Pioglitazone and asthma: a review of current evidence.

OBJECTIVE: This review aims to present existing evidence on the impact of pioglitazone, a thiazolidinedione class anti-diabetic drug, on asthma control and lung function, providing a comprehensive understanding of its potential as a treatment for asthma. DATA SOURCES: The review draws upon data from preclinical animal studies and clinical trials investigating the effects of pioglitazone on asthma, focusing on its role in reducing airway inflammation, hyperreactivity, and remodeling, and its impact on pulmonary function. STUDY SELECTIONS: Relevant studies were selected based on their examination of pioglitazone's therapeutic effects in asthma, including both animal models and clinical trials involving human asthma patients. RESULTS: Animal studies have suggested that pioglitazone could alleviate inflammation, airway hyperreactivity, and airway remodeling, thereby improving pulmonary function in asthma. However, clinical trials have not demonstrated significant therapeutic benefits, with minimal improvements observed in asthma control and lung function, and the presence of notable side effects. CONCLUSION: Despite promising preclinical data, the efficacy of pioglitazone in treating human asthma remains unproven, with safety concerns and limited clinical benefits observed in trials. Further research is needed to assess the safety and effectiveness of pioglitazone in asthma treatment and to explore its impact on other inflammatory mechanisms.

Sodium-Glucose Co-transporter-2 Inhibitors in Type 1 Diabetes Mellitus: The Framework for Recommendations for Their Potential Use.

The growing prevalence of overweight/obesity, the persistence of inadequate glycemic control among the majority of affected individuals, and the still unacceptably high risk of cardiovascular morbidity and mortality among population with type 1 diabetes mellitus (T1D), impose an urgent need for the introduction of non-insulin glucose-lowering agents in the therapeutic armamentarium. Given that their antihyperglycemic mechanism of action is independent of endogenous insulin secretion and that the observed cardio-renal benefits are unrelated to their glucose-lowering properties, one can speculate that the use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) could provide benefits in T1D, similar to the ones observed among individuals with type 2 diabetes mellitus, chronic kidney disease (CKD), and heart failure. Available evidence from randomized controlled trials suggests that treatment with SGLT2is as adjunct to insulin in T1D results in modest reductions in glycated hemoglobin and body weight. Additionally, SGLT2is ameliorate albuminuria, and thus delay or prevent the development of CKD in T1D. However, use of SGLT2is is associated with an increased risk of diabetic ketoacidosis (DKA) in T1D. This commentary aims at providing a framework for practical recommendations regarding the potential use of SGLT2is in adults with T1D, based on the individual's risk level for DKA development, the presence of inadequate glycemic control and related cardio-renal complications.

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.

Amylin analogs for the treatment of obesity without diabetes: present and future.

INTRODUCTION: Obesity is a pandemic, linked with increased morbidity including diabetes mellitus (DM) and certain cancer types. Amylin is a major regulatory hormone for satiation and food intake perception in humans. Amylin analogs (pramlintide and cagrilintide) are emerging as promising anti-obesity agents in non-DM subjects. AREAS COVERED: Pramlintide, the first amylin analog, initially used for the treatment of both type 1 and type 2 DM, has demonstrated weight-lowering action. Clinical trials confirmed a weight loss exceeding 3% in the study period without major untoward effects, which was maintained beyond the follow-up period. Recently, cagrilintide, a long-lasting synthetic amylin analog has been introduced. Cagrilintide has achieved adequate weight loss, reaching even more than 10% of the total weight in early clinical trials. However, adverse gastrointestinal effects, particularly nausea, were more frequent compared with pramlintide. Clinical trials have also confirmed the effectiveness of cagrilintide in comparison with glucagon-like peptide 1 receptor agonists. EXPERT OPINION: Amylin analogs will certainly enrich the growing therapeutic armamentarium aimed at tackling obesity. The most exciting future research venue could be the development of their combinations with other weight-lowering drugs, especially dual and triple incretin-based co-agonists, thus potentially providing massive weight-loss effects.

Obstructive sleep apnoea and type 1 diabetes mellitus: A neglected relationship?

