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Biomedical subjects

S C Kalhan

Publications and source records attributed to S C Kalhan.

At least 19 recordsLinked to original sources
PubMed2001

Glyceroneogenesis and the source of glycerol for hepatic triacylglycerol synthesis in humans.

Glyceroneogenesis, i.e. the synthesis of the glycerol moiety of triacylglycerol from pyruvate, has been suggested to be quantitatively important in both the liver and adipose tissue during fasting. However, the actual contribution of glyceroneogenesis to triacylglycerol synthesis has not been quantified in vivo in human studies. In the present study we have measured the contribution of glycerol and pyruvate to in vivo synthesis of hepatic triacylglycerol in nonpregnant and pregnant women after an overnight fast. Five nonpregnant women were administered [(13)C(3)]glycerol tracer as prime constant rate infusion, and the appearance of tracer in plasma glucose and triacylglycerol was quantified using gas chromatography-mass spectrometry. The contribution of pyruvate to hepatic triacylglycerol was quantified in nonpregnant and pregnant women using the deuterium labeling of body water method. The appearance of [(2)H] in hydrogens on C(1) and C(3) of triacylglycerol was measured following periodate oxidation of the glycerol isolated from hydrolyzed triacylglycerol. After a 16-h fast, approximately 6.1% of the plasma triacylglycerol pool was derived from plasma glycerol, whereas 10 to 60% was derived from pyruvate in nonpregnant women and pregnant women early in gestation. Our data suggest that glyceroneogenesis from pyruvate is quantitatively a major contributor to plasma triacylglycerol synthesis and may be important for the regulation of very low density lipoprotein triacylglycerol production. Our data also suggest that 3-glycerol phosphate is in rapid equilibrium with the triosephosphate pool, resulting in rapid labeling of the triose pool by the administered tracer glycerol. Because the rate of flux of triosephosphate to glucose during fasting far exceeds that to triacylglycerol, more glycerol ends up in glucose than in triacylglycerol. Alternatively, there may be two distinct pools of 3-glycerol phosphate in the liver, one involved in generating triosephosphate from glycerol and the other involved in glyceride-glycerol synthesis.

Blood Glucose↗
PubMed2001

Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States.

South Asians who immigrate to the United States have a propensity toward insulin resistance, central obesity, and elevated total cholesterol:high-density lipoprotein (HDL) ratio. To evaluate whether these alterations are apparent at a younger age, we studied 32 offspring of South Asian immigrants and compared them with 29 of European descent between 18 to 30 years of age. American-born South Asian males had significantly higher total cholesterol, low-density lipoprotein (TC:LDL) ratios, triglycerides, and fasting insulin levels (13.9 +/- 7.1 and 10.0 +/- 5.5 microU/mL, P <.01) than their European counterparts. The South Asian females only had increased plasma insulin levels (15.3 +/- 8.8 and 10.0 +/- 5.1 microU/mL, P =.05). The entire South Asian group had higher truncal skinfold thickness (40.1 +/- 18.1 and 30.3 +/- 12.6 mm, P = <.05) and lower insulin-like growth factor binding protein (IGFBP)-1 levels (46.8 +/- 33.4 and 56.0 +/- 33.4 microg/L, P =.05). Plasma leptin levels were also significantly higher in both males (4.3 +/- 2.5 v 2.8 +/- 1.3 ng/mL, P =.0001) and females (20.5 +/- 10.3 v 10.3 +/- 6.3 ng/mL, P =.002) South Asian subjects. A significant correlation between plasma leptin and insulin, triglycerides, TC, and body mass index (BMI) was seen in the South Asian males. South Asians born in the United States show evidence for an altered metabolic profile in young adulthood. The relative contributions of inheritance and nutritional practices early in life to this alteration remain unclear.

Adolescent↗
PubMed2001

Relationship between leucine oxidation and oxygen consumption during steady-state exercise.

PURPOSE: The purpose of this study was to assess the relationship between whole-body leucine oxidation and oxygen consumption during steady-state exercise. Our hypothesis was that leucine oxidation will be responsive to increased whole-body energy needs. METHODS: Sixteen healthy individuals (7 women and 9 men) were infused with a stable isotope of leucine and, for comparison purposes, lysine during 60 min of moderate-intensity exercise. RESULTS: Leucine oxidation was increased (P < 0.05) and nonoxidative leucine disposal was decreased (P < 0.05), whereas leucine and lysine rate of appearance remained unchanged (P = NS) during exercise. Linear regression analysis indicated a modest relationship between leucine oxidation and steady-state oxygen consumption (R = 0.69; P < 0.003) during steady-state exercise. The coefficient of determination (R(2) = 0.49) indicates that approximately half of the variance in whole-body leucine oxidation during exercise can be explained by whole-body oxygen consumption. CONCLUSION: In a statistically appropriate sample size of humans whose dietary intake was controlled, the whole-body rate of leucine oxidation during exercise was only partially influenced by energy demands.

