New methods for the diagnosis and monitoring of cognitive function in patients with type 2 diabetes

Dementia; Retinal microperimetry; Type 2 diabetesDemencia; Microperimetría retiniana; Diabetes tipo 2Demència; Microperimetria retiniana; Diabetis tipus 2The presence of type 2 diabetes acts as an accelerator of cognitive impairment (mild cognitive impairment and later dementia), with a significant impact on the management of the disease and its complications. Therefore, it is recommended to perform an annual evaluation of cognitive function in patients with diabetes older than 65 years. Current guidelines still recommend the use of the Minimental State Evaluation Test (MMSE) as screening test, but it has a modest sensitivity and specificity for identifying mild cognitive impairment. This represents an important gap because patients with mild cognitive impairment are at risk of progressing to dementia. The neurocognitive diagnosis is based on complex neuropsychological tests, which require specifically trained personnel and are time consuming, making its routine incorporation into daily clinical practice unfeasible. Therefore, at present there are no reliable biomarkers to identify patients with type 2 diabetes at increased risk of developing cognitive impairment. Since the brain and the retina have a common embryological origin, our Research Group, has worked over the last 10 years evaluating the usefulness of the retina as a “window” to the brain. We provided evidence that retinal microperimetry is a simple, feasible and useful tool for screening and monitoring cognitive function in patients with type 2 diabetes. We propose a review of actual tests recommended for screening of cognitive impairment as well as an update of new emerging methods, such as retinal microperimetry

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Physiology to Clinical Outcomes

GLP-1 receptor agonists; Diabetic kidney diseaseAgonistas del receptor de GLP-1; Enfermedad renal diabéticaAgonistes del receptor GLP-1; Malaltia renal diabèticaDiabetic kidney disease (DKD) is one of the most common complications in type 2 diabetes mellitus (T2D) and a major cause of morbidity and mortality in diabetes. Despite the widespread use of nephroprotective treatment of T2D, the incidence of DKD is increasing, and it is expected to become the fifth cause of death worldwide within 20 years. Previous studies have demonstrated that GLP-1 receptor agonists (GLP-1 RA) have improved macrovascular and microvascular outcomes independent of glycemic differences, including DKD. GLP-1Ras’ improvement on kidney physiology is mediated by natriuresis, reduction in hyperfiltration and renin-angiotensin-aldosterone system (RAAS) activity and anti-inflammatory properties. These findings translate into improved clinical outcomes such as an enhanced urine albumin-to-creatinine ratio (UACR) and a reduction in renal impairment and the need for renal replacement therapies (RRT). In this article, we review the role of GLP-1RAs on the mechanisms and effect in DKD and their clinical efficacy.This research received no external funding

Analysis of Effectiveness and Psychological Techniques Implemented in mHealth Solutions for Middle-Aged and Elderly Adults with Type 2 Diabetes: A Narrative Review of the Literature

Diabetis; Gent gran; Tècniques psicològiquesDiabetes; Elderly; Psychological techniquesDiabetes; Ancianos; Técnicas psicológicaBackground: in diabetes, multiple mHealth solutions were produced and implemented for self-management behaviors. However, little research on the effectiveness of psychological techniques implemented within these mHealth solutions was carried out, and even less with the elderly population where technological barriers might exist. Reliable evidence generated through a comprehensive evaluation of mHealth interventions may accelerate its growth for successful long-term implementation and to help to experience mHealth benefits in an enhanced way in all ages. Objective: this study aimed to review mHealth solutions for diabetes self-management in older adults (adherence to treatments and glycemic control) by analyzing the effectiveness of specific psychological techniques implemented. Methods: a narrative review was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. PubMed (Medline) and American Psychological Association (APA) PsycInfo databases were searched for published papers that addressed eHealth solutions’ effectiveness for diabetes self-management. Studies in English, Spanish, and/or German of any design were screened, with no time constraints regarding the year of publication. A qualitative analysis of the selected papers was conducted in several steps. Results: this review found 38 studies setting up and analyzing mHealth solutions for older adults. Most research showed improvements in HbA1c, self-management behaviors, and medication adherence in T2DM patients post intervention. However, different mid-to-long term effects were found across studies, specifically concerning the maintenance and adherence to healthy behaviors. The most employed psychological framework was CBT, including techniques such as self-monitoring of outcome behaviors (mostly targeting glycemia measurements and healthy habits as physical activity and/or diet), tailored motivational feedback from medical staff, and psychoeducation or health coaches. The most successful mHealth intervention combined the feature of tailored feedback messages, interactive communication with healthcare professionals, and multifaceted functions. Conclusions: there is a lack of elaborate and detailed information in the literature regarding the factors considered in the design and development of mHealth solutions used as interventions for T2DM self-management in the elderly. Documentation and inclusion of such vital information will foster a transparent and shared decision-making process that will ultimately lead to the development of useful and user-friendly self-management apps that can enhance the quality of life for diabetes patients. Further research adapting mHealth solutions to older adults’ sensory deficits is necessary.This research received no external funding