Obstructive sleep apnoea (OSA) is regarded as a major health condition, progressively affecting an increased number of people around the world. The interplay between OSA and type 2 diabetes mellitus (T2DM) has been extensively studied. However, little is known on the relationship between OSA and type 1 diabetes mellitus (T1DM). This review provides an insight into the prevalence of OSA in T1DM and its relationship with diabetic complications. Studies have hitherto yielded contradictory results on the occurrence of OSA in T1DM. Indeed, the risk of OSA in T1DM has ranged from 1 in 10 T1DM subjects to more than 1 in 2 T1DM subjects. This high occurrence was confirmed both by objective polysomnography and by widely used subjective questionnaires. Multiple studies revealed the important correlation between OSA and the diabetes complications. Both microvascular (nephropathy, neuropathy and retinopathy) and macrovascular complications appear to be associated with OSA occurrence, although some associations were not significant due to inadequate data. In conclusion, T1DM subjects carry higher risk of OSA, which may be undiagnosed. Additional studies are needed to clarify the exact correlation between the 2 conditions.

Manifestations of Endocrine Disease in the Lower Extremities: Beyond the Diabetic Foot.

The aim of this narrative review was to discuss manifestations of endocrine disease other than diabetic foot in the lower extremities. Acromegaly, Addison's disease, Cushing's syndrome, hypo- and hyperthyroidism, hypo- and hyperparathyroidism, autoimmune polyglandular syndrome, hypopituitarism, and glucagonoma are among the endocrine diseases that may present with clinical manifestations in the lower extremities. Clinical signs vary depending on the underlying condition. Clinical suspicion is necessary for early diagnosis. Treatment of the underlying endocrine disease usually results in improvement of lower-extremity manifestations.

Diabetes Mellitus and its Association with Work Patterns and Characteristics: A Narrative Review.

Diabetes mellitus is a leading cause of disability with adverse effects on the quality of life. It also affects occupational health by impacting several work-related parameters. This review discusses the relationship between diabetes and absenteeism, presenteeism, work impairment and unemployment. The association between work and diabetic complications such as neuropathic pain, diabetic foot, psychological issues and hypoglycemia due to treatment is also examined. Evidence points to a relationship between diabetes and absenteeism, reduced work productivity, and, thus, overall work impairment. A stronger negative impact on work performance is mediated by painful diabetic neuropathy and diabetic foot. In addition, psychological distress has been positively correlated with total workdays lost and frequency of absence. Depression in the diabetic population has also been linked with increased absenteeism, presenteeism, and work disability. Moreover, hypoglycaemia induced by antidiabetic medication may affect work attendance and performance. Finally, diabetes has been associated with inequality in the work environment, lower job satisfaction and higher unemployment rates, mainly because of its complications.

Peroneal Nerve Entrapment in Diabetes Mellitus.

This narrative mini-review discusses the association between peroneal nerve entrapment (PEN) and diabetes mellitus (DM). Generally, PEN is not a common cause of peripheral neuropathy in DM. Poor glycaemic control and DM duration are powerful risk factors for PEN. Underlying mechanisms involve neurodegeneration and entrapment of the peroneal nerve. Patients tend to present with chronic leg pain, gradual foot drop, steppage gait, or weakness of ankle dorsiflexion. Electrodiagnostic and imaging studies are very useful in diagnosis to determine the level at which entrapment occurs. Treatment varies based on the aetiology and severity of symptoms. It is initially conservative. Surgical nerve decompression management is required when entrapment is refractory to non-operative options.

Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in ß-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

Intentional Insulin Overdose and Depression in Subjects with and Without Diabetes Mellitus: A Commentary.

Insulin is an essential medication for people with type 1 diabetes mellitus and for some people with type 2 diabetes. Interestingly, insulin abuse has been reported as a mode of suicide, not only among people with diabetes, but also among their relatives, and among medical and paramedical personnel who have access to insulin. The aim of the present commentary was to raise awareness of potential depression-related intentional insulin overdose and its complications, as well as of the diagnosis and treatment of this entity. Insulin overdose may lead to severe and prolonged hypoglycemia, hypoglycemic coma, and death. Moreover, hypokalemia, hypomagnesemia, hypophosphatemia, and elevated liver enzymes are common. Insulin overdose should be suspected among people with diabetes in case of unexplained prolonged hypoglycemia and among people without diabetes who exhibit hypoglycemia and may have access to diabetic medications. The ratio of insulin to C-peptide helps distinguish exogenous insulin administration from endogenous secretion. The cornerstone of therapy is prompt administration of concentrated glucose infusions for days with simultaneous oral intake, when possible, and intense glucose monitoring to prevent hypoglycemia. Moreover, monitoring of serum electrolyte levels is recommended. Finally, psychiatric evaluation aiming at early identification of depression and suicidality is of paramount importance.

Achievement of normoglycemia with tirzepatide in type 2 diabetes mellitus: A step closer to drug-induced diabetes remission?

We sought to determine whether treatment with tirzepatide in type 2 diabetes mellitus (T2DM) patients can increase the odds for achieving normoglycemia, compatible with glycated hemoglobin levels lower than 5.7 %. We demonstrated that treatment with tirzepatide versus control increased the odds for achievement of normoglycemia by >16 times.

Tirzepatide use and the risk of cancer among individuals with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

BACKGROUND: Tirzepatide has recently been approved for the treatment of type 2 diabetes mellitus (T2DM), based on its impressive effects on glycemia and body weight reduction. We investigated whether tirzepatide affects the risk for cancer in T2DM. METHODS: We conducted a meta-analysis of available, up to 1st April 2024, phase 2/3 randomized controlled trials (RCTs) evaluating the use of tirzepatide in T2DM. We set as primary safety endpoint the risk for any type of cancer, while we assessed as secondary endpoints specific cancer types. Subgroup analyses according to the type of comparator were also performed. RESULTS: We included a total of 9 RCTs with a relatively short study duration, ranging from 36 to 72 weeks. Our preliminary evidence suggests that tirzepatide does not increase the risk for any cancer (primary outcome) or any of the specific cancer types (secondary outcomes). Of course, small number of enrolled participants, short study duration and follow-up, along with scarcity of reported events are considered to be main limitations of the present analysis. CONCLUSIONS: Preliminary evidence from our analysis suggests that tirzepatide may not affect the risk ofcancer among individuals with T2DM. However, our results should be interpreted with extra caution, based on the several limitations of our "hypothesis-generating" analysis Future, well-designed studies are warranted to answer this important research question.

The prevalence of long COVID-19 syndrome in hospitalized patients with COVID-19 pneumonia.

Introduction: Long COVID affects millions of individuals worldwide with a wide range of persistent symptoms. Pathogenesis, prevalence and clinical approach of this syndrome remain not well characterized.The aim of the study is the estimation of prevalence of long-COVID and identification of possible risk factors. Patients and Methods: This is an observational prospective study including COVID-19 patients hospitalized at the Department of Infectious Diseases of the University General Hospital of Alexandroupolis (Greece). Eligible COVID-19 patients were interviewed and examined 6, 12 and 18 months after COVID-19 symptoms onset and hospital discharge in order to evaluate the prevalence and consequences of long-COVID symptoms. Results: A total number of 995 patients were included. The median age at discharge was 55 years and 53% of patients were retired. The majority was males (57%). Vaccination against SARS-CoV-2 was completed in 52% (n=517) COVID-19 patients. More than 40% of COVID-19 patients had at least one symptom at 18 months after hospitalization. Intravenous antiviral 0treatment with remdesivir and complete vaccination status were found to lead to lower rates of Long-COVID. Conclusions: More studies in larger patient cohorts are needed in order to identify the underlying biological mechanisms of long-COVID and create effective interventions for prevention and treatment.

Drawing lines in the sand: The growing threat of obesity in type 1 diabetes.