Adult↗
PubMed2001

Estimation of gluconeogenesis in newborn infants.

The rate of glucose turnover (R(a)) and gluconeogenesis (GNG) via pyruvate were quantified in seven full-term healthy babies between 24 and 48 h after birth and in twelve low-birth-weight infants on days 3 and 4 by use of [(13)C(6)]glucose and (2)H(2)O. The preterm babies were receiving parenteral alimentation of either glucose or glucose plus amino acid with or without lipids. The contribution of GNG to glucose production was measured by the appearance of (2)H on C-6 of glucose. Glucose R(a) in full-term babies was 30 +/- 1.7 (SD) micromol. kg(-1). min(-1). GNG via pyruvate contributed approximately 31% to glucose R(a). In preterm babies, the contribution of GNG to endogenous glucose R(a) was variable (range 6-60%). The highest contribution was in infants receiving low rates of exogenous glucose infusion. In an additional group of infants of normal and diabetic mothers, lactate turnover and its incorporation into glucose were measured within 4-24 h of birth by use of [(13)C(3)]lactate tracer. The rate of lactate turnover was 38 micromol. kg(-1). min(-1), and lactate C, not corrected for loss of tracer in the tricarboxylic acid cycle, contributed approximately 18% to glucose C. Lactate and glucose kinetics were similar in infants that were small for their gestational age and in normal infants or infants of diabetic mothers. These data show that gluconeogenesis is evident soon after birth in the newborn infant and that, even after a brief fast (5 h), GNG via pyruvate makes a significant contribution to glucose production in healthy full-term infants. These data may have important implications for the nutritional support of the healthy and sick newborn infant.

Amino Acids↗
PubMed2001

Gender differences in leucine, but not lysine, kinetics.

There is a controversy in the literature as to the effects of gender on leucine kinetics. Two research groups found that men oxidize more leucine during exercise, whereas another group showed no gender effects. The purpose of our study was to examine the effects of gender on leucine and, for comparison purposes, lysine kinetics. Our subjects (n = 14) were seven matched pairs of men and women selected for their exercise habits and age. After 1 wk of a standardized diet, they exercised at 50% of maximal O(2) uptake for 1 h. There was an effect of exercise in both genders: an increased leucine oxidation and an attenuation in nonoxidative leucine disposal compared with rest (P < 0.05). Furthermore, our study confirms that there are gender differences in leucine, but not lysine, kinetics. Men had a higher rate of leucine oxidation and a lower rate of nonoxidative leucine disposal during exercise (P < 0.05). For women, a larger proportion of their exercise energy needs came from fat; for men, a greater fraction came from carbohydrate (P < 0.05). We conclude that female exercisers rely to a greater extent on fat as an energy source, thereby using less carbohydrate, amino acid, and protein as a fuel source.

Adult↗
PubMed2001

Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus.

OBJECTIVE: We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS(OGTT)) or fasting glucose/insulin levels (IS(QUICKI) and IS(HOMA)) can be used to predict insulin sensitivity in women before and during pregnancy. RESEARCH DESIGN AND METHODS: A 2-h euglycemic-hyperinsulinemic clamp (5 mmol/l glucose, 40 mU. m(-2). min(-1) insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34-36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS(CLAMP)) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6(-2)H(2)]glucose. RESULTS: Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS(CLAMP) and IS(OGTT) (r(2) = 0.74, P < 0.0001), IS(QUICKI) (r(2) = 0.64, P < 0.0001), and IS(HOMA) (r(2) = 0.53, P < 0.0001). The IS(OGTT) provided a significantly better correlation (P < 0.0001) than either IS(QUICKI) or IS(HOMA.) Multivariate analysis showed a significant group effect (P < 0.0003) on the prediction model, and separate equations were developed for the NGT (r(2) = 0.64, P < 0.0001) and GDM (r(2) = 0.85, P < 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS(CLAMP) and IS(OGTT) pregravid was r(2) = 0.63 (P = 0.0002), during early pregnancy was r(2) = 0.80 (P < 0.0001), and during late pregnancy was r(2) = 0.64 (P = 0.0002). CONCLUSIONS: Estimates of insulin sensitivity from the IS(OGTT) during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM.

Analysis of Variance↗
PubMed2000

Protein metabolism in the extremely low-birth weight infant.