Usefulness of Eye Fixation Assessment for Identifying Type 2 Diabetic Subjects at Risk of Dementia

Dementia; Diabetes; MicroperimetryDemència; Diabetis; MicroperimetriaDemencia; Diabetes; MicroperimetríaType 2 diabetic (T2D) subjects have a significantly higher risk of developing mild cognitive impairment (MCI) and dementia than age-matched non-diabetic individuals. However, the accurate evaluation of cognitive status is based on complex neuropsychological tests, which makes their incorporation into the current standard of care for the T2D population infeasible. Given that the ability to maintain visual gaze on a single location (fixation) is hampered in Alzheimer’s disease (AD), the aim of the present study was: (1) To assess whether the evaluation of gaze fixation during fundus-driven microperimetry correlated with cognitive status in T2D subjects; (2) to examine whether the addition of fixational parameters to the assessment of retinal sensitivity increased the predictive value of retinal microperimetry in identifying T2D subjects with MCI. For this purpose, fixation parameters and retinal sensitivity were compared in three age-matched groups of T2D subjects: normocognitive (n = 34), MCI (n = 33), and AD (n = 33). Our results showed that fixation is significantly more unstable in MCI subjects than normocognitive subjects, and even more altered in those affected by AD (ANOVA; p < 0.01). Moreover, adding fixation parameters to retinal sensitivity significantly increases the predictive value in identifying those subjects with MCI: ROC (Receiver Operating Characteristic) Area 0.68 with retinal sensitivity alone vs. ROC Area 0.86 when parameters of fixation are added to retinal sensitivity (p < 0.01). In conclusion, our results suggest that fixational eye movement parameters assessed by fundus-microperimetry represent a new tool for identifying T2D subjects at risk of dementi

Complementary pre-screening strategies to uncover hidden prodromal and mild Alzheimer's disease: Results from the MOPEAD project

Diagnostic gap; Early diagnosis; PopulationBrecha de diagnóstico; Diagnóstico precoz; PoblaciónBretxa de diagnòstic; Diagnòstic precoç; PoblacióIntroduction: The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis. Methods: Four different strategies or RUNs were used: (a) a web-based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care-based protocol for early detection of cognitive decline (PC), and (4) a tertiary care-based pre-screening at diabetologist clinics (DC). Results: A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre-screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC). Conclusion: These four complementary pre-screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD.This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No 115985. This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation program and the European Federation of Pharmaceutical Industries and Associations. www.imi.europa.eu/. All participants provided informed consent

Metabolic footprint of aging and obesity in red blood cells

Aging; Metabolomics; ObesityEnvelliment; Metabolòmica; ObesitatEnvejecimiento; Metabolómica; ObesidadAging is a physiological process whose underlying mechanisms are still largely unknown. The study of the biochemical transformations associated with aging is crucial for understanding this process and could translate into an improvement of the quality of life of the aging population. Red blood cells (RBCs) are the most abundant cells in humans and are involved in essential functions that could undergo different alterations with age. The present study analyzed the metabolic alterations experienced by RBCs during aging, as well as the influence of obesity and gender in this process. To this end, the metabolic profile of 83 samples from healthy and obese patients was obtained by Nuclear Magnetic Resonance spectroscopy. Multivariate statistical analysis revealed differences between Age-1 (≤45) and Age-2 (>45) subgroups, as well as between BMI-1 (<30) and BMI-2 (≥30) subgroups, while no differences were associated with gender. A general decrease in the levels of amino acids was detected with age, in addition to metabolic alterations of glycolysis, the pentose phosphate pathway, nucleotide metabolism, glutathione metabolism and the Luebering-Rapoport shunt. Obesity also had an impact on the metabolomics profile of RBCs; sometimes mimicking the alterations induced by aging, while, in other cases, its influence was the opposite, suggesting these changes could counteract the adaptation of the organism to senescence.This work was supported by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064 and PI20/01588), the Agency for Management of University and Research Grants (AGAUR) of Catalonia (2017SGR1303) and the Ministry of Economy and Competitiveness (SAF2017-89229-R). Equipment employed in this work was partially funded by Generalitat Valenciana and ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020)

