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OBJECTIVE: Current criteria for the diagnosis of diabetic ketoacidosis (DKA) are limited by their nonspecificity (serum bicarbonate [HCO(3)] and pH) and qualitative nature (the presence of ketonemia/ketonuria). The present study was undertaken to determine whether quantitative measurement of a ketone body anion could be used to diagnose DKA. RESEARCH DESIGN AND METHODS: A retrospective review of records from hospitalized diabetic patients was undertaken to determine the concentration of serum beta-hydroxybutyrate (betaOHB) that corresponds to a HCO(3) level of 18 mEq/l, the threshold value for diagnosis in recently published consensus criteria. Simultaneous admission betaOHB and HCO(3) values were recorded from 466 encounters, 129 in children and 337 in adults. RESULTS: A HCO(3) level of 18 mEq/l corresponded with betaOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. With the use of these threshold betaOHB values to define DKA, there was substantial discordance (approximately > or = 20%) between betaOHB and conventional diagnostic criteria using HCO(3), pH, and glucose. In patients with DKA, there was no correlation between HCO(3) and glucose levels on admission and a significant but weak correlation between betaOHB and glucose levels (P < 0.001). CONCLUSIONS: Where available, serum betaOHB levels > or = 3.0 and > or = 3.8 mmol/l in children and adults, respectively, in the presence of uncontrolled diabetes can be used to diagnose DKA and may be superior to the serum HCO(3) level for that purpose. The marked variability in the relationship between betaOHB and HCO(3) is probably due to the presence of other acid-base disturbances, especially hyperchloremic, nonanion gap acidosis. [ABSTRACT FROM AUTHOR]

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at approximately 8.3 mmol/l and insulin was increased to approximately 300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 +/- 2.6 vs. 65.0 +/- 7.9 micro mol. kg(-1). min(-1)). Whole-body glucose disappearance (37.0 +/- 2.2 vs. 70.9 +/- 8.7 micro mol. kg(-1). min(-1); P < 0.001) and leg glucose uptake (24.3 +/- 4.2 vs. 59.6 +/- 10.0 micro mol. kg fat-free mass of the leg(-1). min(-1); P < 0.02) were also lower, whereas splanchnic glucose production (8.2 +/- 0.8 vs. 4.3 +/- 0.7 micro mol. kg(-1). min(-1); P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting whole- body glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome is the most frequent chromosomal aneuploidy in males occurring in about 1 in 660 males. Epidemiological studies have demonstrated increased risk of type 1 diabetes and type 2 diabetes in adults with Klinefelter syndrome. There is only one previous report of neonatal diabetes in a patient with Klinefelter syndrome. We report transient neonatal diabetes due to a pathogenic heterozygous variant in KCNJ11 in a male infant with Klinefelter syndrome. A 78-day old male infant was noted to have sustained hyperglycemia with serum glucose ranging between 148 mg/dL (8.2 mmol/L) and 381 mg/dL (21.2 mmol/L) three days after undergoing a complete repair of an atrioventricular defect. Hemoglobin A1c was 6.6%. The patient was born at term with a birth weight of 2.16 kg following a pregnancy complicated by gestational diabetes that was controlled with diet. The patient was initially started on a continuous intravenous insulin drip and subsequently placed on subcutaneous insulin (glargine, human isophane and regular insulin). Insulin was gradually decreased and eventually discontinued at seven months of age. Chromosomal microarray at 11 weeks of age showed XXY and a panel-based, molecular test for neonatal diabetes revealed a pathogenic heterozygous variant c.685G>A (p.Glu229Lys) in KCNJ11. The patient is now 34 months old and continues to have normal fasting and post-prandial glucose and HbA1C levels. The patient will need prospective follow up for assessment of his glycemic status. To our knowledge this is the second reported case of neonatal diabetes in an infant with Klinefelter syndrome and the first due to a mutation in the KCNJ11 in a patient with Klinefelter syndrome.

Background: Immature ovarian teratoma is very rare in childhood. We report on a 12-year-old girl with immature ovarian teratoma who presented initially with syndrome of inappropriate antidiuretic hormone., Case: A 12-year-old girl presented with acute abdomen and distention. Initial laboratory tests showed hyponatremia (sodium, 123 mmol/L), that did not respond to fluid management. Computed tomography imaging showed a 15 cm × 9 cm × 20 cm mass in the right ovary with multifocal internal fat, and dystrophic calcifications. She underwent exploratory laparotomy with a right salpingo-oophorectomy, omentectomy, and peritoneal stripping. The pathology revealed metastatic immature teratoma. Hyponatremia resolved soon after the surgery., Summary and Conclusion: Although a rare diagnosis, immature ovarian teratoma must be considered in a girl who presents with abdominal mass and hyponatremia., (Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Pediatricians have relied on methods for determining skeletal maturation for >75 years. Bone age continues to be a valuable tool in assessing children's health. New technology for bone age determination includes computer-automated readings and assessments obtained from alternative imaging modalities. In addition, new nonclinical bone age applications are evolving, particularly pertaining to immigration and children's rights to asylum. Given the significant implications when bone ages are used in high-stake decisions, it is necessary to recognize recently described limitations in predicting accurate age in various ethnicities and diseases. Current methods of assessing skeletal maturation are derived from primarily white populations. In modern studies, researchers have explored the accuracy of bone age across various ethnicities in the United States. Researchers suggest there is evidence that indicates the bone ages obtained from current methods are less generalizable to children of other ethnicities, particularly children with African and certain Asian backgrounds. Many of the contemporary methods of bone age determination may be calibrated to individual populations and hold promise to perform better in a wider range of ethnicities, but more data are needed., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

One of the most important aspects of a well-child examination is an assessment of a child's growth. Children who are failing to grow are often labeled "failure to thrive." However, close examination of the pattern of growth on standardized growth charts often allows the caregiver to characterize the growth failure as failure to grow, failure to gain weight, or failure to grow and gain weight. Such refinement of the pattern of growth failure allows for a more specific differential diagnosis and helps to focus laboratory and radiographic evaluation.

