and the MCR of CT. The data suggest that failure to detect elevated iCT levels in chronic hypercalcemia is not the result of an increased MCR of CT. In fact, hypercalcemia should exaggerate the effect of increased CT secretion by decreasing the renal clearance of the hormone.     

The effects of progesterone supplementation on the metabolic clearance rate of progesterone in the pregnant rat

In the pregnant rat, short-term stability of progesterone blood concentrations may involve an active homeostatic mechanism. In the present study, we examined the possibility that the metabolic clearance rate (MCR) of progesterone can respond to a change in progesterone production and thus reduce variation in blood concentrations. Progesterone was administered both acutely and chronically to conscious rats, and the effective production rate, MCR, and blood concentration were monitored on Day 16 of pregnancy. Acute, low-dose progesterone supplementation, which effectively raised production rate by 29%, had no effect on the MCR of progesterone. Acute, high-dose supplementation, which raised total progesterone production by 68%, caused a 35% fall in the MCR of progesterone. Chronically supplemented rats received s.c. injections of progesterone (20 mg) once daily over Days 13-16 of pregnancy. The resultant production rate measured on Day 16 was 114% higher than that in controls, but there was no difference in MCR. Collectively, these experiments demonstrate that no short-term homeostatic mechanism involving the MCR operates to control blood progesterone concentrations in Day 16 pregnant rats. Thus, progesterone homeostasis appears limited to long-term developmental changes rather than short-term physiological control.     

Changes in HDL subfractions in patients with type I diabetes mellitus before and after metabolic control

In order to further investigate the behaviour of high density lipoproteins in diabetes mellitus, we studied HDL subclasses, HDL2 and HDL3, in 10 patients with newly detected, untreated insulin-deficient diabetes before starting insulin treatment and after getting a good metabolic control. We used the extractive method of Abell to determine HDL-cholesterol after LDL and VLDL precipitation with polyanions and HDL3-cholesterol after HDL2 precipitation with dextransulphate 15,000 m.w. After insulin therapy, we observed a significant increase in HDL-cholesterol and a decrease in serum triglycerides. Only HDL2-cholesterol, but not HDL3-cholesterol, raised; moreover, we found a significant inverse relationship between HDL-cholesterol (and also HDL2-cholesterol) and triglycerides. So, we think that an increase of lipoprotein lipase activity, owing to insulin treatment, could account for our results.     

Dietary cystine level affects metabolic rate and glycaemic control in adult mice

Plasma total cysteine (tCys) is strongly and independently associated with obesity in large human cohorts, but whether the association is causal is unknown. Dietary cyst(e)ine increases weight gain in some rodent models. We investigated the body composition, metabolic rate and metabolic phenotype of mature C3H/HeH mice assigned to low-cystine (LC) or high-cystine (HC) diets for 12 weeks.Compared to LC mice, HC mice gained more weight (P=.004 for 12-week weight gain %), with increased fat mass and lean mass, and lowered O₂ consumption and CO₂ production by calorimetry. The HC mice had 30% increase in intestinal fat/body weight % (P=.003) and ～twofold elevated hepatic triglycerides (P=.046), with increased expression of hepatic lipogenic factors, peroxisome proliferator-activated receptor-γ and sterol regulatory element binding protein-1. Gene expression of both basal and catecholamine-stimulated lipolytic enzymes, adipose triglyceride lipase and hormone-sensitive lipase was inhibited in HC mice adipose tissue. The HC mice also had elevated fasting glucose (7.0 vs. 4.5 mmol/L, P<.001) and a greater area under the curve (P<.001) in intraperitoneal glucose tolerance tests, with enhanced expression of the negative regulator of insulin signaling, protein tyrosine phosphatase-1B, in liver and adipose tissue.Overall, high cystine intake promotes adiposity and an adverse metabolic phenotype in mice, indicating that the positive association of plasma tCys with obesity in humans may be causal.     

In vitro metabolism of progestins. III. The metabolic clearance rate of medroxyprogesterone acetate in monkeys.

3H-medroxyprogesterone acetate (MPA) was synthesized by selective catalytic tritiation of the delta1-olefinic bond of 6alpha-methyl-17alpha-hydroxy-pregna-1,4-diene-3,20-dione acetate. The metabolic clearance rate of MPA (MCRMPA) was determined in 9 female Rhesus monkeys by the single injection technique. The blood MCRMPA was 201 +/- 19 L/day (42.2 +/- 4.0 L/day/kg) which was approximately the same as that reported for progesterone clearance in the monkey. We conclude that a greater biological activity of MPA compared to progesterone cannot be related to its prolonged retention in the blood. Although both MPA and amino-glutethimide alter the rate of steroid metabolism in some species, neither of these agents influences the metabolic clearance rate of 3H-MPA in the monkey.     

Bile acid sequestration reduces plasma glucose levels in db/db mice by increasing its metabolic clearance rate

Aims/Hypothesis

Bile acid sequestrants (BAS) reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels. Therefore, in vivo glucose metabolism was assessed in db/db mice on and off BAS using tracer methodology.

Methods

Lean and diabetic db/db mice were treated with 2% (wt/wt in diet) Colesevelam HCl (BAS) for 2 weeks. Parameters of in vivo glucose metabolism were assessed by infusing [U-¹³C]-glucose, [2-¹³C]-glycerol, [1-²H]-galactose and paracetamol for 6 hours, followed by mass isotopologue distribution analysis, and related to metabolic parameters as well as gene expression patterns.

Results

Compared to lean mice, db/db mice displayed an almost 3-fold lower metabolic clearance rate of glucose (p = 0.0001), a ∼300% increased glucokinase flux (p = 0.001) and a ∼200% increased total hepatic glucose production rate (p = 0.0002). BAS treatment increased glucose metabolic clearance rate by ∼37% but had no effects on glucokinase flux nor total hepatic or endogenous glucose production. Strikingly, BAS-treated db/db mice displayed reduced long-chain acylcarnitine content in skeletal muscle (p = 0.0317) but not in liver (p = 0.189). Unexpectedly, BAS treatment increased hepatic FGF21 mRNA expression 2-fold in lean mice (p = 0.030) and 3-fold in db/db mice (p = 0.002).

Conclusions/Interpretation

BAS induced plasma glucose lowering in db/db mice by increasing metabolic clearance rate of glucose in peripheral tissues, which coincided with decreased skeletal muscle long-chain acylcarnitine content.     

Feedback control of human metabolic work rate during robotics-assisted treadmill exercise

A novel approach is presented which suggests the use of human metabolic work rate to define and regulate exercise intensity during robotics-assisted treadmill training. The work describes the design and technical validation of the new method.A feedback structure is proposed which provides automatic regulation of metabolic work rate, in conjunction with an embedded feedback loop for volitional control of mechanical work rate. Human metabolic work rate was derived in real time from breath-by-breath measurements of oxygen uptake and carbon dioxide output.The results show that the feedback method provides close to nominal performance for square-wave and ramp reference tracking tasks and that good disturbance rejection properties are obtained. A collateral finding of this work is an estimate of 14.5% of the metabolic efficiency of robotics-assisted treadmill exercise.The use of feedback control of human metabolic work rate provides a direct measure of exercise intensity as perceived by the exercising human as it directly reflects the energy requirements of the working muscles. This complements previous approaches to guiding robotics-assisted treadmill training based on mechanical work rate, heart rate or oxygen uptake. The new approach based on metabolic work rate may have advantages in populations with compromised and widely varying exercise responses. This provides a new approach for driving and controlling active patient participation during robotics-assisted treadmill exercise.