Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

ENDOCRINE OBESITY: Pituitary dysfunction in obesity.

Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic-pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.

Impact of Simultaneous Pancreas-kidney Transplantation on Cardiovascular Risk in Patients With Diabetes.

BACKGROUND: Cardiovascular disease is the major cause of death in patients with type 1 diabetes. Of the available risk predictors for this population, the Steno Type 1 Risk Engine (STENO T1) is the only one that includes kidney function as a risk factor, which is a well-described independent risk factor for cardiovascular disease. METHODS: We explore how simultaneous pancreas-kidney transplantation (SPKT) modifies the predicted cardiovascular risk by the STENO T1 through a retrospective study including recipients of a first SPKT between 2000 and 2016. RESULTS: Two hundred sixty-eight SPKT recipients with a mean age of 40 y old and a median follow-up of 10 y were included. Before transplantation, the expected incidence of cardiovascular events (CVEs) at 5 and 10 y according to STENO T1 would have been 31% and 50%, respectively, contrasting with an actual incidence of 9.3% and 16% for the same timepoints, respectively (P < 0.05). These differences were attenuated when STENO T1 was recalculated assuming 12th-mo glomerular filtration rate (at 5 and 10 y predicted CVE incidence was 10.5% and 19.4%, respectively). Early pancreas graft failure (hazard ratio [HR] 3.00, 95% confidence interval [CI], 1.14-7.88; P = 0.02) was an independent risk factor for post-SPKT CVE, alongside kidney graft failure (HR 2.90, 95% CI, 1.53-5.48; P = 0.001), and diabetes duration (HR 1.04, 95% CI, 1.00-1.09, P = 0.04). CONCLUSIONS: SPKT decreases in more than two-thirds of the predicted cardiovascular risk by the STENO T1. A functioning pancreas graft further reduces CVE risk, independently of kidney graft function.

Weight gain following pancreas transplantation in type 1 diabetes is associated with a worse glycemic profile: A retrospective cohort study.

AIMS: Evaluate the weight trajectories after pancreas transplantation (PT) and their relationships with pancreas graft outcomes in type 1 diabetes (T1D). METHODS: Retrospective cohort study. T1D individuals who underwent PT were recruited (T1D-PT; n = 194) and divided into three groups according to transplantation date: 1999-2004 (n = 57), 2005-2009 (n = 79), 2010-2015 (n = 58). For weight comparisons, a random sample of T1D without renal impairment was also recruited during 2015 (n = 61; T1D-control). RESULTS: The median follow-up for the T1D-PT group was 11.1 years. Despite significant weight loss at 6 months (65.7 ± 12.4 vs. 64.1 ± 11.4 Kg; p < 0.001), a stepped increase was seen thereafter (60 months: 68.0 ± 14.0 Kg; p < 0.001). Participants from the 2010-2015 period showed higher weight gain (p < 0.001), outweighing that observed in the T1D-control (60 months: +4.69 ± 8.49 vs. -0.97 ± 4.59 Kg; p = 0.003). Weight gain between 6 and 36 months was directly associated with fasting glucose and HbA1c at 36 months, and with HbA1c at 60 months (p < 0.05). However, in Cox-regression models adjusted for age, sex, and several recipient and PT-related variables, the third tertile of weight gain between 6 and 36 months showed a non-significant increase in the graft failure/dysfunction (HR 2.33 [0.75-7.27]). CONCLUSIONS: Weight gain post-PT was associated with glucose-related biochemical markers of graft dysfunction, which needs confirmation in further studies.

Quantification of glycoproteins by nuclear magnetic resonance associated with preclinical carotid atherosclerosis in patients with type 1 diabetes.

BACKGROUND AND AIMS: Glycoproteins play a key role in inflammatory and cardiometabolic processes. Their implication in atherosclerosis in type 1 diabetes (T1D) is unknown. We assessed the relationships between classic inflammatory markers, glycoproteins measured by nuclear magnetic resonance (1H-NMR), and preclinical atherosclerosis in these patients. METHODS AND RESULTS: We selected patients with T1D, without cardiovascular disease (CVD), with: age ≥40 years, nephropathy (micro/macroalbuminuria), or ≥10 years of evolution with another risk factor. The presence of plaque (intima-media thickness >1.5 mm) was determined by ultrasonography. Concentrations of high-sensitive C-reactive protein (hsCRP), circulating leukocytes (classical inflammation markers) and 1H-NMR-glycoproteins (GlycA, GlycB, GlycF, and the height/width [H/W] ratios of GlycA and GlycB) were determined. We included 189 patients (58% male, age 47.0 [40.7-55.2] years). Thirty-five percent presented plaques (22%, ≥2 plaques). There was no association between hsCRP or leukocytes and atherosclerosis. However, in age- and sex-adjusted models, GlycA, GlycF, and the H/W ratios of GlycA and GlycB gradually increased with the number of plaques (0, 1, ≥2 plaques) only in patients without statins (p < 0.05), with no association in patients receiving this drug (p for interaction <0.05; in ≥2 plaques). Finally, in models adjusted for other classical and T1D-specific risk factors, GlycA and GlycB H/W ratios remained associated with carotid plaque (OR 1.39 [1.12-1.90] and OR 6.89 [1.85-25.62], respectively). CONCLUSION: In T1D individuals without lipid-lowering treatment, 1H-NMR-glycoproteins were independently associated with the presence and amount of carotid atherosclerosis, unlike other classical inflammatory markers. Further studies are needed to ascertain their utility as CVD biomarkers.

