Pediatric Magnet Ingestion, Diagnosis, Management, and Prevention: A European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Position Paper.

Magnet ingestion is a special category of foreign body ingestion associated with high levels of morbidity and mortality worldwide, particularly if it is associated with staggered ingestion of multiple magnets or with simultaneous ingestion of other metallic foreign bodies, especially button batteries. A special category of magnet ingestion is the ingestion of earth magnets, which have higher levels of magnetism and therefore, potentially, carries a worse outcome. Legislative bodies, scientific Societies and community-led initiatives have been implemented worldwide with the aim of mitigating the effects of this growing, yet avoidable potential medical emergency. A scoping literature review summarized epidemiology, diagnosis, management, and prevention, including an algorithm for the diagnosis and management of magnet ingestion is presented and compared to previously published reviews and position papers (North American Society of Pediatric Gastroenterology, Hepatology and Nutrition, National Poison Center, Royal College of Emergency Medicine). The main emphasis of the algorithm is on identification of staggered/multiple magnet ingestion, and early joint gastroenterology and surgical consultation and management.

Joint ESPGHAN/NASPGHAN guidelines for the management of helicobacter pylori in children and adolescents (Update 2016)

BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

Eosinophilic esophagitis that develops during therapy with proton pump inhibitors : case series and possible mechanisms.

Therapy with proton-pump inhibitors (PPIs) results in remission in at least one third of patients with esophageal eosinophilia, presumably because of both their acid-related and anti-inflammatory mechanisms of action. However, eosinophilic esophagitis (EoE) may also develop during therapy with PPIs. We present a case series of four children who were initially diagnosed with infectious esophagitis, gastroesophageal reflux disease or gastric ulcer, who had no eosinophilic infiltration of the esophagus, but subsequently developed symptoms, endoscopic features and histological picture of typical EoE. We discuss mechanisms of action of PPIs of likely relevance to an increased risk of development of EoE in some patients, such as their influence on mucosal barrier function, interference with pH-related protein digestion by pepsin, and antigen processing by immune cells.

Pediatric Eosinophilic Esophagitis in Slovenia: Data From a Retrospective 2005-2012 Epidemiological Study.

OBJECTIVES: The aim of the present study was to assess the incidence, characteristics, therapeutic approach, and response to therapy of eosinophilic esophagitis (EoE) in a pediatric population from Slovenia. METHODS: A retrospective study was conducted on a cohort of children newly diagnosed as having EoE, ages 0 to 18 years, residing in Slovenia, in the period between 2005 and 2012. For each child presenting symptoms, family and personal history of allergies, blood, skin and patch allergy tests, endoscopic and histological findings, types of therapy, and therapeutic success were recorded. RESULTS: In total, 25 patients of EoE were identified during the study period. The mean annual incidence (per 100,000 children) was 0.8 (95% confidence interval [CI] 0.58-1.16). The incidences of EoE increased from 0.2 (0.01-1.36), 0.3 (0.01-1.38), and 0.3 (0.01-1.40) in the period 2005-2007, respectively, to 1.8 (0.72-3.76), 1.0 (0.28-2.60), and 1.8 (0.72-3.65) in the period 2010-2012, respectively (P = 0.002). In 9 patients, symptomatic and histological remissions were achieved with specific food elimination diet: in 8 with 6-food elimination diet and in 1 with an additional budesonide. In majority of patients, budesonide improved only symptoms, but esophageal eosinophilia persisted. Twenty percent of our children had improvement of histology and symptoms of EoE in spite of gradual reintroduction of all food and stopping all medication. CONCLUSIONS: The annual incidence of childhood EoE in Slovenia is comparable with the reports from the developed European countries, and it increased by 6-folds in the last decade.

Digital image analysis vs. clinical assessment to evaluate repigmentation after punch grafting in vitiligo.