In this editorial, we comment on the article by Zeng et al published in the recent issue of the World Journal of Diabetes in 2024. We focus on the epidemiological, pathophysiological, and clinical interplay between obesity and type 1 diabetes mellitus (T1DM). Overweight and obesity represent a growing threat for modern societies and people with T1DM could not be an exception to this rule. Chronic exogenous insulin administration, genetic and epigenetic factors, and psy-chosocial and behavioral parameters, along with the modern way of life that incorporates unhealthy eating patterns and physical inactivity, set the stage for the increasing obesity rates in T1DM. As our knowledge of the underlying mechanisms that lead to the development of obesity and hyperglycemia expands, it becomes clear that there are overlap zones in the pathophysiology of the two main types of diabetes. Stereotypes regarding strict dividing lines between "autoimmune" and "metabolic" phenotypes increase the risk of trapping physicians into ineffective therapeutic approaches, instead of individualized diabetes care. In this context, the use of adjuncts to insulin therapy that have the potential to alleviate cardiorenal risk and decrease body weight can reduce the burden of obesity in patients with T1DM.

Preventing Diabetic Foot Re-Ulceration Through an Innovative Pressure and Temperature Monitoring Clinical Device.

This study compared the outcome of an innovative in-shoe pressure and temperature measuring device as an adjunct to standard clinical care for diabetic foot versus standard clinical care alone. It included 88 participants with Type 2 diabetes mellitus with a history of one or more plantar foot ulceration who were already using prescription orthoses. These were randomly divided into the control group (n = 44, standard care only) and the experimental group (n = 44, standard care plus the innovative device). Both groups were monitored for re-ulceration for one year. Overall, the control group exhibited a higher number of re-ulcerations (n = 14) with 2 amputations in comparison with the experimental group (only 2 ulcerations and no amputations) at the end of the study. In conclusion, this innovative in-shoe pressure and temperature measuring device appears to reduce re-ulcerations by offering objective data for clinical decision making in the management of the diabetic high-risk foot.

Mitochondrial Fraction of Circulating Cell-Free DNA as an Indicator of Human Pathology.

Circulating cell-free DNA (ccfDNA) of mitochondrial origin (ccf-mtDNA) consists of a minor fraction of total ccfDNA in blood or in other biological fluids. Aberrant levels of ccf-mtDNA have been observed in many pathologies. Here, we introduce a simple and effective standardized Taqman probe-based dual-qPCR assay for the simultaneous detection and relative quantification of nuclear and mitochondrial fragments of ccfDNA. Three pathologies of major burden, one malignancy (Breast Cancer, BrCa), one inflammatory (Osteoarthritis, OA) and one metabolic (Type 2 Diabetes, T2D), were studied. Higher levels of ccf-mtDNA were detected both in BrCa and T2D in relation to health, but not in OA. In BrCa, hormonal receptor status was associated with ccf-mtDNA levels. Machine learning analysis of ccf-mtDNA datasets was used to build biosignatures of clinical relevance. (A) a three-feature biosignature discriminating between health and BrCa (AUC: 0.887) and a five-feature biosignature for predicting the overall survival of BrCa patients (Concordance Index: 0.756). (B) a five-feature biosignature stratifying among T2D, prediabetes and health (AUC: 0.772); a five-feature biosignature discriminating between T2D and health (AUC: 0.797); and a four-feature biosignature identifying prediabetes from health (AUC: 0.795). (C) a biosignature including total plasma ccfDNA with very high performance in discriminating OA from health (AUC: 0.934). Aberrant ccf-mtDNA levels could have diagnostic/prognostic potential in BrCa and Diabetes, while the developed multiparameter biosignatures can add value to their clinical management.

Diabetic Foot and Work Outcomes: A Review.

The aim of this review article was to discuss impact of diabetic foot ulcers (DFUs) on employment status and work productivity. We performed a literature search from 2000 to 2023 in PubMed, Scopus, Google Scholar and in national repositories. The major work outcomes studied were presenteeism and absenteeism. Many DFUs patients had a poor social and educational background. Overall, DFUs patients experienced increased loss of productivity in their workplaces: either they had to be absent more working hours than average or they faced increased difficulty in meeting their daily requirements. The total loss in productivity is estimated to exceed almost one-third of anticipated working time, while 15 to 34.3% of DFUs patients expressed concerns about severe changes in their working environment, attributed directly to their condition. More than 1 out of 5 DFUs patients (ranging from 20 to 31.7%) were even confronted with overall job loss and unemployment. Amputations had an even more marked negative effect. In conclusion, DFUs negatively affect employment status and work productivity. Therefore, we need more studies with large participant numbers to increase our experience and to explore potential measures to mitigate these adverse effects.