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD)

Fibrosi; Obesitat; Àcid palmític (AP)Fibrosis; Obesidad; Ácido palmítico (AP)Fibrosis; Obesity; Palmitic acid (PA)Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.This work was supported by the MINECO Retos SAF2016-78711, SAF2017-87919-R, PID2020-117827RB-IOO, PID2020-117941RB-IOO, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, AMMF 2018/117, COST Action CA17112 and UCM-25/2019, German Research Foundation (SFB/TRR57/P04, SFB 1382-403224013/A02). F.J.C. and Y.A.N. are Ramón y Cajal Researchers RYC-2014-15242 and RYC-2015-17438. F.J.C. is a Gilead Liver Research Scholar. The research group belongs to the validated Research Groups Ref. 970935 ¨Liver Pathophysiology¨, 920631 ¨Lymphocyte immunobiology¨, 920361 “Inmunogenética e6937 inmunología de las mucosas” and IBL-6 (imas12-associated). O.E.-V. is supported by Beca FPI (associated with MINECO SAF2017-87919R), C.-S.G. by Atracción de Talento 2019-T1/BMD-1331 and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19). F.G. is a Chinese Scholarship Council (CSC) fellow. T.B. is supported by the German Research Foundation SFB 1382-403224013/B07, and P.A. by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971-16) and MCIU/AEI/FEDER, UE (RTI2018-095134-B-100)

Comparison of computed tomography and dual-energy X-ray absorptiometry in the evaluation of body composition in patients with obesity

Body composition; Computed tomography; Morbid obesityComposición corporal; Tomografía computarizada; Obesidad mórbidaComposició corporal; Tomografia computaritzada; Obesitat mòrbidaObjective: a) To evaluate the accuracy of the pre-existing equations (based on cm2 provided by CT images), to estimate in kilograms (Kg) the body composition (BC) in patients with obesity (PwO), by comparison with Dual-energy X-ray absorptiometry (DXA). b) To evaluate the accuracy of a new approach (based on both cm2 and Hounsfield Unit parameters provided by CT images), using an automatic software and artificial intelligence to estimate the BC in PwO, by comparison with DXA. Methods: Single-centre cross-sectional study including consecutive PwO, matched by gender with subjects with normal BMI. All the subjects underwent BC assessment by Dual-energy X-ray absorptiometry (DXA) and skeletal-CT at L3 vertebrae. CT images were processed using FocusedON-BC software. Three different models were tested. Model 1 and 2, based on the already existing equations, estimate the BC in Kg based on the tissue area (cm2) in the CT images. Model 3, developed in this study, includes as additional variables, the tissue percentage and its average Hounsfield unit. Results: 70 subjects (46 PwO and 24 with normal BMI) were recruited. Significant correlations for BC were obtained between the three models and DXA. Model 3 showed the strongest correlation with DXA (r= 0.926, CI95% [0.835-0.968], p<0.001) as well as the best agreement based on Bland – Altman plots. Conclusion: This is the first study showing that the BC assessment based on skeletal CT images analyzed by automatic software coupled with artificial intelligence, is accurate in PwO, by comparison with DXA. Furthermore, we propose a new equation that estimates both the tissue quantity and quality, that showed higher accuracy compared with those currently used, both in PwO and subjects with normal BMI.This study was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, PI20/01806). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Homeostasis; PathogenesisHomeostasis; PatogénesisHomeòstasi; PatogènesiProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.This work was supported by the MICINN Retos RTI2018-095673-B-I00, PID2020-11782RB-I00, PID2020-117941RB-I00, all of which were co-funded with FEDER funds, AMMF 2018/117, COST Action CA17112 and Comunidad de Madrid S2022/BMD-7409. This project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No. 101095679. The research group belongs to the validated Research Groups Ref. 970935 Liver Pathophysiology, 920631 Lymphocyte Immunobiology and IBL-6 (imas12-associated). KZ was supported by the China Scholarship Council. SM-G was supported by a predoctoral scholarship from Complutense University

Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis

Advanced fibrosis; Nonalcoholic steatohepatitis; Type 2 diabetesFibrosis avanzada; Esteatohepatitis no alcohólica; Diabetes tipo 2Fibrosi avançada; Esteatohepatitis no alcohòlica; Diabetis tipus 2Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13–10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63–9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03–77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16–41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14–18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71–650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively