Maturity-onset diabetes of the young: From a molecular basis perspective toward the clinical phenotype and proper management / Maturity onset diabetes of the young: de la base molecular al fenotipo clínico y el manejo adecuado

Maturity-onset diabetes of the young (MODY) comprises a heterogeneous group of monogenic disorders characterized by primary defect in pancreatic β-cell function, early onset and autosomal dominant inheritance, accounting for about 1-5% of all diabetes diagnoses. Mutations in 14 genes are responsible for the majority of all MODY cases described so far. The clinical phenotype relies on genetic defects, with important implications in the optimal treatment and prognosis definition. MODY's early diagnosis remains a challenge, since this group of inherited disorders comprises a large clinical spectrum and it usually overlaps with other types of diabetes, requiring a high index of suspicion even if the definitive statement demands a molecular genetic study. Recent advances on the genetic determinants and pathophysiology of MODY have allowed a better understanding of its underlying molecular mechanisms, providing a proper genetic counseling and early diagnosis. These new management insights will make possible to set up new therapeutic strategies, with drugs able to prevent, correct or at least delay the decline of pancreatic β-cell function, thus affording for a more personalized treatment and, ultimately, for a better patient care

La diabetes tipo MODY (del inglés, maturity onset diabetes of the young) comprende un grupo heterogéneo de enfermedades monogénicas caracterizadas por un defecto primario de la función de las células β-pancreáticas, con inicio precoz y herencia autosómica dominante, que representa aproximadamente el 1-5% de las diabetes diagnosticadas. Las mutaciones descritas hasta la actualidad en 14 genes son responsables de la mayoría de los casos de la diabetes tipo MODY. El fenotipo clínico depende del defecto genético, y su identificación es importante para definir el tratamiento y el pronóstico. El diagnóstico temprano de la diabetes tipo MODY sigue siendo un reto, puesto que abarca un largo espectro de manifestaciones que se solapan con las de otros tipos de diabetes, exigiendo así un elevado grado de sospecha clínica y el diagnóstico definitivo necesita del estudio genético molecular. Los progresos recientes en el conocimiento de los determinantes genéticos y de la fisiopatología de la diabetes tipo MODY han permitido una mejor comprensión de los mecanismos moleculares subyacentes de estos procesos, y han facilitado un adecuado asesoramiento genético y el diagnóstico precoz. Estos nuevos conocimientos el abordaje permitirán el desarrollo de nuevas estrategias terapéuticas con fármacos capaces de prevenir, reparar o al menos retrasar el deterioro de la función de las células β-pancreáticas. Todo ello posibilitará un tratamiento más personalizado y, en última instancia, una mejor atención del paciente

Ectopic Cushing's Syndrome Unveiling a Metastatic Parotid Carcinoma.

INTRODUCTION: Adrenocorticotropic hormone (ACTH) ectopic production is a rare cause of Cushing syndrome (CS). The most commonly associated tumours are small-cell lung carcinoma along with bronchial and thymic carcinoids. To date, only 5 cases have been published in the literature featuring ectopic ACTH secretion from metastatic acinic cell carcinoma (ACC) of the parotid gland. We hereby describe a very uncommon case of ectopic CS (ECS) unveiling a metastatic parotid ACC. CASE PRESENTATION: A 46-year-old man with hypertension and dyslipidemia diagnosed 4-months before, as well as new-onset diabetes mellitus unveiled 1-month earlier, was referred to emergency department for hypokalemia. Hormonal study and dynamic biochemical tests performed indicated ECS. Imaging and cytological findings pointed toward a likely primary right parotid malignancy with liver metastases. Somatostatin receptor scintigraphy has shown an increased uptake in the parotid gland and mild expression in liver metastasis. The patient underwent right parotidectomy, and histopathologic examination confirmed ACC. Meanwhile, hypercortisolism was managed with metyrapone, ketoconazole, and lanreotide. Despite chemotherapy onset, a rapid disease progression and clinical course deterioration was observed. CONCLUSION: The present report highlights a rare ECS, exposing a metastatic parotid ACC, with an aggressive and challenging clinical course, representing the first case whose diagnosis of ECS came prior to ACC.

Analyzing the Impact of Bariatric Surgery in Kidney Function: a 2-Year Observational Study.

