ABSTRACT
AIM: To compare demographic and clinical characteristics among children from ethnic minorities and non-Hispanic white children with new-onset autoimmune Type 1 diabetes. METHODS: We analysed a single-centre series of 712 children with new-onset autoimmune Type 1 diabetes between January 2008 and March 2011. The median (range) age was 9.7 (0.3-18.1) years, the mean (sd) BMI percentile was 69.7 (25.4) and 48.3% of the cohort were girls. The cohort comprised 57.3% non-Hispanic white, 20.5% Hispanic and 14.8% African-American children, and 7.4% were of other, mixed or unknown race. RESULTS: The Hispanic subgroup, compared with non-Hispanic white subgroup, had a higher mean (sd) C-peptide level [0.82 (1.62) vs 0.55 (0.47) ng/ml; P=0.004), and a greater proportion of children with elevated BMI (overweight or obesity; 49.6% vs 32.5%; P<0.001) and diabetic ketoacidosis (51.8% vs 38.2%; P=0.006). The African-American group had a higher mean (sd) glucose level [24.4 (12.8) vs 21.4 (10.7) mmol/l; P=0.017], a greater proportion of children with ketoacidosis (56.7% vs 38.2%; P=0.001), a greater proportion with elevated BMI (52.9% vs 32.5%; P<0.001), and a lower proportion of children at pre-pubertal stage (49.0% vs 61.6%; P=0.01), and tended to have higher C-peptide levels [0.65 (0.59) vs 0.55 [0.47] ng/ml; P=0.079) compared with the non-Hispanic white children. The differences in C-peptide levels compared with non-Hispanic white children persisted for Hispanic (P=0.01) but not African-American children (P=0.29) after adjustment for age, sex, BMI, ketoacidosis, glucose, Tanner stage and autoantibody number. CONCLUSION: At the onset of paediatric autoimmune Type 1 diabetes, Hispanic, but not African-American children had higher C-peptide levels, after adjustment for potential confounders, compared with non-Hispanic white children. These findings suggest that ethnicity may contribute to the heterogeneity of Type 1 diabetes pathogenesis, with possible implications for intervention.
Subject(s)
Diabetes Mellitus, Type 1/ethnology , Ethnicity/statistics & numerical data , Racial Groups/statistics & numerical data , Adolescent , Child , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Female , Humans , Infant , Male , Overweight/complications , Overweight/ethnology , Pediatric Obesity/complications , Pediatric Obesity/ethnologyABSTRACT
Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
Subject(s)
Consensus , Human Growth Hormone/adverse effects , Patient Safety/standards , Societies, Medical/standards , Adult , Child , Education , Endocrinology/standards , Europe , Humans , Pediatrics/standards , Recombinant ProteinsABSTRACT
BACKGROUND/OBJECTIVE: Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity-induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new-onset autoimmune type 1 diabetes. SUBJECTS AND METHODS: We prospectively studied 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune type 1 diabetes and followed them for up to 2 yr. Serum adipokines [leptin, total and high molecular weight (HMW) adiponectin, omentin, resistin, chemerin, visfatin], cytokines [interferon (IFN)-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha] and C-reactive protein (CRP) were measured at a median of 7 wk after diagnosis (range: 3-16 wk). RESULTS: Lean children were 71.9% non-Hispanic White, 21.9% Hispanic, and 6.3% African-American, compared with 27.8, 55.6, and 16.7%, respectively, for obese children (p = 0.01). Compared with lean children, obese children had significantly higher serum leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin after adjustment for race/ethnicity and Tanner stage. African-American race was independently associated with higher leptin among youth ≥10 yr (p = 0.007). Leptin levels at onset positively correlated with hemoglobin A1c after 1-2 yr (p = 0.0001) independently of body mass index, race/ethnicity, and diabetes duration. Higher TNF-alpha was associated with obesity and female gender, after adjustment for race/ethnicity (p = 0.0003). CONCLUSION: Obese children with new-onset autoimmune type 1 diabetes have a proinflammatory profile of circulating adipokines and cytokines that may contribute to the development of cardiovascular disease and diabetic complications.
