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Biomedical subjects

K S Nair

Publications and source records attributed to K S Nair.

At least 19 recordsLinked to original sources
PubMed1999

Regional leptin kinetics in humans.

BACKGROUND: Leptin is known to be cleared by the kidney, a tissue with substantial leptin receptor mRNA expression; however, lung, liver, and muscle tissues also express leptin receptor messenger RNA and it is not known whether these tissues also clear leptin from the circulation. OBJECTIVE: This study was conducted to determine whether net leptin clearance takes place in the pulmonary, splanchnic, and leg tissue beds to a similar extent as in the kidney. DESIGN: Plasma leptin concentrations were measured in blood entering and exiting the renal bed, pulmonary bed, splanchnic bed, and leg in 4 groups of subjects. Regional plasma flow was measured in 3 of the 4 groups. RESULTS: Renal leptin uptake was substantial, whereas no net uptake of leptin by the splanchnic or pulmonary vascular beds was detected; leg tissue was a net leptin producer. Net leptin release by leg tissue, relative to leg adipose tissue mass, was comparable with that reported previously for abdominal subcutaneous adipose tissue. CONCLUSION: These results confirm that the kidney is a significant site of leptin clearance in humans, whereas pulmonary and splanchnic beds are not.

Absorptiometry, Photon↗
PubMed1999

Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization.

To investigate the underlying molecular mechanisms for surgery-induced insulin resistance in skeletal muscle, six otherwise healthy patients undergoing total hip replacement were studied before, during, and after surgery. Patients were studied under basal conditions and during physiological hyperinsulinemia (60 microU/ml). Biopsies of vastus lateralis muscle were used to measure GLUT-4 translocation, glucose transport, and glycogen synthase activities. Surgery reduced insulin-stimulated glucose disposal (P < 0.05) without altering the insulin-stimulated increase in glucose oxidation or suppression of endogenous glucose production. Preoperatively, insulin infusion increased plasma membrane GLUT-4 in all six subjects (P < 0.05), whereas insulin-stimulated GLUT-4 translocation only occurred in three patients postoperatively (not significant). Moreover, nonoxidative glucose disposal rates and basal levels of glycogen synthase activities in muscle were reduced postoperatively (P < 0.05). These findings demonstrate that peripheral insulin resistance develops immediately postoperatively and that this condition might be associated with perturbations in insulin-stimulated GLUT-4 translocation as well as nonoxidative glucose disposal, presumably at the level of glycogen synthesis.

Arthroplasty, Replacement, Hip↗
PubMed1999

Whole body protein kinetics using Phe and Tyr tracers: an evaluation of the accuracy of approximated flux values.

Phenylalanine (Phe) kinetics are increasingly used in studies of amino acid kinetics, because the metabolic fate of Phe is limited to incorporation into protein (protein synthesis, Sp) and catabolism via hydroxylation (Qpt) to tyrosine (Tyr). Besides an infusion of labeled Phe to measure Phe flux (Qp), a priming dose of Tyr and an independent Tyr tracer are used to measure Tyr flux (Qt) and Qpt. Alternatively, Qt, Qpt, and Sp can be approximated by using equations, based on Phe and Tyr concentrations in body proteins, that eliminate the need for a Tyr tracer. To evaluate the accuracy of this approach, data were obtained from 12 type I diabetic patients and 24 nondiabetic control subjects who were studied with the full complement of tracers both with and without insulin infusion. Sp approximations closely matched measured values in both groups (mean difference <2%, all values <5%), but the agreement was poor for Qpt (error range = -8 to +43%) and Qt (error range -22 to +41%). Insulin status had no effect on these comparisons. The lower approximation error for Sp vs. Qpt is due to the small contribution ( approximately 10%) of Qpt to Qp. Approximation error for Qpt (r > 0.99) can be explained by variability in the ratio of Tyr to Phe coming from protein breakdown, (Qt - Qpt)/Qp. Ideally, all fluxes should be directly measured, but these data suggest that whole body Sp can be approximated with an acceptably small margin of error. However, the same equations do not yield reliably accurate values for Qpt or Qt.

Adult↗
PubMed1999

Insulin regulation of regional free fatty acid metabolism.