Lack of a uniform definition is responsible for underrecognition of the prevalence of malnutrition and its impact on outcomes in children. A pediatric malnutrition definitions workgroup reviewed existing pediatric age group English-language literature from 1955 to 2011, for relevant references related to 5 domains of the definition of malnutrition that were a priori identified: anthropometric parameters, growth, chronicity of malnutrition, etiology and pathogenesis, and developmental/ functional outcomes. Based on available evidence and an iterative process to arrive at multidisciplinary consensus in the group, these domains were included in the overall construct of a new definition. Pediatric malnutrition (undernutrition) is defined as an imbalance between nutrient requirements and intake that results in cumulative deficits of energy, protein, or micronutrients that may negatively affect growth, development, and other relevant outcomes. A summary of the literature is presented and a new classification scheme is proposed that incorporates chronicity, etiology, mechanisms of nutrient imbalance, severity of malnutrition, and its impact on outcomes. Based on its etiology, malnutrition is either illness related (secondary to 1 or more diseases/injury) or non-illness related, (caused by environmental/behavioral factors), or both. Future research must focus on the relationship between inflammation and illness-related malnutrition. We anticipate that the definition of malnutrition will continue to evolve with improved understanding of the processes that lead to and complicate the treatment of this condition. A uniform definition should permit future research to focus on the impact of pediatric malnutrition on functional outcomes and help solidify the scientific basis for evidence-based nutrition practices.

Background: Although minimally invasive surgery has been accepted for a variety of disorders, laparoscopic resection of colorectal cancer is performed by few. Concern about oncological radicality and long term outcome has limited the adoption of laparoscopic surgery for colorectal cancer., Objectives: To determine long-term outcome after laparoscopically-assisted versus open surgery for non-metastasised colorectal cancer., Search Strategy: The Cochrane library, EMBASE, Pub med and Cancer Lit were searched for published and unpublished randomised controlled trials., Selection Criteria: Randomised clinical trials comparing laparoscopically-assisted and open surgery for non-metastasised colorectal cancer were included. Studies that did not report any long-term outcomes were excluded., Data Collection and Analysis: Two reviewers independently assessed the studies and extracted data. RevMan 4.2 was used for statistical analysis., Main Results: Thirty-three randomised clinical trials (RCT) comparing laparoscopically-assisted versus open surgery for colorectal cancer were identified. Twelve of these trials, involving 3346 patients, reported long-term outcome and were included in the current analysis. No significant differences in the occurrence of incisional hernia, reoperations for incisional hernia or reoperations for adhesions were found between laparoscopically assisted and open surgery (2 RCT, 474 pts, 7.9% vs 10.9%;P = 0.32 and 2 RCT, 474 pts, 4.0% vs 2.8%; P = 0.42 and 1 RCT, 391 pts, 1.1% vs 2.5%;P = 0.30, respectively). Rates of recurrence at the site of the primary tumor were similar (colon cancer: 4 RCT, 938 pts, 5.2% vs 5.6%; OR (fixed) 0.84 (95% CI 0.47 to 1.52)(P = 0.57); rectal cancer: 4 RCT, 714 pts, 7.2% vs 7.7%; OR (fixed) 0.81 (95% CI 0.45 to 1.43) (P = 0.46). No differences in the occurrence of port-site/wound recurrences were observed (P=0.16). Similar cancer-related mortality was found after laparoscopic surgery compared to open surgery ( colon cancer: 5 RCT, 1575 pts, 14.6% vs 16.4%; OR (fixed) 0.80 (95% CI 0.61 to 1.06) (P=0.15); rectal cancer: 3 RCT, 578 pts, 9.2% vs 10.0%; OR (fixed) 0.66 (95% CI 0.37 to 1.19) (P=0.16). Four studies were included in the meta-analyses on hazard ratios for tumour recurrence in laparoscopic colorectal cancer surgery. No significant difference in recurrence rate was observed between laparoscopic and open surgery (hazard ratio for tumour recurrence in the laparoscopic group 0.92; 95% CI 0.76-1.13). No significant difference in tumour recurrence between laparoscopic and open surgery for colon cancer was observed (hazard ratio for tumour recurrence in the laparoscopic group 0.86; 95% CI 0.70-1.08)., Authors' Conclusions: Laparoscopic resection of carcinoma of the colon is associated with a long term outcome no different from that of open colectomy. Further studies are required to determine whether the incidence of incisional hernias and adhesions is affected by method of approach. Laparoscopic surgery for cancer of the upper rectum is feasible, but more randomised trials need to be conducted to assess long term outcome.

Objective: Current criteria for the diagnosis of diabetic ketoacidosis (DKA) are limited by their nonspecificity (serum bicarbonate [HCO(3)] and pH) and qualitative nature (the presence of ketonemia/ketonuria). The present study was undertaken to determine whether quantitative measurement of a ketone body anion could be used to diagnose DKA., Research Design and Methods: A retrospective review of records from hospitalized diabetic patients was undertaken to determine the concentration of serum beta-hydroxybutyrate (betaOHB) that corresponds to a HCO(3) level of 18 mEq/l, the threshold value for diagnosis in recently published consensus criteria. Simultaneous admission betaOHB and HCO(3) values were recorded from 466 encounters, 129 in children and 337 in adults., Results: A HCO(3) level of 18 mEq/l corresponded with betaOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. With the use of these threshold betaOHB values to define DKA, there was substantial discordance (approximately > or = 20%) between betaOHB and conventional diagnostic criteria using HCO(3), pH, and glucose. In patients with DKA, there was no correlation between HCO(3) and glucose levels on admission and a significant but weak correlation between betaOHB and glucose levels (P < 0.001)., Conclusions: Where available, serum betaOHB levels > or = 3.0 and > or = 3.8 mmol/l in children and adults, respectively, in the presence of uncontrolled diabetes can be used to diagnose DKA and may be superior to the serum HCO(3) level for that purpose. The marked variability in the relationship between betaOHB and HCO(3) is probably due to the presence of other acid-base disturbances, especially hyperchloremic, nonanion gap acidosis.

The prevalence of obesity in children and adolescents has increased dramatically in the past 3 decades. Childhood and adolescent obesity are associated with serious comorbidities including type 2 diabetes mellitus, hyperlipidemia, and hypertension. Most obese children and adolescents have no defined underlying endocrine or genetic syndrome. Evaluation of an obese child or adolescent involves a detailed personal and family history, physical examination, and selected laboratory evaluation. Lifestyle interventions and behavioral modification aimed at decreasing caloric intake and increasing caloric expenditure are essential to management of childhood and adolescent obesity. Surgical approaches have a role in management of morbid obesity and serious obesity-related comorbidities in adolescents. Further research is needed to evaluate the role of various dietary approaches and pharmacotherapy in the treatment of obesity in childhood and adolescence.