Subject(s)
Adiposity , Biomarkers/blood , Diabetes Mellitus, Type 1/blood , Pediatric Obesity/blood , Thinness/blood , Adipokines/blood , Adolescent , Age of Onset , Child , Child, Preschool , Cytokines/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/epidemiology , Female , Follow-Up Studies , Humans , Male , Pediatric Obesity/complications , Thinness/complicationsABSTRACT
Although childhood obesity is common, many paediatric practitioners are not familiar with screening for its associated, serious comorbidities. We aimed to determine the adequacy of screening for nine well-recognized comorbidities in outpatients with severe morbid obesity (body mass index [BMI] ≥50 kg m(-2) ) seen in a large tertiary paediatric hospital. Patients with a BMI of ≥50 kg m(-2) seen at Texas Children's Hospital during calendar year 2009 were identified. Their medical records were reviewed for any documentation where hypertension, cardiac dysfunction, sleep apnoea, hepatosteatosis, diabetes, pseudotumour cerebri, dyslipidemia, orthopaedic issues and depression were noted and/or addressed as evidence of clinician awareness of these problems. We identified 123 patients seen at least once in 2009, with an average of 3.4 physician visits per patient and by an average of 2 different specialists. Hypertension screening was the most documented (91% of patients) and depression screening was the least documented (41%) in this patient cohort. Twelve patients (10%) had documented screening for all nine comorbidities. Overall, 55 patients (45%) had five or fewer of the nine comorbidities noted and/or addressed in the medical record. Adequate screening for comorbidities occurs in approximately half of children with severe morbid obesity, which means that many of these comorbidities are not being identified or treated. Educational programmes and new methodologies are needed to ensure comprehensive care of children with morbid obesity.
ABSTRACT
The prevalence of overweight and obese children has doubled, and the incidence of type 2 diabetes in children (0-19 y) has increased 4-fold during the past several decades. As a result we can anticipate an increased number of metabolic studies in children. There are few data on measures of glucose metabolism in normal children, and virtually none relating to their reproducibility. The aims of this study were 1) to provide new data on energy expenditure and glucose, lipid, and protein metabolism in nonobese, healthy children and adolescents; 2) to evaluate their reproducibility; and 3) on the basis of these data, to perform power calculations for metabolic studies. Eight nonobese subjects (8-16 y) were studied on two occasions, preceded by 7 d of a diet with identical energy content and macronutrient distribution. Gluconeogenesis, measured by deuterium oxide, accounted for 50% of glucose production. Insulin sensitivity, measured by the labeled minimal model, averaged 4.9 x 10(-4) mL(mU x min)(-1). Glucose appearance rate was significantly higher (p < 0.01) in the children than in the adolescents. Furthermore, we demonstrated that for energy intake and expenditure, plasma concentrations of glucose and C-peptide, and rates of appearance of glucose and leucine, a 10% difference can be detected in fewer than five subjects with a power of 80% and a type I error of 5%. Insulin concentration, gluconeogenesis, insulin secretory indices, insulin sensitivity, and glucose effectiveness were more variable, but with the above power a difference of 25% could be detected in 7-11 subjects using a paired study design.
Subject(s)
Gluconeogenesis , Glucose/biosynthesis , Insulin Resistance , Adolescent , Child , Female , Humans , Hydrolysis , Lipolysis , Male , Reproducibility of ResultsABSTRACT
OBJECTIVE: Children with type 1 diabetes are frequently difficult to manage during times of gastroenteritis or poor oral intake of carbohydrates because of mild or impending hypoglycemia. The present study describes the effective use of small doses of subcutaneous glucagon in these children. RESEARCH DESIGN AND METHODS: We analyzed 33 episodes of impending or mild hypoglycemia in 28 children (ages 6.6 +/- 0.7 years). All were healthy except for type 1 diabetes and an episode of gastroenteritis. Using a standard U-100 insulin syringe, children ages < or = 2 years received two "units" (20 microg) of glucagon subcutaneously and those ages >2 years received one unit/year of age up to 15 units (150 microg). If the blood glucose did not increase within 30 min, the initial dosage was doubled and given at that time. We used patients' self-glucose monitoring devices, aqueous glucagon, standard insulin syringes, and frequent phone contact with a physician and/or a diabetes nurse educator in this study. RESULTS: Blood glucose was 3.44 +/- 0.15 mmol/l before and 8.11 +/- 0.72 mmol/l 30 min after glucagon. In 14 children, relative hypoglycemia recurred, requiring retreatment (3.48 +/- 0.18 to 6.94 +/- 0.72 mmol/l). In four children, a third dose was required. The glucagon was well tolerated In 28 of the 33 episodes of impending hypoglycemia, the children remained at home and fully recovered. Five children were taken to their local hospital because of concerns of dehydration or fever, but none for hypoglycemia. CONCLUSIONS: Mini-dose glucagon rescue, using subcutaneous injections, is effective in managing children with type 1 diabetes during episodes of impending hypoglycemia due to gastroenteritis or poor oral intake of carbohydrate.