BACKGROUND: Repigmentation as a treatment outcome in vitiligo is not assessed in a standard way, making results of clinical trials hard to compare. Different types of repigmentation assessments after punch grafting have not been compared so far. OBJECTIVE: To compare assessments of repigmentation by a digital image analysis system (DIAS) with those of clinical observers and patients after punch grafting for vitiligo. METHODS: One vitiligo patch was selected in each patient (n = 21). This patch was treated with the punch grafting technique. The grade of repigmentation (%) after 3 months was assessed by: (i) DIAS; (ii) 3 clinical observers ; and (iii) the patient, scoring the grade of repigmentation on photographs. Physicians and patients also evaluated the global result on a 7-point scale. RESULTS: There was an almost perfect agreement between the three clinical observers and the DIAS (ICC 0.83). As expected, variation was found between the clinical observers. Patients' scores showed a moderate agreement with the DIAS (ICC 0.49) and a poor agreement with the physicians (ICC 0.28). Overall, the patients were more satisfied with the results than the physicians. CONCLUSIONS: Whereas the results of the digital and clinical assessments were comparable, patients' ratings diverged. The DIAS can overcome the inevitable differences between observers, which are intrinsic to a visual grading method, and is advisable for clinical trials on vitiligo to objectively assess repigmentation in limited lesions.

A randomized comparison of excimer laser versus narrow-band ultraviolet B phototherapy after punch grafting in stable vitiligo patients.

Background Ultraviolet radiation following punch grafting may stimulate the migration of melanocytes from the grafts into the vitiliginous skin, thereby increasing the rate of repigmentation. We compared the effects of the 308-nm xenon chloride excimer laser (EL) vs. narrow-band ultraviolet B (NB-UVB) after punch grafting in patients with vitiligo. Objectives The aims of this study were to evaluate (i) repigmentation (%); (ii) treatment satisfaction; and (iii) patient preferences for EL vs. NB-UVB therapy after punch grafting in vitiligo. Methods Fourteen patients were treated with the punch-grafting technique on two symmetrical vitiligo patches. Starting 1 week after the punch grafting, the vitiligo patches were treated twice a week during 3 months, with EL on one side and with NB-UVB on the other side. Repigmentation (%) was measured by a digital image analysis system. Patients' satisfaction and preference for treatment were also assessed. Results Whereas both treatment modalities induced repigmentation, no statistically significant difference was found in grade of repigmentation after 3 months. With EL, 71.4% lower cumulative dose was reached. Patients were significantly more satisfied with NB-UVB and preferred it over EL. Conclusions The choice between EL and NB-UVB cannot solely be based on repigmentation, but rather on other factors, such as patients' preferences. However, given the lower UV dose of EL, we recommend its use in vulnerable populations, such as in small children and patients with sun-damaged skin with a history of long-term UVB treatment.

Impact of childhood vitiligo on adult life.

BACKGROUND: The onset of vitiligo occurs before the age of 20 years in 50% of patients. Having a chronic disease in childhood can impede a child's health-related quality of life (HRQL). OBJECTIVES: Firstly, to compare the social and psychosexual development and current HRQL of young adult patients with childhood vitiligo with those of a group of healthy controls. Secondly, to compare these outcomes in patients reporting negative childhood experiences with those of patients not reporting negative childhood experiences. METHODS: Eligible patients were mailed questionnaires on (i) sociodemographic and clinical characteristics, (ii) social and psychosexual development, (iii) generic and dermatology-specific HRQL, (iv) presence of negative childhood experiences related to vitiligo, (v) specification of these negative experiences and (vi) patients' recommendations for further care. RESULTS: A total of 232 patients with vitiligo completed the questionnaires. Social and psychosexual development and generic HRQL in young adult patients with childhood vitiligo were not different from those of healthy controls. However, patients reporting negative childhood experiences reported significantly more problems in social development than those not reporting negative experiences. Furthermore, negative childhood experiences were significantly associated with more HRQL impairment in early adulthood. CONCLUSIONS: Reporting negative experiences from childhood vitiligo appears to be associated with HRQL impairment in young adults with vitiligo.

Expression of apoptosis related proteins during malignant progression in chronic ulcerative colitis.