Background: Graves disease is the most common cause of hyperthyroidism in children. Medical therapy, radioiodine ablation, and thyroidectomy are all treatment options. To evaluate the safety and efficacy of operative therapy, we updated our operative experience with pediatric Graves disease at a single tertiary care center., Methods: The medical records of children <18 years old who underwent thyroidectomy for Graves disease between 1986-2003 were reviewed., Results: We identified 78 patients (median age, 13.8 years; 87% female). The most common presenting signs and symptoms included heat intolerance (61%), decreased academic performance (50%), tremor (49%), and ophthalmopathy (43%). All patients had clinical and laboratory evidence of autoimmune thyrotoxicosis. Sixty-nine percent chose operative therapy because of failure of medical therapy or adverse drug reactions. Near-total thyroidectomy was the most common surgical procedure performed (65%). Pathology demonstrated previously unrecognized thyroid malignancies in 4 (5%) patients. Operative morbidities were transient and included hypoparathyroidism (6%) and recurrent laryngeal nerve neuropraxia (1%). Three (4%) patients who underwent subtotal thyroidectomy developed recurrent hyperthyroidism; all were treated successfully with radioiodine ablation. Of patients presenting with ophthalmopathy, 85% noted improvement postoperatively, while 1 (3%) patient experienced worsening of symptoms. Only 5% developed new-onset Graves ophthalmopathy after operation., Conclusions: Near-total thyroidectomy for Graves disease in children is safe and effective when performed by experienced thyroid surgeons. In addition to relief of systemic symptoms, the majority of patients presenting with Graves ophthalmopathy experienced improvement of their ocular disease after operation. In 5% of patients, surgical management allowed for detection and treatment of clinically occult thyroid malignancies.

Unlabelled: Since the first reported efficacious use of human growth hormone in 1958, numerous children have been treated with this hormone. This review discusses the five indications for use of human growth hormone in children that have been approved to date by the United States Food and Drug Administration., Conclusion: Further, long-term studies will be needed to address the optimal use of this hormone in each of these conditions.

To determine whether the insulin dose-response curves for suppression of endogenous glucose production (EGP) and stimulation of splanchnic glucose uptake (SGU) differ in nondiabetic humans and are abnormal in type 2 diabetes, 14 nondiabetic and 12 diabetic subjects were studied. Glucose was clamped at approximately 9.5 mmol/l and endogenous hormone secretion inhibited by somatostatin, while glucagon and growth hormone were replaced by an exogenous infusion. Insulin was progressively increased from approximately 150 to approximately 350 and approximately 700 pmol/l by means of an exogenous insulin infusion, while EGP, SGU, and leg glucose uptake (LGU) were measured using the splanchnic and leg catheterization methods, combined with a [3-3H]glucose infusion. In nondiabetic subjects, an increase in insulin from approximately 150 to approximately 350 pmol/l resulted in maximal suppression of EGP, whereas SGU continued to increase (P < 0.001) when insulin was increased to approximately 700 pmol/l. In contrast, EGP progressively decreased (P < 0.001) and SGU progressively increased (P < 0.001) in the diabetic subjects as insulin increased from approximately 150 to approximately 700 pmol/l. Although EGP was higher (P < 0.01) in the diabetic than nondiabetic subjects only at the lowest insulin concentration, SGU was lower (P < 0.01) in the diabetic subjects at all insulin concentrations tested. On the other hand, in contrast to LGU and overall glucose disposal, the increment in SGU in response to both increments in insulin did not differ in the diabetic and nondiabetic subjects, implying a right shifted but parallel dose-response curve. These data indicate that the dose-response curves for suppression of glucose production and stimulation of glucose uptake differ in nondiabetic subjects and are abnormal in people with type 2 diabetes. Taken together, these data also suggest that agents that enhance SGU in diabetic patients (e.g. glucokinase activators) are likely to improve glucose tolerance.

To determine whether regulation of fasting endogenous glucose production (EGP) and glucose disappearance (R(d)) are both abnormal in people with type 2 diabetes, EGP and R(d) were measured in 7 "severe" (SD), 9 "mild" (MD), and 12 nondiabetic (ND) subjects (12.7 +/- 0.6 vs. 8.1 +/- 0.4 vs. 5.1 +/- 0.4 mmol/l) after an overnight fast and during a hyperglycemic pancreatic clamp. Fasting insulin was higher in both the SD and MD than ND subjects, whereas fasting glucagon only was increased (P < 0.05) in SD. Fasting EGP, glycogenolysis, gluconeogenesis, and R(d) all were increased (P < 0.05) in SD but did not differ in MD or ND. On the other hand, when glucose ( approximately 11 mmol/l), insulin ( approximately 72 pmol/l), and glucagon ( approximately 140 pg/ml) concentrations were raised to values similar to those observed in the severe diabetic subjects, EGP was higher (P < 0.001) and R(d) lower (P < 0.01) in both SD and MD than in ND. The higher EGP in the SD and MD than ND during the clamp was the result of increased (P < 0.05) rates of glycogenolysis (4.2 +/- 1.7 vs. 3.5 +/- 1.0 vs. 0.0 +/- 0.8 micromol.kg(-1).min(-1)), since gluconeogenesis did not differ among groups. We conclude that neither glucose production nor disappearance is appropriate for the prevailing glucose and insulin concentrations in people with mild or severe diabetes. Both increased rates of gluconeogenesis (likely because of higher glucagon concentrations) and lack of suppression of glycogenolysis contribute to excessive glucose production in type 2 diabetics.