Although extensive data are available on the impact of nutrient and protein administration on growth, plasma amino acids, and nitrogen balance in the newborn and growing infants, relatively few studies have carefully examined the dynamic aspects of protein metabolism in vivo and particularly in the micropremie or ELBW infant. These studies show that the very preterm infants, either because of immaturity or because of the intercurrent illness, have high rates of protein turnover and protein breakdown. This high rate of proteolysis is not as responsive to nutrient administration. Intervention strategies aimed at promoting nitrogen accretion, such as insulin, human growth hormone, or glutamine, have not thus far resulted in enhanced protein accretion and growth. This may be, in part, due to limitations in delivery of adequate calorie and nitrogen.

Energy Metabolism↗
PubMed2000

Protein metabolism in pregnancy.

Adaptation to pregnancy involves major changes in maternal metabolism to provide for the growing demands of the conceptus. Although changes in glucose metabolism, and possibly in fatty acid metabolism, occur in parallel with the increasing energy demands of the mother and the fetus, adaptation of protein metabolism appears to be in anticipation of maternal and fetal needs. During pregnancy, there is an excess of maternal nitrogen in the form of lean body mass over that deposited in the fetus and the products of conception; there is also a pregnancy-induced hypoaminoacidemia and a diminished amino acid response to protein intake, suggesting an increased uptake of amino acids in the splanchnic compartment. With the use of stable-isotope-labeled tracers, it was shown that there is a decreased rate of urea synthesis during pregnancy that is evident early in gestation. Kinetic studies of leucine metabolism showed no significant change in leucine carbon turnover but a significantly lower rate of leucine nitrogen turnover, suggesting a lower rate of leucine transamination. These data suggest an integral regulation of whole-body protein and nitrogen metabolism starting early in gestation and aimed at conservation and accretion of nitrogen by the mother and the fetus.

Adaptation, Physiological↗
PubMed2000

Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds.

The definition of clinically significant hypoglycemia remains one of the most confused and contentious issues in contemporary neonatology. In this article, some of the reasons for these contentions are discussed. Pragmatic recommendations for operational thresholds, ie, blood glucose levels at which clinical interventions should be considered, are offered in light of current knowledge to aid health care providers in neonatal medicine. Future areas of research to resolve some of these issues are also presented.

Adaptation, Physiological↗
PubMed1999

Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus.

OBJECTIVE: This study prospectively evaluated the longitudinal changes in insulin sensitivity, insulin response, and endogenous (primarily hepatic) glucose production and suppression during insulin infusion in women with normal glucose tolerance (control) and gestational diabetes mellitus before and during a planned pregnancy. STUDY DESIGN: Eight control subjects and 7 subjects in whom gestational diabetes mellitus developed were evaluated with an oral glucose tolerance test, an intravenous glucose tolerance test, and hyperinsulinemic-euglycemic clamp with infusion of [6,6 (2)H2 ]glucose before conception and at 12 to 14 and 34 to 36 weeks' gestation. Insulin response was estimated as the area under the curve during the intravenous glucose tolerance test. Basal endogenous glucose production was estimated from isotope tracer dilution during steady state with [6,6 (2)H2 ]glucose and suppression during insulin infusion. Insulin sensitivity to glucose was defined as the glucose infusion rate required to maintain euglycemia during steady-state insulin infusion. Body composition was estimated with hydrodensitometry. Data were analyzed with 2-way analysis of variance with repeated measures for 2 groups. RESULTS: There were increases in first-phase (P =.006) and second-phase (P =. 0001) insulin responses in both groups with advancing gestation, but the increase in second-phase response was significantly greater (P =. 02) in the gestational diabetes mellitus group than in the control group. Basal glucose production increased significantly (P =.0001) with advancing gestation, and there was resistance to suppression during insulin infusion in both groups (P =.0001). There was less suppression of endogenous glucose production however, in the gestational diabetes mellitus group than in the control group (P =. 01). Insulin sensitivity decreased with advancing gestation in both groups (P =.0001), and there was lower insulin sensitivity in the gestational diabetes mellitus group than in the control group (P =. 04). Significant decreases in insulin sensitivity with time (P =. 0001) and between groups (P =.03) remained when the data were adjusted for differences in insulin concentration or residual hepatic glucose production. CONCLUSION: Obese women in whom gestational diabetes mellitus develops have a significant increase in insulin response but decreases in insulin sensitivity and suppression of hepatic glucose production during insulin infusion with advancing gestation with respect to a matched control group. These metabolic abnormalities in glucose metabolism are the hallmarks of type 2 diabetes, for which these women are at increased risk in later life.

Adult↗
PubMed1999

Effect of reduced inspired oxygen on fetal growth and maternal glucose metabolism in rat pregnancy.

