Plasma dosage of ghrelin, IGF-1, GLP- 1 and leptin related to gastric emptying and esophageal pH-impedance in children with obesity.

PURPOSE: The main aim of the study was to assess the relationship between leptin, ghrelin, insulin-like growth factor 1 (IGF-1), and glucagon-like peptide 1 (GLP-1) blood levels and gastric motility in children with obesity compared to healthy children. Secondary aims were to assess the possible association between these hormones and obesity, reflux impedance parameters, reflux symptoms, other GI disorders, and quality-of-life scores within the same groups. METHODS: Children with obesity plus GERD symptoms and 2 control groups of children with obesity without GERD and healthy lean children aged 4-17 years underwent an auxological evaluation, an assessment of gastro-intestinal symptoms and quality of life, hormonal dosages, and an evaluation of gastric emptying time (GET) through 13C-octanoic acid breath test. RESULTS: No significant association was found between hormones and gastric motility. Leptin and ghrelin levels were significantly associated with obesity parameters. No significant differences were found between GET and hormones of the patients with obesity, either with or without GERD. CONCLUSION: Although we found an association between auxological parameters and both leptin and ghrelin levels, this association did not imply an effect on the upper GI motility. Therefore, our hypothesis that alterations of these hormones in children with obesity could affect gastric emptying, triggering GERD, was not supported by our data.

Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage.

OBJECTIVE: The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage. METHODS AND RESULTS: We identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. We evaluated the role of wild-type (wt) and mutant UCP3 proteins in palmitate oxidation and in triglyceride storage in human embryonic kidney cells (HEK293). Palmitate oxidation was ∼60% lower (P<0.05; P<0.01) and triglyceride storage was higher in HEK293 cells expressing the four UCP3 mutants than in cells expressing wt UCP3. Moreover, mutants V56M and Q252X exerted a dominant-negative effect on wt protein activity (P<0.01 and P<0.05, respectively). Telmisartan, an angiotensin II receptor antagonist used in the management of hypertension, significantly (P<0.05) increased palmitate oxidation in HEK293 cells expressing wt and mutant proteins (P<0.05; P<0.01), including the dominant-negative mutants. CONCLUSIONS: These data indicate that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Our results also suggest that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants.

Persistent influence of precession on northern ice sheet variability since the early Pleistocene.

Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

A case of Klinefelter syndrome, mosaicism (46,XY/47,XXY), associated with anorexia nervosa.

We report the case of a 12.4-yr-old boy who presented Klinefelter syndrome (KS) mosaicism (46,XY/47,XXY), associated with mental retardation and anorexia nervosa (AN). KS was undiagnosed before hospitalization in a psychiatric unit. The patient was referred to a child psychiatric unit for restrictive eating. The medical history showed long standing feeding difficulties and failure to thrive. The patient was pre-pubertal and other clinical characteristics were: microcephaly, short stature and dysmorphic traits. Cytogenetic analysis revealed a mosaicism, 46,XY[11] and 47,XXY[19] karyotype. The psychiatric assessment demonstrated the presence of AN and low mood. No specific pathophysiological links between the alterations of KS and the development of AN should be hypothesized on the basis of this case report. In pre-pubertal boys with mental disorders, the possibility of KS should be considered, independently of the presence of eating disorders. Nevertheless, the case shows that KS can be first detected during an assessment for eating disorders. Few cases of the association of KS with AN have been previously reported in literature. This is the first description of KS, mosaicism (46,XY/47,XXY), associated with AN and mental retardation. This case report illustrates the need, for clinicians who work with eating disorders, to investigate the possible association between AN and KS, a rare but intriguing one.

Insulin resistance is a risk factor for high blood pressure regardless of body size and fat distribution in obese children.

