Effects of glucagon-like peptide-1 receptor agonists on glycated haemoglobin and continuous glucose monitoring metrics as adjunctive therapy to insulin in adults with type 1 diabetes: A meta-analysis of randomized controlled trials.

AIMS: To conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) metrics as an adjunct to insulin therapy in adults with type 1 diabetes mellitus (T1D). METHODS: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library, and Google Scholar up to 27 May 2024. Dual-independent study selection, data extraction, and quality assessment were performed. Results were summarized using random-effects meta-analysis. RESULTS: Six RCTs were identified, involving a total of 378 individuals with T1D. The use of GLP-1RAs in addition to standard insulin therapy was associated with a significant reduction in HbA1c (mean difference [MD] -0.21%, 95% confidence interval [CI] -0.36 to -0.06; p = 0.007) and a similar time in range (TIR) compared to placebo (MD -0.22%, 95% CI -2.39 to 1.95; p = 0.84). GLP-1RA therapy resulted in a significantly higher time below range (MD 1.13%, 95% CI 0.50 to 1.76; p < 0.001) and a lower time above range compared with placebo (MD -1.83%, 95% CI -2.51 to -1.15; p < 0.001). Nonsignificant differences were noted for the secondary outcomes, including the mean amplitude of glucose excursion, continuous overall net glycaemic action for 60 min, mean daily glucose, coefficient of variation, and mean standard deviation of weekly glucose levels. CONCLUSION: Our findings suggest that, in individuals with T1D, add-on therapy with GLP-1RAs does not confer significant benefits in terms of CGM metrics and is associated with a longer time below the target glycaemic range.

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.

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.

Sodium-Glucose Co-transporter 2 Inhibitors Versus Metformin as the First-Line Treatment for Type 2 Diabetes: Is It Time for a Revolution?

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a promising therapeutic option for hyperglycemia and its complications. However, metformin remains the first-line pharmacological treatment in most algorithms for type 2 diabetes (T2D). Although metformin is generally believed to exert positive effects on cardiovascular (CV) outcomes, relevant data are mainly observational and potentially overinterpreted. Yet, it exerts numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities. CV outcome trials have demonstrated cardiorenal protection with SGLT2i among people at high CV risk and mostly on concomitant metformin therapy. However, post hoc analyses of these trials suggest that the cardiorenal effects of gliflozins are independent of background treatment and consistent across the full spectrum of CV risk. Considering the importance of addressing hyperglycemia as a means of preventing diabetic complications and significant knowledge gaps, particularly regarding the cost-effectiveness of SGLT2i in drug-naïve populations with T2D, the position of metformin in the management of people with diabetes at low CV risk remains solid for the moment. On the other hand, available evidence-despite its limitations-suggests that specific groups of people with T2D, particularly those with heart failure and kidney disease, could probably benefit more from treatment with SGLT2i. This narrative mini-review aims to discuss whether current evidence justifies the use of SGLT2i as the first-line treatment for T2D.

Different patterns of changes in free 25-hydroxyvitamin D concentrations during intermittent fasting among meat eaters and non-meat eaters and correlations with amino acid intake.

We prospectively assessed changes in free 25-hydroxyvitamin D [25(OH)D] and vitamin D binding protein (VDBP) among overweight adults who followed a pescatarian Orthodox intermittent fasting regimen (n = 59) and controls who followed a low-fat 12:12 diet (n = 46). Total and free 25(OH)D, parathyroid hormone, VDBP, anthropometric data, and amino acid intake were evaluated in both groups at three time points: at baseline, 7 weeks after diet implementation, and 5 weeks after participants returned to their usual eating habits (12 weeks from baseline). An increase in amino acid intake between baseline and 12 weeks was independently correlated with higher free 25(OH)D values at 12 weeks for both groups. Our findings suggest that diet can affect free 25(OH)D concentrations, through variations in amino acid intake, independently of exposure to sunlight, providing novel mechanistic insights into the future planning of vitamin D supplementation strategies. However, this hypothesis needs to be tested in larger studies.

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.

Changes in the Global Epidemiology of Type 1 Diabetes in an Evolving Landscape of Environmental Factors: Causes, Challenges, and Opportunities.

The worldwide incidence of type 1 diabetes mellitus (T1DM) has increased in recent decades. The reasons behind this phenomenon are not yet fully understood. Early life infections, prenatal and perinatal factors, and diet composition have been associated with the triggering of autoimmunity and the risk of presentation of T1DM. However, the rapid increase in new cases of the disease raises the hypothesis that lifestyle factors, which have traditionally been associated with type 2 diabetes, such as obesity and unhealthy eating patterns could also play a role in the genesis of autoimmune diabetes. This article aims to highlight the changing epidemiology of T1DM and the importance of properly recognizing the environmental factors behind it, as well as the connections with the pathogenesis of the disorder and the need to prevent or delay T1DM and its long-term complications.

