Hypothalamic Inflammation Improves Through Bariatric Surgery, and Hypothalamic Volume Predicts Short-Term Weight Loss Response in Adults With or Without Type 2 Diabetes.

OBJECTIVE: Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiological biomarkers of HI and the association between the severity of such radiological alterations and post-BS weight loss (WL) trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEVs) enriched for microglial and astrocyte markers in studying HI was also explored. RESEARCH DESIGN AND METHODS: We included 72 individuals with obesity (20 with and 52 without type 2 diabetes) and 24 control individuals. Participants underwent lumbar puncture and 3-T MRI at baseline and 1-year post-BS. We assessed hypothalamic mean diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEVs enriched for glial and astrocyte markers were determined by flow cytometry. RESULTS: Compared with control group, the obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL 1 and 2 years after BS. CSF-lEVs did not differ among groups and were unrelated to WL trajectories. CONCLUSIONS: These findings suggest HI improvement after BS and may support a role for HI in modulating the WL response to these interventions.

Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Severe hypoglycemia and hypoglycemia awareness are associated with preclinical atherosclerosis in patients with type 1 diabetes without an estimated high cardiovascular risk.

AIMS: To explore the relationship between severe hypoglycemia (SH) and hypoglycemia awareness with preclinical atherosclerosis in type 1 diabetes (T1D). MATERIALS AND METHODS: Cross-sectional study in patients with T1D without cardiovascular disease (CVD), and with ≥1 of the following: ≥40 years, diabetic kidney disease, or ≥10 years of T1D duration with another risk factor. CVD risk was estimated with the Steno T1 Risk Engine (Steno-Risk). Carotid plaque was evaluated using standardised ultrasonography protocol. Logistic regression models adjusted for CVD risk factors were constructed to test the independent associations with SH or hypoglycemia awareness assessed by the Clarke questionnaire (Clarke). The inclusion of SH and Clarke in Steno-Risk was further evaluated. RESULTS: We included 634 patients (52.4% men, age 48.3 ± 10.8 years, T1D duration 27.4 ± 11.1 years, 39.9% harbouring plaque). A stepped increase in the presence of plaque according to Steno-Risk was observed (13.5%, 37.7%, and 68.7%, for low, moderate, and high risk, respectively; p < 0.001). SH history (OR 4.4 [1.3-14.6]) and Clarke score (OR 1.7 [1.2-2.2]) were associated with plaque in low-risk patients (n = 192). Clarke score was also associated with plaque burden in low-moderate-risk participants (n = 436; ≥2 plaques: OR 1.2 [1.0-1.5], p = 0.031; ≥3 plaques: OR 1.4 [1.1-2.0], p = 0.025). The inclusion of SH and Clarke scores in Steno-Risk significantly improved the identification of low-risk individuals with atherosclerosis (area under the curve: 0.658 vs. 0.576; p = 0.036). CONCLUSIONS: In patients with T1D without an estimated high CVD risk, SH and hypoglycemia awareness assessment score were independently associated with preclinical atherosclerosis and improved identification of patients who would benefit from an intensive approach.

Adherence to an energy-restricted Mediterranean diet is associated with the presence and burden of carotid atherosclerosis in people with type 1 diabetes.

AIMS: People with type 1 diabetes (T1D) have an increased risk of cardiovascular disease (CVD). The Mediterranean diet is associated with reduced CVD; however, the evidence in T1D is scarce. We aimed to analyse the relationships between adherence to the energy-restricted Mediterranean diet (erMEDd) and carotid atherosclerosis. MATERIALS AND METHODS: We included children with T1D without CVD, with ≥1 of the following: age ≥40 years, diabetic kidney disease, or ≥10 years of disease duration with another risk factor. Plaque presence (intima-media thickness ≥1.5 mm) was determined by ultrasonography. The PREDIMED-Plus 17-item questionnaire (PP-17) was used to assess adherence to the erMEDd. RESULTS: Four hundred one individuals were included (48% males, age 48.3 ± 11 years, diabetes duration 26.8 ± 11.4 years). Those harbouring plaques (42%) showed lower adherence to the erMEDd (PP-17: 8.9 ± 2.3 of a maximum of 17 vs. 9.8 ± 2.5, p < 0.001). Greater adherence to the erMEDd was correlated with an overall better metabolic profile. After adjusting for multiple confounders, adherence to the erMEDd was independently associated with carotid atherosclerosis (OR 0.86 [0.77-0.95] for plaque presence and OR 0.85 [0.75-0.97] for ≥2 plaques). The consumption of fruit and nuts and preference of white over red meat was higher in individuals without atherosclerosis (p < 0.05). Fruit and nut consumption was associated with lower plaque prevalence in the fully adjusted models (OR 0.38 [0.19-0.73] and 0.51 [0.29-0.93]). CONCLUSIONS: Greater adherence to the erMEDd is associated with less carotid atherosclerosis in children with T1D at high risk of CVD. Strategies to improve and implement healthy dietary patterns in this population should be encouraged.