BACKGROUND AND AIM: The prevalence of children with hypertension is increasing, especially in obese children. This study was to assess the relationship between blood pressure, indexes of adiposity, body fat distribution and insulin resistance. SAMPLE: 1044 children (M/F: 484/560; aged 6-11 years). Anthropometry and blood pressure were measured and fasting blood samples were tested for triacylglycerol, total cholesterol, HDL cholesterol, glucose, insulin and ALT. The prevalence of high blood pressure in overweight males and females was 14.3 and 6.4%, respectively (chi(2)=16.73, p<0.001) and in obese it was 40.4 and 32.8%, respectively (chi(2)=5.56, p<0.001). High blood pressure increased progressively with BMI z-score categories (chi(2)=67.99, p<0.001) as well as with waist/height ratio (W/Hr) categories (chi(2)=23.51, p<0.001). Hypertensive subject had significantly higher insulin (15.6+/-9.8 vs 11.9+/-7.2, p<0.001 and 20.63+/-14.7 vs 15.26+/-9.8, p<0.001 in males and females respectively) and HOMA(IR) (3.23+/-2.1 vs 2.42+/-1.49, p<0.001 and 4.12+/-2.87 vs 3.07+/-1.98, p<0.001 in males and in females, respectively) than non-hypertensive ones. Among metabolic and cardiovascular risk factors, HOMA(IR) was the only variable able to predict high blood pressure in obese boys and girls, in addition to BMI or body fat distribution (waist, W/Hr). The highest HOMA(IR) category was the most important predicting factor of high blood pressure in overweight and obese children in addition to body size or body fat distribution. CONCLUSIONS: Blood pressure is associated with the degree of overweight and the indices of body fat distribution. Insulin resistance is an independent additional risk factor for hypertension.

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children?

OBJECTIVES: To assess the features of fat redistribution, detected by clinical and ultrasound (US) methods, and the presence of metabolic disorders in HIV-infected children undergoing antiretroviral therapy. To evaluate if serum levels of resistin, a hormone produced only by visceral adipose tissue, are a marker of fat redistribution in these patients. DESIGN AND METHODS: Forty-five consecutive symptomatic HIV-infected children were considered for inclusion in the study. Patients were enrolled if treated for at least 6 months with antiretroviral therapy with or without protease inhibitor (PI) and if compliant to the study protocol. Patients were evaluated for: anthropometric measures, fat redistribution by clinical and US methods, serum lipids, parameters of insulin resistance by homeostasis model assessment for insulin resistance, serum resistin levels by an enzyme-linked immunosorbent assay. RESULTS: Eighteen children fulfilled the inclusion criteria and were enrolled in the study. Twelve (66%) children had clinical and/or US evidence of fat redistribution; 9 (75%) of them were on PI therapy; only 3 of 6 children without fat redistribution were on PI therapy (p<0.05). Serum lipids and insulin resistance parameters did not differ between children with or without fat redistribution. There was a highly significant linear correlation between visceral fat detected by US and circulating resistin levels (r=0.87; p<0.0001). CONCLUSIONS: Fat redistribution occurred in most HIV-infected children undergoing PI therapy. Because serum resistin levels reflect the amount of visceral fat, they could be considered a sensitive marker of fat redistribution in HIV-infected children.

Glucokinase deficit and birthweight: does maternal hyperglycemia always meet fetal needs?

AIMS: Many authors do not recommend hypoglycemic treatment during pregnancy in women affected by monogenic diabetes due to heterozygous glucokinase (GCK) mutations (MODY 2) in case of affected fetus, because maternal hyperglycemia would be necessary to achieve a normal birthweight. We aimed to evaluate differences in birthweight between MODY 2 affected children according to the parent who carried the mutation. METHODS: We retrospectively studied 48 MODY 2 affected children, whose mothers did not receive hypoglycemic treatment during pregnancy, divided into two groups according to the presence of the mutation in the mother (group A) or in the father (group B). Data were extracted from the database of the Regional Centre of Pediatric Diabetology of the University of Campania, Naples, collected from 1996 to 2016. We analyzed birthweight and centile birthweight. RESULTS: Percentage of small for gestational age was significantly higher in group B than in group A. We found three large for gestational age in the group that inherited the deficit from the mother, all with the same novel GCK mutation (p.Lys458-Cys461del). CONCLUSIONS: We hypothesize that not all MODY 2 affected fetuses need the same levels of hyperglycemia to have an appropriate growth, maybe because different kinds of GCK mutations may result in different phenotypes. Consequently, a "tailored therapy" of maternal hyperglycemia, based on fetal growth frequently monitored through ultrasounds, is essential in MODY 2 pregnancies.

