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.

Peroneal nerve entrapment in diabetes mellitus.

The aim of this narrative mini-review is to discuss 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 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 in determining 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.

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.

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.

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.

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.

Expert Opinion on Current Trends in the Use of Insulin in the Management of People with Type 2 Diabetes from the South-Eastern European Region and Israel.

Despite the availability of various antihyperglycaemic therapies and comprehensive guidelines, glycaemic control in diabetes management has not improved significantly during the last decade in the real-world clinical setting. Treatment inertia arising from a complex interplay among patient-, clinician- and healthcare-system-related factors is the prime reason for this suboptimal glycaemic control. Also, the key factor leading to inadequate glycaemic levels remains limited communication between healthcare professionals (HCPs) and people with type 2 diabetes (PwT2D). Early insulin administration has several advantages including reduced glucotoxicity, high efficacy and preserved ß-cell mass/function, leading to lowering the risk of diabetes complications. The current publication is based on consensus of experts from the South-Eastern European region and Israel who reviewed the existing evidence and guidelines for the treatment of PwT2D. Herein, the experts emphasised the timely use of insulin, preferably second-generation basal insulin (BI) analogues and intensification using basal-plus therapy, as the most-potent glucose-lowering treatment choice in the real-world clinical setting. Despite an increase in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the experts urged timely insulin initiation for inadequate glycaemic control in PwT2D. Furthermore, the combination of BI and GLP-1 RA addressing both fasting plasma glucose and post-prandial excursions as a free- or fixed-ratio combination was identified to reduce treatment complexity and burden. To minimise discontinuation and improve adherence, the experts reiterated quality, regular interactions and discussions between HCPs and PwT2D/carers for their involvement in the diabetes management decision-making process. Clinicians and HCPs should consider the opinions of the experts in accordance with the most recent recommendations for diabetes 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.

Diabetic Sensorimotor Polyneuropathy: An Overview on Epidemiology, Risk Factors, Classification, Diagnosis, and Treatment.

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) is a common complication of diabetes with devastating consequences. Hyperglycaemia is the major aetiological factor, while emerging data demonstrate that cardiometabolic risk factors also contribute to its development. Diagnosis of DSPN involves interview of medical and neurological history, foot inspection, and sensory and motor function examination with specific tests such as temperature and pinprick perception for small nerve fibers, and vibration and light touch assessments for large nerve fibers. Management includes optimised glycaemic control, treatment of cardiovascular risk factors, and symptomatic treatment aiming at improving life quality. This article provides an overview on epidemiology, risk factors, classification, diagnosis and current treatment of DSPN.

Diabetic Foot Screening Guidelines and the Role of Artificial Intelligence: Time to Turn the Tide!

Despite medical and technological advancements, foot amputations continue to rise. Thus, the effort of diabetic foot management should be toward prevention and early diagnosis. Healthcare professionals need to be trained, equipped, and supported with adequate resources to be able to identify and deliver appropriate foot care. Every effort should be made to minimize the impact of complications and to ensure prompt access to care for everyone. Artificial intelligence and smart technology could provide a significant opportunity to improve efficiency in diabetes care, which may reduce diabetic foot complications. The possible potential of the new technologies which are emerging together with their current developing applications for diabetic foot care are suggested. A call for immediate change in diabetes foot screening guidelines is imperative to save limbs and lives.

Menopausal Hormone Therapy in Women with Type 2 Diabetes Mellitus: An Updated Review.

Menopause is accompanied by several metabolic adaptations, which are related to insulin resistance, increased total body fat mass, and central abdominal fat accumulation, predisposing women to type 2 diabetes mellitus (T2DM) development. Metabolic syndrome has a high prevalence in postmenopausal women, indicating the loss of estrogen protection on metabolic and cardiovascular health. Moreover, earlier age at menopause has been related to increased risk of T2DM. Menopausal hormone therapy (MHT) has favorable results in glucose metabolism. Indeed, it reduces the risk of T2DM in women without this condition and improves glycemic control in women with T2DM. Before MHT initiation in women with clinical indications, it is imperative to assess their cardiovascular disease (CVD) risk, using official electronic algorithms for score calculation. The latter will determine regimen, dose, and administration route of MHT. Oral estrogens are preferable in women with low CVD risk, while transdermal administration is indicated in those with moderate and high CVD risk, as the risk of stroke and venous thromboembolism (VTE) is increased with oral administration. Oral 17ß-estradiol is usually preferred in women with T2DM, as this route has more beneficial effects on glucose metabolism. Oral estrogens are also suggested in perimenopausal or recently postmenopausal women with low CVD risk. Although oral estrogens have favorable effects when indicated, the risk of VTE or stroke should always be considered. Micronized progesterone, dydrogesterone, and transdermal norethisterone are the progestogens used in postmenopausal women with T2DM and intact uterus. MHT should not be initiated in women > 60 years or > 10 years in menopause, as there is an increased thromboembolic risk in women with established atherosclerosis and no additional cardiovascular benefit in women without atherosclerosis. In conclusion, MHT administration in postmenopausal women with T2DM can be safe and effective as long as the therapeutic regimen has been properly selected according to their cardiovascular, metabolic, and fracture risk.

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

What is New on Diabetic Neuropathy? Insights from the 2023 ADA and EASD Conferences.

Diabetic neuropathy is a common complication of diabetes; yet its pathophysiology is still incompletely understood and until today, there is no specific treatment against it. In the two 2023 large congresses on diabetes (American Diabetes Association, ADA, European Association for the Study of Diabetes, EASD), several high-level studies have been presented. They have attempted to delineate the pathophysiology of DN, the characteristics of affected patients, and future potential treatments. We herein review the presented studies on diabetic neuropathy at these diabetes congresses and discuss the needs for future research on this topic.