What is the evidence regarding the safety of new obesity pharmacotherapies.

The use of gut-hormone receptors agonists as new therapeutic options for obesity and some of its related comorbidities, such as type 2 diabetes, has resulted in an unprecedented efficacy in the medical management of people living with obesity (PLWO). Appraisal of the safety of these drugs is of utmost importance considering the large number of PLWO, and the potentially long exposure to these pharmacotherapies. In this narrative review we summarize the evidence on the safety of liraglutide, semaglutide, and tirzepatide as derived from randomized clinical trials conducted in adults living with obesity. Additionally, the safety of these drugs is put into perspective with that of other drugs currently approved for the treatment of PLWO. Overall, the available data support a favorable efficacy versus safety balance for gut-hormone hormone receptor analogues in the treatment of these subjects. Nonetheless, it should be acknowledged that in the context of a chronic disease that has reached epidemic proportions, data from randomized clinical trials aimed primarily at proving the efficacy of these drugs may have been insufficient to unveil all the safety issues. Thus, continuous surveillance on the adverse effects of liraglutide, semaglutide, and tirzepatide is required as we use these drugs in a broader population than that represented in currently available clinical trials.

Neutrophil-to-lymphocyte ratio is independently associated with carotid atherosclerosis burden in individuals with type 1 diabetes.

BACKGROUND AND AIMS: Recent studies have identified a relationship between innate versus. Adaptative immunity and cardiovascular disease (CVD) in the general population, but information on type 1 diabetes (T1D) is lacking. We aimed to study the relationship between inflammatory biomarkers and preclinical atherosclerosis in this population. METHODS AND RESULTS: Cross-sectional study in T1D individuals without CVD and with ≥1 of the following: ≥40 years, diabetic kidney disease, or ≥10 years of diabetes duration with classical CVD risk factors. Carotid plaques were evaluated by ultrasonography. C-reactive protein, total leukocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index were assessed as inflammatory markers. Multivariate-adjusted models including age, sex, and other CVD risk factors were constructed to test their independent associations with atherosclerosis burden. We included 602 subjects (52.8% men, 48.7 ± 10.2 years old and 27.0 ± 10.5 years of diabetes duration). Carotid plaques were found in 41.2% of the individuals (12.8%, ≥3 plaques). The number of carotid plaques (none, 1-2, ≥3 plaques), was directly associated with the leukocyte count (6570 [5445-8050], 6640 [5450-8470] and 7310 [5715-8935] per mm3, respectively; p for trend = 0.021) and the NLR (1.63 [1.28-2.13], 1.78 [1.38-2.25] and 2.14 [1.58-2.92], respectively; p for trend <0.001), but only the NLR remained directly associated in fully-adjusted models (presence of plaques; OR 1.285 [1.040-1.587]; ≥3 plaques, OR 1.377 [1.036-1.829]). CONCLUSIONS: The NLR was independently and directly associated with carotid plaque burden in T1D individuals. Our data support the role of innate versus. Adaptative immunity in atherosclerosis also among the T1D population.

Preparing Enteral Formulas for Adult Patients with Phenylketonuria: A Minor Necessity but Major Challenge-A Case Report.