To determine the mechanism(s) by which insulin inhibits endogenous glucose production (EGP) in nondiabetic humans, insulin was infused at rates of 0.25, 0.375, or 0.5 mU. kg(-1). min(-1) and glucose was clamped at approximately 5.5 mmol/l. EGP, gluconeogenesis, and uridine-diphosphoglucose (UDP)-glucose flux were measured using [3-(3)H]glucose, deuterated water, and the acetaminophen glucuronide methods, respectively. An increase in insulin from approximately 75 to approximately 100 to approximately 150 pmol/l ( approximately 12.5 to approximately 17 to approximately 25 microU/ml) resulted in progressive (ANOVA; P < 0.02) suppression of EGP (13.1 +/- 1.3 vs. 11.7 +/- 1.03 vs. 6.4 +/- 2.15 micromol x kg(-1) x min(-1)) that was entirely due to a progressive decrease (ANOVA; P < 0.05) in the contribution of glycogenolysis to EGP (4.7 +/- 1.7 vs. 3.4 +/- 1.2 vs. -2.1 +/- 1.3 micro mol x kg(-1) x min(-1)). In contrast, both the contribution of gluconeogenesis to EGP (8.4 +/- 1.0 vs. 8.3 +/- 1.1 vs. 8.5 +/- 1.3 micro mol x kg(-1) x min(-1)) and UDP-glucose flux (5.0 +/- 0.4 vs. 5.0 +/- 0.3 vs. 4.0 +/- 0.5 micro mol x kg(-1) x min(-1)) remained unchanged. The contribution of the direct (extracellular) pathway to UDP-glucose flux was minimal and constant during all insulin infusions. We conclude that higher insulin concentrations are required to suppress the contribution of gluconeogenesis of EGP than are required to suppress the contribution of glycogenolysis to EGP in healthy nondiabetic humans. Since suppression of glycogenolysis occurred without a decrease in UDP-glucose flux, this implies that insulin inhibits EGP, at least in part, by directing glucose-6-phosphate into glycogen rather than through the glucose-6-phosphatase pathway.

To determine if enteral delivery of glucose influences splanchnic glucose metabolism, 10 subjects were studied when glucose was either infused into the duodenum at a rate of 22 micromol x kg(-1) x min(-1) and supplemental glucose given intravenously or when all glucose was infused intravenously while saline was infused intraduodenally. Hormone secretion was inhibited with somatostatin, and glucose (approximately 8.5 mmol/l) and insulin (approximately 450 pmol/l) were maintained at constant but elevated levels. Intravenously infused [6,6-(2)H(2)]glucose was used to trace the systemic appearance of intraduodenally infused [3-(3)H]glucose, whereas UDP-glucose flux (an index of hepatic glycogen synthesis) was measured using the acetaminophen glucuronide method. Despite differences in the route of glucose delivery, glucose production (3.5 +/- 1.0 vs. 3.3 +/- 1.0 micromol x kg(-1) x min(-1)) and glucose disappearance (78.9 +/- 5.7 vs. 85.0 +/- 7.2 micromol x kg(-1) x min(-1)) were comparable on intraduodenal and intravenous study days. Initial splanchnic glucose extraction (17.5 +/- 4.4 vs. 14.5 +/- 2.9%) and hepatic UDP-glucose flux (9.0 +/- 2.0 vs. 10.3 +/- 1.5 micromol x kg(-1) x min(-1)) also did not differ on the intraduodenal and intravenous study days. These data argue against the existence of an "enteric" factor that directly (i.e., independently of circulating hormone concentrations) enhances splanchnic glucose uptake or hepatic glycogen synthesis in nondiabetic humans.

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to approximately 1 mmol/l by an 8-h Intralipid/heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n = 5, low glycerol) or double (n = 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at approximately 8.3 mmol/l, and insulin was increased to approximately 300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 +/- 3.5 vs. 48.3 +/- 9.3 and 57.8 +/- 11.7 micromol x kg(-1) leg x min(-1)) was lower (P < 0.001) during IL/Hep than the low- or high-glycerol infusions, confirming that elevated FFAs caused insulin resistance in muscle. IL/Hep did not alter splanchnic glucose uptake or the contribution of the extracellular direct pathway to UDP-glucose flux. On the other hand, total UDP-glucose flux (13.2 +/- 1.7 and 12.5 +/- 1.0 vs. 8.1 +/- 0.5 micromol x kg(-1) x min(-1)) and flux via the indirect intracellular pathway (8.4 +/- 1.2 and 8.1 +/- 0.6 vs. 4.8 +/- 0.05 micromol x kg(-1) x min(-1)) were greater (P < 0.05) during both the IL/Hep and high-glycerol infusions than the low-glycerol infusion. In contrast, only IL/Hep increased (P < 0.05) splanchnic glucose production, indicating that elevated FFAs impaired the ability of the liver to autoregulate. Splanchnic insulin extraction, directly measured using the arterial and hepatic vein catheters, did not differ (67 +/- 3 vs. 71 +/- 5 vs. 69 +/- 1%) during IL/Hep and high- and low-glycerol infusions. We conclude that elevated FFAs exert multiple effects on glucose metabolism. They inhibit insulin- and glucose-induced stimulation of muscle glucose uptake and suppression of splanchnic glucose production. They increase the contribution of the indirect pathway to glycogen synthesis and impair hepatic autoregulation. On the other hand, they do not alter either splanchnic glucose uptake or splanchnic insulin extraction in nondiabetic humans.

Objective: To evaluate neurodevelopmental status as well as endocrine and exocrine pancreatic function in children who have undergone subtotal pancreatectomy for hypoglycemia due to congenital hyperinsulinism., Patients and Methods: Out of 15 identified patients, eight children (mean age 12.7 +/- 0.8 yr) participated in detailed psychometric testing and studies assessing glucose homeostasis, secretion of proinsulin, insulin, glucagon and C-peptide during a test meal. Additionally, a 24-h fast, glucagon challenge test, 72-h stool collection, and ultrasonography of the pancreatic remnant were performed., Results: Five of the 15 initially identified children had seizure disorders, including two with mental retardation. Diabetes developed in two of 15 children. All eight children investigated in the present study had evidence for attentional control impairment and 50% had subnormal intellectual functioning. Two had symptomatic hypoglycemia during the 24-h fast, while one had an elevated fasting glucose concentration. Four children, including the latter patient, had proinsulin/insulin ratios resembling patients with type 2 diabetes. Exocrine pancreatic function was normal in all eight children. No correlation was found between pancreatic endocrine function and pancreatic remnant size, nor between multiple pre- and postoperative factors (i.e., age at diagnosis and surgery) and neurodevelopmental outcome., Conclusion: While severe mental retardation or diabetes occurred infrequently in our patient population compared with previous reports, all of the studied children had subtle anomalies in their cognitive performance tests and the majority had endocrine test results indicative of abnormal insulin secretion and stressed pancreatic beta cells. Although partial pancreatectomy remains the treatment of choice after medical therapy fails, improved therapeutic means are necessary to achieve better clinical outcome.