Studies were conducted to determine whether regional free fatty acid (FFA) release is differentially regulated by insulin. Systemic, leg, and splanchnic palmitate rate of appearance ([9,10-(3)H]palmitate) was measured in 26 healthy adults using the euglycemic-hyperinsulinemic clamp technique to achieve a physiological range of plasma insulin concentrations. We found that insulin inhibited systemic, leg, and splanchnic palmitate release in a dose-dependent fashion over the range of insulin infused (0-1.0 mU x kg(-1) x min(-1)). Progressive hyperinsulinemia changed the leg from a net producer to a net FFA consumer, whereas the splanchnic bed converted from a net FFA consumer to a net producer. At the 0.5 mU x kg(-1) x min(-1) insulin infusion rate, leg FFA release was almost completely suppressed, whereas even with the 1.0 mU x kg(-1) x min(-1) insulin infusion rate, splanchnic FFA release decreased by only approximately 65% (P < 0.05 leg vs. splanchnic). These results demonstrate the regional heterogeneity of insulin-regulated FFA release in vivo, and indicate that visceral adipose tissue lipolysis is more resistant to insulin suppression than is leg lipolysis in humans.

Adult↗
PubMed1998

Preoperative oral carbohydrate administration reduces postoperative insulin resistance.

UNLABELLED: Infusions of carbohydrates before surgery reduce postoperative insulin resistance. We in-vestigated the effects of a carbohydrate drink, given shortly before surgery, on postoperative metabolism. METHOD: Insulin sensitivity, glucose turnover ([6,6, 2H2]-D-glucose) and substrate utilization were measured using hyperinsulinemic normoglycemic clamps and indirect calorimetry in two matched groups of patients before and after elective colorectal surgery. The drink group (n = 7) received 800 ml of an isoosmolar carbohydrate rich beverage the evening before the operation (100 g carbohydrates), as well as another 400 ml (50 g carbohydrates) 2 h before the initiation of anesthesia. The fasted group (n = 7) was operated after an overnight fast. RESULTS: After surgery, energy expenditure increased in both groups. Endogenous glucose production was higher after surgery and the difference was significant during low insulin infusion rates in both groups (P < 0.05). The supressibility of endogenous glucose production by the two step insulin infusion was similar pre-and postoperatively in both groups. At the high insulin infusion rate postoperatively, whole body glucose disposal was more reduced in the fasted group (-49 +/- 6% vs -26 +/- 8%, P < 0.05 vs drink). Furthermore, during high insulin infusion rates, glucose oxidation decreased postoperatively only in the fasted group (P < 0. 05) and postoperative levels of fat oxidation were greater in the fasted group (P < 0.05 vs drink). Only minor postoperative changes in cortisol and glucagon were found and no differences were found between the treatment groups. CONCLUSIONS: Patients given a carbohydrate drink shortly before elective colorectal surgery displayed less reduced insulin sensitivity after surgery as compared to patients who were operated after an overnight fast.

Adolescent↗
PubMed1998

Is there a case for DHEA replacement?

There are many hormonal changes that occur with ageing in humans, of which the most dramatic and intriguing change occurs for the adrenal androgenic steroid dehydroepiandosterone (DHEA). There are tantalizing epidemiological data demonstrating a significant association between the changes in circulating DHEA level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's disease and other age-related changes. The pharmacological effects in animals such as rodents and rabbits have demonstrated many beneficial effects, for example increased immune function, the prevention of atherosclerosis, cancer, diabetes and obesity, and the improvement of memory. Clinical studies carried out in small groups of subjects have clearly demonstrated that the administration of DHEA to the elderly increases many hormone levels, including that of insulin-like growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and oestradiol. It remains to be clearly defined whether these changes are clinically beneficial, and there is only insufficient information on the side-effects on long-term use. Results from short-term intervention studies in small groups of subjects have not demonstrated any convincing beneficial effects so far. A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term DHEA replacement in elderly people.

Adult↗
PubMed1998

Protein metabolism in insulin-dependent diabetes mellitus.

Patients with insulin-dependent diabetes are in a catabolic state without insulin replacement. The mechanism of insulin's anticatabolic effect has been investigated in whole-body and regional tracer kinetic studies. Whole-body studies have demonstrated that there are increases in both protein breakdown and protein synthesis during insulin deprivation. Because the magnitude of the increase in protein breakdown is greater than the magnitude of the increase in protein synthesis, there is a net protein loss during insulin deprivation. Regional studies have shown that insulin replacement inhibits protein breakdown and synthesis in splanchnic tissue but only inhibits protein breakdown in skeletal muscle. Because the increase in protein synthesis in splanchnic tissues is greater than the increase in protein breakdown, insulin deprivation results in a net accretion of protein in the splanchnic bed. In contrast, in skeletal muscle, there is a net increase in protein breakdown during insulin deprivation, resulting in a net release of amino acids. There are no human data concerning the site of protein accretion in the splanchnic bed or the specific protein whose synthesis is increased during insulin deprivation. It appears that insulin exerts its overall anticatabolic effect in insulin-dependent diabetes mainly through the inhibition of muscle protein breakdown.