Update on coeliac disease and type 1 diabetes mellitus in childhood.

The increased prevalence of coeliac disease (CD) among children with type 1 diabetes mellitus (DM1) implies that there is more than a simple association. A link between the gut immune system and DM1 has been suggested both in animal models and in humans. We review the literature on the epidemiology and genetic and clinical aspects shared by these two diseases and speculate on the role of gluten on the possible relationship between CD and DM1, on the basis of recent animal and human studies. The data suggest a failure in oral tolerance mechanisms in DM1 other than that in CD. It remains to be understood why only a small proportion of patients with DM1 proceed to the production of coeliac-associated antibodies and to overt enteropathy.

Long-term follow-up of diabetes in two patients with thiamine-responsive megaloblastic anemia syndrome.

OBJECTIVE: To describe a 15-year follow-up of diabetes and to present data regarding pancreatic beta-cell function in two adolescents affected by the thiamine-responsive megaloblastic anemia (TRMA) syndrome. CASE REPORTS: The first patient (PMR) is a 17.5-year-old Italian girl who presented megaloblastic anemia at 7.5 months of age. At age 2.5 years, because of the presence of diabetes and sensorineural deafness, she was diagnosed with TRMA syndrome and started treatment with thiamine-HCl, followed very early by benzoyloxymethyl-thiamine (BOM-T). The second patient (PF) is a 16.8-year-old Italian boy born to consanguineous parents. Sensorineural deafness was diagnosed at age 1.5 years, while diabetes with ketoacidosis and megaloblastic anemia were diagnosed at age 3 years. Treatment with thiamine HCl was started immediately after diagnosis and changed to BOM-T 2 months later. Subsequent to the initiation of the vitamin, the two patients did not require insulin for approximately 7 and 10 years, respectively. Puberty was determinant in deteriorating the metabolic control in these patients, leading to treatment with an oral hypoglycemic agent and finally to a reinstitution of insulin therapy. CONCLUSIONS: The hormonal assessment in our patients (normal insulin response to oral glucose in childhood, preserved C-peptide secretion in case 2) and the good response to an oral hypoglycemic agent would indicate that the pancreatic disease may initiate as type 2 diabetes and may progress after several years to an insulin-requiring diabetes, as indicated by the exhaustion of the insulin secretory capacity.

Gastric emptying delay and gastric electrical derangement in IDDM.

OBJECTIVE: Patients with diabetes can develop gastrointestinal motor complications; however, prevalence of gut dysmotility in children with diabetes is poorly understood. We measured gastric emptying time and gastric electrical activity in children with IDDM; presence of dyspeptic symptoms was also assessed. RESEARCH DESIGN AND METHODS: Gastric emptying time and gastric electrical activity were measured by ultrasonography and electrogastrography (EGG), respectively, in 40 consecutive IDDM children (median age: 9 years [6-14]) without autonomic neuropathy; 15 healthy children (median age: 7 years [4-15]) served as control subjects. The EGG variables studied were percent of electrical dysrhythmias (bradygastria or 0.5-2.0 cpm, tachygastria or 4.0-9.0 cpm; normal rhythm is 2.0-4.0 cpm) and fed-to-fasting ratio of the dominant EGG power. Blood glucose level in the fasting state and 180 min after feeding and HbA1C concentration were also measured. Data are given as median (ranges) and means +/- SD. Statistical analysis was performed using the parametric t test and the nonparametric signed-rank tests, with P < 0.05 considered significant. RESULTS: Gastric emptying time was delayed in 26 patients (group A), whereas in 14 patients (group B), it was in the same range as control values; group A patients significantly differed from group B for increased prevalence of gastric electrical dysrhythmias (P < 0.01) and for a lower fed-to-fasting ratio of the dominant EGG power (P < 0.01). Group B patients did not differ from control subjects for the EGG variables measured. Diabetic children with gastroparesis had significantly higher levels of both HbA1C and blood glucose measured 180 min after feeding than those with normal gastric emptying time (P < 0.05); there was a significant correlation between levels of HbA1C and degree of gastric emptying delay, whereas a significant inverse correlation between gastric emptying time and fed-to-fasting ratio of the dominant EGG power was found both in patients and control subjects. CONCLUSIONS: Delay of gastric emptying time and gastric electrical abnormalities are found in a high proportion of children with diabetes and can contribute to poor glycemic control, most likely by causing a mismatch between the onset of insulin action and the delivery of nutrients into the small intestine. Diabetic children with unexplained poor glycemic control should be investigated for abnormalities in gastric motility.

