Antidiabetic Research Articles

Prevalence and incidence of heart failure in patients with type 2 diabetes mellitus. Results of the prospective DIABET-IC study

Abstract Introduction Heart failure (HF) is one of the major health problems in our environment today. Type 2 diabetes mellitus (DM2) is an important cardiovascular risk factor and can increase the burden of HF through various mechanisms. The incidence of HF in DM2 has not been well studied. Purpose The aim of our study was to evaluate the prevalence and incidence of HF in patients with DM2 followed in hospital cardiology and endocrinology departments. Methods The DIABET-IC study is a longitudinal cohort, prospective, multicenter follow-up study that included 1,249 consecutive patients with DM2 in 2018-2019 in 30 Spanish centers in cardiology and endocrinology outpatient clinics. HF was diagnosed according to the clinical records and following the criteria of the European Society of Cardiology. The prevalence of HF at the inclusion visit was analyzed, as well as the incidence of HF (new diagnoses) during a 3-year follow-up. Results Mean age was 67.3±+9.9 years, with 31.7% of the patients being women. Cardiology clinics included 61.9% of patients and endocrinology clinics the remaining 38.1%. There was a previous history of coronary artery disease in 38.6%, hypertensive heart disease in 21% and atrial fibrillation in 31.9%. Cardiovascular and antidiabetic drugs prescribed at the baseline and 3-year visits are shown in figure 1. Figure 2 summarizes the results of the study. The prevalence of HF at the baseline visit was 39.2%, 490 cases (with reduced LVEF 17.3%, mildly reduced 8.1% and preserved 13.8%). After a follow-up of 1,935/100 persons-year of cases without baseline HF, 58 incident cases of HF were diagnosed, 7.6% (32 in the first year, 13 in the second and 13 in the third year of follow-up). The incidence rate was 3.01/100 person-years (95%CI: 2.30-3.92). Of these 58 cases, 23.7% were with reduced LVEF, 28.9% with slightly reduced LVEF and 47.4% preserved. The incidence was higher in patients followed by endocrinology (3.90 vs 2.90/100 persons-year; p=0.042). At the end of the 3-year follow-up, including baseline prevalence, 46.8% of all patients had HF. Conclusions The prevalence and incidence of HF in patients with DM2 are very high. The incidence of HF is around 3% per year, which is almost 8 times higher than the rate found in large studies in the general population. Approximately half of the new cases were HF with preserved LVEF, and the other half with LVEF < 50%. The use of new antidiabetic drugs, such as iSGLT2, which have been shown to reduce the incidence of HF, should be encouraged.

Association of HbA1C with mortality and cardiovascular outcome in patients with type 2 diabetes using drugs with different hypoglycemic risk