Diabetes Mellitus, Type 1↗
PubMed1998

Age-related sarcopenia in humans is associated with reduced synthetic rates of specific muscle proteins.

Sarcopenia of aging is not explained entirely on the basis of age-associated reduced physical activity. Progressive neuromuscular changes and diminishing anabolic hormone levels are thought to contribute to the pathogenesis of sarcopenia. Decline in muscle mass indicates a decline in muscle protein content. Recent studies demonstrated an age-related decline in synthesis rate of mixed muscle proteins, myosin heavy chain and mitochondrial protein. Reductions in myosin heavy chain and mitochondrial protein synthesis rates have been correlated with age-associated decrements in muscle strength and aerobic exercise tolerance, respectively. These changes have been reported as early as 50 y of age and are related to the decline in insulin-like growth factor (IGF)-I, testosterone and dehydroepiandrosterone (DHEA)-sulfate. The declining ability to remodel these important muscle proteins may therefore play a role in the development of muscle wasting, metabolic abnormalities and impaired physical functioning seen in old age.

Aging↗
PubMed1998

Reproducibility and simplification of 13C-octanoic acid breath test for gastric emptying of solids.

OBJECTIVE: The accuracy of the 13C-octanoic acid breath test is enhanced by breath sampling over 6 h rather than 4 h, but this increases the cost of the test. Our aim was to validate a less costly but accurate sequence of breath sampling for measuring gastric emptying of solids. METHODS: We performed the 13C-octanoic acid breath test and tested its reproducibility relative to simultaneous scintigraphy in 30 healthy volunteers. RESULTS: There was a significant but weak correlation between t1/2 measured by the two tests (rs = 0.54, p < 0.005), but not between the duration of the lag phase. The differences in the t1/2 measurements between the tests were different between subjects but were highly reproducible within subjects. Within- and between-subject variations of measurements of gastric emptying with the 13C-octanoic acid breath test were not significantly different from the variations observed with scintigraphy. A subset of 11 breath samples collected over 6 h (24 samples) predicted (r2 > 0.95) the variables characterizing the cumulative appearance of 13CO2 in breath; these samples were at 35, 50, 95, 110, 140, 155, 215, 245, 260, 290, and 335 min. The accuracy of this subset of sampling times was confirmed in a separate set of breath test samples over 6 h from the same 30 subjects. CONCLUSIONS: The 13C-octanoic acid breath test for gastric emptying of solids is as reproducible as scintigraphy. A subset of 11 sampling times provides sufficient information to characterize the whole breath-test curve, but the sampling period should be extended to 6 h after dosing.

Adolescent↗
PubMed1998

Measurement of dermal collagen synthesis rate in vivo in humans.

Accumulation of collagen produces organ dysfunction in many pathological conditions. We measured the fractional synthesis rate (FSR) of dermal collagen in five human volunteers from the increment of [13C]proline in detergent-soluble dermal collagen hydroxylated to hydroxyproline during a continuous infusion of L-[1-13C]proline. In these and eight other volunteers, we measured [13C]proline enrichment in skin aminoacyl-tRNA, skin tissue fluid amino acid, and plasma. The prolyl-[13C]tRNA enrichment was one-half that in tissue fluid proline and more than threefold less than in plasma. The FSR of dermal collagen was 0.076 +/- 0.063%/h (mean +/- SD), similar to previously reported rates for skeletal muscle contractile proteins and substantially slower than hepatically derived circulating proteins such as albumin or fibrinogen. We conclude that the FSR of human dermal collagen resembles that of other human proteins considered to display slow turnover. The current method for its measurement may be used to determine the regulation of collagen synthesis in other organs and disease states.

Collagen↗
PubMed1998

Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery.

Elective surgery was performed after overnight fasting, a routine that may affect the metabolic response to surgery. We investigated the effects of insulin and glucose infusions before and during surgery on postoperative substrate utilization and insulin sensitivity. Seven patients were given insulin and glucose infusions 3 h before and during surgery (insulin group), and a control group of six patients underwent surgery after fasting overnight. Insulin sensitivity and glucose kinetics (D-[6,6-2H2]glucose) were measured before and immediately after surgery using a hyperinsulinemic, normoglycemic clamp. Glucose infusion rates and whole body glucose disposal decreased after surgery in the control group (-40 and -29%, respectively), whereas no significant change was found in the insulin group (+16 and +25%). Endogenous glucose production remained unchanged in both groups. Postoperative changes in cortisol, glucagon, fat oxidation, and free fatty acids were attenuated in the insulin group (vs. control). We conclude that perioperative insulin and glucose infusions minimize the endocrine stress response and normalize postoperative insulin sensitivity and substrate utilization.