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.

The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications.

Hepatocellular carcinoma (HCC) occurs in the setting of prolonged liver inflammation, hepatocyte necrosis and regeneration in patients with cirrhosis. Despite the progress made in the medical management of the disorder during the past decades, the available pharmacological options remain limited, leading to poor survival rates and quality of life for patients with HCC. Sodium-glucose cotransporter 2 inhibitors (SGLT2) originally emerged as drugs for the treatment of hyperglycemia; however, they soon demonstrated important extra-glycemic properties, which led to their evaluation as potential treatments for a wide range of non-metabolic disorders. Evidence from animal studies suggests that SGLT2i have the potential to modulate molecular pathways that affect hallmarks of HCC, including inflammatory responses, cell proliferation, and oxidative stress. The impressive benefits of neurohormonal modulation observed with SGLT2i in congestive heart failure set the stage for human trials in cirrhotic ascites. However, future studies need to evaluate several aspects of the benefit to risk ratio of such a therapeutic strategy, including the co-administration with antineoplastic agents and diuretics, infections, use in hospitalized individuals, renal safety and hypovolemia. In this narrative review, we discuss the putative role of SGLT2i in the treatment of patients with HCC, starting with the mechanisms that could justify a possible benefit and ending with potential clinical implications and areas for future research.

Implementation of Christian Orthodox fasting improves plasma adiponectin concentrations compared with time-restricted eating in overweight premenopausal women.

The exact mechanisms mediating the metabolic effects of Orthodox fasting remain unclear. Plasma adiponectin, biochemical and anthropometrical data were evaluated in 55 Orthodox fasters (OF) and 42 time-restricted eating controls (all women, mean age 47.8 years) at three time points: baseline, end of the dietary intervention (7 weeks) and 5 weeks after participants returned to their typical dietary habits (12 weeks from baseline). In the OF group, there was an increase in adiponectin values at 12 weeks compared with baseline (9815.99 vs 8983.52 mg/ml, p = 0.02) and a reduction in body fat mass between baseline and 12 weeks (35.44 vs 32.17%, p = 0.004) and between 7 and 12 weeks (35.33 vs 32.17%, p = 0.003). In the same group, an inverse correlation between adiponectin and waist circumference values was observed over the entire study period. Our results provide novel evidence that Orthodox fasting has favourable metabolic effects related to improved adiponectin concentrations.

Treating latent autoimmune diabetes in adults in the era of cardiovascular outcomes trials: Old dog should learn new tricks.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) is characterised by pathophysiological and clinical heterogeneity. Hence, the optimal treatment strategy for this type of diabetes remains a clinical challenge. AIM: To discuss the potential of a modern therapeutic approach for LADA in the context of the novel findings of cardiovascular outcomes trials and stress the controversies surrounding LADA and the barriers in the effective management of people with this type of diabetes. METHODS: We performed a literature search in major biomedical databases in order to retrieve relevant literature. The results of key studies, along with the authors' clinical experience and perspective, are summarised and discussed in this narrative, mini review article. RESULTS: Insulin remains the primary treatment choice in individuals with low C-peptide levels. Although cardiovascular outcomes trials have mainly recruited participants with type 2 diabetes, recent data suggest that the cardiorenal protective properties of the new therapies are even present in people without diabetes and thus, the extrapolation of their results on LADA individuals sounds reasonable. Therefore, sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists should be considered for the management of people with preserved insulin production being at high cardiovascular risk. The risk of diabetic ketoacidosis with SGLT2is requires increased vigilance by treating physicians. CONCLUSIONS: Individualisation, preservation of beta-cell mass and function and cardiorenal protection are the new challenges in LADA therapy.

Intestinal SGLT1 as a therapeutic target in COVID-19-related diabetes: A "two-edged sword" hypothesis.

Emerging data are linking coronavirus disease 2019 (COVID-19) with an increased risk of developing new-onset diabetes. The gut has been so far out of the frame of the discussion on the pathophysiology of COVID-19-induced diabetes, with the pancreas, liver, and adipose tissue being under the spotlight of medical research. Sodium-glucose co-transporters (SGLT) 1 represent important regulators of glucose absorption, expressed in the small intestine where they mediate almost all sodium-dependent glucose uptake. Similar to what happens in diabetes and other viral infections, SGLT1 upregulation could result in increased intestinal glucose absorption and subsequently promote the development of hyperglycaemia in COVID-19. Considering the above, the question whether dual SGLT (1 and 2) inhibition could contribute to improved outcomes in such cases sounds challenging, deserving further evaluation. Future studies need to clarify whether putative benefits of dual SGLT inhibition in COVID-19 outweigh potential risks, particularly with respect to drug-induced euglycaemic diabetic ketoacidosis, gastrointestinal side effects, and compromised host response to pathogens.