The effect of prolonged exposure to a reduced fraction of inspired oxygen ([FiO2] 0.17 for 3 days) on maternal glucose kinetics, placental glucose transporters GLUT1 and GLUT3, and fetal growth was examined in rat pregnancy. Arterial and venous catheters were placed 3 days before the study. [3-(3)H]glucose tracer and deuterium labeling of water were used to measure the rates of glucose turnover and gluconeogenesis (GNG), respectively. Glucose uptake by maternal tissues was measured using [14C]2-deoxyglucose. Exposure to a reduced FiO2 resulted in a significant decrease (mean +/- SE) in fetal weight (room air, 4.02 +/- 0.04 g; 0.17 FiO2, 3.27 +/- 0.6 g, P < .02). There was a significant increase in the maternal-fetal glucose gradient (maternal-fetal glucose ratio: room air, 1.48 +/- 0.11; 0.17 FiO2, 2.26 +/- 0.24, P < .05), but there was no change in the maternal or fetal blood lactate concentration. No significant change in maternal blood pH was observed; however, a significant decrease in the blood partial pressure of O2 (PO2) occurred (room air, 97 +/- 0.5 torr; 0.17 FiO2, 81 +/- 1.8) on day 3. There was no change in the rate of turnover of glucose or GNG in the maternal compartment, nor was there any effect on glucose uptake by the maternal tissues. Placental GLUT1 and GLUT3 mRNA were not different in the control or experimental animals. We conclude that a mild reduction in the FiO2 for 3 days in rat pregnancy results in a significant fetal growth restriction that is not related to any observed alteration in maternal glucose metabolism. The lower glucose concentration in the fetal blood may be the consequence of an increase in fetal glucose metabolism, thereby resulting in an increased maternal-fetal gradient of glucose.

Animals↗
PubMed1999

A model analysis of lactate accumulation during muscle ischemia.

PURPOSE: The mechanistic basis of the relationship between tissue [O2] and tissue or blood lactate (LA) concentration during tissue hypoxia are not fully understood. However, blood and tissue lactate accumulation are still used as indicators of tissue hypoxia in critically ill patients. To investigate this relationship, we applied a previously developed mathematical model of human bioenergetics to simulate the integrated responses (cellular, tissue, and whole body) to moderate (10% to 45%) and severe (50% to 80%) reductions in muscle blood flow. MATERIALS AND METHODS: Model simulations of muscle ischemia predicted metabolite concentration changes in muscle, splanchnic bed, and other tissues, and were compared with experimental data in humans for model validation. RESULTS: In general, simulations closely predicted the pattern of change in substrates and control metabolites to that observed experimentally. Specifically, simulations showed that most of the increase in muscle LA production during moderate ischemia was due to an increase in pyruvate (PY) and notto the change in redox state induced by a small decrease in O2 consumption. However, during severe ischemia, changes in [LA]/[PY] ratio in venous blood corresponded very closely to changes in tissue redox state. Because both blood [LA] and [LA]/[PY] tracked changes in tissue redox state very well, these can be used reliably as indices of tissue hypoxia during severe muscle ischemia. CONCLUSIONS: Based on the simulations, the commonly used threshold value for venous [LA]/[PY] = 14 as evidence of tissue hypoxia seems appropriate during severe ischemia.

Computer Simulation↗
PubMed1999

Carbohydrate as nutrient in the infant and child: range of acceptable intake.

Carbohydrates are the major source of energy for humans. Following their digestion, almost all ingested carbohydrates are converted to glucose. Glucose is the primary oxidative fuel for the brain. Although few studies have been done in infants and children to define the upper and lower limits of carbohydrate intake, such information may be derived from the published data on glucose metabolism in vivo. The upper and lower limits are determined by the need to provide for total energy expenditure, need for other essential nutrients such as protein and fats, requirements of the glucose dependent tissues such as the brain, and the need to minimize the protein cost of gluconeogenesis and thus irreversible loss of nitrogen. With these considerations, the upper and lower boundaries of carbohydrate intake in relation to age are described.

Body Weight↗
PubMed1999

Pregnancy, insulin resistance and nitrogen accretion.