Arthroplasty, Replacement, Hip↗
PubMed1998

Age effect on fibrinogen and albumin synthesis in humans.

A strong association has been reported between atherosclerotic diseases and fibrinogen levels, and a decreased whole body protein synthesis has also been reported with aging. We investigated the effect of age on fractional synthesis rates (FSR) of fibrinogen and albumin in 12 human subjects of young (20-30 yr), middle (45-60 yr), and old (65-79 yr) age by use of L-[1-13C]leucine and L-[15N]phenylalanine as tracers. An age-related decline in FSR of fibrinogen (P < 0.01) was observed with use of both tracers, with the maximal decrease (average 37% with alpha-[13C]ketoisocaproate as the precursor) occurring by middle age and with no further changes thereafter. In contrast, plasma concentrations of fibrinogen increased with age (P < 0.002). There was no age-related change in synthesis rate and concentrations of albumin. An age-related decline in fibrinogen FSR, but not FSR of albumin, indicates a differential effect of age on synthesis rate of these two liver proteins. This study also demonstrated that the increased circulating levels of fibrinogen represent a slower rate of disposal of fibrinogen rather than an increased production rate.

Adult↗
PubMed1998

Disruption of the relationship between fat content and leptin levels with aging in humans.

Leptin released from adipose tissue is believed to participate in a negative feedback loop regulating appetite, and malfunction of this mechanism could lead to obesity. We measured plasma leptin and body composition (dual energy x-ray absorptiometry) in 70 healthy subjects, divided into 3 age groups (young, 25 +/- 1 yr; middle-aged, 53 +/- 1 yr; old, 70 +/- 1 yr), while on a 5-day weight-maintaining diet. Pairwise correlations were assessed using product-moment correlation, and regression analysis was used to evaluate relationships between leptin and other variables. Leptin concentrations and relative body fat content were correlated in young females (r = 0.71; P = 0.009) and in young males (r = 0.76; P = 0.007), but not in the combined middle-aged and elderly groups (r = 0.19; P = 0.36 and r = 0.19; P = 0.38 in females and males, respectively). Regression analysis showed a clear correlation between circulating leptin and relative fat mass in the young subjects (P = 0.0001), but not in the older subjects (P = 0.199). We conclude that body fat content in young subjects correlates with plasma leptin in both genders, whereas this relationship is disrupted in elderly subjects, thus possibly contributing to the obesity occurring with age.

Absorptiometry, Photon↗
PubMed1998

Role of hyperglucagonemia in catabolism associated with type 1 diabetes: effects on leucine metabolism and the resting metabolic rate.

The catabolic state of poorly controlled type 1 diabetes has largely been attributed to insulin deficiency. However, the role of hyperglucagonemia, which occurs concomitantly with insulin deficiency, has not been fully investigated. We studied the effects of hyperglucagonemia during insulin deprivation on energy expenditure (using indirect calorimetry) and protein metabolism (using L-[1-(13)C,15N]leucine and L-[1-(13)C]leucine as tracers) in 12 type 1 diabetic subjects. Five protocols were used: insulin treatment, insulin deprivation, insulin deprivation with suppression of endogenous glucagon with somatostatin (SRIH) and growth hormone replacement, insulin deprivation with endogenous glucagon suppression with SRIH (no growth hormone replacement), and insulin deprivation with SRIH and a high level of glucagon replacement (no growth hormone replacement). It was observed that leucine oxidation and the resting metabolic rate (RMR) were significantly lower during insulin treatment and insulin deprivation with concomitant SRIH infusion (lowering glucagon) than during insulin deprivation alone. Replacement of glucagon at a high level during SRIH infusion in the insulin-deprived state increased leucine oxidation and the RMR. Hyperglucagonemia was also associated with a trend for decreased protein synthesis. Hyperglucagonemia did not affect leucine transamination. Insulin replacement decreased leucine flux and oxidation. Leucine oxidation (R2 = 0.79) and the RMR (R2 = 0.81) were seen, by multiple regression analysis, to correlate with glucagon levels and not with other hormones. We conclude that while insulin deficiency increases protein breakdown, hyperglucagonemia is primarily responsible for the increased leucine oxidation and RMR seen during insulin deprivation.