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Gastroenteritis/complications , Glucagon/therapeutic use , Hypoglycemia/drug therapy , Insulin/adverse effects , Adolescent , Blood Glucose/drug effects , Blood Glucose Self-Monitoring , Child , Child, Preschool , Diabetes Mellitus, Type 1/complications , Gastroenteritis/physiopathology , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/therapeutic use , Glucagon/administration & dosage , Humans , Hypoglycemia/etiology , Injections, Subcutaneous , Parents/educationABSTRACT
To determine the effect of glucose availability on glutamine metabolism, glutamine kinetics were assessed under conditions of hyperglycemia resulting from 1) intravenous infusion of 7.5% dextrose in healthy adults and 2) insulin deficiency in young adults with insulin-dependent diabetes mellitus (IDDM). Eight healthy adults and five young adults with IDDM were studied in the postabsorptive state by use of a primed continuous infusion of D-[U-(14)C]glucose, L-[5,5,5-(2)H(3)]leucine, and L-[3, 4-(13)C]glutamine. Whether resulting from insulin deficiency or dextrose infusion, the rise in plasma glucose was associated with increased glucose turnover (23.5 +/- 0.7 vs. 12.9 +/- 0.3 micromol. kg(-1). min(-1), P < 0.01 and 20.9 +/- 2.5 vs. 12.8 +/- 0.4 micromol. kg(-1). min(-1), P = 0.03, in health and IDDM, respectively). In both cases, high blood glucose failed to alter glutamine appearance rate (R(a)) into plasma [298 +/- 9 vs. 312 +/- 14 micromol. kg(-1). h(-1), not significant (NS) and 309 +/- 23 vs 296 +/- 26 micromol. kg(-1). h(-1), NS, in health and IDDM, respectively] and the estimated fraction of glutamine R(a) arising from de novo synthesis (210 +/- 7 vs. 217 +/- 10 micromol. kg(-1). h(-1), NS and 210 +/- 16 vs. 207 +/- 21 micromol. kg(-1). h(-1), NS, in health and IDDM, respectively). When compared with the euglycemic day, the apparent contribution of glucose to glutamine carbon skeleton increased when high plasma glucose resulted from intravenous dextrose infusion in healthy volunteers (10 +/- 0.8 vs. 4.8 +/- 0.3%, P < 0.01) but failed to do so when hyperglycemia resulted from insulin deficiency in IDDM. We conclude that 1) the contribution of glucose to the estimated rate of glutamine de novo synthesis does not increase when elevation of plasma glucose results from insulin deficiency, and 2) the transfer of carbon from glucose to glutamine may depend on insulin availability.
Subject(s)
Diabetes Mellitus, Type 1/metabolism , Glucose/physiology , Glutamine/metabolism , Adult , Blood Glucose/metabolism , Breath Tests , Carbon Dioxide/analysis , Diabetes Mellitus, Type 1/blood , Female , Glucose/metabolism , Glutamine/blood , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacology , Infusions, Intravenous , Insulin/administration & dosage , Insulin/pharmacology , Leucine/metabolism , Male , Oxidation-Reduction , Radioisotope Dilution TechniqueABSTRACT
To improve upon the [U-(13)C]glucose method to estimate "gluconeogenesis" as described by J. Katz and J. A. Tayek (Am. J. Physiol. Endocrinol. Metab. 272: E476-E484, 1997, and 275: E537-E542, 1998), we describe the reciprocal pool model by using only the isotopomer data of plasma glucose during infusion of [U-(13)C]glucose. The glucose pool serves as both precursor and product for the calculation of the fraction of molecules generated by gluconeogenesis and to correct for exchange and loss of labeled carbon at the level of the tricarboxylic acid cycle. We have applied this model to both our own data and those of other investigators using [U-(13)C]glucose and have demonstrated excellent agreement between the Katz and Tayek model and our reciprocal pool model. When we compare the results of the reciprocal pool model with those of Hellerstein ([2-(13)C]glycerol) and Landau ((2)H(2)O-glucose-C-5), the results are similar in short- and long-term fasted adult humans. Finally, when we apply the reciprocal pool model to our data from premature infants, it is clear that we account for the inflow of unlabeled glycerol and presumably amino acids. This is not surprising, because the vast majority of gluconeogenesis is the result of recycling of glucose and pyruvate carbon.