Phenylketonuria (PKU) is the most frequent of the congenital errors of amino acid (AA) metabolism worldwide. It leads to the accumulation of the essential AA phenylalanine (Phe) and it is associated with severe neurological defects. The early diagnosis and treatment of this rare disease, achieved through newborn screening and low-Phe diet, has profoundly changed its clinical spectrum, resulting in normal cognitive development. We face the first generation of PKU patients perinatally diagnosed and treated who have reached adulthood, whose special needs must be addressed, including feeding through enteral nutrition (EN). However, recommendations regarding EN in PKU constitute a gap in the literature. Although protein substitutes for patients with PKU are offered in multiple forms (Phe-free L-amino acid or casein glycomacropeptide supplements), none of these commercial formulas ensures the whole provision of daily total energy and protein requirements, including a safe amount of Phe. Consequently, the combination of different products becomes necessary when artificial nutrition via tube feeding is required. Importantly, the composition of these specific formulas may result in physicochemical interactions when they are mixed with standard EN products, leading to enteral feeding tubes clogging, and also gastrointestinal concerns due to hyperosmolality. Herein, we present the first reported case of EN use in an adult patient with PKU, where the separate administration of protein substitutes and the other EN products avoided physicochemical interactions.

Impact of preeclampsia and parity on sex-based discrepancies in subclinical carotid atherosclerosis in type 1 diabetes.

CONTEXT: The excess risk of fatal and non-fatal cardiovascular events is roughly twice as high in women than in men with type 1 diabetes (T1D). OBJECTIVE: To evaluate the impact of preeclampsia and parity on sex-based discrepancies in preclinical atherosclerosis and on the diagnostic performance of a cardiovascular risk scale. DESIGN: Cross-sectional study. SETTING: Single tertiary hospital. PATIENTS: 728 T1D (48.5% women) without cardiovascular disease and age ≥40 years, nephropathy, and/or ≥10 years of diabetes duration with another risk factor. INTERVENTION: Standardized carotid ultrasonography. MAIN OUTCOME MEASURES: Carotid plaque determined by ultrasonography and cardiovascular risk estimated according to the Steno T1 Risk Engine (Steno-Risk). RESULTS: Nulliparous women and parous women without previous preeclampsia had a lower risk for carotid plaque than men (adjusted odds ratio [OR]: 0.48, 95% confidence interval [0.28-0.82]; adjusted OR: 0.51 [0.33-0.79], respectively), without differences in the preeclampsia group. The prevalence of carotid plaque increased as the estimated cardiovascular risk increased in all subgroups except for preeclampsia group. The area under the curve (AUC) of the Steno-Risk for identifying ≥2 carotid plaques was lower in the preeclampsia group (men: 0.7886, nulliparous women: 0.9026, women without preeclampsia: 0.8230, preeclampsia group: 0.7841; p between groups=0.042). Neither the addition of parity nor preeclampsia in the Steno-Risk led to a statistically significant increase in the AUC. CONCLUSIONS: The risk for carotid plaque in women compared to men decreased as exposure to obstetric factors diminished. However, the addition of these factors did not improve the prediction of the Steno-Risk.

Lysinuric Protein Intolerance and Its Nutritional and Multisystemic Challenges in Pregnancy: A Case Report and Literature Review.

Lysinuric protein intolerance (LPI) is a rare inborn error of metabolism (IEM), classified as an inherited aminoaciduria, caused by mutations in the SLC7A7 gene, leading to a defective cationic amino acid transport. The metabolic adaptations to the demands of pregnancy and delivery cause significant physiological stress, so those patients affected by IEM are at greater risk of decompensation. A 28-year-old woman with LPI had experienced 3 early miscarriages. While pregnancy was finally achieved, diverse nutritional and medical challenges emerged (food aversion, intrauterine growth restriction, bleeding risk, and preeclampsia suspicion), which put both the mother and the fetus at risk. Moreover, the patient requested a natural childbirth (epidural-free, delayed cord clamping). Although the existence of multiple safety concerns rejected this approach at first, the application of novel strategies made a successful delivery possible. This case reinforces that the woman's wish for a non-medicated, low-intervention natural birth should not be automatically discouraged because of an underlying complex metabolic condition. Achieving a successful pregnancy is conceivable thanks to the cooperation of interdisciplinary teams, but it is still important to consider the risks beforehand in order to be prepared for possible additional complications.

Bariatric Surgery Outcomes in Patients with Chronic Kidney Disease.