BACKGROUND: Chronic ulcerative colitis (CUC) is associated with increased risk of developing colon cancer through a dysplasia (intraepithelial neoplasia)-carcinoma sequence. AIMS: To investigate the expression of apoptosis and inflammatory related proteins in CUC. METHODS: The expression of proteins involved in apoptosis and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Bcl-xl, Fas, and active caspase 3) was investigated and compared with that seen in sporadic colon carcinoma. RESULTS: COX-2 was negative in the epithelium of all samples. iNOS was clearly present in inflammatory areas in CUC epithelium, weakly expressed in dysplasia, and absent or weakly expressed in tumour cells. Bcl-xl was absent in CUC, increased in dysplasia, and highly expressed in most carcinomas. Fas expression was positive in the surface epithelium of CUC, dysplasia, and most tumour cells. Activated caspase 3 was weakly positive in all samples, indicating limited apoptosis. Compared with CUC associated carcinoma, iNOS was consistently expressed in sporadic colon carcinoma cells, whereas Bcl-xl was almost absent in these tumour cells and Fas was only weakly expressed. Activated caspase 3 was present in normal mucosal samples and some tumour cells. CONCLUSION: Apoptosis related proteins--particularly iNOS, Bcl-xl, and Fas-show a distinct pattern of expression in the CUC to carcinoma sequence, which differs from that seen in sporadic carcinoma, but bears a striking resemblance to that seen during neoplastic progression in Barrett's oesophagus. These results support a causal role for chronic inflammation in cancer development in CUC, and treatment of ulcerative colitis should aim to minimise inflammation.

Diffuse and intestinal type gastric carcinomas differ in their expression of apoptosis related proteins.

BACKGROUND: Gastric carcinomas can be divided into intestinal and diffuse types, with the last type having a worse prognosis. AIMS: To investigate whether specific patterns in the expression of apoptosis related proteins correlate with carcinoma type and/or prognosis METHODS: The expression of Fas, Bcl-2, Bax, Bcl-xl, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) was studied immunohistochemically and the extent of apoptosis and proliferation was investigated in 11 cases of intestinal type and in eight cases of diffuse type carcinoma. RESULTS: Fas was expressed in all intestinal type and in one diffuse type carcinoma. Bcl-xl was expressed in 10 of 11 intestinal type and in one of eight diffuse type carcinomas. Bcl-2 was expressed in lamina propria immune cells. iNOS was expressed in six of 11 intestinal type and in four of eight diffuse type carcinomas, and COX-2 was expressed in eight of 11 intestinal type and in six of eight diffuse type carcinomas. CONCLUSION: Fas and Bcl-xl expression can differentiate between intestinal type and diffuse type gastric carcinomas. No differences in apoptosis and proliferation between intestinal type and diffuse type gastric carcinomas were observed.

Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype.

Barrett's esophagus, or columnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma. Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens. Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE. Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.

[An analysis of medical expenses of outpatient service for the elderly at one health insurance society in Fukuoka prefecture--focused on medical service and concentration of medical expenses].

To determine the best way to reduce medical expenses of the elderly, we analyzed the aged outpatients' receipts covered by the Health and Medical Service Law for the Aged at one health insurance society in Fukuoka prefecture. We used 312 medical receipts during July, 1997. The proportion of frequency of each medical service was 89.7% for medications, 45.8% for laboratory tests and 26.3% for procedures. The proportion of expenses of each medical service was 38.3% for medications, 20.0% for examinations and 12.1% for laboratory tests. Medication is considered as one of the main causes of increasing medical expenses. As a result of multiple regression analysis, the number of consulting days, urinary and genital disorder, the number of diseases, home care, laboratory tests and prescriptions for outside pharmacies were detected as statistically significant factors associated with medical expenses. There was a concentration of medical expenses, i.e. about 10% of higher rank receipts consumed around 40% of total outpatients' expenses and included 6 of 10 home medical care receipts. One of the causes of expensive outpatients' medical expenses was medication. The separation of dispensary and prescription of drugs does not contribute to the reduction of medical expenses. In the higher rank of the expenses group, compared with the lower rank of the expenses group, the consultation days were longer, the number of diseases was greater and the proportions of expenses for procedures and home care were larger. Medical expenditures for patients receiving home medical care were higher than those of others, but home care should be compared with admissions. Because the insurance societies are now facing financial difficulties in Japan, analyzing the data of medical receipts is very important. During our analysis, we had to make an enormous effort to combine two data sources, because the receipts were made separately by clinics and pharmacies. It is strongly suggested that a computerized information system with a standardized format for clinics and pharmacies be developed.

[An individual based analysis of medical expenses of outpatient services for the elderly at one health insurance society in Fukuoka Prefecture. Focus on multiple or redundant consultations].

PURPOSE: To ascertain way to reduce medical expenses of the elderly, we analyzed old outpatients' receipts covered by the Health and Medical Services Law for the Aged at one health insurance society in Fukuoka prefecture. In addition, an attempt was made to find better ways to share medical information and construct a system of receipt analysis. SUBJECTS AND METHODS: We used 312 receipts for 179 old outpatients in July in 1997. The number of prescriptions was internalized into the number of outpatients' receipt. We classified the patients as "multiple" who consulted several clinics a month and as "redundant" who consulted several clinics for the same diseases. RESULTS AND CONCLUSION: 1) The expenses of outpatients accounted for about 1/3 of the total. Average values for patients were 78.3 years old of age, 7.7 diseases, 1.5 pharmacies, 1.7 clinics, 7 consulting days, and the medical expenses of 40,482 yen per month. 2) The rate of multiple including redundant consultations was 49.7% and that for those that were redundant was 9.5%. Redundant consultations increased as the number of consultation clinics increased. 3) Factors considered to increase medical expenses were the number of diseases, the consulting days, and the number of consultation/prescription organizations. Multiple and redundant consultations amounting to half of the whole fulfilled all of these criteria. 4) The average medical expense for non-multiple and non-redundant patients was 28,314 yen, as compared with 52,786 yen for multiple and redundant and 64,306 yen for redundant cases. If there were no multiple consultations, thirty percent of the expenses could be avoided and if there were no redundant consultations, the reduction might be 6%, although more detailed clinical records are necessary for firm conclusions. To reduce excess expenditure, instructions for patients having home doctors and passing through introductions are important. 5) Regarding the expense of medical services, medication was accounted for 39.2% as the greatest outlay. Cautions for suitable use of drugs are required for multiple and redundant patients, because they tend to visit many pharmacies. Considering the rate rise of separation of pharmacy and clinic, fixing of field division of work and the sharing of medical information are inadequate. For example, introduction of an IC card system might be very useful to facilitate the development of community-based medical information system. 6) It is strongly suggested that a computerized information system with a standardized format should be developed on the initiative of a national organization such as the National Federation of Health Insurance Societies.

The effect of exercise training on beta-adrenergic stimulation of fat metabolism in obese men.

OBJECTIVE: To investigate the in vivo effect of exercise training at high and low intensity on beta-adrenergic stimulated fat metabolism in obese men at rest. METHOD: Twenty-three obese, healthy subjects were randomly divided in a low-intensity exercise training program (40% VO(2max), n=7), a high-intensity exercise training program (70% VO(2max); n=8), or a non-exercising control group (n=8). The exercise training program lasted for 12 weeks with a training frequency of 3 times per week. Before and after the intervention body composition and maximal aerobic capacity were measured as well as fat metabolism at rest and during beta-adrenergic stimulation by isoprenaline. For comparison, six lean subjects served as a control group. They participated in a low-intensity exercise training program and underwent the same measurements as the obese subjects. RESULTS: Relative fat oxidation decreased significantly during infusion of an increasing dose of isoprenaline in the obese low-intensity and high-intensity exercise training groups as well as in the lean group (P<0.01). Exercise training failed to influence the effect of beta-adrenergic stimulation on relative fat oxidation in obese men at both intensities and in lean men. In addition, beta-adrenergic-mediated lipolysis did not seem to be different after low intensity exercise training in lean and obese men. Lipolysis might be increased after high-intensity exercise training in obese men. CONCLUSION: Low- and high-intensity exercise training in obese men failed to affect beta-adrenergic mediated relative fat oxidation in vivo. beta-Adrenergic-mediated lipolysis might be increased in obese men after HI exercise training only. The effect of low-intensity exercise training on beta-adrenergic-mediated fat metabolism was similar in lean and obese men. International Journal of Obesity (2001) 25, 16-23

Agreement between symptom surveys, physical examination procedures and electrodiagnostic findings for the carpal tunnel syndrome.

OBJECTIVES: The goal of this study was to evaluate the concordance between various clinical screening procedures for carpal tunnel syndrome. METHODS: The subject population consisted of 824 workers from 6 facilities. The evaluated procedures included bilateral sensory nerve conduction testing, physical examinations, and symptom surveys, including hand diagrams. The agreement between the outcomes of various combinations of these procedures was assessed by determining the kappa coefficient. RESULTS: There was relatively poor overlap between the reported symptoms, the physical examination findings, and the electrodiagnostic results consistent with carpal tunnel syndrome. Overall, only 23 out of 449 subjects (5%) with at least 1 positive finding met all 3 criteria (symptoms, physical examination findings, and electrophysiological results consistent with carpal tunnel syndrome) for the dominant hand. The screening procedures showed poor or no agreement with kappa values ranging between 0.00 and 0.18 for all the case definitions evaluated for carpal tunnel syndrome. CONCLUSIONS: The poor overlap between the various screening procedures warns against the use of electrodiagnostic findings alone without the symptom presentation being considered. The results of this study also point to a need for the further development and evaluation of methods for detecting carpal tunnel syndrome.

Glucose turnover in presence of changing glucose concentrations: error analysis for glucose disappearance.

The present studies were undertaken to determine whether 1) the cold- and hot-GINF techniques used with Steele's model provide equivalent estimates of the rates of glucose appearance (R(a)) and disappearance (R(d)) in the presence of physiological changes in glucose and insulin concentrations, 2) the conditions for the best estimation of R(a) are the same as those for R(d), 3) the magnitude of error (if present) differs in diabetic and nondiabetic subjects, and 4) situations exist in which the knowledge of R(d) allows inferences to be made on whole body glucose uptake. To do so we performed experiments in non-insulin-dependent diabetes mellitus and nondiabetic subjects using simultaneous infusions of [6-3H]glucose and [6-14C]glucose; glucose and insulin were infused to mimic normal postprandial glucose and insulin profiles; the infused glucose contained [6-14C]glucose but not [6-3H]glucose. Compared with the hot-GINF method, the traditional cold-GINF method underestimated (P < 0.05) R(a) and R(d) by 10-15% and hepatic glucose release by 25-50% during the 1st h of the study, with the magnitude of error being the same in both diabetic and nondiabetic subjects. Error analysis demonstrated that errors in R(a) and R(d) have different analytic expressions containing common structural but different volume errors. Both R(a) and R(d) can be accurately measured in diabetic and nondiabetic subjects if glucose specific activity is kept constant and the volume of the accessible pool is used to calculate glucose disappearance. The relationship between R(d) and whole body glucose uptake was also derived. Although R(d) can be determined by relying on measurements in the accessible pool only, the assessment of whole body glucose uptake requires a model of the nonaccessible portion of the glucose system. However, knowledge of R(d) can provide useful insights into the behavior of whole body glucose uptake.

Psychological size and distance in the relationships of adult children of alcoholics with their parents.