Hypertension, non-insulin-dependent diabetes, and intracellular sodium metabolism.

The present study was designed to investigate whether non-insulin-dependent diabetic hypertensive patients exhibit abnormalities in intracellular sodium metabolism similar to those described for essential hypertensive patients. Both normotensive and hypertensive non-insulin-dependent diabetic patients had similar average values of both Na+-Li+ countertransport and Na+-K+ cotransport compared with nondiabetic controls. Within the group of diabetic patients, hypertensive patients did not exhibit any abnormalities in either of the sodium transport pathways studied. The possible implications of these findings are addressed.

Relations of left ventricular geometry and function to body composition in children with high casual blood pressure.

To determine whether abnormal casual blood pressure (BP) is associated with left ventricular (LV) abnormalities in children, 190 6- to 11-year-old children (77 girls, 113 boys) were studied at a school site in Naples, Italy, by limited echocardiography and bioelectric impedance to calculate fat-free body mass (FFM). Single-visit BP measurements (defined as casual BP) were high (based on the Italian tables of BP) in 34 children (18%; 9 girls, 25 boys; 133+/-8/81+/-10 mm Hg) and obesity was present in 44 (23%; 15 girls, 29 boys). Sex- and age-independent risk of high casual BP value was 2.9-fold (odds ratio) greater in obese than in normal-weight children (95% confidence interval, 1.3 to 6.5; P<.01). LV mass (as both absolute value and normalized for height or FFM) was higher and relative wall thickness increased in children with high casual BP (all P<.01). Prevalence of LV hypertrophy was 21% among children with high casual BP (P<.004 versus 4.3% in normal group). Risk of LV hypertrophy was 5.5-fold higher in the presence of high casual BP (P<.004), whereas obesity, age, and sex did not have independent effects. Endocardial shortening was slightly higher in children with high casual BP (36.8+/-8.2%) than in children with normal BP (34.3+/-4.8%, P<.02), whereas midwall shortening was identical in the two groups (20%). Both endocardial shortening and midwall shortening were negatively related to end-systolic stress (r=-.62, SEE=3.8% and r=-.32, SEE=2.4% in normal children). Shortening as a percentage of predicted from wall stress was increased in children with high casual BP at the endocardial level (P<.001), whereas it was normal at the midwall. Therefore, (1) casual detection of high BP in school children is associated with LV geometric abnormalities similar to those found in adults with sustained hypertension (LV hypertrophy, concentric pattern); (2) similar to in adult hypertension, endocardial chamber function in children is supranormal; and (3) in contrast to findings in adults, midwall shortening is normal in children with high casual BP.

Red blood cell Na content, Na, Li-countertransport, family history of hypertension and blood pressure in school children.

This study focuses on the relationship between some aspects of intra-erythrocytic sodium metabolism (intra-erythrocytic Na content, Na,Li-countertransport), blood pressure, and family history of hypertension, in a group of 84 randomly selected school children (45 males, 39 females). Na,Li-countertransport was significantly related to both systolic blood pressure (SBP) and diastolic blood pressure (DBP) only in boys at the univariate level, but both of these associations lost statistical significance after the possible confounding role of weight and height were taken into consideration. In both sexes, participants with a family history of hypertension had similar values of both intra-erythrocytic Na content and Na,Li-countertransport to participants with no family history. We conclude that family history of hypertension does not seem to play an important role in the determination of either intra-erythrocytic Na content or Na,Li-countertransport at this age. Although the positive association between Na,Li-countertransport and blood pressure observed in adult males is already present in childhood, this probably is still, at least in part, dependent upon body size.

Domperidone is more effective than cisapride in children with diabetic gastroparesis.