Similar late effects of a 7-week orthodox religious fasting and a time restricted eating pattern on anthropometric and metabolic profiles of overweight adults.

A hypocaloric diet, based on Orthodox fasting (OF) was followed by 29 overweight adults. A low-calorie, 16/8, time restricted eating (TRE) pattern was followed by 16 age- and weight-matched participants. Anthropometric, lipid, glycaemic and inflammation markers were assessed at baseline, at the end of the intervention (7 weeks from baseline) and 6 weeks after the cessation of diets (13 weeks from baseline). There was a trend of weight loss in both groups, which was evident at week 7 (TRE: -2.1 ± 1.0; OF: -2.0 ± 0.5 kg, p < 0.001 from baseline) and remained significant at week 13 (TRE: -2.9 ± 0.7; OF: -2.6 ± 0.3 kg, p < 0.001 from baseline). In the OF group, lipid concentrations declined at week 7 compared with baseline, increasing at week 13 compared with week 7. Our findings suggest that OF promotes a decrease in lipid concentrations, which however, is not evident 6 weeks after its end.

Effects of orthodox religious fasting versus combined energy and time restricted eating on body weight, lipid concentrations and glycaemic profile.

For seven weeks, 37 overweight adults followed a hypocaloric diet based on Orthodox Fasting (OF). A hypocaloric, time restricted eating (TRE) plan (eating between 08:00 to 16:00 h, water fasting from 16:00 to 08:00 h) was followed by 23 Body Mass Index (BMI)-matched participants. Anthropometric, glycaemic and inflammation markers and serum lipids were assessed before and after the diets. Both OF and TRE groups demonstrated reductions in BMI (28.54 ± 5.45 vs 27.20 ± 5.10 kg/m2, p < 0.001 and 26.40 ± 4.11 vs 25.81 ± 3.78 kg/m2 p = 0.001, respectively). Following the intervention, the OF group presented lower concentrations of total and low-density lipoprotein-cholesterol, compared with the pre-fasting values (178.40 ± 34.14 vs 197.17 ± 34.30 mg/dl, p < 0.001 and 105.89 ± 28.08 vs 122.37 ± 29.70 mg/dl, p < 0.001, respectively). Neither group manifested significant differences in glycaemic and inflammatory parameters. Our findings suggest that OF has superior lipid lowering effects than the TRE pattern.

Rising Glucagon-Like Peptide 1 Concentrations After Parathyroidectomy in Patients With Primary Hyperparathyroidism.

BACKGROUND: Although primary hyperparathyroidism has been associated with insulin resistance, potential optimal effects of parathyroidectomy (PTX) on glucose homeostasis remain controversial. Accordingly, the impact of PTX on glucose-stimulated incretin (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide) secretion has not been evaluated. The aim of this pilot study was to compare glucose-stimulated incretin secretion (GSIS) in patients with asymptomatic primary hyperparathyroidism with normal glucose homeostasis, before and after PTX. METHODS: Fourteen patients were included in the study. Fasting calcium, parathyroid hormone, glucose, insulin, GLP-1, and gastric inhibitory peptide were measured pre- and post-operatively. Homeostasis Model Assessment 2, QUICKI, and Matsuda indexes were used as markers of insulin sensitivity and resistance before and after PTX. Preoperatively, a 75 g oral glucose tolerance test (OGTT) was performed to evaluate the response of glucose, insulin, and GSIS. OGTT measurements were repeated 6 ± 2 wk post-PTX. RESULTS: Patients had a mean age of 52.93 ± 9.96 y, and female-to-male ratio was 12:2. Pre- and post-operatively, a positive correlation between parathyroid hormone and Homeostasis Model Assessment 2 for ß-cell function was evident (r = 0.74, P = 0.002 and r = 0.55, P = 0.04, respectively). After PTX, a significant increase in GSIS for GLP-1 during OGTT was observed (in 60 min: 63.06 ± 44.78 versus 102.64 ± 40.19 pg/mL, P = 0.02; and in 120 min: 71.20 ± 35.90 versus 102.49 ± 40.02 pg/mL, P = 0.03). CONCLUSIONS: The increase of GLP-1 response following oral glucose load after PTX may reflect an initial recovery phase of glucose homeostasis. Long-term studies are required to elucidate the physiological interplay between the normalization of calciotropic axis and the rising GLP-1 concentrations post-PTX.

Profile and factors associated with glycaemic control of patients with type 2 diabetes in Greece: results from the diabetes registry.

