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Over the last few years, given the increase in the incidence and prevalence of both type 2 diabetes mellitus (T2DM) and heart failure (HF), it became crucial to develop guidelines for the optimal preventive and treatment strategies for individuals facing these coexisting conditions. In patients aged over 65, HF hospitalization stands out as the predominant reason for hospital admissions, with their prognosis being associated with the presence or absence of T2DM. Historically, certain classes of glucose-lowering drugs, such as thiazolidinediones (rosiglitazone), raised concerns due to an observed increased risk of myocardial infarction (MI) and cardiovascular (CV)-related mortality. In response to these concerns, regulatory agencies started requiring CV outcome trials for all novel antidiabetic agents [i.e., dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2is)] with the aim to assess the CV safety of these drugs beyond glycemic control. This narrative review aims to address the current knowledge about the impact of glucose-lowering agents used in T2DM on HF prevention, prognosis, and outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were drugs originally intended for the management of diabetes, while their role on the treatment of nonalcoholic steatohepatitis (NASH), and NASH-related hepatocellular carcinoma (HCC), has been at the forefront of medical investigation in recent years. This review presents a comprehensive compilation of extensive data on the putative role of GLP-1 RAs in the treatment of HCC, providing a solid foundation for further clarification of the molecular pathways involved. Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research. [ABSTRACT FROM AUTHOR]

The available data suggest differences in the course of type 2 diabetes mellitus (T2DM) between men and women, influenced by the distinguishing features of the sex. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a relatively new class of antidiabetic drugs that act by mimicking the function of endogenous glucagon-like peptide 1. They constitute valuable agents for the management of T2DM as, in addition to exerting a strong hypoglycemic action, they present cardiorenal protective properties, promote weight loss, and have a good safety profile, particularly with respect to the risk of hypoglycemia. Due to the precedent of studies having identified sexual dimorphic elements regarding the action of other antidiabetic agents, ongoing research has attempted to examine whether this is also the case for GLP-1 RAs. Until now, sex differences have been observed in the impact of GLP1-RAs on glycemic control, weight reduction, and frequency of adverse events. On the contrary, the question of whether these drugs differentially affect the two sexes with respect to cardiovascular risk and incidence of major adverse cardiovascular events remains under investigation. Knowledge of the potential sex-specific effects of these medications is extremely useful for the implementation of individualized therapeutic plans in the treatment of T2DM. This narrative review aims to present the available data regarding the sex-specific action of GLP-1 RAs as well as to discuss the potential pathophysiologic mechanisms explaining these dissimilarities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Efforts to unravel the pathophysiological mechanisms of type 2 diabetes (T2D) have been traditionally trapped into a metabolic perspective. However, T2D is a phenotypically and pathophysiologically heterogenous disorder, and the need for a tailored approach in its management is becoming increasingly evident. There is emerging evidence that irregular immune responses contribute to the development of hyperglycemia in T2D and, inversely, that insulin resistance is a component of the pathogenesis of autoimmune diabetes. Nevertheless, it has not yet been fully elucidated to what extent the presence of conventional autoimmune markers, such as autoantibodies, in subjects with T2D might affect the natural history of the disease and particularly each response to various treatments. The challenge for future research in the field is the discovery of novel genetic, molecular, or phenotypical indicators that would enable the characterization of specific subpopulations of people with T2D who would benefit most from the addition of immunomodulatory therapies to standard glucose‐lowering treatment. This narrative review aims to discuss the plausible mechanisms through which the immune system might be implicated in the development of metabolic disturbances in T2D and obesity and explore a potential role of immunotherapy in the future management of the disorder and its complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

People with diabetes, particularly those being insulin treated, have been for many years considered ineligible for diving, because of the high risk of adverse events. Blood glucose levels tend to decline during diving, probably because of changes in insulin requirements and resistance, due to increased physical activity and effects of hyperbaric environment on glucose tolerance. Strict adherence to safety protocols, in conjunction with optimal physical status, lack of diabetic complications (especially impaired awareness of hypoglycaemia) and satisfactory baseline glycaemic control, seem to minimise the risk of complications during diving. The integration of modern technology into diabetes management, providing potential for underwater continuous glucose monitoring, can be useful in optimising metabolic control before, during and after diving. Despite the significant progress been made on safety issues, there is still a need to implement the relevant recommendations into divers' everyday practice. Existing evidence is mainly derived from small studies and there is a wide heterogeneity in terms of study designs and explored outcomes, rendering the extraction of definitive conclusions challenging. The aim of this review is to present and critically evaluate available evidence, use of technology, and gaps in existing knowledge that deserve further evaluation by future studies. [ABSTRACT FROM AUTHOR]