Aims/hypothesis: Our aim was to determine whether an alteration in splanchnic glucose metabolism could contribute to postprandial hyperglycaemia in people with Type I (insulin-dependent) diabetes mellitus., Methods: Splanchnic glucose extraction, hepatic glycogen synthesis and endogenous glucose production were compared in 8 Type I diabetic patients and in 11 control subjects. Endogenous hormone secretion was inhibited with somatostatin while insulin (approximately 550 pmol/l) and glucagon (approximately 130 ng/l) concentrations were matched with exogenous hormone infusions. Glucose containing [3-3H] glucose was infused into the duodenum at a rate of 20 micromol.kg(-1).min(-1). Plasma glucose concentrations were maintained at about 8.5 mmol/l in both groups by means of a separate variable intravenous glucose infusion., Results: Initial splanchnic glucose uptake, calculated by subtracting the systemic rate of appearance of [3-3H] glucose from the rate of infusion of [3-3H] glucose into the duodenum, did not differ in the diabetic and non-diabetic patients (4.1 +/- 0.8 vs 3.0 +/- 1.0 micromol/kg/min). In addition, hepatic glycogen synthesis, measured using the acetaminophen glucuronide method did not differ (10.7 +/- 2.4 vs 10.1 +/- 2.7 micromol.kg(-1).min(-1)). On the other hand, suppression of endogenous glucose production, measured by an intravenous infusion of [6,6-2H2] glucose, was greater (p < 0.05) in the diabetic than in the non-diabetic subjects (1.7 +/- 1.6 vs 5.8 +/- 1.9 micromol.kg(-1).min(-1))., Conclusion/interpretation: When glucose, insulin and glucagon concentrations are matched in individuals with relatively good chronic glycaemic control, Type I diabetes does not alter initial splanchnic glucose uptake of enterally delivered glucose or hepatic glycogen synthesis. Alterations in splanchnic glucose metabolism are not likely to contribute to postprandial hyperglycaemia in people with well controlled Type I diabetes.

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 micromol. kg(-1). min(-1) while supplemental glucose was given intravenously to clamp glucose at approximately 10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at approximately 300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was approximately 35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes.

We tested the hypothesis that a lack of suppression of glucagon causes postprandial hyperglycemia in subjects with type 2 diabetes. Nine diabetic subjects ingested 50 g glucose on two occasions. On both occasions, somatostatin was infused at a rate of 4.3 nmol/kg x min, and insulin was infused in a diabetic insulin profile. On one occasion, glucagon was also infused at a rate of 1.25 ng/kg x min to maintain portal glucagon concentrations constant (nonsuppressed study day). On the other occasion, glucagon infusion was delayed by 2 h to create a transient decrease in glucagon (suppressed study day). Glucagon concentrations on the suppressed study day fell to about 70 ng/L during the first 2 h, rising thereafter to approximately 120 ng/L. In contrast, glucagon concentrations on the nonsuppressed study day remained constant at about 120 ng/L throughout. The decrease in glucagon resulted in substantially lower (P < 0.001) glucose concentrations on the suppressed compared with the nonsuppressed study days (9.2+/-0.7 vs. 10.9+/-0.8 mmol/L) and a lower (P < 0.001) rate of release of [14C]glucose from glycogen (labeled by infusing [1-14C]galactose). On the other hand, flux through the hepatic UDP-glucose pool (and, by implication, glycogen synthesis), measured using the acetaminophen glucuronide method, did not differ on the two occasions. We conclude that lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes at least in part by accelerating glycogenolysis. These data suggest that agents that antagonize glucagon action or secretion are likely to be of value in the treatment of patients with type 2 diabetes.

Insulin-induced stimulation of muscle glucose uptake (MGU) is impaired in people with type 2 diabetes. To determine whether insulin-induced stimulation of splanchnic glucose uptake (SGU) is also impaired, we simultaneously measured leg glucose uptake (LGU) and SGU in 14 nondiabetic subjects and 16 subjects with type 2 diabetes using a combined organ catheterization-tracer infusion technique. Glucose was clamped at approximately 9.3 mmol/l, while insulin concentrations were maintained at approximately 72 pmol/l (low) and approximately 150 pmol/l (high) for 3 h each. Endogenous hormone secretion was inhibited with somatostatin. Total body glucose disappearance was lower (P < 0.01) and glucose production higher (P < 0.01) during both insulin infusions in the diabetic compared with the nondiabetic subjects, indicating insulin resistance. Splanchnic glucose production was higher (P < 0.05) in the diabetic subjects during the low but not the high insulin infusion. SGU was slightly lower in the diabetic than in the nondiabetic subjects during the low insulin infusion and 50-60% lower (P < 0.05) during the high insulin infusion. LGU (P < 0.001), but not SGU, was inversely correlated with the degree of visceral adiposity. The contribution of the indirect pathway to hepatic glycogen synthesis did not differ in the diabetic and nondiabetic subjects. In contrast, both flux through the UDP-glucose pool (P < 0.05) and the contribution of the direct pathway to glycogen synthesis (P < 0.01) were lower in the diabetic than in the nondiabetic subjects, indicating decreased uptake and/or phosphorylation of extracellular glucose. On the other hand, glycogenolysis was equally suppressed in both groups. In summary, type 2 diabetes impairs the ability of insulin to stimulate both MGU and SGU. The defect appears to reside at a proximal (e.g., glucokinase) metabolic step and is not related to the degree of visceral adiposity. These data suggest that impaired hepatic glucose uptake as well as MGU contribute to hyperglycemia in people with type 2 diabetes.

We describe clinical, biochemical, and molecular findings in a 2(1/2)-year-old girl with a phosphomannose isomerase deficiency who presented with severe and persistent hypoglycemia and subsequently developed protein-losing enteropathy, liver disease, and coagulopathy. Six months of therapy with mannose supplementation resulted in clinical improvement and partial correction of biochemical abnormalities.