Cardiovascular risk factors and cardiovascular disease in patients with type 1 diabetes and end-stage renal disease candidates for kidney-pancreas transplantation: Trends from 1999 to 2017.

AIMS: To evaluate the changes in cardiovascular risk factors (CVRFs) and cardiovascular disease (CVD) in patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD) who were candidates for kidney-pancreas transplantation (KPTx) from 1999 to 2017. METHODS: Patients with T1D referred for KPTx evaluation were included. The cohort was divided into five groups according to the year of evaluation (1999-2002, 2003-2006, 2007-2010, 2011-2014 and 2015-2017). The control of CVRFs and the prevalence of prior CVD were evaluated. RESULTS: We evaluated 360 patients (64.4% men, age 38.9 ± 7.1 years). LDL-cholesterol <100 mg/dl increased from 22.7% to 76.9% (1999-2002 vs. 2015-2017; p < 0.001), as did the use of statins (from 24.7% to 74.5%; p < 0.001). Systolic blood pressure decreased from 138.8 ± 27.6 to 125.1 ± 27.9 mmHg (p = 0.001) and current smokers from 48% to 25% (p = 0.018). Intensive insulin treatment increased from 34.4% to 93.6% (p < 0.001). Diabetes duration before the initiation of renal replacement therapy increased from 23 ± 5.5 to 26.9 ± 8.9 years (p = 0.001). Overall, 30.3% had previous CVD, without significant changes over time (p = 0.699), albeit patients were older and had longer diabetes duration. CONCLUSIONS: Patients with T1D and ESRD referred for KPTx have better control of CVRFs over time, which might lead to a decrease in cardiovascular events.

Insulin resistance is associated with preclinical carotid atherosclerosis in patients with type 1 diabetes.

AIM: Although insulin resistance (IR) is a growing trait among type 1 diabetes (T1D) population, its relationship with atherosclerosis has been scarcely studied. We assessed the association between IR indexes and carotid atherosclerosis in T1D, a population at high cardiovascular disease (CVD) risk. MATERIALS AND METHODS: We evaluated 191 participants with T1D and no prior CVD with at least one of the following criteria: ≥40 years old; diabetic nephropathy; or T1D duration ≥10 years harbouring ≥1 additional CVD risk factor. IR was assessed with the metabolic syndrome (MetS) harmonized definition proposed in 2009 and the estimated glucose disposal rate (eGDR), a T1D-specific IR surrogate marker (lower values indicating higher IR). Standardized carotid ultrasonography was performed, recording intima-media thickness (IMT), plaque presence and maximum height of plaque. Comparisons between patients according to their MetS status as well as concerning eGDR values were performed. RESULTS: The participants' median age was 47.4 (41.1-53.3) years and diabetes duration 25.7 (21.6-32.5) years. Plaque prevalence was higher in patients with greater IR (49.1%, 29.1% and 20%, P = .001, for any plaque according to decreasing eGDR tertiles). Conversely, no statistically significant higher plaque prevalence was found in participants with MetS. In multivariate analyses (adjusted for general- and T1D-specific risk factors, and statin treatment), MetS was associated with neither IMT nor plaque. On the contrary, eGDR was independently related to ≥2 plaques (P = .018) and maximum plaque height (P < .01). CONCLUSIONS: In T1D, IR assessed through eGDR but not by MetS definition was independently associated with plaque burden, a predictor of CVD.

Primary adrenal insufficiency due to hereditary apolipoprotein AI amyloidosis: endocrine involvement beyond hypogonadism.

Several mutations in the gene encoding apolipoprotein AI (apoAI) have been described as a cause of familial amyloidosis. Individuals with apoAI-derived (AApoAI) amyloidosis frequently manifest with liver, kidney, laryngeal, skin and myocardial involvement. Although primary hypogonadism (PH) is considered almost pathognomonic of this disease, until now, primary adrenal insufficiency (PAI) has not been described as a common clinical feature. Here, we report the first kindred with AApoAI amyloidosis in which PAI is well-documented. All family members with the Leu60_Phe71delins60Val_61Thr heterozygous mutation who were regularly followed-up at our centre were considered. Nineteen individuals had the confirmed APOA1 deletion/insertion mutation, with detailed medical records available in 11 cases. Of these, 6 had PAI and 3 (all males) had PH. Among them, one 47-year-old man, not previously diagnosed with PAI, developed adrenal crisis after liver transplantation, precipitated by an opportunistic infection. Transplantation due to organ failure, which necessitates use of immunosuppressive medication such as corticosteroids, is frequently required during the course of hereditary amyloidosis. Consequently, PAI can remain masked, being discovered only when an adrenal crisis develops. Therefore, according to the present evidence, patients with AApoAI amyloidosis should be submitted to regular testing of corticotrophin and cortisol levels in order to avoid delaying corticosteroid replacement.