Caffeine and adenosine Ribeiro, Joaquim A; Sebastião, Ana M
Journal of Alzheimer's disease,
01/2010, Volume:
20 Suppl 1, Issue:
s1
Journal Article
Peer reviewed
Open access
Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all ...brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction: Sarcopenic obesity (SO), characterized by concurrent excessive body fat and reduced muscle mass, amplifies the risk of metabolic abnormalities, especially insulin resistance (IR). ...Irisin, a myokine linked to energy homeostasis, has shown inconsistent associations with sarcopenia. This study investigated irisin levels in T2DM patients with SO or non-sarcopenic obesity (NSO). Methods: Patients with T2DM and BMI >30 kg/m² underwent glycometabolic assessment and irisin measurements. Muscle efficiency was evaluated using Handgrip Strength (HGS) and 5-times Sit To Stand Test (5-STST). Patients were categorized into SO and NSO groups per the 2022 ESPEN/EASO Consensus. Results: Of 67 patients affected by obesity and T2DM, 50 had NSO and 17 SO. SO patients were older (70 6 vs 66 7 years, p=0.028), with higher BMI (36.7 4.3 vs 34.7 4 kg/m², p=0.036), FM (41.9 7.7 vs 37.6 8.7 kg, p=0.049), alcohol use (47.1% vs 22%, p=0.048), 5-STST (13.3 4.1 vs 10.8 3.1 s, p=0.016), and lower HGS results (24 7.9 vs 36.4 10.2 kg, p<0.001). No difference in HOMA-IR, HbA1c or irisin levels was found between SO and NSO patients. Irisin correlated negatively with HbA1c (r=-0.288, p=0.018), HGS (r=-0.249, p=0.042), muscle mass (r=-0.26, p=0.033), and creatinine (r=-0.308, p=0.011), and positively with relative FM (r=-0.274, p=0.025). Increasing HGS results predicted lower irisin levels (beta=-316, p=0.032). Multivariate logistic regression analysis associated older age with higher SO risk (OR=1.16, p=0.02), with a trend relationship for insulinemia (OR=1.05, p=0.073) and 5-STST (OR=1.19, p=0.068) (p=0.039, area under the curve=0.804). Conclusion: People with T2DM and SO exhibit poorer lifestyle, anthropometric profile and physical performance. Irisin levels are linked with better glycemic control, negatively correlating with muscle mass and strength, suggesting a compensatory role in this context. Disclosure E. Rossi: None. L. Di Gioia: Consultant; Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk, Sanofi. N. Marrano: None. S. Perrini: None. L. Laviola: Speaker's Bureau; A. Menarini Diagnostics, Abbott, AlfaSigma. Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk. Speaker's Bureau; AstraZeneca. Advisory Panel; Roche Diabetes Care, Sanofi. Speaker's Bureau; Terumo Corporation. A. Natalicchio: Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly and Company. F. Giorgino: Consultant; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, LifeScan Diabetes Institute, Merck Sharp & Dohme Corp., Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. Research Support; Eli Lilly and Company, Roche Diabetes Care.
Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of ...life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66Shc is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PPARγ activation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole-body insulin sensitivity. Adipose tissue is the ...major mediator of PPARγ action on insulin sensitivity. PPARγ activation in mature adipocytes induces the expression of a number of genes involved in the insulin signaling cascade, thereby improving insulin sensitivity. PPARγ is the master regulator of adipogenesis, thereby stimulating the production of small insulin-sensitive adipocytes. In addition to its importance in adipogenesis, PPARγ plays an important role in regulating lipid, metabolism in mature adipocytes by increasing fatty acid trapping. Finally, adipose tissue produces several cytokines that regulate energy homeostasis, lipid and glucose metabolism. Disturbances in the production of these factors may contribute to metabolic abnormalities, and PPARγ activation is also associated with beneficial effects on expression and secretion of a whole range of cytokines.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in
, which encodes for the y
LAT1 transporter. LPI patients ...suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible
knockout mouse (
). The
model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the
mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the
model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Irisin is a hormone secreted by skeletal muscle, able to improve metabolic homeostasis and promote energy expenditure. We have previously demonstrated that irisin protects human and rodent β-cells ...and pancreatic islets from lipotoxicity-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS), and promotes β-cell proliferation, both in vitro and in vivo in mice. Irisin may also restore the defects that are characteristic of islets from T2D patients. Although it has been demonstrated that irisin mediates its effects on bone and fat via αV integrin receptors, the presence of an irisin receptor in β-cells has not been reported. In INS-1E cells, we found that irisin activates its intracellular signalling and enhances GSIS in the presence of a specific αV integrin knockdown or a chemical inhibitor of cellular integrins (RGDS), thus excluding the involvement of integrin receptors in irisin effects. Through a pull-down assay/mass spectrometry approach, we identified 102 irisin interactors in human pancreatic islets, mostly belonging to intracellular compartments (i.e., vesicles and membrane rafts), and not including canonical membrane receptors. We therefore hypothesized that irisin could be endocytosed in pancreatic β-cells and confirmed this by immunoblotting and immunofluorescence techniques. In addition, nystatin, an inhibitor of lipid-raft dependent endocytosis, reduced irisin entry into β-cells. These results suggest for the first time that irisin effects on pancreatic β-cells are independent of engaging the αV integrin receptor and may instead depend on its endocytosis. These results are important beyond irisin, as they propose a potential new mechanism of action for peptide hormones. In addition, we highlight the possibility that the same hormone, i.e. irisin, may signal through different receptors in different target tissues.
Disclosure
N.Marrano: None. A.Borrelli: None. G.Biondi: None. M.Rella: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. S.Perrini: None. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly.
Aim
To evaluate the effect on glucose control of professional continuous glucose monitoring (p‐CGM)‐based care as compared with standard care in the management of patients with type 1 and type 2 ...diabetes.
Materials and methods
The PubMed database was searched comprehensively to identify prospective or retrospective studies evaluating p‐CGM as a diagnostic tool for subsequent implementation of lifestyle and/or medication changes and reporting glycated haemoglobin (HbA1c) as an outcome measure.
Results
We found 872 articles, 22 of which were included in the meta‐analysis. Overall, the use of p‐CGM was associated with greater HbA1c reduction from baseline (−0.28%, 95% confidence interval CI −0.36% to −0.21%, I2 = 0%, P < 0.00001) than usual care, irrespective of type of diabetes, length of follow‐up, frequency of continuous glucose monitoring (CGM) use and duration of CGM recording. In the few studies describing CGM‐derived glucose metrics, p‐CGM showed a beneficial effect on change in time in range from baseline (5.59%, 95% CI 0.12 to 11.06, I2 = 0%, P = 0.05) and a neutral effect on change in time below the target range from baseline (−0.11%, 95% CI −1.76% to 1.55%, I2 = 33%, P = 0.90).
Conclusions
In patients with type 1 and type 2 diabetes, p‐CGM‐driven care is superior to usual care in improving glucose control without increasing hypoglycaemia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The landscape of internationally recognized rights is increasingly expanding the web and the Information technology law contributes, through the creation of new situations arising from practices ...identified by the doctrine, to the recognition of new digital rights. The typical path of the affirmation of a ‘New right’ find sudden recognition through national or international case studies that generate the actual recognition of rights that were previously only expectations and that automatically become necessities. The birth of the right to oblivion, i.e., the right to forget and to be forgotten, should be understood as the right to have memories related to a particular subject and to the processes of indexing and storage, including the ability to manage and establish them in hands of third parties. The recent case from the European Union Court of Justice in 2014 is a mirror for the right to be forgotten and censorship in the different landscape of USA and European Law. The present research is a tool for evaluation and analysis of the proposed European regulations.