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Monogenic Diabetes is relatively rare, representing only 1-2% of total diabetes cases; nevertheless, it is often misdiagnosed primarily as type 1 diabetes, leading to unnecessary insulin therapy and delayed recognition of affected family members. In the present article, we describe a case of a young, male patient who presented with hyperglycemia in the absence of ketosis and following genetic testing; he proved to harbor the loss-of-function p.Arg1353His (c.4058G>A) mutation in the ABCC8 gene, inherited from his mother. This mutation has been previously described in patients with Congenital Hyperinsulinism. Furthermore, different mutations in the ABCC8 gene have been linked with MODY 12, type 2, and gestational diabetes; however, to the best of our knowledge, this is the first report that associates this specific mutation with diabetes phenotype. ABCC8-related diabetes is characterized by remarkable heterogeneity in terms of clinical presentation and therapeutic approach. Early diagnosis and individualized treatment are essential to achieving metabolic targets and avoiding long-term diabetes complications. [ABSTRACT FROM AUTHOR]

Aims: To assess the effect of liraglutide on 24‐hour ambulatory blood pressure and heart rate in patients with hypertension (pre‐ and stage 1 hypertension) and inadequately controlled Type 2 diabetes (glycated haemoglobin 7%–10% [53‐86 mmol/mol]). Materials and methods: Eligible patients for this investigator‐initiated, parallel‐group, randomized, double‐blind trial were on stable background antihyperglycaemic therapy excluding insulin, glucagon‐like peptide‐1 receptor agonists and dipeptidyl‐peptidase‐4 inhibitors. Participants were centrally randomized in a 1:1 ratio to daily liraglutide 0.6 mg, titrated to 1.2 mg after the first week, or placebo for 5 weeks. The primary outcome was change in 24‐hour ambulatory systolic blood pressure (SBP), and secondary outcomes included change in ambulatory diastolic blood pressure (DBP) and heart rate. We also assessed renal sodium handling. Results: Of 87 patients assessed for eligibility, 62 (66.1% men) with a mean age of 60.2 years were randomized to liraglutide (n = 31) or placebo (n = 31). All participants received background therapy with metformin, whilst 35.5% were treated concomitantly with sulphonylureas and 14.5% with pioglitazone. Compared with placebo, liraglutide reduced 24‐hour SBP by −5.73 mm Hg (95% confidence interval [CI] –9.81 to −1.65) and had a neutral effect on 24‐hour DBP (mean difference − 1.42 mm Hg; 95% CI –4.25 to 1.40), whilst increasing 24‐hour heart rate by 6.16 beats/min (95% CI 3.25 to 9.07). Findings were consistent for daytime and night‐time measurements. Liraglutide did not increase urine sodium excretion. Conclusion: Based on 24‐hour ambulatory measurements, short‐term treatment with liraglutide had a favourable effect on SBP whilst increasing heart rate. [ABSTRACT FROM AUTHOR]

The maternally inherited 8344 A>G mutation in the mitochondrial Lys tRNA is classically associated with the myoclonic epilepsy, ragged-red muscle fiber (MERRF) syndrome. Multiple lipomatosis (Madelung's disease) is occasionally described. Here we report a large kindred with a statistically significant clustering of very unusual clinical manifestations. We have studied a Greek family that includes seven symptomatic cases of 8344 A>G. Clinical features, glucose tolerance and heteroplasmy in fat, muscle and blood were analyzed. The patients, aged 34-76 at the time of assessment, all suffer from progressive proximal limb-girdle myopathy and extensive lipomatosis. Four of the seven have either impaired glucose tolerance or diabetes but none has had epilepsy, a cardinal feature of MERRF. Heteroplasmy was not higher in adipose tissue than that found in the literature. Compared to literature reports, the familial clustering of this unusual combination of manifestations (lipomatosis in all, epilepsy in none) is statistically significant. The clustering of unusual manifestations in this large kindred strongly suggests that much of the phenotypic variability of 8344 A>G is determined by mitochondrially encoded modifiers in cis. [ABSTRACT FROM AUTHOR]