Adult↗
PubMed1998

Differential regulation of amino acid exchange and protein dynamics across splanchnic and skeletal muscle beds by insulin in healthy human subjects.

To define the mechanism of insulin's anticatabolic action, the effects of three different dosages of insulin (0.25, 0.5, and 1.0 mU x kg(-1) x min(-1)) versus saline on protein dynamics across splanchnic and skeletal muscle (leg) beds were determined using stable isotopes of phenylalanine, tyrosine, and leucine in 24 healthy subjects. After an overnight fast, protein breakdown in muscle exceeded protein synthesis, causing a net release of amino acids from muscle bed, while in the splanchnic bed protein synthesis exceeded protein breakdown, resulting in a net uptake of these amino acids. Insulin decreased (P < 0.003) muscle protein breakdown in a dose-dependent manner with no effect on muscle protein synthesis, thus decreasing the net amino acid release from the muscle bed. In contrast, insulin decreased protein synthesis (P < 0.03) in the splanchnic region with no effect on protein breakdown, thereby decreasing the net uptake of the amino acids. In addition, insulin also decreased (P < 0.001) leucine nitrogen flux substantially more than leucine carbon flux, indicating increased leucine transamination (an important biochemical process for nitrogen transfer between amino acids and across the organs), in a dose-dependent manner, with the magnitude of effect being greater on skeletal muscle than on the splanchnic bed. In conclusion, muscle is in a catabolic state in human subjects after an overnight fast and provides amino acids for synthesis of essential proteins in the splanchnic bed. Insulin achieves amino acid balance across splanchnic and skeletal muscle beds through its differential effects on protein dynamics in these tissue beds.

Adult↗
PubMed1997

Sequential purification of human apolipoprotein B-100, albumin, and fibrinogen by immunoaffinity chromatography for measurement of protein synthesis.

A determinant of the accuracy of protein synthesis measurement using stable isotope is the purity of the protein under study. An Immunoaffinity chromatographic technique to sequentially purify human plasma albumin, fibrinogen, and apolipoprotein B-100 (ApoB-100) was developed to measure isotopic enrichment in these proteins. The technique, utilizing immobilized mouse monoclonal antibodies specific to human plasma ApoB-100, albumin, and fibrinogen onto an affinity matrix, allowed purification of very low density lipoprotein (VLDL) ApoB-100, albumin, and fibrinogen from 1- to 2-ml plasma samples. Analytical sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining demonstrated consistent purity of the three purified proteins. The identity and the purity of the proteins separated by this technique were also confirmed by amino acid sequence analysis. This technique was applied to sequentially purify and measure the isotopic enrichment in those proteins by mass spectrometry from human plasma samples collected after orally ingesting L[1-13C]-leucine. Reproducibility of the enrichment measurements is within 5% of the coefficient of variation. Measurements [13C]leucine in these proteins purified from plasma samples collected during a 10-h primed continuous intravenous infusion of L-[1-13C]leucine confirmed that this technique provides an efficient way to purify plasma VLDL ApoB-100, albumin, and fibrinogen for measuring their synthetic rates in human metabolism studies.

Animals↗
PubMed1997

[13C]octanoic acid breath test for gastric emptying of solids: accuracy, reproducibility, and comparison with scintigraphy.

BACKGROUND & AIMS: Previous work suggested that a breath test using 13C accurately measures gastric emptying of solids. Thus, breath test half emptying time (t1/2) minus 66 minutes was claimed to estimate accurately t1/2 by scintigraphy. The aim of this study was to evaluate the accuracy and reproducibility of this breath test in healthy subjects. METHODS: Fifteen volunteers (8 men and 7 women; mean age, 41 +/- 13 years) underwent simultaneous scintigraphy and [13C]octanoic acid breath test. Scans and breath samples were obtained every 15 minutes for 4 and 6 hours, respectively. The breath test was repeated three times within a 3-week period. RESULTS: Parameters from scintigraphy and breath test were not correlated significantly. Differences of lag phase and t1/2 between the two tests were highly variable (range for t1/2, -33.1 to 169.6; mean, 48.0 minutes). Increasing breath test "duration" (samples over 4, 5, or 6 hours) yielded decreasing estimates of the lag phase and t1/2. Although widely different values were observed in some subjects, repeated breath tests showed a high degree of reproducibility within individuals (mean coefficient of variation, 12%). CONCLUSIONS: [13C]Octanoic acid breath test for gastric emptying of solids requires further validation before it can substitute for scintigraphy as a diagnostic test, but it seems useful for intraindividual comparisons.

Adult↗