Obesity increases the risk of developing chronic kidney disease (CKD), which has a major negative impact on global health. Bariatric surgery (BS) has demonstrated a substantial improvement of obesity-related comorbidities and thus, it has emerged as a potential therapeutic tool in order to prevent end-stage renal disease. A limited number of publications to date have examined the beneficial effects and risks of BS in patients with non-advanced stages of CKD. We aimed to investigate the safety of BS in patients with CKD stages 3-4 (directly related or not to obesity) and both the metabolic/renal outcomes post-BS. A total of 57 individuals were included (n = 19 for CKD-group; n = 38 for patients with obesity, but normal eGFR [control-group]). Weight loss and obesity comorbidities resolution after BS were similar in both groups. Renal function (eGFR [CKD-EPI]) improved significantly at the 1-year follow-up: Δ10.2 (5.2-14.9) (p < 0.001) for CKD-group and Δ4.0 (-3.9-9.0) mL/min/1.73 m2 (p = 0.043) for controls. Although this improvement tended to decrease in the 5-year follow-up, eGFR remained above its basal value for the CKD-group. Noteworthy, eGFR also improved in those patients who presented CKD not directly attributed to obesity. For patients with CKD, BS appears to be safe and effective regarding weight loss and obesity comorbidities resolution, irrespective of the main cause of CKD (related or not to obesity).

Effects of Bariatric Surgery on Blood and Vascular Large Extracellular Vesicles According to Type 2 Diabetes Status.

CONTEXT: Large extracellular vesicles (lEVs) enriched for endothelial and blood cell markers are increased in metabolic conditions such as obesity or type 2 diabetes (T2D), actively contribute to the atherosclerotic process, and have been identified as diagnostic and prognostic biomarkers for cardiovascular disease (CVD). Although bariatric surgery (BS) in individuals with obesity is related to decreased cardiovascular (CV) risk and increased life expectancy, after BS these subjects are still at higher CV risk than the general population. OBJECTIVE: We aimed to compare the lEV profiles between individuals with obesity, with or without T2D, before and 1 year after BS, and normal-weight controls. METHODS: Prospective longitudinal study with individuals eligible for BS, with or without T2D (T2D and OB groups, respectively) and healthy controls (HC group) matched by age and sex. The concentration and phenotype of lEVs were assessed by flow cytometry. RESULTS: The study cohort included 108 individuals (age 48.0 ± 10.5 years; 84.3% females). Before BS, the OB group presented higher concentrations of lEV enriched for endothelial and blood cell biomarkers than the HC group, but lower concentrations than those observed in the T2D group (P < .05). BS resulted in a significant reduction in most of the lEVs enriched for cell-specific markers in both subgroups. lEV differences between OB and T2D groups were no longer observed after BS (P > .05). However, compared with HC group, OB and T2D groups still showed increased concentrations of lEVs enriched for platelet and endothelial cell markers (P < .05). CONCLUSION: At 1 year after BS, lEV concentrations remain above the physiological range. These abnormalities might contribute to explaining the increased CV risk after BS and underscore the importance of long-term CV risk factor control in post-BS individuals.

Advanced lipoprotein profile identifies atherosclerosis better than conventional lipids in type 1 diabetes at high cardiovascular risk.

BACKGROUND AND AIMS: People with type 1 diabetes (T1D) present lipoprotein disturbances that could contribute to their increased cardiovascular disease (CVD) risk. We evaluated the relationship between lipoprotein alterations and atherosclerosis in patients with T1D. METHODS AND RESULTS: Cross-sectional study in subjects with T1D, without previous CVD, but high-risk (≥40 years, nephropathy, or ≥10 years of evolution of diabetes with another risk factor). The presence of plaque (intima-media thickness ≥1.5 mm) in the different carotid segments was determined by ultrasound. The advanced lipoprotein profile was analysed by magnetic resonance imaging (1H NMR). We included 189 patients (42% women, 47.8 ± 10.7 years, duration of diabetes 27.3 ± 10.1 years, HbA1c 7.5% [7-8]). Those with carotid plaques (35%) were older, with longer diabetes duration, had a higher prevalence of hypertension, and showed lower and smaller LDL particles (LDL-P) and HDL particles (HDL-P), but higher VLDL particles (VLDL-P). Some LDL, HDL and VLDL-related parameters were associated with atherosclerosis in sex, age and statin use adjusted models (p < 0.05), but after adjusting for multiple confounders, including conventional lipid parameters, only HDL-P (OR 0.440 [0.204-0.951]; p = 0.037), medium HDL-P (OR 0.754 [0.590-0.963]; p = 0.024), HDL-P cholesterol content (OR 0.692 [0.495-0.968]; p = 0.032), 1H NMR LDL-P number/conventional LDL-cholesterol (OR 1.144 [1.026-1.275]; p = 0.015), and 1H NMR non-HDL particle number/conventional non-HDL-cholesterol ratios (OR 1.178 [1.019-1.361], p = 0.026) remained associated with atherosclerosis. CONCLUSIONS: In adults with T1D at high-risk, variables related to HDL, LDL and total atherogenic particle number are independently associated with preclinical atherosclerosis. Advanced lipoprotein profiling could be used to identify those at the highest risk of CVD.