Abstract The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy balance. Any form of ...weight loss dramatically affects the natural history of T2D, favoring prevention, treatment, and even remission in the case of significant weight loss. However, weight regain, which is often accompanied by the recurrence or worsening of obesity complications such as T2D, is an inevitable biological phenomenon that is an integral part of the pathophysiology of obesity. This can occur not only after weight loss, but also during obesity treatment if it is not effective enough to counteract the physiological responses aimed at restoring adiposity to its pre-weight-loss equilibrium state. Over the past few years, many controlled and randomized studies have suggested a superior efficacy of bariatric surgery compared to conventional therapy in terms of weight loss, glycemic control, and rates of T2D remission. Recently, the therapeutic armamentarium in the field of diabetology has been enriched with new antihyperglycemic drugs with considerable efficacy in reducing body weight, which could play a pathogenetic role in the remission of T2D, not through the classical incretin effect, but by improving adipose tissue functions. All these concepts are discussed in this position statement, which aims to deepen the pathogenetic links between obesity and T2D, shift the paradigm from a “simple” interaction between insulin resistance and insulin deficiency, and evaluate the efficacy of different therapeutic interventions to improve T2D management and induce diabetes remission whenever still possible.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction & Objective: Type 2 diabetes (T2D) is considerably heterogeneous due to different pathogenetic mechanisms that may affect response to treatment. We aimed to assess the efficacy of ...GLP-1RA according to the phenotypes described by Ahlqvist et al. (Diabetes, 2000). Methods: In this retrospective monocentric study, every individual attending our outpatient clinic since 2013 was evaluated for eligibility. Main inclusion criteria were age at T2D diagnosis ≥50 years, T2D duration ≤5 years, BMI ≥25 kg/m2, first users of a GLP-1RA with at least one follow-up visit at 6-12 months. Main exclusion criteria were type 1 diabetes, LADA, ketoacidosis. The assignment to T2D phenotypes (MARD, mild age-related diabetes; MOD, mild obesity-related diabetes; SIDD, severe insulin deficient diabetes; SIRD, severe insulin resistant diabetes) was performed via the algorithm developed by Bello-Chavolla et al. (BMJ, 2020). The primary outcome was difference in HbA1c change from baseline, evaluated with ANOVA. SHapley Additive exPlanations (SHAP) allowed to rank predictors of HbA1c reduction. Kaplan-Meier analysis and log-rank test were used to estimate differences in time to treatment failure, defined as time to HbA1c ≥7.0%. Results: We enrolled 128 patients. The SIDD phenotype was associated with a significantly greater HbA1c reduction (-1.9% vs. -0.67% MARD, -0.75% MOD, -0.56% SIRD; p<0.001) following GLP-1RA initiation after a median follow-up of 8 months. However, SHAP analysis identified baseline HbA1c, rather than SIDD phenotype, as the most relevant predictor of HbA1c change, accounting for ~0.5% HbA1c reduction. Yet, belonging to the SIDD phenotype was associated to earlier treatment failure (p<0.01). Conclusion: Easily available clinical variables such as baseline HbA1c might be more useful to predict response to GLP-1RA than T2D subclassification. However, the diverse pathogenesis of T2D phenotypes might account for differences in treatment durability. Disclosure I. Caruso: Other Relationship; Eli Lilly and Company, Novo Nordisk, Laboratori Guidotti SpA. F. Giordano: None. L. Di Gioia: Consultant; Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk, Sanofi. I.I. Matichecchia: None. A. Cignarelli: None. G. Sorice: None. S. Perrini: None. A. Natalicchio: Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly and Company. L. Laviola: Speaker's Bureau; A. Menarini Diagnostics, Abbott, AlfaSigma. Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk. Speaker's Bureau; AstraZeneca. Advisory Panel; Roche Diabetes Care, Sanofi. Speaker's Bureau; Terumo Corporation. F. Giorgino: Consultant; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, LifeScan Diabetes Institute, Merck Sharp & Dohme Corp., Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. Research Support; Eli Lilly and Company, Roche Diabetes Care.
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