Hypoglycemia is more common in the pediatric patient than in adults. This article discusses the many diagnoses that can be associated with hypoglycemia in infancy and childhood. A guide to help practitioners evaluate such patients and suggested treatments for many of these disorders are provided. As genetic diagnosis continues to develop, it is anticipated that the list of specific disorders associated with hypoglycemia in infancy and childhood will increase.

Objective: To assess the level of glycemic control and to determine whether more normal glycemic control, as measured by glycosylated hemoglobin, leads to frequent hypoglycemic episodes in young patients with type 1 diabetes mellitus., Material and Methods: We undertook a retrospective review of the medical records of 59 children with type 1 diabetes diagnosed at age 9 years or younger, who underwent follow-up at our institution for at least 2 years. For each follow-up, insulin requirements, levels of glycosylated hemoglobin, and frequency of hypoglycemic reactions were analyzed for three age-groups--0 to 2 years, 2 to 5 years, and 5 to 9 years old., Results: The mean glycosylated hemoglobin for the first 2 years after diagnosis of type 1 diabetes was higher in children 0 to 2 years old in comparison with the other age-groups. This increased glycosylated hemoglobin occurred despite increased administration of insulin, expressed in units per kilogram daily, to these children (P < 0.05). Severe hypoglycemic reactions were more common in infants (55%) and children between 2 and 5 years old (45%) than in children from 5 to 9 years old (13%). In all age-groups, the mean glycosylated hemoglobin value closest to a hypoglycemic event and the mean glycosylated hemoglobin value for the 2-year study period were similar but were both less than 8% (the standard established by the Diabetes Control and Complications Trial). Most reactions had no clear cause in the youngest age-group, whereas a specific reason could usually be determined in children 2 to 5 years old., Conclusion: Tight glycemic control is achievable in young patients with type 1 diabetes mellitus. Such tight control, however, may lead to an increase in the frequency of severe hypoglycemic reactions in this patient population. Our data support the guideline that children younger than 5 years should have a higher goal for premeal plasma glucose levels.

Objective: To compare the accuracy and precision of insulin syringes and pen devices used by children with type 1 diabetes and their parents., Research Design and Methods: There were 48 subjects (32 patients, a parent of an additional 16 patients) instructed to measure out morning insulin doses three times from vials and/or cartridges containing saline mixed with small amounts of [14C]glucose (solution used as regular insulin) and [3H]glucose (solution used as NPH insulin) and to dispense the contents into a scintillation vial. Statistical analysis was used to determine the accuracy and precision of both methods of insulin delivery., Results: The absolute error in measuring out doses of regular insulin < 5 U was greater with insulin syringes compared with pen injection devices (9.9 +/- 2.4 vs. 4.9 +/- 1.6%, respectively). Both were comparable for regular insulin doses > 5 U (3.2 +/- 0.6 vs. 2.2 +/- 0.4% for syringes and pens, respectively). The accuracy in drawing up NPH doses was similar for low and high insulin doses (mean percent error of 7.5 +/- 1.5 vs. 5.6 +/- 1.1%)., Conclusions: Pen devices are more accurate than insulin syringes in measuring out insulin at low insulin doses. The accuracy of insulin syringes improves when higher doses of regular insulin are measured out and becomes comparable to pen devices.

Human milk has been shown to be the ideal source of nutrition for most growing infants. Its composition continues to be an active area of investigation. In several studies in preterm and term infants, long-chain polyunsaturated fatty acids were found to improve the maturation of visual evoked potentials. The clinical significance of this finding, however, remains unclear. Nucleotides present in breast milk or added to infant formula seem to enhance the humoral immune response to vaccination. Whether breastfeeding protects susceptible infants from the risk of the development of diabetes mellitus type 1 is still controversial. Breastfeeding by mothers infected with the human immunodeficiency virus is not recommended. Other viruses and pollutants have also been found in breast milk. The importance of these in the long-term health of children remains to be established.

NIDDM is associated with excessive rates of endogenous glucose production in both the postabsorptive and postprandial states. To determine whether this is due to an intrinsic increase in hepatic sensitivity to glucagon, 9 NIDDM and 10 nondiabetic subjects were studied on three occasions. On each occasion, glycogen was labeled the evening before the study with subjects ingesting meals containing [6-3H]galactose. Beginning at 6:00 A.M. on the following morning, somatostatin was infused to inhibit endogenous hormone secretion. Insulin concentrations were maintained constant at basal levels (defined as that necessary to keep glucose at approximately 5 mmol/l) in each individual. On one occasion, glucagon was infused at a rate of 0.65 ng x kg(-1) x min(-1) throughout the experiment, resulting in glucagon concentrations of approximately 130 pg/ml and a slow but comparable fall in endogenous glucose production with time in both groups. On the other two occasions, the glucagon infusion was increased at 10:00 A.M. to either 1.5 or 3.0 ng x kg(-1) x min(-1), resulting in an increase in glucagon concentrations to approximately 180 and 310 pg/ml, respectively. The increment in endogenous glucose production (i.e., area above basal) did not differ in diabetic and nondiabetic subjects during either the 1.5 ng x kg(-1) x min(-1) (0.75 +/- 0.055 vs. 0.78 +/- 0.048 mmol/kg) or 3.0 ng x kg(-1) x min(-1) (1.06 +/- 0.066 vs. 1.10 +/- 0.073 mmol/kg) glucagon infusions. In contrast, the amount of [6-3H]glucose released from glycogen was lower (P < 0.05) in the diabetic than nondiabetic subjects during both glucagon infusions. The specific activity of glycogen, calculated as the integrated release of [6-3H]glucose divided by the integrated release of unlabeled glucose, was lower (P < 0.05) in diabetic subjects than in nondiabetic subjects during both the 1.5 ng x kg(-1) x min(-1) (19.0 +/- 3.9 vs. 41.4 +/- 5.7 dpm/micromol) and 3.0 ng x kg(-1) x min(-1) (19.1 +/- 3.1 vs. 36.5 +/- 7.2 dpm/micromol) glucagon infusions, implying that a greater portion of the glucose released from glycogen was derived from the indirect pathway. We concluded that although NIDDM is not associated with an intrinsic alteration in hepatic sensitivity to glucagon, it does alter the relative contributions of the direct and indirect pathways to nocturnal glycogen synthesis.