Subject(s)
Gluconeogenesis , Glucose/metabolism , Infant, Premature/metabolism , Models, Biological , Adult , Carbon Isotopes , Humans , Infant, NewbornABSTRACT
In this article, the authors have attempted to provide a reasonable, working, and dynamic model incorporating a number of factors that are known to be involved in the regulation of glucose homeostasis in infants, children, and adults. Through the understanding of this model and its application, it is hoped that some of the authors' speculations regarding the pathophysiology of hyperglycemia and hypoglycemia might be challenged and either supported or rejected. In the meantime, the model can provide a framework for several of the facts and observations about the regulation of glucose homeostasis.
Subject(s)
Blood Glucose/metabolism , Homeostasis , Carbohydrate Metabolism, Inborn Errors , Child , Child, Preschool , Gluconeogenesis , Glycogen/metabolism , Humans , Insulin/physiology , KineticsABSTRACT
Endpoints in the treatment and management of adults with growth hormone (GH) deficiency (GHD) can be problematic. Changes in body composition with recombinant human GH (rhGH) treatment may be one of the most objective measures that could be applied in judging the effectiveness and long-term efficacy. The relative strengths and weaknesses of measures of body composition and their potential for clinical utility in the setting of rhGH replacement in GHD in adults are discussed. Measurement of changes in body fat, regardless of the method employed, from pretreatment baseline through 2-6 months of treatment may be quite useful in demonstrating the efficacy of rhGH in each patient. Other changes in body composition are compromised by the imprecision of the measurements, shifts in extracellular water, and the small real changes which occur in bone and muscle in the GHD subject. Use of body composition measures of change in fat content as an endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot be implemented on the basis of current data and would require a carefully designed prospective, controlled study. Until such criteria are established and accepted, endocrinologists must continue to manage these patients purely on the basis of their clinical judgment.
Subject(s)
Body Composition , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Adipose Tissue , Adult , Humans , Sensitivity and SpecificityABSTRACT
The aldonitrile pentaacetate and other derivatives lack ions in the electron ionization (EI) spectra possessing an intact hexose structure and thus must be analyzed by chemical ionization GC/MS in order to study multiple isotopomers. We report methods for quantitation of hexose di-O-isopropylidene acetate (IPAc) or pentafluorobenzoyl (PFBz) esters. These were prepared in a two-step procedure using inexpensive reagents that do not adversely impact the isotopomer structure of the sugar. The acetate derivative possesses an abundant [M - CH3] ion in the EI spectrum which is suitable for quantitative analysis of isotopomers. The negative chemical ionization (NCI) spectrum of the corresponding pentafluorobenzoyl derivative has a dominant molecular anion. Moreover, the PFBz derivative is about 100-fold more sensitive than the acetate, which offers some advantages for analysis of minor hexoses found in plasma. Isotopic calibration curves of [U-13C]glucose are linear over the 0.1-60% tracer/tracee range tested. The useful range for isotopic tracer studies is 25-2500 pmol for EI analysis of the acetate derivative and 0.1-55 pmol for NCI analysis of PFBz derivative (sample amount injected). For most studies where sample size is not limited, EI-GC/MS analysis of the IPAc derivative is preferred. NCI-GC/MS analysis is reserved when sample size is limiting or when studies involve hexoses other than glucose that are normally present at low concentration.