BACKGROUND: Strict glycaemic control early in the treatment process has been shown to reduce the occurrence of micro- and macro- vascular complications of diabetes in the long-term. Thus, treatment guidelines advise early intensification of treatment to achieve glycaemic control goals. However, evidence in Greece suggests that, despite guideline recommendations, glycaemic control among patients with T2DM remains challenging. This study presents the demographic and clinical characteristics of patients with T2DM in Greece using data from an electronic registry designed specifically for this treatment category and investigates the factors that are independently associated with glycaemic control. METHODS: This is a multi-center, observational, cross-sectional study to investigate epidemiological and clinical factors affecting glycaemic control among patients with T2DM in Greece. Data was collected via a web-based disease registry, the Diabetes Registry, which operated from January 1st to December 31st, 2017. Five large specialized diabetes centers operating in Greek hospitals participated in the study. RESULTS: Data for 1141 patients were retrieved (aged 63.02 ± 12.65 years, 56.9% male). Glycaemic control (Hb1Ac < 7%) was not achieved in 57.1% of patients. Factors independently associated with poor glycaemic control were: family history of diabetes [OR: 1.53, 95% CI: 1.06-2.23], BMI score between 25 to 30 [OR: 2.08, 95% CI: 1.05-4.13] or over 30 [OR: 2.12, 95% CI 1.12-4.07], elevated LDL levels [OR: 1.53, 95% 1.06-2.21] and low HDL levels [OR: 2.12, 95% CI: 1.44-3.12]. Lastly, use of injectable antidiabetic agents (in monotherapy or in combination) was less likely to be associated with poor glycaemic control versus treatment with combination of oral and injectable agents [OR: 0.50, 95% CI: 0.24-1.01]. This association was found to be marginally statistically significant. CONCLUSION: Inadequate lipid control, family history of diabetes and presence of obesity (ΒΜΙ ≥ 30 kg/m2) were associated with poor glycaemic control among study sample, whereas use of injectable antidiabetic agents was less likely to be associated with poor glycaemic control. These findings indicate how complex optimal glycaemic control is, highlighting the need for tailored interventions in high-risk subpopulations with T2DM.

The use of sodium-glucose co-transporter 2 inhibitors in the inpatient setting: Is the risk worth taking?

WHAT IS KNOWN AND OBJECTIVE: In the outpatient setting, sodium-glucose co-transporter 2 inhibitors (SGLT2i) are recognized as effective agents to optimize glycaemia and also developing robust evidence for cardiovascular (CV) and renal protection in people with type 2 diabetes, particularly those at higher risk. However, data on the safety and efficacy of these drugs in hospitalized patients remain limited. The purpose of this review is to discuss the balance between risks and benefits of SGLT2i use in the inpatient setting. METHODS: PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the mechanisms of action and the safety profile of SGLT2i in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. RESULTS AND DISCUSSION: The rationale behind the use of these agents in the inpatient setting is based on the low risk of hypoglycaemia, the practical dosing scheme and the potential to decrease subsequent heart failure admission rates. In addition, data from animal studies indicate the ability of SGLT2i to ameliorate oxidative stress, suppress sympathetic activity, enhance autophagy and promote cardiac remodelling, when administered in the acute phase of CV episodes. On the other hand, these drugs have been linked to specific adverse events related to their mechanism of action, including an increased risk of euglycaemic diabetic ketoacidosis and volume depletion, which raises concerns over their usefulness in inpatients, particularly individuals with multimorbidities. WHAT IS NEW AND CONCLUSION: Potential benefits deriving from the use of SGLT2i in the inpatient setting cannot mitigate possible risks, at least until robust evidence on their efficacy in hospitalized individuals become available. The concept of administering these agents in the acute phase of CV episodes, in people with or without diabetes, requires further evaluation in appropriately designed clinical studies.

Effects of Orthodox religious fasting on human health: a systematic review.

PURPOSE: Different studies have pointed towards a positive effect of religious fasting on human health. Orthodox fasting (OF) regime could be characterized as a periodical vegetarian diet, demonstrating several common characteristics with the typical Mediterranean diet. The present systematic review aimed to synthesize available results regarding the potential impact of OF on human health. METHODS: Key biomedical databases were searched to identify studies examining the effects of OF on humans. Following implementation of specific criteria, ten studies were included in the analysis and their results were systematically reported and critically appraised in this review. RESULTS: According to the available limited results, OF periods are characterized by a restriction in total energy and fat intake, an increase in carbohydrate and fiber consumption, while in terms of protein intake, results are contradictive. The overall effect of OF on lipids profile seems to be optimal, with the reduction of total cholesterol and LDL-C levels, being a consistent finding across studies (up to 17.8 and 31.4%, respectively). However, the effect on HDL-C is still unclear. Conclusions regarding the impact on body weight and glucose homeostasis cannot be drawn, given that relevant data are limited with conflicting results. Any potential negative aspects of OF, mainly attributed to reduced dietary intake of vitamin D and B12 and minerals (mainly calcium), require further investigation. CONCLUSIONS: Given the limitations of available evidence, more studies are required before reaching definite conclusions about the effects of OF on human health.