Metabolic adaptation to pregnancy in humans and animals is aimed at provision of nutrients for the growth and energy metabolism of the growing conceptus, as well as for the mother. Kinetic studies in human pregnancy have shown that fluxes of energy-yielding substrates, i.e. glucose, fatty acids and glycerol, increase in parallel with the increasing demands of the fetus and the mother. Resistance to insulin action, measured by hyperinsulinemic euglycemic clamp, appears early in gestation and is correlated with the infant's birth weight. Adaptive responses in nitrogen metabolism, decreased plasma urea concentration and decreased rate of urea synthesis, are apparent early in pregnancy, much before any significant increase in fetal demands. Recent studies of branched chain aminoacid (leucine) kinetics show a lower flux of leucine nitrogen and an unchanged flux of leucine carbon in gestation. A linear correlation between rate of deamination of leucine and rate of urea synthesis was observed in pregnant women. It is speculated that decreased anaplerotic carbon flux in the tricarboxylic acid cycle, as a consequence of insulin resistance, may have an important role in the down-regulation of transamination of leucine during pregnancy, and may contribute to the conservation and accretion of nitrogen by the mother and the fetus.

Female↗
PubMed1999

A dietary intervention (high carbohydrate) during the neonatal period causes islet dysfunction in rats.

Artificial rearing of 4-day-old rat pups on a high-carbohydrate (HC) milk formula results in the immediate onset of hyperinsulinemia. To evaluate these early changes, studies on pancreatic function were carried out on 12-day-old HC rats and compared with age-matched mother-fed (MF) pups. The plasma insulin and glucagon contents were increased sixfold and twofold, respectively, in HC rats compared with MF rats. There was a distinct leftward shift in the glucose-stimulated insulin secretory pattern for HC islets. HC islets secreted insulin in the absence of any added glucose and in the presence of Ca(2+) channel inhibitors. The activities of glucokinase, hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate dehydrogenase complex were significantly increased in HC islets compared with MF islets. The protein contents of GLUT-2 and hexokinase were significantly increased in HC islets. These findings indicate that a nutritional intervention in the form of a HC formula only during the suckling period has a profound influence on pancreatic function, causing the onset of hyperinsulinemia.

Age Factors↗
PubMed1999

Lactate metabolism during exercise: analysis by an integrative systems model.

To provide a framework for quantitative analysis of metabolic and transport processes associated with ATP production during exercise, we adapted a recently developed model that links cellular metabolism and its control to whole body responses at rest. The enhanced model is based on dynamic mass balances for glycogen, glucose, pyruvate (PY), lactate (LA), O(2), and CO(2) and is solved numerically to simulate responses to acute (<20 min), moderate exercise (i.e., below the LA threshold, less than approximately 60% maximal rate of O(2) uptake). Simulations of responses to a step change in muscle ATP turnover predict substrate changes in muscle, splanchnic, and other tissues compartments, as well as changes in other metabolites (e.g., NADH, ADP) whose reactions are coupled to the main reactions. Even a significant (64%) decrease in muscle O(2) concentration (C(m, O(2))) did not affect muscle O(2) consumption. Model simulations of moderate exercise show that 1) muscle oxygenation is sufficient (C(m, O(2)) >2 mM) even during the transient state; 2) transient increases in concentration of muscle LA and arterial concentration of LA are associated with increases in glycolysis from increases in ADP/ATP and in LA production associated with a rise in NADH/NAD; 3) muscle ADP/ATP reaches a higher steady state that stimulates glycolysis, glycogenolysis, and oxidative phosphorylation to match the ATP demand; and 4) muscle NADH/NAD reaches a lower steady state that stimulates LA oxidation. It is suggested that the continuous stimulation of ATP synthesis processes during moderate exercise is mainly due to a higher ADP/ATP, not to a higher NADH/NAD. Critical measurements needed to quantify metabolic control mechanisms are identified.

Adenosine Triphosphate↗
PubMed1999

Comparison of leucine kinetics in endurance-trained and sedentary humans.

Whole body leucine kinetics was compared in endurance-trained athletes and sedentary controls matched for age, gender, and body weight. Kinetic studies were performed during 3 h of rest, 1 h of exercise (50% maximal oxygen consumption), and 2 h of recovery. When leucine kinetics were expressed both per unit of body weight and per unit of fat-free mass, both groups demonstrated an increase in leucine oxidation during exercise (P < 0.01). Trained athletes had a greater leucine rate of appearance during exercise and recovery compared with their sedentary counterparts (P < 0.05) and an increased leucine oxidation at all times on the basis of body weight (P < 0.05). However, all of these between-group differences were eliminated when leucine kinetics were corrected for fat-free tissue mass. Therefore, correction of leucine kinetics for fat-free mass may be important when cross-sectional investigations on humans are performed. Furthermore, leucine oxidation, when expressed relative to whole-body oxygen consumption during exercise, was similar between groups. It is concluded that there was no difference between endurance-trained and sedentary humans in whole body leucine kinetics during rest, exercise, or recovery when expressed per unit of fat-free tissue mass.

Adult↗