[Incidence of type 1 diabetes in Navarre (2009-2016): higher in the southern regions of the autonomous community]. / Incidencia de diabetes tipo 1 en Navarra (2009-2016): mayor en la zona sur de la comunidad.

BACKGROUND: Geographical and seasonal variations of type 1 diabetes (T1D) are useful for establishing the key ethio-pathogenic factors of the disease. The present work seeks to analyze the incidence rates of T1D in Navarre for the 2009-2016 period, its geographical distribution and seasonal variations in birth and diagnosis in affected persons. METHODS: Prospective study with one primary and three secondary sources. The completeness of the registry, determined using the capture-recapture method, was 96.08%. The confidence intervals of zone and onset season incidence rates were determined assuming an underlying Poisson distribution. Adjusted effect of onset age, sex, onset season and geographical area over changes in incidence rates were analyzed using a Poisson regression model. Comparison among areas was carried out after the corresponding adjustments of incidence by the indirect standardization method. RESULTS: Four hundred and twenty-eight new cases were detected (incidence= 8.36/100,000 inhabitants per year, CI95%: 7.58-9.19). The disease is predominant in males (63% of patients). The incidence in children under 15 years was higher than in adults (21.54, CI95%: 18.43-25.02 vs. 5.94, CI95%: 5.23-6.71; p<0.001). Incidence was highest in the four southern regions of Navarre, most of the cases being in winter and spring. No differences were found regarding birth season over incidence. CONCLUSION: Navarre maintains a high T1D incidence in childhood that decreases progressively with age. Sex, age group, geographical zone and onset season are independently associated with the incidence rates observed in the study.

[Incidence of type 1 diabetes in Navarre, 2009-2012]. / Incidencia de la diabetes tipo 1 en Navarra, 2009-2012.

BACKGROUND: A north-south gradient for the incidence of type 1 diabetes (DM1) has been described in Europe, with higher incidence in the northern countries. The aim of this study is to describe the incidence data for DM1 in Navarre from 2009-2012, regardless of age at diagnosis, including geographical distribution and age and sex characteristics. PATIENTS AND METHODS: Prospective study, based on one primary and three secondary sources. Completeness of records was assessed, using the capture-recapture method, at 98.42%. Incidence was compared between different gender and age groups by estimating the incidence ratio using Poisson regression methods. To compare the incidence between the different geographical areas, adjustments were made to the values obtained by the indirect standardization method. RESULTS: A total of 216 cases were detected (incidence: 8.4/100,000 population/year; 95 % CI: 7.3-9.5). Incidence was higher in children than in adults, although the number of new cases was highest in those aged over 15. The age group with the highest incidence was 10 to 14 years; however, the highest percentage of patients fell in the 15 to 29-year-old group. Incidence was higher in men than in women. The incidence rates in the three southern regions were generally higher than the mean for Navarre. CONCLUSIONS: Navarre has a very high incidence of DM1 in children and adults aged 15 to 29. DM1 is more common in men and shows some geographic variability.

Influence of age at diagnosis on glycaemic control evolution in patients with type 1 diabetes.

AIM: The objective of this study was to describe the relationship between age at onset, with no age limits, and glycaemic control evolution from the time of onset in patients with type 1 diabetes (T1D). METHODS: This observational retrospective follow-up study included 716 patients with T1D onset between 1990 and 2008 treated at the Navarre Hospital Complex. The mean (SD) follow-up lasted 10.1 (5.3) years. Information on their HbA(1c) levels was collected at onset and every year thereafter. Generalized additive mixed models and linear models were used, with patients' annual HbA1c levels as the response variable and the number of years since onset together with age at onset as covariates. RESULTS: The evolution of glycaemic control is not linear and differs across all age groups. Children reach their highest values in adolescence, while patients with onset at ages 10-15 years stabilize their HbA(1c) values after 7 or 8 years. In adults, it is notable that an age of onset ≥ 45 years is associated with the worst control. CONCLUSION: A non-linear increase in HbA(1c) levels can be observed from the time of T1D diagnosis, with significant differences across all age groups.

Papel de los polimorfismos de los genes CFH y ARMS2 en el desarrollo de la retinopatía y la cardiopatía isquémica en la diabetes tipo 1 / Role of CFH and ARMS2 polymorphisms in retinopathy and coronary artery disease in type 1 diabetes

Fundamento. La diabetes tipo 1 (DT1) es un enfermedad con elevada morbilidad vascular. El objetivo de este estudio es valorar la asociación de los polimorfismos rs1410996 del gen CFH y rs10490924 del gen ARMS2 en pacientes con DT1. Material y métodos. Se trata de un estudio retrospectivo, en el que se han analizado las características clínicas y los polimorfismos rs1410996 del gen CFH y rs10490924 del gen ARMS2 de 147 pacientes con DT1 valorados en la consulta de Endocrinología. Resultados. Todos los pacientes que desarrollaron retinopatía diabética proliferativa en los primeros 20 años de evolución eran portadores del polimorfismo rs1410996 del gen CFH. La frecuencia del alelo de riesgo fue significativamente mayor en los pacientes con cardiopatía isquémica que en los que no la presentaban (75 frente a 53%, p<0,001). Conclusiones. Parece existir una tendencia a aumentar el riesgo de desarrollar retinopatía diabética proliferativa en los pacientes con DT1 asociado con el polimorfismo rs1410996 del gen CFH. Este polimorfismo parece asociarse también con el desarrollo de cardiopatía isquémica en estos pacientes. Sin embargo, el polimorfismo rs10490924 del gen ARMS2 no parece asociarse con la retinopatía ni con la cardiopatía isquémica(AU)

Background. Type 1 diabetes is associated with vascular morbidity. The aim of this study was to evaluate the role of polymorphisms rs1410996 CFH and rs10490924 ARMS2 with proliferative diabetic retinopathy and coronary disease in type 1 diabetes patients. Material and methods. We present a retrospective study that analyses the clinical characteristics and the polymorphisms rs1410996 CFH and rs10490924 ARMS2 of 147 type 1 diabetes patients. Results. The patients who developed proliferative diabetic retinopathy in the first 20 years carried the rs1410996 CFH polymorphism. The overall risk-allele frequency was significantly higher among patients with coronary artery disease than in those without it (75 vs.53%, p<0.001). Conclusions. rs1410996 CFH polymorphism could be associated with both proliferative diabetic retinopathy and coronary artery disease in type 1 diabetes patients. However, rs10490924 ARMS2 does not seem to be associated either with retinopathy or coronary artery disease(AU)

[Role of CFH and ARMS2 polymorphisms in retinopathy and coronary artery disease in type 1 diabetes]. / Papel de los polimorfismos de los genes CFH y ARMS2 en el desarrollo de la retinopatía y la cardiopatía isquémica en la diabetes tipo 1.

BACKGROUND: Type 1 diabetes is associated with vascular morbidity. The aim of this study was to evaluate the role of polymorphisms rs1410996 CFH and rs10490924 ARMS2 with proliferative diabetic retinopathy and coronary disease in type 1 diabetes patients. MATERIAL AND METHODS: We present a retrospective study that analyses the clinical characteristics and the polymorphisms rs1410996 CFH and rs10490924 ARMS2 of 147 type 1 diabetes patients. RESULTS: The patients who developed proliferative diabetic retinopathy in the first 20 years carried the rs1410996 CFH polymorphism. The overall risk-allele frequency was significantly higher among patients with coronary artery disease than in those without it (75 vs. 53%, p<0.001). CONCLUSIONS: rs1410996 CFH polymorphism could be associated with both proliferative diabetic retinopathy and coronary artery disease in type 1 diabetes patients. However, rs10490924 ARMS2 does not seem to be associated either with retinopathy or coronary artery disease.

Diabetes MODY tipo 5: a proposito de un caso / Maturity-onset diabetes of the young type 5: a case report

La diabetes MODY-5 es un tipo de diabetes monogenica infrecuente, causada por mutación en el gen del factor de transcripción nuclear hepático 1-beta (HNF-1¦Â). Esta mutación puede ser de tipo puntual o bien corresponder a delecciones grandes, y a su vez, puede aparecer de novo por mutación espontanea o bien ser transmitida de forma hereditaria con caracter autosomicodominante. Está asociada con un alto riesgo de complicaciones microvasculares de aparición temprana en las personas afectas, así como con alteraciones renales características del tipo quistes y anomalías del tracto genital, que estan presentes incluso antes del nacimiento. Por ello, está justificado hacer pruebas de detección para las mutaciones de HNF-1 en diabíticos no obesos, sobre todo, cuando existen alteraciones renales o genitales asociadas, sin tener en cuenta losantecedentes familiares (AU)

MODY-5 diabetes is an infrequent type of monogenic diabetes, caused by mutation in the gene of the nuclear hepatic transcription factor 1-beta (HNF-1¦Â).This mutation can be of a momentary type or it might correspond to big deletions, and, in its turn, it can appear due to spontaneous de novo mutation or it can be transmitted by hereditary with an autosomal dominant character. It is associated with a high risk of microvascular complications that appear early in affected people, as well as with characteristic renal alterations of the cyst type, and anomalies of the genital tract, which are present even before birth. That is why it is justified to carry out detection tests for HNF-1¦Â mutations in non-obese diabetics, above all when there are associated renal or genital alterations, without consideration of family antecedents (AU)

[Glucocorticoid hypofunction in myotonic dystrophy]. / Hipofunción glucocorticoide en la distrofia miotónica.

INTRODUCTION: Myotonic dystrophy (DM1) is an autosomal dominant disorder whose genetic defect consists of the amplification of an unstable CTG trinucleotide repeat in the 3' untranslated region of the dystrophia myotonica protein kinase gene (DMPK). This is a multi-systemic disease with a well-known endocrinological repercussion. With respect to the adrenal function variable results have been described, although lately they are interpreted as indicators of a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. MATERIAL AND METHODS: Twenty-five patients (13 men and 12 women) with DM1 were recruited. They were analysed for: basal cortisol and ACTH, stimulus test with 0.25 mg of ACTH for cortisol and CRH test for cortisol and ACTH. Similarly, the degree of expansion of CTG was evaluated by Southern blot and PCR. Twenty-five healthy individuals, comparable by age and sex, were studied as a control group; the CRH test was carried out on 11 of them. RESULT: One patient was diagnosed with primary non-autoimmune adrenal failure. In the rest of the cases there were no differences between the basal ACTH of patients and controls, and the cortisol response to ACTH was normal. The patients showed a lower level of basal cortisol (p<0.01) and also showed, following stimulation with CRH, a lower cortisol response (p<0.05) with higher average values of ACTH. CONCLUSIONS: Our data differs from the latest publications and point to an adrenal hypofunction due to lack of efficacy of the ACTH on its receptor or at the post-receptor level. We suggest that the etiology might be related to the underlying defect in the gene that codifies DMPK.

The malignant potential of a succinate dehydrogenase subunit B germline mutation.

Familial catecholamine secreting tumors have been associated with multiple endocrine neoplasia type 2, Von Hippel-Lindau disease and neurofibromatosis type 1. In the last years, mutations of genes encoding subunits B, C and D of the succinate dehydrogenase have been discovered as other causes of pheochromocytomas and paragangliomas. We diagnosed a malignant retroperitoneal paraganglioma in a 64-yr-old man with bone metastasis in 2001. Two years later a retroperitoneal benign paraganglioma was found and resected in his 32-yr-old daughter. Thus we diagnosed in this family a paraganglioma syndrome. We performed molecular genetic analyses of the genes SDHB, SDHC, and SDHD. We detected in the SDHB gene the mutation SDHB c. 558-3 C> G affecting the splice site of exon 5. In a second daughter the mutation was also detected, thorough clinical investigation revealed normal results. We conclude that the SDHB mutation predisposes to abdominal extra-adrenal and potential malignant pheochromocytoma with incomplete penetrance.

Primary care nursing of coronary patients and reduction of re-infarction risk: a nested case-control study.

OBJECTIVES: To estimate the risk reduction for re-infarction achieved in primary health care centres. STUDY DESIGN: This was a case-control study nested in a cohort of coronary patients. POPULATION: Nine hundred and eighty-five coronary patients, aged less than 76 years who had survived for more than 6 months after their first acute myocardial infarction (AMI), were recruited from two public hospitals in Navarre, Spain. Cases (repeated myocardial infarction, n = 137) and controls (patients with one AMI who had not had a second infarction, [n = 137) who had not been treated with invasive procedures were extracted from this cohort and matched by gender, age, hospital and the secondary prevention time frame. OUTCOMES MEASURED: Re-infarction. RESULTS: In total, 31.4% of cases and 51.8% of controls attended the primary care nurse clinic regularly. This difference accounted for a significant reduction of the risk of re-infarction, even after adjustment for regular visits to the family physician, life styles (smoking, walking habit and dietary changes) and drug treatments (odds ratio: 0.48; 95% confidence interval: 0.26-0.89). A regular schedule of visits to the family physician showed no association with further coronary risk reduction. CONCLUSIONS: Regular attendance of coronary patients at a primary care nurse clinic is associated with a lower risk for re-infarction. Psychological rehabilitation could be the main reason for this benefit, since protection persists after adjustments for other known risk factors.

Polimorfismos genéticos en TNFalfa y PPARgamma2 y síndrome de resistencia a insulina

El síndrome de resistencia insulínica aparece como consecuencia de la interacción de factores genéticos y ambientales. Entre los primeros se ha descrito la influencia que ejercen determinados polimorfismos sobre la sensibilidad a la insulina. Con objeto de conocer el efecto que tienen ciertos polimorfismos en los genes de TNFalfa y PPARgamma2 sobre los componentes del síndrome de insulinresistencia en nuestra población, hemos estudiado 313 personas 159 obesos y 154 con peso normal, con un diseño casos-controles, a los que se ha practicado: valoración de medidas antropométricas y TA, analítica plasmática de: glucosa, perfil lipídico, insulina y leptina, índice HOMA y análisis genético para los polimorfismos -238 G/A y -308 G/A en la región promotora del gen de TNFalfa y el polimorfismo Pro 12A1a en el gen de PPARgamma2. Resultados: La frecuencia alélica y prevalencia de los mencionados polimorfismos en nuestros pacientes fueron las esperadas. Los obesos, en su conjunto, mostraron valores significativamente más bajos de HDL colesterol y más elevados en todos los parámetros restantes. Los obesos que presentaban la mutación -308 A en el gen de TNFalfa tenían mayores IMC y por ciento de grasa corporal que aquellos sin esa mutación. Los obesos que presentaban la mutación -238A en el gen de TNFalfa tenían menores: índice HOMA, TA diastólica y niveles de leptina. Los obesos que presentaban la mutación A1a 12 en el gen de PPARy2 tenían menores niveles de insulina e índice HOMA. Conclusión: El polimorfismo -308 A en el gen de TNFalfa se asocia con mayor obesidad aunque no con mayor resistencia a la insulina mientra que los polimorfismos -238 A en TNFa y Prol2Aaa en PPARy2 se acompañan de mayor sensibilidad a la insulina (AU)

Effects of cholinergic blockade on nocturnal thyrotropin and growth hormone (GH) secretion in type I diabetes mellitus: further evidence supporting somatostatin's involvement in GH suppression.

