The Mediterranean diet, but not time-restricted eating, mediates the effects of nesfatin on beta cell function among overweight, metabolically healthy individuals.

Nesfatin concentrations are positively correlated with beta cell function. However, it is unclear whether diet composition mediates this relationship. We recruited 27 overweight individuals who practiced Orthodox fasting (OF), a subset of the Mediterranean diet (MedDiet), for 7 weeks. Fourteen overweight people who practiced 16:8 time-restricted eating served as control group. Anthropometric parameters, biochemical data and adipokine levels were evaluated at baseline and after the end of the diet period (7 weeks from baseline). Subsequently, participants were asked to return to their usual eating plans, and an additional evaluation was performed 5 weeks after the end of the research diets (12 weeks from baseline). We observed a significant and negative correlation between HOMA-B and nesfatin values at 12 weeks, only in the OF group (r = -0.455, p = 0.01). In conclusion, returning to normal eating habits after 7 weeks of strict adherence to MedDiet affects the homeostatic balance between insulin secretion and nesfatin.

Pathophysiology and Clinical Management of Dyslipidemia in People Living with HIV: Sailing through Rough Seas.

Infections with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst HAART regimens, darunavir and atazanavir, tenofovir disoproxil fumarate, nevirapine, rilpivirine, and especially integrase inhibitors have demonstrated the most favorable lipid profile, emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates, or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

Progenitor Cell Function and Cardiovascular Remodelling Induced by SGLT2 Inhibitors.

Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to 90% of renal glucose uptake, while SGLT1 receptors are found mainly in the small intestine, facilitating glucose absorption. SGLT2 inhibitors (SGLT2i) originally emerged as agents for the treatment of type 2 diabetes mellitus; however, they soon demonstrated remarkable cardio- and renoprotective actions that led to their licensed use for the treatment of heart failure and chronic kidney disease, regardless of the diabetic status. Cardiovascular remodelling represents an umbrella term that encompasses changes that occur in the cardiovascular system, from the molecular and cellular level, to tissue and organs after local injury, chronic stress, or pressure. SGLT modulation has been shown to positively affect many of these molecular and cellular changes observed during pathological remodelling. Among the different pathophysiological mechanisms that contribute to adverse remodelling, various stem and progenitor cells have been shown to be involved, through alterations in their number or function. Recent studies have examined the effects of SGLT2i on stem and progenitor cell populations and more specifically on endothelial progenitor cells (EPCs). Although some found no significant effect, others showed that SGLT2i can modulate the morphology and function of EPCs. These preliminary observations of the effect of SGLT2i on EPCs may be responsible for some of the beneficial effects of gliflozins on pathological remodelling and, by extension, on cardiovascular disease. The purpose of this narrative review is to critically discuss recent evidence on the cardioprotective effects of SGLT2is, in the context of cardiac remodelling.

Metformin in Esophageal Carcinoma: Exploring Molecular Mechanisms and Therapeutic Insights.

Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin's influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin's potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin's candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin's role in EC management, potentially improving patient care and outcomes.

The Effects of Olive Oil Consumption on Biochemical Parameters and Body Mass Index of People with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder, is closely associated with insulin resistance, obesity, and metabolic syndromes. A body of research has proposed that olive oil, a basic component of the Mediterranean diet with antioxidant and anti-inflammatory properties, may alleviate metabolic disturbances and retard the progression of NAFLD. We conducted a systematic review and meta-analysis to assess the effectiveness of olive oil intake in people with NAFLD. We systematically searched the major electronic databases (PubMed/MEDLINE, Scopus, Cochrane Central Register of Controlled Trials), as well as grey literature sources, to identify randomized controlled trials (RCTs) investigating the effects of olive oil consumption on biochemical and anthropometric parameters of individuals with NAFLD. The quality of the studies was evaluated using the risk-of-bias tool 2.0 (RoB 2). The mean difference (MD) and the 95% confidence interval (CI) were calculated using fixed-effects and random-effects models. Seven RCTs involving 515 subjects were included in the analysis. In the random-effects model, no statistically significant differences were identified with respect to alanine transaminase (MD = -1.83 IU/L, 95% CI: -5.85, 2.19 IU/L, p = 0.37, I2 = 69%) and aspartate transaminase (MD = -1.65 IU/L, 95% CI: -4.48, 1.17 IU/L, p = 0.25, I2 = 72%) levels or waist circumference values (MD = -0.23 cm, 95% CI: -1.23, 0.76 cm, p = 0.65, I2 = 0%). However, a significant effect on body mass index was observed (MD = -0.57 kg/m2, 95% CI: -1.08, -0.06 kg/m2, p = 0.03, I2 = 51%) for subjects who received olive oil compared to those who received an alternative diet or placebo. The findings of the present meta-analysis suggest a modestly positive impact of olive oil intake on body weight in people with NAFLD.

Association between variants in TCF7L2, CTRB1/2, and GLP-1R genes and response to therapy with glucagon-like peptide-1 receptor agonists.

OBJECTIVES: The factors determining the response to treatment with glucagon-like peptide-1 receptor agonists (GLP-1- RAs) have not been clarified. The present study investigated the association between polymorphisms in TCF7L2, CTRB1/2, and GLP-1 R genes and response to GLP-1 RAs regarding glycemic control and weight loss among Greek patients with type 2 diabetes mellitus (T2DM). METHODS: Patients (n = 191) treated with GLP-1 RAs for at least 6 months were included. Participants were genotyped for TCF7L2 rs7903146 (C>T), CTRB1/2 rs7202877 (T>G) and GLP-1 R rs367543060 (C>T) polymorphisms. Clinical and laboratory parameters were measured before, 3, and 6 months after treatment initiation. The patients were classified into responders and non-responders according to specific criteria. RESULTS: Carriers of at least one rs7903146 'T' allele and rs7202877 'G' allele presented similar glucose control and weight loss response to GLP-1 RAs with the respective homozygous wild-type genotypes [odds ratio (OR): 1.08, 95% confidence interval (CI): 0.5, 2.31, p = 0.85 and OR: 1.35, 95% CI: 0.66, 2.76, p = 0.42; OR: 1.4, 95% CI: 0.56, 3.47, p = 0.47 and OR: 1.28, 95% CI: 0.55, 2.98, p = 0.57, respectively]. Regarding the GLP-1 R polymorphism, all participants were homozygous for the wild-type allele; thus, no comparisons were feasible. Female sex (p = 0.03) and lower baseline weight (p = 0.024) were associated with an improved glycemic and weight loss response, respectively. CONCLUSION: There is no evidence suggesting a role for the variants studied in response to GLP-1 RA therapy in people with T2DM. However, specific demographic and clinical factors may be related to a better response to treatment with these agents.

Effect of sodium-glucose cotransporter-2 inhibitors on continuous glucose monitoring metrics, as adjunctive to insulin in adults with type 1 diabetes mellitus: a meta-analysis of randomized controlled trials.

AIMS: This meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on continuous glucose monitoring metrics as adjunctive to insulin in adults with type 1 diabetes mellitus (T1D). METHODS: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library and Google Scholar until October 25, 2023. Dual-independent study selection, data extraction and quality assessment were conducted. Results were summarized with random effects meta-analysis. RESULTS: Eight RCTs were identified, involving a total of 2310 T1D patients. The use of SGLT2is on top of standard insulin therapy was associated with a significantly higher time in range (TIR) compared to placebo (mean difference (MD) 9.7 %; 95 % confidence interval (CI) [8.3, 1.11]; P < 0.001). The time above range was significantly lower in patients receiving SGLT2is (MD -8.71 %; 95 % CI [-11.62, -5.79]; P < 0.001), whereas no difference was observed regarding the time below range (TBR) (MD 0.34 %; 95 % CI [-0.17, 0.85]; P = 0.19). A significantly lower sensor-recorded mean daily glucose was noted in the group receiving SGLT2is (MD -16.55 mg/dL; 95 % CI [-19.82, -13.29]; P < 0.001). When considering the metrics of glucose variability, SGLT2is demonstrated a significant favorable effect on the mean amplitude of glucose excursions (MD -16.92 mg/dL; 95 % CI [-25.31, -8.13]; P < 0.001) and the mean standard deviation of weekly glucose levels (MD -7.67 mg/dL; 95 % CI [-11, -4.35]; P < 0.001). No significant effect was observed concerning the coefficient of variation (MD -1 %; 95 % CI [-2.39, 0.4]; P = 0.16). Regarding safety outcomes, SGLT2is were significantly linked to higher odds of diabetic ketoacidosis compared to insulin alone (OR 3.18; 95 % CI [1.79, 5.66]; P < 0.001), with no significant impact on severe hypoglycemia events (OR 1; 95 % CI [0.54, 1.85]; P = 0.1). CONCLUSION: Our findings suggest that in individuals with T1D, adjunct therapy with SGLT2is provides a significant benefit in terms of TIR and reduced glucose variability, without an increase in TBR.

Management of type 2 diabetes in patients with compensated liver cirrhosis: Short of evidence, plenty of potential.

BACKGROUND AND AIMS: Treatment of type 2 diabetes (T2D) in patients with compensated cirrhosis is challenging due to hypoglycemic risk, altered pharmacokinetics, and the lack of robust evidence on the risk/benefit ratio of various drugs. Suboptimal glycemic control accelerates the progression of cirrhosis, while the frequent coexistence of nonalcoholic fatty liver disease (NAFLD) with T2D highlights the need for a multifactorial therapeutic approach. METHODS: A literature search was performed in Medline, Google Scholar and Scopus databases till July 2023, using relevant keywords to extract studies regarding the management of T2D in patients with compensated cirrhosis. RESULTS: Metformin, sodium-glucose co-transporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are promising treatment options for patients with T2D and compensated liver cirrhosis, offering good glycemic control with minimal risk of hypoglycemia, while their pleiotropic actions confer benefits on NAFLD and body weight, and decrease cardiorenal risk. Sulfonylureas cause hypoglycemia, thus should be avoided, while in specific studies, dipeptidyl peptidase-4 inhibitors have been correlated with increased risk of decompensation and variceal bleeding. Despite the benefits of thiazolidinediones in nonalcoholic steatohepatitis, concerns about edema and weight gain limit their use in compensated cirrhosis. Insulin does not exert hepatotoxic effects and can be administered safely in combination with other drugs; however, the risk of hypoglycemia should be considered. CONCLUSIONS: The introduction of new hepatoprotective diabetes drugs into clinical practice, including tirzepatide, SGLT2i, and GLP-1 RA, sets the stage for future trials to investigate the ideal therapeutic regimen for people with T2D and compensated cirrhosis.

The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). METHODS: The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. RESULTS: In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95% CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03 mL/min/1.73 m2; 95% CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23 mL/min/1.73 m2; 95% CI = [- 3.62, - 0.84]; P = 0.002). CONCLUSION: Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.

Teplizumab: promises and challenges of a recently approved monoclonal antibody for the prevention of type 1 diabetes or preservation of residual beta cell function.

INTRODUCTION: Type 1 diabetes (T1D) is a chronic autoimmune endocrinopathy with increasing incidence that results in the depletion of pancreatic beta cells and exogenous insulin dependence. Despite technological advances in insulin delivery, disease control remains suboptimal, while previous immunotherapy options have failed to prevent T1D. Recently, teplizumab, an immunomodulating monoclonal antibody, was approved to delay or prevent T1D. AREAS COVERED: Five randomized controlled trials have tested different regimens of administration, mostly 14-day schemes with dose escalation. In participants with new-onset T1D, teplizumab delayed C-peptide decline, improved glycemic control, and reduced insulin demand for a median of 1 or 2 years. Studies in at-risk relatives of patients showed a decrease in T1D incidence during 2 years of follow-up. Subgroups of responders with unique metabolic and immunological characteristics were identified. Mild to moderate adverse effects were reported, including transient rash, cytopenia, nausea, vomiting, and infections. EXPERT OPINION: Teplizumab marks a turning point in T1D therapy. Areas of future research include the ideal population for screening, cost-effectiveness, and challenges in treatment accessibility. More studies are essential to evaluate the ideal duration of the regimen, the potential benefit of combinations with other drugs, and to identify endophenotypes with a high probability of response.

A Mediterranean Eating Pattern Combining Energy and Time-Restricted Eating Improves Vaspin and Omentin Concentrations Compared to Intermittent Fasting in Overweight Individuals.

Athonian Orthodox fasting (AOF) is characterized by energy- and time-restricted eating (TRE) and is based on the Mediterranean diet. We aimed to investigate the impact of AOF compared to another TRE model on vaspin, omentin, nesfatin, and visfatin levels. We included 25 individuals (mean age 50.3 ± 8.6 years, 24% men) who practiced AOF and abstained from animal products, with the exception of seafood and fish. This group adopted a 12 h eating interval (08.00 to 20.00). In total, 12 participants (mean age 47.7 ± 8.7 years, 33.3% men) who practiced 16:8 TRE (eating from 09:00 to 17:00) and were allowed to consume meat served as the controls. Anthropometric and dietary data and adipokine levels were prospectively collected at three time points: at baseline, after the end of the diets (7 weeks), and 5 weeks after the participants returned to their typical eating habits (12 weeks from baseline). Vaspin levels decreased [795.8 (422.1-1299.4) (baseline) vs. 402.7 (203.8-818.9) (7 weeks) pg/mL, p = 0.002] and omentin levels increased [568.5 (437.7-1196.5) (baseline) vs. 659.0 (555.7-1810.8) (12 weeks) pg/mL, p = 0.001] in the AOF group, while none of the analyzed adipokines changed significantly in the TRE group. The variations observed in vaspin and omentin concentrations in the AOF group were independent of age, sex, changes in anthropometry and fat intake. In conclusion, AOF can significantly reduce vaspin and increase omentin, whose levels are known to increase and decrease, respectively, in obesity and type 2 diabetes. The implications of these findings for cardiometabolic health warrant further investigation.

Epidemiological, Pathophysiological, and Clinical Considerations on the Interplay between Thyroid Disorders and Type 2 Diabetes Mellitus.

Thyroid disorders (TD) and diabetes mellitus (DM) are the two endocrinopathies with the highest prevalence in the general population that frequently coexist. Thyroid dysfunction is more common in people with type 2 diabetes mellitus (T2DM) compared to normoglycemic individuals. Untreated TD can impair glycemic control, increasing the risk of diabetes complications. Hyperinsulinemia can affect the morphology of the thyroid gland by promoting the proliferation of thyroid tissue and increasing the size of thyroid nodules. Metformin can confer benefits in both endocrinopathies, while other antidiabetics, such as sulfonylureas, can negatively affect thyroid function. Animal and human observational data suggest an increased risk of medullary thyroid carcinoma after treatment with glucagon-like peptide-1 receptor agonists. However, randomized trials have so far been reassuring. Furthermore, some observational studies suggest an association between thyroid cancer and T2DM, especially in women. This narrative review aims to shed light on the epidemiological, pathophysiological, and clinical aspects of the interplay between TD and T2DM. Taking into account the important clinical implications of the coexistence of T2DM and TD, proper screening and management strategies are needed for both endocrinopathies to ensure optimal patient care.

Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis: Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches.

The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.

From an Empty, to an Almost Full, and Eventually to a Never Full Glass: The Evolving Challenges of Medical Education.

It has traditionally been considered that the larger the amount of knowledge, the greater the competency of a physician. However, the vertiginously fast accumulation of novel knowledge in modern medicine raises the risk that students and residents get lost in the chaos of information to which they are exposed. Thus, it becomes evident that redefining the model of medical education (and possibly rethinking what a "good" doctor means) becomes inevitable. Current challenges in medical training include early engagement of medical students in research activities and evidence-based medicine procedures, as well as adoption of new technologies, such as artificial intelligence. Gradually, the paradigm of the competent physician will transform from the "one who knows well" to "one who knows well where to search for knowledge." Given that person-centeredness remains an essential goal of medical education, supervision and assistance by academic staff are needed to ensure that the new training model has a positive impact on person-centered and doctor-patient relationships.

The new evidence on cardiorenal benefits of sodium-glucose cotransporter 2 inhibitors in type 1 diabetes: one step closer to their use in this setting?

Chronic kidney disease (CKD) affects 30-40% of persons with type 1 diabetes mellitus (T1DM), markedly increasing the risk of kidney failure and cardiovascular events. The excessive mortality observed in T1DM compared to the general population can be attributed to the presence of CKD, with cardiovascular disease as the leading cause of premature death. A recently published, robust real-world study investigated the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) adjunctive therapy on blood glucose levels, adverse events, and cardio-renal outcomes among individuals with T1DM. GLP-1 RA provided greater reduction in glycated hemoglobin in comparison to SGLT2i therapy, whereas the latter reduced the risk of CKD, heart failure, and hospitalization for any cause. However, the SGLT2i treated cohort had a higher risk of diabetic ketoacidosis (DKA). The study provides promising evidence that the protective cardiorenal effects of SGLT2i, previously confirmed in people with and without type 2 diabetes mellitus, might also be present in T1DM. However, the benefits and risks, especially the risk of DKA, should be further examined in dedicated large-scale randomized controlled trials.

The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.