To assess whether acetaminophen glucuronide accurately reflects uridyl diphosphate-glucose (UDP-glucose) derived from gluconeogenesis during fasting, three mongrel dogs received infusions of [U-14C]lactate, [1-13C]galactose, and [6-3H]glucose (after fasting overnight or for 2.5 days). After initiation of the isotopes (3 h), acetaminophen was given, and the urinary acetaminophen glucuronide was isolated. The mean plasma [14C]glucose specific activity (SA) was similar to the mean urinary acetaminophen glucuronide SA both after fasting overnight [299 +/- 19 vs. 296 +/- 14 disintegrations.min-1 (dpm).mumol-1, respectively] and after 2.5 days of fasting (511 +/- 8 vs. 562 +/- 32 dpm/mumol, respectively). Mean plasma glucose flux calculated using [6-3H]glucose decreased (P < 0.05) with two additional days of fasting (18.7 +/- 1.2 vs. 13.6 +/- 0.6 mumol.kg-1.min-1), as did intrahepatic (P < 0.05) UDP-glucose flux measured using [1-13C]galactose (8.6 +/- 0.7 vs. 5.5 +/- 0.3 mumol.kg-1.min-1). We conclude that, in fasted dogs, plasma glucose and UDP-glucose, as sampled by acetaminophen, equally reflect gluconeogenesis and appear to come from the same pool of glucose 6-phosphate. In addition, cycling of glucose moieties through UDP-glucose and glycogen decreases with an increased period of fasting.

Children with glycogen storage disease type I (GSD I) lack the ability to convert glucose 6-phosphate to glucose and yet are able to produce glucose endogenously. To test the hypothesis that the source of this glucose is increased cycling of glucose moieties through hepatic glycogen, six children with GSD I were studied on two occasions during which they received enteral glucose for 6 h at 35 or 50 mumol.kg-1.min-1 along with [6,6-2H2]glucose to measure plasma glucose flux and [1-13C]galactose to label intrahepatic uridyl diphosphate (UDP)-glucose. After 3 h, acetaminophen was given to estimate UDP-glucose flux (reflecting the rate of glycogen synthesis). Mean steady-state plasma glucose concentrations (4.8 +/- 0.2 vs. 5.8 +/- 0.1 mM) and total flux (34.8 +/- 1.7 vs. 47.5 +/- 2.0 mumol.kg-1.min-1) were increased (P < 0.05 or better) on the high-infusion day. Endogenous glucose production was detectable only on the low-infusion day (2.0 +/- 0.5 mumol.kg-1.min-1). UDP-glucose flux was increased (P < 0.05) on the high-infusion day (25.8 +/- 1.6 vs. 34.7 +/- 4.1), ruling out cycling of glucose moieties through glycogen with release of glucose by debrancher enzyme as the source of glucose production.

To validate a method to "biochemically biopsy" the immediate precursor of intrahepatic glycogen [uridyl diphosphate (UDP)-glucose] using acetaminophen and to assess how fasting affects the direct and indirect pathways of glycogen synthesis, dogs were fasted overnight (group 1, n = 5) or for 2.5 days (group 2, n = 5) and then given a 4-h duodenal infusion of unlabeled glucose, [3-3H]glucose, and [U-14C]lactate to label hepatic glycogen via the direct and indirect pathways, respectively, and [1-13C]galactose to measure intrahepatic UDP-glucose flux. After 3 h for equilibration, acetaminophen was given and urine was collected for acetaminophen glucuronide. Multiple liver biopsies were obtained. The mean 3H/14C ratios of glucose derived from glycogen (10.4 +/- 4.1 and 1.1 +/- 0.3 for groups 1 and 2, respectively) and glucose derived from acetaminophen glucuronide (11.5 +/- 4.0 and 1.0 +/- 0.1 for groups 1 and 2, respectively) were similar. Fasting significantly increased UDP-glucose flux, the rate of glycogen synthesis, and the contribution of the indirect pathway. We conclude that, in dogs, 1) no functional hepatic zonation exists with regard to acetaminophen glucuronidation and liver glycogen synthesis and 2) with appropriate choice of isotopic tracers and study design, UDP-glucose flux can accurately reflect rates of hepatic glycogen synthesis.

The nonketotic hyperglycemic syndrome is rare during childhood and may occur as the initial manifestation of insulin-dependent diabetes mellitus or during an episode of gastroenteritis. In this article, we report an unusual case of this syndrome in a female infant who had atypically severe hyperglycemia in association with gastroenteritis. In addition, we provide a review of the literature and summarize the pathophysiologic mechanisms of the nonketotic hyperglycemic syndrome.

Objective: To evaluate whether rehydration of young patients with diabetic ketoacidosis (DKA) by use of a solution that contained 75 mmol/L of sodium would be associated with a decline in serum sodium concentrations., Design: We retrospectively studied 18 episodes of moderate to severe DKA (mean plasma bicarbonate concentration of 7.8 +/- 0.9 mmol/L) in 17 patients younger than 18 years of age who had been examined at the Mayo Clinic between 1986 and 1990., Material and Methods: All patients had received an initial fluid bolus (about 20 mL/kg) of 0.9% saline or Ringer's lactate (or both), followed by rehydration with solutions that contained 75 mmol/L of sodium at rates of approximately 3,000 mL/m2 per day. Mean corrected and uncorrected serum sodium concentrations and effective serum osmolality (before and after administration of the fluid bolus and at 6 and 12 hours into treatment) were compared by use of the paired Student t test., Results: After 12 hours of therapy, we found a significant increase in the mean uncorrected serum sodium level from 135.1 +/- 0.9 mmol/L to 138.1 +/- 0.7 mmol/L (P < 0.05), whereas the mean corrected serum sodium value declined slightly from 143.1 +/- 1.1 mmol/L to 140.4 +/- 0.7 mmol/L (statistically not significant). Serum osmolality based on uncorrected serum sodium concentrations decreased at a rate of 2.6 mmol/kg per hour during the first 6 hours of treatment and remained stable thereafter., Conclusion: In 18 episodes of DKA in young patients, rehydration with fluids that contained 75 mmol/L of sodium at rates of approximately 3,000 mL/m2 per day after administration of a fluid bolus of 0.9% saline or Ringer's lactate (or both) was not associated with a decline in the uncorrected serum sodium concentration.