Abstract: The prevalence of obesity has increased dramatically during the last thirty years in western countries with severe complications for health and economy. Obesity is the outcome of the strong interplay between genetic and environmental factors and is therefore widely expected that the discovery of the many genetic factors underlying the heritable risk of obesity will contribute critically to our basic knowledge of the disease etiopathogenesis and the identification of new targets for therapeutic intervention. The aim of the present study was to assess the genetic contribution of known polymorphisms in two genes that are linked to the pathogenetic mechanism of obesity. Analysis of vitamin D receptor (VDR) TaqI (rs731236; T/C) and fat mass and obesity-associated (FTO) (rs9930506; A/T) polymorphisms in 82 obesity subjects and 102 controls showed significant association for VDR TaqI ‘T’ allele and obesity (OR: 2.07; 1.123–3.816; P =0.019), contributing to an elevated BMI of 3kg/m2 per risk allele. No association was observed for the FTO polymorphism. These results further support a role for VDR as risk factor for obesity and suggest its further validation in larger independent populations as well as highlight a target for functional analysis towards therapeutic intervention in obese individuals. [Copyright &y& Elsevier]

There continues to be interest in understanding the role of vitamin D in the pathogenesis, epidemiology and prevention of cardiovascular disease (CVD). In fact vitamin D deficiency has been associated to an increased risk of developing CVD given to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which vitamin D deficiency leads from endothelial dysfunction to myocardial infarction and stroke are not fully understood. Thus, the goal of this review is to provide an updated review of the literature on the basic science of how vitamin D may affect the cardiovascular system and in particular to analyze the role that vitamin D may have in the whole dynamic process from the initiation of endothelial dysfunction to the development of myocardial infarction and stroke. [ABSTRACT FROM AUTHOR]

• 95 SNPs within the CUBN gene were genotyped in 716 patients with T2DM and 542 controls. • rs11254375, rs7071576, rs6602175, rs1801224 and rs4366393 were linked to T2DM risk. • rs41301097 was strongly associated with higher 25(OH)D levels. Accumulating evidence suggests a potential implication of vitamin D biological network in the pathogenesis of diabetes mellitus. The megalin-cubilin endocytotic system constitutes a key transport structure, with a modulating role in vitamin D metabolism. We aimed to assess the contribution of variants in the CUBN gene to the genetic risk of Type 2 Diabetes Mellitus (T2DM). 95 polymorphisms within CUBN were genotyped in 716 patients with T2DM and 542 controls of Greek origin. Samples were analyzed on Illumina Human PsychArray. Permutation test analysis was implemented to determine statistical significance. Twenty-five-hydroxy-vitamin-D [25(OH)D)] levels were measured in a sub-group of participants (n = 276). Permutation analysis associated rs11254375_G/T (p emp = 0.00049, OR = 1.482), rs6602175_G/T (p emp = 0.016, OR = 0.822), rs1801224_G/T (p emp = 0.025, OR = 0.830), rs4366393_A/G (p emp = 0.028, OR = 0.829) and rs7071576_A/G (p emp = 0.04, OR = 1.219) with T2DM. Mean 25(OH)D concentrations were significantly lower in patients with T2DM compared to controls (16.70 ± 6.69 ng/ml vs 18.51 ± 6.71 ng/ml, p < 0.001), although both groups were vitamin D deficient. In a further quantitative analysis, rs41301097 was strongly associated with higher 25(OH)D concentrations (p = 5.233e-6, beta = 15.95). Our results indicate a potential role of CUBN gene in T2DM genetic susceptibility in the Greek population. These findings may also denote an indirect effect of vitamin D metabolism dysregulation on the pathogenesis of T2DM. Further studies are required to replicate our findings and clarify the complex underlying mechanisms. [ABSTRACT FROM AUTHOR]