Subject(s)
Alkenes/analysis , Monosaccharides/analysis , Alkenes/blood , Blood Glucose/analysis , Gas Chromatography-Mass Spectrometry , Humans , Indicators and Reagents , Monosaccharides/bloodABSTRACT
Very low birth weight (VLBW) infants are dependent on total parenteral nutrition (TPN) to prevent hypoglycemia and provide a sufficient energy intake. However, diminished tolerance for parenteral glucose delivered at high rates frequently provokes hyperglycemia. We hypothesized that when their glucose supply is reduced to prevent hyperglycemia, VLBW infants can maintain normoglycemia via gluconeogenesis from glycerol and amino acids. Twenty infants born at 27 +/- 0.2 (mean +/- SE) gestational weeks and having a birth weight of 996 +/- 28 g, received lipids (1.6 +/- 0.1 mg x kg(-1) x min(-1)), protein (2.2 +/- 0.1 mg x kg(-1) x min(-1)), and glucose (3.1 +/- 0.1 mg x kg(-1) x min(-1) [17.1 +/- 0.2 micromol x kg(-1) x min(-1)]) parenterally over a period of 8-12 h on day 5.0 +/- 0.2 of life. Gluconeogenesis was estimated using [U-13C]glucose (n = 8) or [2-(13)C] glycerol (n = 6) and mass isotopomer distribution analysis (MIDA), or 2H2O (n = 6) and the rate of deuterium incorporation in carbon 6 of glucose. Blood glucose averaged 3.0 +/- 0.1 mmol/l; plasma glucose appearance rate (glucose Ra), 28.8 +/- 1.1 micromol x kg(-1) x min(-1); and glucose production rate (GPR), 10.7 +/- 1.0 micromol x kg(-1) x min(-1). The [U-13C]glucose and [2-(13)C]glycerol tracers provided similar estimates of gluconeogenesis, averaging 28 +/- 2 and 26 +/- 2% of glucose Ra and 72 +/- 5 and 73 +/- 9% of GPR, respectively. Glycerol contributed 64 +/- 5% of total gluconeogenesis. Gluconeogenesis measured by 2H2O, which does not include the contribution from glycerol, was comparable to the nonglycerol fraction of gluconeogenesis derived by the [2-(13)C]glycerol MIDA. We conclude that in VLBW infants receiving TPN, normoglycemia was maintained during reduced glucose infusion by glucose production primarily derived from gluconeogenesis, and that glycerol was the principal gluconeogenic substrate.
Subject(s)
Gluconeogenesis/physiology , Infant, Low Birth Weight/metabolism , Parenteral Nutrition, Total , Blood Glucose/metabolism , Female , Glycerol/metabolism , Humans , Infant, Newborn , MaleABSTRACT
None of the metabolic indicators which have been used to date provides a single or necessarily ideal endpoint for interventional management in wasting disorders. Some of these indicators may provide better endpoints for the acute rather than the chronic wasting conditions. In addition, it is imperative that more than one endpoint be selected to be assured that there is concordance in the findings. However, prior to the selection of any endpoint measure, the investigators involved must be fully cognizant of the potential pitfalls and errors that can occur in every one of the selected methodologies. In anticipating these potential problems, developing strategies for the interpretation of the data is critical at the outset of any interventional management strategy. The manufacturers, the regulators and the investigators involved in the interventional management of chronic and acute wasting disorders must agree on the endpoints to be used and these endpoints must provide the most appropriate and valid information. Selection of nutritional and metabolic endpoints must be in part dependent on the disease process involved, the potential magnitude of the interventional effect and must be utilized in the context of a carefully designed experimental protocol with a well focused question(s).
Subject(s)
Nutritional Physiological Phenomena/physiology , Outcome Assessment, Health Care , Wasting Syndrome/physiopathology , Wasting Syndrome/therapy , Amino Acids/metabolism , Blood Proteins/analysis , Child Development/physiology , Child, Preschool , Humans , Immunocompetence/physiology , Nitrogen/metabolism , Wasting Syndrome/metabolismABSTRACT
To determine whether whole body protein kinetics are altered in Duchenne muscular dystrophy (DMD), six 9 +/- 1-year-old children with DMD and five weight and height matched controls, received intravenous infusion of L-[1-(13)C]leucine and L-[2-(15)N]glutamine in the post-absorptive state. Glutamine rate of appearance was approximatly 24% lower in DMD boys than in controls (321 +/- 22 vs 425 +/- 37 micromol kg(-1)h(-1), P< 0.05) resulting from a 32% decrease in glutamine de novo synthesis (230 +/- 21 vs 340 +/- 34 micromol kg(-1)h(-1), P< 0.05). Whereas there was no difference between groups in estimates of protein degradation and synthesis, leucine oxidation rate was 44% higher in DMD boys than in controls (23 +/- 2 vs 16 +/- 2 micromol kg(-1)h(-1), P< 0.05). The data suggest that the dramatic mucle mass loss observed in DMD boys is associated with a) significant protein wasting, since increased leucine oxidation reflects a more negative whole body leucine balance, and b) a significant decrease in glutamine availability in the postabsorptive state. Glutamine might therefore be a 'conditionally essential' amino-acid in DMD.