BACKGROUND: Obesity is an independent risk factor for chronic kidney disease (CKD). Our aims were: (1) to evaluate the impact of bariatric surgery (BS) on kidney function, (2) clarify the factors determining postoperative evolution of glomerular filtration rate (ΔGFR) and urinary albumin-to-creatinine ratio (ΔUACR), and (3) access the occurrence of oxalate-mediated renal complications. METHODS: We investigated a cohort of 1448 obese patients who underwent BS. Those with baseline-estimated GFR (eGFR0) < 30 mL/min or without information about the 2-year post-surgical eGFR (eGFR2) were excluded. RESULTS: A total of 725 patients were included. At baseline, 38(5.2%) had hyperfiltration with eGFR0 ≥ 125 mL/min/1.73m2 (G0), 492 (67.9%) had eGFR0 90-124 mL/min/1.73m2 (G1), 178 (24.6%) had eGFR0 60-89 mL/min/1.73m2 (G2), and 17 (2.3%) had eGFR0 < 60 mL/min/1.73m2 (G3). ΔGFR significantly increased in 96.6% (ΔGFR = 23.8 (IQR 15.9-29.8)) and 82.4% (ΔGFR = 18.6 (IQR 3.6-44.0)) of the subjects with G2 and G3 CKD, respectively (p < 0.001). The variables independently associated with ΔGFR were baseline body mass index (BMI) (positively), high blood pressure (HBP) (negatively), and fasting plasma glucose (FPG) (negatively), as well as FPG variation (positively). An overall prevalence of high UACR (≥ 30 mg/g-1) of 17.9% was found, with 81.5% of these subjects presenting A2(30-300 mg/g-1) and 18.5% A3(> 300 mg/g-1) UACR. UACR significantly decreased after BS (p < 0.001). Significant predictors of ΔUACR were BMI, systolic blood pressure, and HbA1c. Urinary excretion of calcium oxalate crystals was found in 77(11.1%) patients, with only 1 presenting oxalate-mediated renal complications. CONCLUSIONS: ΔGFR seems to be influenced by the initial kidney function, as it decreases in subjects with hyperfiltration but tends to increase in those with kidney dysfunction. These results suggest that BS is associated with improvement of kidney outcomes, without a significant increase in renal complications.

Effect of Weight Loss after Bariatric Surgery on Thyroid-Stimulating Hormone Levels in Patients with Morbid Obesity and Normal Thyroid Function.

BACKGROUND: Several studies have reported that morbid obesity is associated with increased thyroid-stimulating hormone (TSH) levels. However, it is not clear what is the impact of bariatric surgery on postoperative thyroid function. The aim of this study was to evaluate the effect of weight loss after bariatric surgery on TSH levels in euthyroid patients with morbid obesity. METHODS: We performed a retrospective observational study of 949 euthyroid patients (86.1% female; age 42.0 ± 10.3 years, BMI 44.3 ± 5.7 kg/m2) with morbid obesity submitted to bariatric surgery (laparoscopic adjustable gastric band, Roux-en-Y gastric bypass, or sleeve gastrectomy). Patients were subdivided in two groups: normal TSH group (TSH <2.5 mU/L) and high-normal TSH group (TSH ≥2.5 mU/L). The impact of anthropometric parameters, comorbidities, TSH, free thyroxine (FT4), free triiodothyronine (FT3), type of surgery, and excessive body weight loss (EBWL) on TSH variation 12 months after surgery was evaluated. RESULTS: The high-normal TSH group (24.3% of patients) included more women, presented a higher BMI, higher systolic blood pressure, and higher FT3 levels. There was a significant decrease of TSH 12 months after surgery that was more marked in the high-normal TSH group (normal TSH group: 1.57 ± 0.49 to 1.53 ± 0.69 mIU/L, p = 0.063; high-normal TSH group: 3.23 ± 0.59 to 2.38 ± 0.86 mIU/L, p < 0.001). In a multivariate analysis, after adjusting for relevant covariates, EBWL, baseline BMI, and baseline FT3 were significantly associated with TSH decrease 12 months after bariatric surgery. CONCLUSION: Bariatric surgery promotes a decrease of TSH that is significantly greater in patients with high-normal TSH and is independently associated with EBWL after surgery.