Nuclear Magnetic Resonance-Based Lipidomics in the Assessment of Cardiometabolic Risk in Type 1 Diabetes: An Exploratory Analysis.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of mortality in type 1 diabetes (T1D). However, there is a need for daily practice tools for identifying those more prone to suffer from these events. We aimed to assess the relationships between nuclear magnetic resonance (1H NMR)-based lipidomic analysis and several CVD risk variables (including preclinical carotid atherosclerosis) in individuals with T1D at high risk. METHODS: We included patients with T1D without CVD, with at least one of the following: age ≥ 40 years, diabetic kidney disease, or ≥ 10 years of evolution with another risk factor. The presence of plaque (intima-media thickness > 1.5 mm) was determined by standardized ultrasonography protocol. Lipidomic analysis was performed by 1H NMR. Bivariate and multivariate-adjusted differences in 1H NMR lipidomics were evaluated. RESULTS: We included n = 131 participants (49.6% female, age 46.4 ± 10.3 years, diabetes duration 27.0 ± 9.5 years, 47.3% on statins). Carotid plaques were present in 28.2% of the individuals (n = 12, with ≥ 3 plaques). Glucose (HbA1c), anthropometric (body mass index and waist circumference), and insulin resistance-related (fatty liver index and estimated glucose disposal rate) variables were those most associated with 1H NMR-derived lipidomic analysis (p < 0.01 for all). Regarding preclinical atherosclerosis, sphingomyelin was independently associated with carotid plaque presence (for 0.1 mmol/L increase, OR 0.50 [0.28-0.86]; p = 0.013), even after adjusting for age, sex, hypertension, statin use, mean 5-year HbA1c and diabetes duration. Furthermore, linoleic acid and ω-6 fatty acids remained independently associated with higher plaque burden (≥ 3 plaques) in multivariate models (0.17 [0.03-0.93] and 0.27 [0.07-0.97], respectively; p < 0.05 for both). CONCLUSION: In our preliminary study of individuals with T1D at high risk, several 1H NMR-derived lipidomic parameters were independently associated with preclinical atherosclerosis. Specifically, ω-6 fatty acids and linoleic acid seem promising for identifying those with higher plaque burden.

Diabetic Neuropathy Is Independently Associated With Worse Graft Outcomes and Incident Cardiovascular Disease After Pancreas Transplantation: A Retrospective Cohort Study in Type 1 Diabetes.

BACKGROUND: Information about the impact of diabetic neuropathy (DN) on outcomes after pancreas transplantation (PT) is scarce. We assessed the independent relationship between DN markers with both graft survival and incident cardiovascular disease (CVD) after transplantation. METHODS: A cohort study in individuals with type 1 diabetes and end-stage kidney disease who underwent PT between 1999 and 2015 was conducted. DN was assessed with vibration perception thresholds (VPTs) and orthostatic hypotension (pre-PT and 6 mo, 2-3, 5-6, and 8-10 y after transplantation). Pretransplantation and posttransplantation DN markers were related with graft failure/dysfunction and incident CVD during follow-up. RESULTS: We included 187 participants (70% men, age 39.9 ± 7.1 y, diabetes duration 27.1 y), with a median follow-up of 11.3 y. Abnormal VPTs (≥25 V) were observed in 53%. After transplantation, VPTs improved (22.4 ± 8.4 pretransplant versus 16.1 ± 6.1 V at 8-10 y post-PT; P < 0.001); additionally, the prevalence of abnormal VPTs decreased (53% pretransplant versus 24.4% at 8-10 y; P < 0.001). After adjusting for age, sex, diabetes duration, blood pressure, body mass index, and previous CVD, pretransplant VPTs ≥25 V were independently associated with pancreas graft failure/dysfunction (hazard ratio [HR], 2.01 [1.01-4.00]) and incident CVD (HR, 2.57 [1.17-5.64]). Furthermore, persistent abnormal VPTs after 6 mo posttransplantation were associated with the worst outcomes (HR, 2.80 [1.25-6.23] and HR, 3.19 [1.14-8.96], for graft failure/dysfunction and incident CVD, respectively). CONCLUSIONS: In individuals with type 1 diabetes and end-stage kidney disease, PT was associated with an improvement of VPTs. This simple and widely available DN study was independently associated with pancreas graft function and CVD posttransplantation.

Bariatric Surgery Outcomes in Patients with Kidney Transplantation.

Obesity and kidney transplantation (KTx) are closely related. Obesity increases the risk of chronic kidney disease and can be a relative contraindication for KTx. Besides, KTx recipients are predisposed to obesity and its comorbidities. Consequently, bariatric surgery (BS) emerges as a powerful therapeutic tool either before or after KTx. Since evidence regarding the best approach is still scarce, we aimed to describe renal and metabolic outcomes in a single centre with more than 15-year experience in both surgeries. METHODS: A retrospective study including patients who had received a KTx either before or after BS. Usual metabolic and renal outcomes, but also new variables (as renal graft dysfunction) were collected for a minimum follow-up of 1-year post-BS. RESULTS: A total of 11 patients were included: n = 6 (BS-post-KTx) and n = 5 (BS-pre-KTx). One patient was assessed in both groups. No differences in the main outcomes were identified, but BS-post-KTx group tended to gain more weight during the follow-up. The incidence of renal graft dysfunction was comparable (4/6 for BS-post-KTx, 3/5 for BS-pre-KTx) between groups. CONCLUSIONS: BS in patients with KTx appears to be safe and effective attending to metabolic and renal outcomes. These results seem irrespective of the time course, except for weight regain, which appears to be a common pattern in the BS-post-KTx group.

Use of the Steno T1 Risk Engine Identifies Preclinical Atherosclerosis Better Than Use of ESC/EASD-2019 in Adult Subjects With Type 1 Diabetes at High Risk.

OBJECTIVE: To evaluate the concordance between the 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD (ESC/EASD-2019) and the Steno T1 Risk Engine (Steno-Risk) cardiovascular risk scales for individuals with type 1 diabetes (T1D) without cardiovascular disease (CVD) and to analyze the relationships of their use with identification of preclinical atherosclerosis. RESEARCH DESIGN AND METHODS: We consecutively selected patients with T1D, without CVD, age ≥40 years, with nephropathy, and/or with ≥10 years of T1D evolution with another risk factor. The presence of plaque at different carotid segments was determined by ultrasonography. Cardiovascular risk was estimated in accord with ESC/EASD-2019 risk groups (moderate/high/very high) and the Steno-Risk (<10%, low; 10-20%, moderate; ≥20%, high), as T1D-specific scores. In an exploratory analysis, we also evaluated the non-T1D-specific 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk (ACC/AHA-2013) pooled cohort equation for individuals between 40 and 79 years of age. RESULTS: We included 501 patients (53% men, mean age 48.8 years, median T1D duration 26.5 years, 41.3% harboring plaques). Concordance between T1D-specific scales was poor (κ = 0.19). A stepped increase in the presence of plaques according to Steno-Risk category was seen (18.4%, 38.2%, and 64.1%, for low, moderate, and high risk, respectively; P for trend <0.001), with no differences according to ESC/EASD-2019 (P = 0.130). Steno-Risk identified individuals with plaques, unlike ESC/EASD-2019 (area under the curve [AUC] 0.691, P < 0.001, vs. AUC 0.538, P = 0.149). Finally, in polynomial regression models (with adjustment for lipid parameters and cardioprotective treatment), irrespective of the ESC/EASD-2019 category, high risk by Steno-Risk was directly associated with atherosclerosis (in moderate/high-risk by ESC/EASD-2019 odds ratio 2.91 [95% CI 1.27-6.72] and 4.94 [2.35-10.40] for the presence of plaque and two or more plaques). Similar results were obtained with discordant higher Steno-Risk versus ACC/AHA-2013 (P < 0.001). CONCLUSIONS: Among T1D patients undergoing primary prevention, use of Steno-Risk seems to result in better recognition of individuals with atherosclerosis in comparison with ESC/EASD-2019. Notwithstanding, carotid ultrasound could improve the categorization of cardiovascular risk.