Subject(s)
Glutamine/metabolism , Leucine/metabolism , Muscular Dystrophy, Duchenne/metabolism , Adolescent , Case-Control Studies , Child , Gas Chromatography-Mass Spectrometry , Glutamine/administration & dosage , Humans , Infusions, Intravenous , Kinetics , Leucine/administration & dosage , Male , Protein BiosynthesisABSTRACT
The role of endogenous androgens in enhancing the body's protein anabolic capacity has been controversial. To examine this question we chose to study whole-body protein and glucose kinetics in a group of 21 young, postpubertal females (16.3 +/- 0.6 yr), 8 of whom had clinical and laboratory evidence of ovarian hyperandrogenism (OH) (BMI = 37.8 +/- 1.3 kg/m2). We used L-[1-13C]leucine and [6,6,2H2]glucose tracer infusions before and after suppression of their endogenous androgens with estrogen/progesterone supplementation in the form of Triphasil for 4 weeks. Their baseline data were also compared with those of similar aged girls, 7 obese (OB) (BMI = 36.4 +/- 1.5) and 6 lean (LN) (BMI = 20.9 +/- 0.7) who were normally menstruating and had no evidence of androgen excess. Despite comparable glucose concentrations, both OH and OB groups had significant hyperinsulinemia (OH > OB), both basally and after iv glucose stimulation, as compared to LN controls (basal insulin: OH, 252 +/- 52 pmol/L; OB, 145 +/- 41; LN, 60 +/- 9, P = 0.009 OH vs. LN; peak insulin: OH, 2052 +/- 417; OB, 1109 +/- 127, LN, 480 +/- 120, P = 0.0009 OH vs. LN). The rate of appearance (Ra) of glucose, a measure of glucose production, was greater in the LN controls than in the OH or OB groups (OH, 2.0 +/- 0.1 mg/kg.fat free mass.min; OB, 1.9 +/- 0.1; LN, 3.3 +/- 0.1, P < 0.004 vs. LN). Calculated total rates of whole-body protein breakdown (leucine Ra), oxidation, and protein synthesis (nonoxidative leucine disposal) were substantially higher in the OH and OB groups as compared with LN controls (P < 0.04 vs. LN); however, when data are expressed on a per kilogram of fat free mass basis, the OH group had higher rates of proteolysis than the OB and LN, with indistinguishable rates between the latter two groups. None of the above-mentioned parameters changed after 1 month of administration of Triphasil, despite marked improvement in circulating testosterone and free testosterone concentrations after treatment (testosterone, -50%, P = 0.003; free testosterone, -70%, P = 0.02). We conclude that obesity in young postpubertal females is associated with insulin resistance for both peripheral carbohydrate and protein metabolism, and that patients with the OH syndrome have even greater insulin resistance as compared with simple obesity, regardless of treatment for the androgen excess. Carefully designed studies targeting interventions to improve both the hyperandrogenic and hyperinsulinemic state may prove useful even in the early juvenile stages of this disease.
