Belén Roldán

Genetic Basis of Metabolic Abnormalities in Polycystic Ovary Syndrome Implications for Therapy

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. The syndrome is frequently associated with an increased risk for insulin resistance and type 2 diabetes mellitus; obesity exacerbates insulin resistance and favors the progression from impaired glucose tolerance to diabetes in these patients. In young women, precocious pubarche and hyperinsulinemia are early manifestations of PCOS.The familial clustering of women with PCOS suggests that heredity is implicated in the origin of the syndrome. However, genetic approaches to its pathogenesis have been hampered by the heterogeneity of phenotypic features within families, and the lack of uniform criteria for diagnosis.Currently, PCOS is considered a polygenic trait that might result from the interaction of susceptibility and protective genomic variants under the influence of environmental factors. Both linkage analysis and association studies are valid tools for the study of the genetics of PCOS.Candidate genes for PCOS include those related to androgenic pathways and metabolic associations of the syndrome. More recently, genes encoding inflammatory cytokines have been identified as target genes for PCOS, as proinflammatory genotypes and phenotypes are also associated with obesity, insulin resistance, type 2 diabetes, PCOS, and increased cardiovascular risk.This paper reviews the candidate genes involved in the metabolic pathways that are altered in patients with PCOS. Despite a significant amount of research in this area, none of the genes studied so far has been identified as the PCOS susceptibility gene for the majority of cases. PCOS is the first component of the metabolic syndrome to be detected in many women, so the identification and correct diagnosis of PCOS has important preventive and therapeutic implications for the affected women and their families. In the future, new therapeutic approaches to PCOS will rely on knowing the genes, environmental influences, and etiologic mechanisms associated with the disorder.

Intramural haematoma of the duodenum following endoscopic biopsy: an unusual complication of non-therapeutic endoscopy in children

This case report points out the rarity of intramural duodenal haematomas after intestinal biopsy in children and serves as a reminder to paediatric endoscopists to be aware of this complication. A 4-year-old girl with short stature and increased anti-gliadin antibodies and no history of bleeding disorders underwent upper gastrointestinal endoscopy to obtain a small bowel biopsy. Results of laboratory tests performed prior to the procedure showed a normal platelet count, prothrombin time, and activated partial thromboplastin time. Five duodenal biopsy specimens were obtained using endoscopic grasp forceps with no excessive bleeding being observed. Six hours later the patient presented with abdominal pain and bilious vomiting. Physical examination disclosed normal vital signs and diffuse abdominal tenderness. Levels of haemoglobin, haematocrit, amylase and serum electrolytes were normal. Abdominal ultrasound showed a solid and cystic mass in the second and third duodenal portions. An abdominal CT scan was performed and confirmed the presence of an asymmetrical 4·5 cm mass located within the second and third duodenal portions consistent with an intramural haematoma. The patient followed conservative treatment with total parenteral nutrition. Complete resolution of the haematoma was observed on ultrasound examination on day 19. Two days later the patient was discharged from the hospital. The histological investigation of the intestinal biopsy was normal. Three years later the girl remains asymptomatic and without sequelae. In most cases, intramural duodenal haematoma is an entity caused by abdominal trauma and a complication of therapeutic upper gastrointestinal endoscopy. The development of an intramural duodenal haematoma after endoscopic small bowel biopsy has been reported in nine children, some of them being leukaemic patients or bone marrow transplant recipients [1] and in seven children when using capsule biopsy. It is difficult to state the frequency of intramural duodenal haematoma after biopsy; complications of this procedure develop in less than 2% of cases and are usually mild [4]. In our institution we have performed 2,640 intestinal capsule biopsies and 2,797 upper gastrointestinal endoscopies in children. The only one patient who presented with clinical manifestations of an intramural haematoma is the one described in this report. No other serious complications were observed in our population. The cause of the duodenal haematoma in patients with no underlying disease or therapy-altered coagulation is not clear. Some special features of duodenal anatomy have been involved [3]. Two other facts that could increase the likelihood of haematoma occurrence when biopsies are obtained by endoscopy are the greater number of biopsy specimens obtained and the shear injury associated with obtaining deeper portions of biopsy specimens [5]. In order to prevent this complication, Zinelis et al. [6] have suggested obtaining biopsies from the duodenum extending the forceps no more than 2–3 cm from the endoscope. The clinical presentation of intramural duodenal haematoma is similar in almost all cases and includes severe abdominal pain and vomiting, frequently associated with pancreatitis. Diagnosis is confirmed using imaging techniques with ultrasound, CT scan and upper intestinal series being the most frequently used [2]. Once diagnosis is confirmed and intestinal perforation excluded, conservative treatment with nasogastric C. Camarero (&) AE D. Herrera AE F. Olivares AE B. Roldan Servicio de Pediatria, Hospital Ramon y Cajal, Universidad de Alcala, Madrid, Spain E-mail: ccamareros@yahoo.es Tel.: +34-91-3165443 Fax: +34-91-3368417