Carotid ultrasonography as a strategy to optimize cardiovascular risk management in type 1 diabetes: a cohort study.

BACKGROUND AND AIMS: Although cardiovascular disease (CVD) remains the leading cause of mortality in type 1 diabetes (T1D), the use of cardioprotective drugs is scarce. We aimed to evaluate the impact of carotid ultrasonography (US) on the improvement in cardiovascular risk factors (CVRFs) in T1D. METHODS AND RESULTS: T1D patients without CVD meeting criteria for lipid treatment according to guidelines (age ≥ 40 years, nephropathy and/or ≥ 10 years of diabetes duration with ≥ 1 additional CVRFs) were included. The carotid-US group (US-G) underwent a standardized US protocol and CVRF assessment; recommendations were made according to subclinical atherosclerosis status. The control group (CG) followed usual clinical practice. Changes in CVRFs, specially statin use and LDL cholesterol levels, at 1 year were analysed. A total of 318 patients were included (51.3% female, mean age of 49.1 years and 25.5 years of diabetes duration): 211 in the US-G and 107 in the CG. Participants in the US-G had a higher baseline LDL cholesterol than controls (114 vs. 102 mg/dL; p < 0.001). Lipid-lowering treatment was modified in 38.9% in the US-G and 6.5% in the CG (p < 0.001). At 1 year, the US-G was more frequently on statins, had lower LDL cholesterol and 27% had stopped smoking (p < 0.001 for all). Changes were more pronounced in those with plaques (p < 0.001). In multivariate analyses adjusted for age, sex and other CVRFs, belonging to the US-G was independently associated with the intensification of lipid-lowering treatment (OR 10.47 [4.06-27.01]). Propensity score-matching analysis yielded similar results (OR 20.09 [7.86-51.37]). CONCLUSION: Carotid-US is independently associated with an intensification of lipid-lowering therapy in a high-risk T1D population.

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.

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-loss thresholds after bariatric surgery and cardiovascular outcomes: more is better.

BACKGROUND/OBJECTIVES: Whether the extent of weight loss (WL) modulates bariatric surgery (BS) cardiovascular benefits has scarcely been assessed. Several WL thresholds have been commonly used to classify BS patients as good or poor responders without a proven clinical relevance. We examined the relationship between the magnitude of WL after BS and post-surgery major adverse cardiovascular-event (MACE) incidence. We also compared the performance of three different insufficient weight-loss (IWL) criteria for their association with MACE. SUBJECTS AND METHODS: All individuals who underwent a primary Roux-en Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in our institution at least six years before data analysis (12/2020) were included in the study. Data on MACE were available in 1638 of 1700 participants (96.4%). Proportional-hazard Cox analyses were performed to ascertain the association between MACE, WL, and the three IWL criteria. IWL was defined as: <50% excess weight loss (<50% EWL), <20% total body-weight loss (<20% TBWL), and -1 standard deviation of alterable weight-loss percentage (<1 SD% AWL). RESULTS: During a mean follow-up of 10.2 ± 2.8 years, 86 participants experienced a first post-surgery MACE. Higher WL at one year (HR: 0.77 (95% CI: 0.61-0.98)) and 5 years (HR: 0.63 (95% CI: 0.42-0.92)) was related to a lower incidence of MACE. All short-term criteria for defining IWL were similarly associated with MACE, yet <1 SD% AWL identified more at-risk subjects. Five-year TBWL < 20% and 5-year <1 SD-AWL% were significantly associated with a higher risk for CV events. TBWL < 20% identified more subjects at risk. CONCLUSIONS: The extent of WL is closely related to long-term MACE incidence. Patients who lost -1SD% AWL at one year or <20% TBWL at five years may be considered poor responders.