Subject(s)
Blood Glucose/metabolism , Hyperandrogenism/metabolism , Insulin Resistance , Ovary/metabolism , Proteins/metabolism , Adolescent , Androgens/metabolism , Body Mass Index , Calorimetry, Indirect , Carbon Isotopes , Deuterium , Ethinyl Estradiol-Norgestrel Combination , Female , Human Growth Hormone/blood , Humans , Hyperandrogenism/complications , Insulin-Like Growth Factor I/metabolism , Kinetics , Lipid Metabolism , Obesity/complications , Oxidation-ReductionABSTRACT
The present study was designed to determine whether sodium phenylbutyrate (phi B) acutely induces a decrease in plasma glutamine in healthy humans, and, if so, will decrease estimates of whole body protein synthesis. In a first group of three healthy subjects, graded doses (0, 0.18, and 0.36 g.kg-1.day-1) of phi B were administered for 24 h before study: postabsorptive plasma glutamine concentration declined in a dose-dependent manner, achieving an approximately 25% decline for a dose of 0.36 g phi B.kg-1.day-1. A second group of six healthy adults received 5-h infusions of L-[1-14C]leucine and L-[1-13C]glutamine in the postabsorptive state on two separate days: 1) under baseline conditions and 2) after 24 h of oral treatment with phi B (0.36 g.kg-1.day-1) in a randomized order. The 24-h phenylbutyrate treatment was associated with 1) an approximately 26% decline in plasma glutamine concentration from 514 +/- 24 to 380 +/- 15 microM (means +/- SE; P < 0.01 with paired t-test) with no change in glutamine appearance rate or de novo synthesis; 2) no change in leucine appearance rate (Ra), an index of protein breakdown (123 +/- 7 vs. 117 +/- 5 mumol.kg-1.h-1; not significant); 3) an approximately 22% rise in leucine oxidation (Ox) from 23 +/- 2 to 28 +/- 2 mumol.kg-1.h-1 (P < 0.01), resulting in an approximately 11% decline in nonoxidative leucine disposal (NOLD = Ra-Ox), an index of protein synthesis, from 100 +/- 6 to 89 +/- 5 mumol.kg-1.h-1 (P < 0.05). The data suggest that, in healthy adults, 1) large doses of oral phenylbutyrate can be used as a "glutamine trap" to create a model of glutamine depletion; 2) a moderate decline in plasma glutamine does not enhance rates of endogenous glutamine production; and 3) a short-term depletion of plasma glutamine decrease estimates of whole body protein synthesis.
Subject(s)
Glutamine/deficiency , Leucine/blood , Phenylbutyrates/pharmacology , Adult , Dose-Response Relationship, Drug , Female , Glutamine/blood , Humans , Kinetics , Male , Osmolar ConcentrationABSTRACT
We determined whether glutamine has a protein anabolic effect in six 8-13-y-old boys with Duchenne muscular dystrophy. Children received a 5-h i.v. infusion of L-[1-13C]leucine and L-[2-15N]glutamine in the postabsorptive state on two consecutive days while drinking: 1) flavored water on one day, and 2) the same drink mixed with L-glutamine (800 micromol x kg[-1] x h[-1]), the other day. Oral glutamine administration was associated with an 8% decrease in leucine release from protein breakdown, from 116 +/- 5 to 107 +/- 6 micromol x kg(-1) h(-1) (p < 0.01), and a 35% decrease in leucine oxidation rate from 23 +/- 2 to 15 +/- 2 micromol x kg(-1) x h(-1) (p < 0.01), resulting in no change in the nonoxidative leucine disposal, an index of protein synthesis. Whole body glutamine exchange in plasma doubled from 321 +/- 22 to 623 +/- 24 micromol x kg(-1) x h(-1), p < 0.01, but glutamine from protein degradation and glutamine de novo synthesis both decreased (91 +/- 4 versus 84 +/- 5 micromol x kg(-1) x h(-1), p < 0.01, and 230 +/- 21 versus 163 +/- 25 micromol x kg(-1) x (h-1), p = 0.02, respectively). These data suggest that acute oral glutamine administration might have a protein-sparing effect in children with Duchenne muscular dystrophy, decreasing estimates of whole body protein degradation and glutamine de novo synthesis, therefore sparing nitrogen precursors.