Adult children of alcoholics' (n = 68) perceptions of their relationships with parents were compared with those of a control sample (n = 37) to examine independent and joint influences of interpersonal status and affect on family dynamics. Visual metaphors for relationships using circle drawings and a status-affect rating scale from the Grasha-Ichiyama Psychological Size and Distance Scale were employed. Compared with the control group, adult children of alcoholics drew smaller circles to represent themselves, i.e., indicating less interpersonal status, only when assessing their relationships with their fathers. Analyses of status-affect ratings showed that the drawings of smaller circles reflected feeling less competent, i.e., having less personal knowledge and expertise, rather than perceptions of being submissive in the relationship. The distance drawn between the circles of adult children of alcoholics and their parents, i.e., psychological distance, was much larger than that of the control group. Ratings showed that perceptions of a negative emotional climate and submissiveness together accounted for 25% of the unique variance in predicting psychological distance. Perceptions of being submissive, however, were not associated with perceptions of psychological distance among adult children of nonalcoholic parents.

Assessment of insulin action in NIDDM in the presence of dynamic changes in insulin and glucose concentration.

Both glucose and insulin are important regulators of glucose uptake and hepatic glucose release. Because insulin concentrations rarely if ever increase under daily living conditions, unless glucose concentrations also increase, we sought to determine whether hepatic and extrahepatic responses to changes in insulin and glucose concentration are impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). To address this question, glucose metabolism was measured in diabetic and nondiabetic subjects. A computer-driven infusion system was used to produce a nondiabetic postprandial insulin profile in both groups while sufficient exogenous glucose was infused to mimic nondiabetic postprandial glucose concentrations. Although NIDDM was associated with greater (P < 0.05) hepatic glucose release both before and during the prandial insulin infusion, suppression did not differ in the diabetic and nondiabetic subjects (-1.06 +/- 0.20 vs. -0.86 +/- 0.15 mmol/kg every 4 h). In contrast, stimulation of both glucose disappearance (0.77 +/- 0.27 vs. 1.68 +/- 0.27 mmol/kg every 4 h) and forearm glucose uptake (187 +/- 81 vs. 550 +/- 149 mumol/dl every 4 h) was lower (P < 0.05) in diabetic than in nondiabetic subjects. Thus, despite increased basal rates of glucose production, obese individuals with NIDDM had decreased stimulation of glucose disappearance but normal suppression of hepatic glucose release in response to nondiabetic prandial glucose and insulin concentrations. These data indicate that the increase in glucose that occurs with carbohydrate ingestion is likely to compensate for hepatic but not extrahepatic insulin resistance.

Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error.

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.

Use of [3-3H]glucose and [6-14C]glucose to measure glucose turnover and glucose metabolism in humans.

[3-3H]glucose is frequently used to measure glucose turnover in humans. If fructose 6-phosphate-fructose 1,6-diphosphate cycling (Fpc) is negligible in both liver and muscle, then [3-3H]- and [6-14C]glucose (corrected for Cori cycle activity) should provide equivalent measures of glucose turnover. In addition, if glycogenolysis is fully suppressed, then [14C]lactate specific activity should equal that of [6-14C]glucose from which it was derived, and oxidation of [6-14C]glucose, as measured by rate of generation of 14CO2, should equal total glucose oxidation (i.e., that derived from intra- and extracellular pools) as measured by indirect calorimetry. To address these questions, glucose turnover was measured simultaneously with [3-3H]- and [6-14C]glucose in the basal state and in presence of low (approximately 200 pM) and high (approximately 750 pM) insulin concentrations. Glucose turnover rates measured with [3-3H]- and [6-14C]glucose were equivalent at all insulin concentrations, indicating that Fpc had no detectable effect on measurement of glucose appearance. [14C]lactate specific activity was lower (P less than 0.01) than that of [6-14C]glucose in the basal state but not during either low- or high-dose insulin infusion, implying that all lactate was derived from extracellular glucose. On the other hand, glucose oxidation as measured by rate of generation of 14CO2 was lower (P less than 0.05) than glucose oxidation as measured by indirect calorimetry during both insulin infusions, implying either that suppression of glycogenolysis was not complete in all tissues or that one or both of these techniques do not accurately measure glucose oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)