To investigate the influence of cholinergic pathways on somatostatin (SS) tone in type I diabetes mellitus, we studied the effect of the muscarinic receptor antagonist pirenzepine ([PZP] 100 mg orally) on spontaneous nocturnal growth hormone (GH) and thyrotropin (TSH) secretion and on their response to GH-releasing hormone (GHRH) in the morning in a group of nine insulin-dependent diabetic patients with poor diabetic control. When the nocturnal period was divided into two phases (11:00 PM to 2:30 AM and 3:00 AM to 6:00 AM), both GH and TSH mean concentrations during the first phase were higher than those seen in the second half of the night following placebo administration (GH, 13.4 +/- 1.1 v 4.15 +/- 0.9 ng/mL, P < .001; TSH, 1.9 +/- 0.21 v 1.57 +/- 0.1 microU/mL, P < .05). Pretreatment with PZP induced a significant reduction of GH secretion (3.17 +/- 1.1 v 13.4 +/- 1.1 ng/mL, P < .001) and TSH secretion (1.61 +/- 0.21 microU/mL, P < .05) in the first phase of the night, accounting for a 64% and 11% reduction in the GH and TSH nocturnal peak, respectively. PZP reduced the GH response to GHRH in the morning (17.9 +/- 2.7 v 36.7 +/- 6.3 ng/mL, P < .05), but did not induce any change in TSH values at that time. A positive relationship (r = .73, P < .01) was observed between the percent reduction of the GH response to GHRH and that of the nocturnal GH peak following PZP administration. PZP caused a significant reduction in glucose levels during the second phase of the night (6.4 +/- 0.92 v 9.81 +/- 0.85 mmol/L, P < .05). These results demonstrate that administration of PZP reduces GH and TSH secretion, providing further support for the involvement of SS in the inhibition of GH secretion induced by cholinergic antagonists in type I diabetics. The inhibitory effect of PZP on GHRH-induced GH secretion may help to predict nocturnal GH behavior following administration of the drug.

[Administering toxins with antithyroids. Does this prevent recidivism of Graves disease? ]. / Administrar torixina junto a antitiroideos previene la recidiva de la enfermedad de Graves?

There are three possibilities in the treatment of Graves-Basedow disease: antithyroids drugs, sub-total thyroidectomy and I131. In the USA there is a clear preference for definitive therapy with I131 once the thyrotoxicosis has been controlled. In Europe and Japan, however, the preference is for trying a conservative treatment, in the hope of inducing a permanent remission without recourse to radical methods. The most usual conservative pattern involves starting with high doses of antithyroids which are progressively reduced over the course of one year. The high rate of recurrence obtained with this method has fired the imagination of the endocrinologists in the search for other patterns that would provide more satisfactory results. One of these alternative patterns consists of combining thyroxine with antithyroids drugs. In this paper the characteristics of this combined pattern are reviewed. Following the justification, the clinical and experimental foundations on which it is based are outlined. Thirdly, details are given of clinical experiences taken from the medical literature and, finally, our own clinical experience is described after a five years follow up. It is concluded that: 1. The combined treatment delays the appearance of recurrence but does not reduce its frequency. 2. The addition of thyroxine alone following a course of combined treatment is not justified and 3. Prospective studies are needed in which hyperthyroid patients are grouped according to the variables that can affect recurrence.

[Clinical usefulness of the glucagon test in the study of pancreatic islet cell function]. / Utilidad clínica del test de glucagón en el estudio de la función insular pancreática.

In an attempt to assess the utility of glucagon test as an index of beta cell function, we have studied the C-Peptide response to intravenous injection of 1 mg of glucagon in 77 patients with type I diabetes, 27 type II diabetics and 14 normal subjects. A significant difference between basal and glucagon-stimulated C-Peptide levels as well as a good relationship between both values were observed in all groups (r values 0.91, 0.80 and 0.89 respectively). Both basal and stimulated C-Peptide concentrations showed significant relationship with the body mass index and total cholesterol levels, whereas both parameters were negatively related to insulin requirements in type I diabetic group. Absolute C-Peptide increment was different in all groups, despite it was not related to basal C-Peptide levels. These findings confirm the usefulness of glucagon test as an investigative tool to assess the secretory capacity of beta-cell, suggesting that estimation of C-Peptide increment represents the best parameter to evaluate beta-cell reserve.

