Leonor Gomes

Mutational Analysis of Portuguese Families with Multiple Endocrine Neoplasia Type 1 Reveals Large Germline Deletions

objective To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation‐carriers.

Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population.

The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of type 1 diabetes often produced conflicting results in different ethnic backgrounds. The aim of this study was to test for association between common VDR polymorphisms and the genetic susceptibility to type 1 diabetes in the Portuguese population. We genotyped 207 patients with type 1 diabetes and 249 controls for the FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI G>T (rs7975232), and TaqI C>T (rs731236) single nucleotide polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. The distribution of VDR genotype, allele, and haplotype frequencies did not differ significantly between patients and controls. These data suggest that the single nucleotide polymorphisms of the VDR gene are unlikely to contribute significantly to type 1 diabetes susceptibility in the Portuguese population.

Screening for pancreatic exocrine insufficiency in patients with diabetes mellitus

OBJECTIVES:Fecal elastase 1 (E1) is a relatively sensitive and specific indirect test of pancreatic exocrine function. Despite the high functional reserve of the pancreas, it is recognized that a significant proportion of diabetic patients may also have a deficit of the exocrine function. The aim of this study was to screen patients with diabetes mellitus (DM) for pancreatic exocrine insufficiency.METHODS:A total of 80 patients were enrolled in this prospective study, including 42 patients with DM and 38 nondiabetic controls. Exclusion criteria were as follows: age >75 yr; alcohol intake >40 g/day; intake of orlistat or acarbose; and history of diarrhea, pancreatitis, GI surgery, immunodeficiency, or cancer. All patients underwent the same study protocol, which included clinical evaluation, determination of fecal E1, plain x-rays of the abdomen, and abdominal ultrasound. An immunoenzymatic method (ScheBoTech, Wettenburg, Germany) was used for E1 determination. Diagnosis of pancreatic insufficiency was established for a fecal E1 <200 μg/g.RESULTS:The DM and control groups were comparable regarding age (62 ± 10 yr vs 56 ± 10 yr), sex (18 men and 24 women vs 15 men and 23 women), and proportion of patients with excess weight (50% vs 42%). Patients had DM diagnosed for 11.5 ± 8 yr, with structural changes of the pancreas detected on ultrasound in three cases and calcifications in one case. There was no relationship between E1 determination <200 μg/g and the duration or the type of therapy for DM. Fifteen patients (36%) in the DM group had a fecal E1 <200 μg/g, compared with two patients (5%) in the control group (p < 0.05). In the DM group (n = 42), 11 patients with excess weight presented a fecal E1 <200 μg/g, whereas four patients with a BMI <25 presented this result (p < 0.05).CONCLUSIONS:Pancreatic exocrine insufficiency occurs more frequently in diabetic patients than in controls. Diabetic individuals with excess weight (BMI >25) may be at increased risk for underlying exocrine pancreatic insufficiency.

PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency

Objective  Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD.

Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI study

Type 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes.

Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer

Objective  Xenobiotic‐metabolizing enzymes are widely polymorphic and confer interindividual variation in the ability to detoxify carcinogens or to activate pro‐carcinogens. A common polymorphism of cytochrome P450 2D6 (CYP2D6) results in lack of enzyme activity and has been associated with an altered susceptibility to several cancers. The aim of this study was to investigate the association between the CYP2D6 poor metaboliser genotype and the risk of papillary thyroid cancer (PTC).

Combined GSTM1 and GSTT1 null genotypes are associated with a lower risk of papillary thyroid cancer

Individual susceptibility to cancer is influenced by polymorphisms of genes encoding drug-metabolizing enzymes such as the glutathione S-transferases (GST). The null polymorphisms of the GSTM1 and GSTT1 genes have been associated to a modified risk of several cancers but studies of thyroid cancer have produced conflicting results. The aim of this study was to investigate the relationship between these polymorphisms and the risk of papillary thyroid cancer (PTC). A total of 188 patients with PTC and 247 controls were genotyped using a PCR-based assay. Odds ratios (OR) and 95% confidence intervals (CI) for each homozygous null genotype were determined. The frequency of each of the GSTM1 and GSTT1 null genotypes did not differ significantly between patients and controls (OR=0.83, 95%CI: 0.56–1.21; p=0.328; and OR=0.66, 95%CI: 0.39–1.12; p=0.123, respectively), but the frequency of individuals that had the combined GSTM1 null/GSTT1 null genotypes was significantly lower in the patient group (OR=0.50, 95%CI: 0.26–0.97; p=0.040). The GSTM1 null genotype was associated with a lower risk of advanced cancer stages (III/IV) (OR=0.50, 95%CI: 0.26–0.96; p=0.036) and the GSTT1 null genotype was associated with a lower risk of the follicular variant of PTC (OR=0.31, 95%CI: 0.10–0.97; p=0.044). These results suggest that GSTM1 and GSTT1 null genotypes are weak, yet possible, modifiers of the risk of PTC. This protective effect may be due to a role of the GSTM1 and GSTT1 encoded enzymes in the metabolic activation of putative thyroid carcinogens or in other pathways involved in thyroid carcinogenesis.

Short- and long-term mortality after bariatric surgery: A systematic review and meta-analysis

The objective of this study was to investigate short‐ (≤ 30 days) and long‐term (≥ 2 years) all‐cause mortality after bariatric surgery among adult patients with obesity.

Controversies in the management of hyperglycaemic emergencies in adults with diabetes

Hyperglycaemic emergencies are associated with significant morbi-mortality and healthcare costs. Management consists on fluid replacement, insulin therapy, and electrolyte correction. However, some areas of patient management remain debatable. In patients without respiratory failure or haemodynamic instability, arterial and venous pH and bicarbonate measurements are comparable. Fluid choice varies upon replenishment phase and patients condition. If patient is severely hypovolaemic, normal saline solution should be the first option. However, if patient has mild/moderate dehydration, fluid choice must take in consideration sodium concentration. Insulin therapy should be guided by β-hydroxybutyrate normalization and not by blood glucose. Variations of conventional insulin infusion protocols emerged recently. Priming dose of insulin may not be required, and fixed rate insulin infusion represents the best option to suppress hepatic glucose production, ketogenesis, and lipolysis. Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis resolution and prevents rebound hyperglycaemia. Simpler protocols using subcutaneous rapid-acting insulin analogues for mild/moderate diabetic ketoacidosis treatment have proven to be safe and effective, but further studies are required to confirm these results. Treatment with bicarbonate, phosphate, and low-molecular-weight heparin is still disputable, and randomized controlled trials are urgently needed to optimize patient management and decrease the morbi-mortality of hyperglycaemic emergencies.

Diabetic peripheral neuropathy assessment through corneal nerve morphometry

Diabetic peripheral neuropathy is one of the most common complications of diabetes. It affects 50% of the patients after 25 years of disease. Its early diagnosis and accurate assessment are important to define the higher risk patients. A non-invasive technique for its assessment was developed. The technique is based on morphometric parameters of corneal nerves, obtained by analysis of corneal confocal microscopy images of the sub-basal nerve plexus. We examined 12 type-2 diabetic patients (average age: 58±10 years) and 8 healthy controls (54±7 years). We found differences statistically significant for nerve length, density, width and branching parameters, when we compare individuals with and without neuropathy. The corneal sub-basal nerve plexus morphology has the potential for identifying the presence of diabetic peripheral neuropathy and evaluating its severity.