BACKGROUND: Disorders of gastrointestinal motility are commonly detected in patients with insulin-dependent diabetes mellitus and are associated with significant morbidity. They contribute to poor metabolic control of diabetes. AIM: To assess the effect of an 8-week course of domperidone or cisapride on gastric electrical activity, gastric emptying time and dyspeptic symptoms in children with insulin-dependent diabetes mellitus and gastroparesis. METHODS: Dyspeptic symptoms were assessed by a score system, gastric emptying time was measured by ultrasonography and gastric electrical activity was obtained by electrogastrography. Fourteen children received domperidone and 14 received cisapride. The median (range) ages were 11.6 years (5-15 years) and 12 years (6-16.9 years), respectively. Symptom assessment, ultrasonography and electrogastrography were repeated at the end of the trial. Fasting and fed (180 min after feeding) glycaemia and haemoglobin A, C (HbA1c) levels were also measured. RESULTS: At the end of the trial both groups showed a significant decrease in symptomatic score; however, the score was markedly lower in the domperidone group than in the cisapride group (P < 0.01). Domperidone was significantly more effective than cisapride in reducing the gastric emptying time (P < 0.05), normalizing gastric electrical activity (P < 0.05) and decreasing the prevalence of episodes of gastric dysrhythmia (P < 0.01). Domperidone was also more effective than cisapride in improving diabetic metabolic control. No potentially drug-related adverse effects occurred. CONCLUSIONS: In children with insulin-dependent diabetes mellitus complicated by dyspeptic symptoms and gastroparesis, domperidone is superior to cisapride in reversing gastric emptying delay and gastric electrical abnormalities, as well as in improving dyspeptic symptoms and diabetic metabolic control.

Endorphins in male impotence: evidence for naltrexone stimulation of erectile activity in patient therapy.

In the present study we evaluated whether naltrexone administration could stimulate sexual function in 30 male patients, ages 25 to 50 years, with idiopathic impotence of at least one year's duration and not of organic etiology. The patients received naltrexone (50 mg/day) or placebo, on a random basis for two weeks. Sexual performance, expressed as the number of full coitus/week, was assessed before (time 0) and during (on days 7 and 15) each treatment. The naltrexone therapy significantly increased the number of successful coitus compared to placebo after 7 and 15 days of treatment: improvement of sexual performance was evident in 11 out of the 15 treated patients. All the patients experienced a significant increase in morning and spontaneous full penile erections/week. No significant side effects were reported. Endocrine studies revealed no significant modification of plasma LH, FSH or testosterone by naltrexone, suggesting that the positive effect of the drug on sexual behavior was exerted at a central level. A two-month follow-up, at which time patients were off treatment, erectile capacity had returned to baseline in 10 patients, while five reported complete recovery of their sexual ability. We hypothesize that an alteration in central opioid tone is present in idiopathic impotence and is involved in the impairment of sexual behavior.

Diabetes mellitus in Kearns-Sayre syndrome: a case with a 10-year follow-up.

An 11-year-old girl with Kearns-Sayre Syndrome developed diabetes mellitus with ketoacidosis at onset and immediate insulin-requirement. In a 10-year follow-up, while neuromuscular disease was progressively increasing, diabetes was well controlled by once-a-day insulin therapy. Insulin secretion appears low, but without impairment during the years. This case points out the diabetes' features in Kearns-Sayre syndrome.

Management of diabetes in childhood: are children small adults?

Diabetes in childhood is the most common chronic disease and generally fits the type 1 category, even though other forms of non-autoimmune diabetes are now emerging in this age. At variance with adults, children and adolescents undergo physiological process, which may frequently require adjustments of clinical management of diabetes. Moreover, the hormonal and psychological changes during puberty may be crucial in conditioning management. Furthermore, common illnesses frequently affecting children may also destabilise metabolic control. Consequently, education in children is the cornerstone of treatment. This review focuses on the several and peculiar aspects of practical management of diabetes in paediatric age, which require professional figures such as paediatricians, nurses, dieticians, psychologists, social assistants originally trained in paediatric area, able to deal with the age-related medical, educational, nutritional and behavioural issues of diabetes.