[Treatment with octreotide (SMS 201-995) in a case of intestinal carcinoid tumor]. / Tratamiento con octreotide (SMS 201-995) en un caso de tumor carcinoide intestinal.

Over the past few years the usefulness of some somatostatin's analogues in the treatment of intestinal tract endocrine tumors has been demonstrated. Notwithstanding, the results obtained are variable. The case of a carcinoid tumor with a hepatic metastasis is presented and its clinical as well as its biochemical and its morphological results are evaluated after treatment with octreotide over a seven months period. It is important to highlight the great clinical improvement obtained at the beginning of treatment. Treatment was not effective in the control of tumor progression. After the injection of such a drug, a decrease in serotonin and 5-hydroxy-indoleacetic acid serum levels was observed as well as a reduction in the urinary metabolite. It is concluded that octreotide is very useful for the symptomatic treatment of carcinoid syndrome.

[Influence of the initial treatment of endometriosis and results obtained by in-vitro fertilization]. / Influence du traitement initial de l'endométriose et résultats obtenus en fécondation in vitro.

The authors have investigated the results obtained by in-vitro fertilization in cases of pelvic endometriosis. Fifty-eight (58) stimulation cycles have been analyzed in function of the previous curative treatment, which may have been a combine medico-surgical treatment or a conventional surgical treatment. Six pregnancies which progressed to full term were achieved in the 8 patients who had previously received medico-surgical treatment. Twenty punctures were performed. In patients who received an initial medical treatment, there were no pregnancies carried to full term and three clinical terminations of pregnancy for a total of 15 punctures. A celioscopy check-up revealed persistent endometriosis in 10 of the patients involved. No clinical pregnancy was observed following primary surgical treatment. In all these cases, there were lesions affecting the ovary and the numbers of ovocytes and embryos were significantly reduced.

Insulin requirements and residual beta-cell function 12 months after concluding immunotherapy in type I diabetic patients treated with combined azathioprine and thymostimulin administration for one year.

An increase in clinical and functional remissions with immunosuppression, as well as abnormal T-cell function, in Type I diabetic patients has been reported in the early stages of diabetes. A controlled trial with azathioprine and thymostimulin in separate and combined administration was performed in 45 recently diagnosed Type I diabetic patients. Phenotyping of the T-lymphocyte subsets, levels of CD25 positive cells and interleukin-2 production by patients' lymphocytes, as well as remission rate and stimulated C-peptide levels, were serially assessed. Remission was defined as mean weekly glycemic profiles less than or equal to 7 mmole/l, serial HbA1 values in the normal range and no insulin requirements for at least 2 consecutive months. At 3,6,9 and 12 months of immunotherapy, remission occurred respectively in 0%, 8.3%, 16.6% and 0% of the conventionally treated diabetic controls and in 42.8%, 50%, 42.8% and 36.2% of the subjects submitted to combined azathioprine and thymostimulin administration. Patients receiving azathioprine or thymostimulin alone did not achieve better remission rates than controls. C-peptide levels were significantly higher (above 0.6 pmol/ml) in patients with remission than in those not in remission (P less than 0.02) throughout the trial. Excessive interleukin-2 production in recently diagnosed diabetics returned to normal levels in patients in remission. In the group receiving combined therapy, 38.5%, 25% and 23% were still in clinical remission at 6, 9 and 12 months after drug withdrawal. Twelve months after stopping treatment, patients who had remitted exhibited significantly lower insulin requirements and greater endogenous insulin secretion than those who had not remitted; the former also maintained near normal glycemic control. No side effects were detected except mild and transient leucopenia in a reduced number of patients receiving azathioprine. Remission was related to the time of beginning immunotherapy after the onset of diabetes (17.1 +/- 7 vs 42.5 +/- 15 days; P less than 0.01) and to age (17.7 +/- 5.6 vs 13 +/- 7 years; P less than 0.05). Interleukin-2 production seems to be negatively associated with clinical remission in the early stages of diabetes. Results suggest a complementary effect of the drugs used in this study that may enhance long-term remission in recently diagnosed Type I diabetic patients.