Insulin is a well-known anabolic hormone. The mechanism of insulin's protein anabolic effect remains controversial. Although insulin undoubtedly inhibits protein degradation, its effect on protein synthesis is incompletely defined. Recent studies reviewed in this article highlight the methodologic limitations in studying the effect of insulin on protein synthesis. These methodological issues are related to the hypoaminoacidemia that ensues after insulin administration and to the difficulty in measuring the obligatory precursor pool (aminoacyl tRNA) label. Differential responses to unweighing in different muscle proteins has been demonstrated. The protein loss during unweighing is due to the loss of myofibrillar proteins, although sarcoplasmic proteins are spared. A recent study has found that lipid emulsion has no effect on whole protein degradation but decreases forearm protein degradation and synthesis. Age-related muscle wasting in humans has been shown to be related to a decline in fractional myofibrillar protein synthesis rate. Although some progress has been made by recent studies, refined methodologies are needed to define the regulation of muscle protein turnover in humans.

The effect of thyroid hormone treatment on thyromegaly was evaluated in 69 patients < or = 18 years of age with goitrous Hashimoto disease. Changes in goiter size were related to pretreatment thyroid function (serum thyroxine and thyrotropin concentrations). We found that only hypothyroid patients had a clear diminution of their thyromegaly when given thyroid hormone.

It is well established that patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin. However, the contribution of hepatic and extrahepatic tissues to insulin resistance remains controversial. The uncertainty may be at least in part due to errors introduced by the unknowing use in previous studies of impure isotopes to measure glucose turnover. To determine hepatic and extrahepatic responses to insulin in the absence of these errors, steady-state glucose turnover was measured simultaneously with [6-3H]- and [6-14C]glucose during sequential 5- and 4-h infusions of insulin at rates of 0.4 and 10 mU.kg-1.min-1 in diabetic and nondiabetic subjects. At low insulin concentrations, [6-3H]- and [6-14C]glucose gave similar estimates of glucose turnover. Hepatic glucose release was equal to but not below zero in the nondiabetic subjects, but persistent glucose release (P less than 0.001) and decreased glucose uptake (P less than 0.001) was observed in the diabetic patients. At high insulin concentrations, both isotopes underestimated glucose turnover during the 1st h after initiation of the high-dose insulin infusion. More time (P less than 0.05) was required to reachieve steady state in NIDDM than nondiabetic subjects. At steady state, [6-3H]- but not [6-14C]glucose systematically underestimated (P less than 0.05) glucose turnover in both groups due to the presence of a tritiated nonglucose contaminant. The percentage of radioactivity in plasma due to tritiated contaminants was linearly related to turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

We have recently reported that during infusion of commercially available [6-3H]glucose, a radioactive nonglucose contaminant may accumulate in plasma causing errors in the measurement of glucose turnover. To determine whether purification of this tracer by HPLC (high-performance liquid chromatography) before infusion would eliminate the contaminant in plasma and remove the underestimation of glucose turnover reported during hyperinsulinemia, four normal subjects each underwent two 5-h euglycemic clamps during infusion of insulin (1 mU.kg-1.min-1). Glucose turnover was measured with either commercially available [6-3H]glucose or with HPLC-purified [6-3H]glucose. HPLC analysis of samples from the clamps done with commercially available [6-3H]glucose showed that 9.7% of the infused tracer and 26% of the "plasma glucose 3H radioactivity" were contaminants. In contrast, no contaminant was observed in the plasma during infusion of HPLC-purified [6-3H]glucose. During the last hour of the clamp, mean glucose turnover using commercially available [6-3H]glucose was less (P less than 0.01) than the mean glucose infusion rate (7.6 +/- 0.3 vs. 10.5 +/- 0.3 mg.kg-1.min-1) yielding apparent "negative" (P less than 0.001) hepatic glucose release. In contrast, when HPLC-purified [6-3H]glucose was employed, glucose turnover equaled the glucose infusion rate (10.4 +/- 0.9 vs. 10.2 +/- 0.9 mg.kg-1.min-1) and hepatic glucose release was no longer negative. We conclude that removal of a tritiated nonglucose contaminant in [6-3H]glucose by HPLC yields correct estimations of glucose turnover at steady state.

Both the immediate and long-term effects of chest physical therapy administered by a parent were evaluated in eight children with cystic fibrosis. Spirometric and plethysmographic evaluations were performed pre-CPT and at 5 and 30 minutes post-CPT. The pre-CPT measurements after a three-week period with no CPT were compared with the values while receiving CPT on a regular twice daily basis. There was a significant decrease after three weeks without CPT for FVC (P less than 0.025), FEV1 (P less than 0.005), FEF25-75 (P less than 0.005), and Vmax60TLC (P less than 0.025). When the patients had been receiving CPT on a regular basis, the only immediate effect was an increase in PEFR after 30 minutes post-CPT (P less than 0.05). After three weeks without CPT, there were increases at 30 minutes post-CPI for FVC (P less than 0.005) and Vmax60TLC (P less than 0.05). These findings indicate that although there may be little immediate functional improvement when CPT is received on a regular basis, a three-week period without CPT leads to a worsening of the functional status, which is reversed with renewal of regular CPT.

Leucine and/or its alpha-keto acid, alpha-ketoisocaproate (KIC), have been reported to spare protein in humans. To determine whether specific amino acid infusions affect whole-body protein metabolism as estimated by changes in leucine flux and oxidation, five groups of normal subjects were infused with saline, leucine (0.47 and 0.94 mumol . kg-1 . min-1), isoleucine (0.47 mumol . kg-1 . min-1), or threonine (0.47 mumol . kg-1 . min-1). Independent estimates of leucine metabolism were obtained using simultaneous infusions of [3H]-leucine and alpha-[14C]ketoisocaproate. Nearly identical results were obtained using either tracer compared with the saline controls. Compared with the saline controls, leucine infusion 1) had no effect on estimated rates of appearance of endogenous leucine, 2) stimulated leucine oxidation, 3) decreased plasma concentrations of other amino acids, and 4) stimulated non-oxidized leucine disappearance in a dose-dependent fashion. In contrast, isoleucine and threonine infusions had no effect on leucine metabolism. Assuming the validity of the isotope model employed, these data suggest that the purported anabolic effect of leucine infusion on whole-body protein metabolism is mediated via stimulation of protein synthesis rather than decreased proteolysis.