Subject(s)
Glutamine/therapeutic use , Muscular Dystrophies/drug therapy , Muscular Dystrophies/metabolism , Proteins/metabolism , Administration, Oral , Adolescent , Child , Glutamine/administration & dosage , Glutamine/pharmacokinetics , Humans , Indicator Dilution Techniques , Leucine/metabolism , MaleABSTRACT
Recently, significant incorporation of labeled carbon into plasma glucose was documented during infusion of 14C-labeled glutamine in postabsorptive humans. Such labeling of plasma glucose can occur as a result of two different processes: either 1) through incorporation of glutamine carbon into glucose via glutamine entering Krebs cycle at alpha-ketoglutarate or 2) through simple fixation of labeled CO2 resulting from oxidation of labeled glutamine. Therefore, these studies were designed to determine 1) whether glutamine contributes carbon to gluconeogenesis other than through mere CO2 fixation, and, if so, 2) whether the apparent transfer of carbon from glutamine to glucose increases with fasting. Eight healthy adults were studied on two consecutive days: once after an overnight (18-h) fast and again on the second day of fasting (42-h fast). On each study day, subjects received a simultaneous 5-h infusion of D-[6,6-2H2lglucose, L-[3,4-13C2lglutamine, and L-[1-14C]leucine. Apparent rates of incorporation of glutamine carbon into glucose were estimated from the appearance of 13C into plasma glucose; glucose and glutamine production rates (appearance rate [Ra]) were determined from plasma [2H2]glucose and [13C2]glutamine enrichments, respectively. The appearance of 14C into plasma glucose was used to correct the measured rates of carbon transfer from glutamine to glucose as a result of CO2 fixation. We observed that of the apparent contribution of labeled glutamine to gluconeogenesis, only 4% occurred as a result of fixation of labeled CO2, while 96% seemed to occur through other routes. We also observed that between 18 and 42 h of fasting, 1) the relative contribution of protein breakdown to glutamine production was enhanced, while that of de novo synthesis declined; 2) the apparent contribution of glutamine to glucose production rose from 8 +/- 1 to 16 +/- 3% of overall glucose Ra; and 3) the relative apparent contribution of glutamine to gluconeogenesis remained constant. From the current data, it cannot be ascertained to what extent the apparent carbon transfer from glutamine to glucose represents a true contribution of glutamine to gluconeogenesis or mere carbon exchange between the trichloroacetic acid cycle and the gluconeogenic pathway. These findings are nevertheless compatible with a role of glutamine as a significant precursor of glucose in fasting humans.
Subject(s)
Blood Glucose/metabolism , Gluconeogenesis , Glutamine/metabolism , Adult , Amino Acids/metabolism , Carbon Dioxide/metabolism , Carbon Isotopes , Carbon Radioisotopes , Deuterium , Energy Metabolism , Female , Glutamine/blood , Humans , Isotope Labeling , Kinetics , Leucine/metabolism , MaleABSTRACT
The metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) were compared using bolus vs. continuous subcutaneous infusions. Subjects (n = 5, 29 +/- 3 yr) received rhIGF-I as subcutaneous infusions by a Minimed pump (200 microg x kg(-1) x day(-1) over 16 h/day), and their data were compared with those of subjects (n = 6, 24 +/- 2 yr) who received subcutaneous 200 microg x kg(-1) x day(-1) injections twice a day. L-[1-14C]leucine and [6,6-2H2]glucose infusion studies and indirect calorimetry were performed, and total and free IGF-I, insulin, and glucose concentrations were measured before and after 5-7 days of rhIGF-I. Estimates of protein breakdown, oxidation, and synthesis did not change after pump therapy; in contrast, after bolus doses, protein oxidation decreased (P = 0.001) and whole body protein synthesis increased (P = 0.04). There was no change in lipid oxidation after pump treatment, whereas the bolus group had lower lipid oxidation (P = 0.035). Both treatment modalities increased glucose oxidation (P < 0.02) and glucose production rates (P < 0.03). Overnight fasting insulin concentrations decreased in both groups, whereas plasma glucose remained invariant in the bolus group and decreased modestly in the pump group. Total IGF-I concentrations increased comparably in both groups, but the increase in free IGF-I was greater in the bolus-treated group (P = 0.001). We conclude that, in GH-sufficient postabsorptive individuals, the metabolic effects of rhIGF-I are in part dependent on the mode of administration, with a robust protein-anabolic effect when rhIGF-I is given as twice daily bolus injections but no detectable effect on protein turnover after a continuous mode of delivery. There were higher free IGF-I levels in the bolus-treated subjects, suggesting that this form of the molecule may be important for mediating IGF-I's protein-anabolic effects at the tissue level. The data also suggest that carbohydrate metabolism is more responsive than protein metabolism to the continuous subcutaneous modality of rhIGF-I administration. Even though the mechanism of these differences in metabolic effects is not entirely clear, it should be taken into account when patients are given rhIGF-I as prolonged treatment.