Impact of insulin pump therapy on long-term glycemic control in a pediatric Spanish cohort

AIMS To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. METHODS Retrospective longitudinal study including ninety patients [10.5 (6.5-13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. RESULTS HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 ± 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 ± 1.8 at one year of CSII to 6.7 ± 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CONCLUSIONS CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort.

Infusión subcutánea continua de insulina en menores de 6 años: evolución a largo plazo

OBJECTIVE The aims of the study are to evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) treatment in pre-school children with type I diabetes, and to assess whether the criteria of good metabolic control are achieved. METHOD A review was performed on the medical charts of patients<6 years of age who started CSII treatment between 2003 and 2014. The cohort consisted of 27 patients (mean age 4 (2.9-4.7) years, 56% males). An analysis was made including the age at onset, type I diabetes duration, HbA1c (HPLC, Menarini, normal value 5.1±0.31%), insulin dose (u/kg/day), number of capillary blood glucose measurements, number of baseline processes per day, % baseline/total insulin (B/TI), insulin ratios (I/HC) at different meals, severe hypoglycaemia (HS episodes/100 patients years), DKA events, percentages of normal blood glucose (70-180mg/dl), hyperglycaemia (>180mg/dl), and hypoglycaemia (<70mg/dl), mean blood glucose, standard deviation and coefficient of variation (SD/mean glucose ×100). Statistical analysis was performed using SPSS. RESULTS HbA1c decreased from 6.9% (6.7-7.5) to 6.8% (6.4-7.1) after one year of CSII. Afterwards, it remained under 6.8% during the follow-up (median 5 years [3-6]). Prior to CSII, 74% of children had HbA1c levels < 7.5%. It increased to 96% after one year of CSII. Median blood glucose measurements /day was 10 (9-11). Total insulin dose did not change significantly. During the follow-up, there was one episode of DKA and one episode of HS. I/HC at breakfast were higher than at other meals (0.92 vs. 0.55, 0.6 and 0.5, respectively). CONCLUSIONS CSII is effective and safe in pre-school children. It allows good metabolic control (based on Society for Paediatric and Adolescent Diabetes / American Diabetes Association criteria) to be achieved and maintained for long periods of time without an increase in adverse events.

La respuesta monofásica a la sobrecarga oral de glucosa como factor predictivo del riesgo de diabetes tipo 2 en pacientes pediátricos con obesidad

INTRODUCTION The onset of obesity at young ages is strongly associated with the early development of type 2diabetes (T2D). The shape of the curves of glucose and insulin curves during an oral glucose tolerance test (OGTT) could predict the risk of developing T2D. OBJECTIVE To analyse the morphology of the OGTT and determine T2D risk factors in a mainly Caucasian population of children and adolescents. METHODS Observational retrospective study including 588 patients (309 males, 279 females) with a mean age of 11.1±2years, and of whom 90.3% were Caucasian. Risk factors for T2D were compared in patients with a monophasic or biphasic pattern during the performance of an OGTT, as well as anthropometric and biochemical variables, insulin resistance, and beta-cell function. RESULTS The shape of the glucose curve was monophasic in 50.2% of patients (50.8% male), biphasic in 48.5% (47.6% males), and indeterminate in 1.3%. The monophasic pattern showed lower insulin-sensitivity and worse beta-cell function. Patients with a biphasic pattern had a higher BMI, waist circumference, and blood pressure, although the results were not significant. Latin-American patients had significantly lower serum glucose levels with higher insulin levels during the OGTT. CONCLUSIONS The pattern of response to an OGTT reflects different metabolic phenotypes. Paediatric patients with a biphasic pattern have lower risk-profiling for T2D. The performing of an OGTT could be useful to implement early intervention strategies in children and adolescents with obesity, in order to prevent the development of pre-diabetes or T2D.