Abstract Background Previous clinical trials showed that intensive glucose control did not reduce macrovascular events and mortality. It was speculated that severe hypoglycaemia contributed to these adverse outcomes. More contemporary clinical trials using newer anti-diabetic agents with less hypoglycaemic potential showed a linear relationship between major adverse cardiovascular events (MACE) and HbA1c reduction according to a meta-regression analysis. Purpose The aim of this study was to examine the association between clinical outcomes and HbA1c under different treatment backgrounds in the real-world setting. We hypothesised that when using drugs with minimal hypoglycaemic risk, lower HbA1c would be associated with better outcomes. Methods This was a retrospective population-based cohort study using a multi-centre electronic medical record database. Eligible patients were those diagnosed with type 2 diabetes between 2009 and 2020 who received non-insulin antidiabetic drugs. Patients were stratified into two groups based on the drugs received: drugs with high hypoglycaemic risk (sulphonylurea, meglitinide) and drugs with low hypoglycaemic risk (thiazolidinediones, acarbose, DPP4 inhibitors, GLP1 agonists, SGLT-2 inhibitors). Patients were excluded if they had received these drugs for less than 180 days or had received both high and low hypoglycaemic risk oral drugs simultaneously. HbA1c levels were assessed from the index date to the date of the interested outcome or the end of the study period (31 December 2021), whichever came first. The relationship between HbA1c and clinical outcomes was examined using a Cox proportional hazards model. The outcomes of interest included all-cause mortality and MACE. Results The study population consisted of 6,923 patients, including 3,639 high hypoglycaemic risk drug users and 3,284 low hypoglycaemic risk drug users. Patients with lower HbA1c levels during the follow-up period were older and frailer. After adjusting for baseline covariates, the association between the risk of death and HbA1c presented a U-shaped pattern, and this U-shaped association was similar in the two treatment cohorts (Table 1). On the other hand, the association between the risk of MACE and HbA1c presented a J-shaped pattern. In the high hypoglycaemic risk drug cohort, patients with the highest HbA1c levels (mean HbA1c 9.6%) were associated with a higher risk of MACE compared to the group with a mean HbA1c of 7.2% (hazard ratio [HR] 4.16, 95% confidence interval [CI] 2.07-8.37); lower HbA1c levels were not associated with a lower risk of MACE (Table 2). In contrast, in the low hypoglycaemic risk drug cohort, lower HbA1c levels were associated with a higher risk of MACE (HR 3.82, 95% CI 1.29-11.28). Conclusion Lower HbA1c levels were not associated with a lower risk of all-cause mortality and MACE. Furthermore, this phenomenon was independent of the hypoglycaemic risk of anti-diabetic drugs.

Use of new antidiabetic drugs in patients with cardiovascular diseases - real life data

Abstract Introduction and aim Cardiovascular diseases (CVD) are among the most common and significant complications of type 2 diabetes mellitus (T2DM). Despite significant therapeutic progress in the prevention of CVD, T2DM remains a leading cause of major adverse cardiac events (MACE). Patients with T2DM and clinical manifestations of atherosclerotic CVD, or those at high risk of developing it, should receive cardioprotective and nephroprotective medications such as GLP-1 receptor agonists (GLP-1) and SGLT-2 inhibitors (SGLT2). This study aims to determine to what extent patients undergoing treatment at the general practitioner (GP) level comply with the recommendations. Methodology Retrospectively, in the period January 2022 to September 2023, records in the EHR were reviewed in the five GP offices. For all patients ( ≥18 years) with DMT2, all demografic as well as data on chronic therapy, stage of chronic kidney disease (CKD), presence of any cardiovascular (CV) risk factors and/or history of cardiovascular diseases (CVD), and the therapy applied were observed. Results A total of 6,941 patients' data were reviewed, out of which 483 (6.96%) had a diagnosis of DMT2. Table 1. shows the characteristics of the study population. Table 2. presents the values of HbA1c according to the criteria of good, acceptable, and poor DMT2 control, as well as the CKD stage by eGFR. Among the associated comorbidities, the most common was arterial hypertension, observed in 79.5% of the participants, followed by obesity in 28.2%. In terms of the applied therapy, the majority of participants were on metformin (76.8%). There were no significant differences in body mass index (BMI) and glycemic control between the group with and without CVD. However, compared to the group without CVD, patients with both DMT2 and CVD had a higher frequency of SGLT2 inhibitors (27% vs. 18.5%) [chi²=4.336, df=1, p=0.032] and GLP-1 receptor agonists (10.7% vs. 4.6%) [chi²=6.336, df=1, p=0.012] use, but a lower frequency of metformin (67.9% vs. 81.2%) [chi²=10.510, df=1, p=0.001]. Discussion According to current guidelines, all patients with CVD and CKD should have SGLT2 inhibitors and/or GLP-1 receptor agonists in their therapy. Comparing our study with the CAPTURE study, our patients were older and had slightly fewer associated CVD (38.7% vs. 32.9%). According to the CAPTURE study, less than 25% of patients with DMT2 in therapy have an antidiabetic medication with proven cardiovascular benefit, while in our sample, this was the case for 31.4% of the participants. This suggests that progress is being made, but it is still insufficient. Conclusion Over the past decade, there has been a rapid increase in knowledge regarding the appropriate treatment and management of risk factors in the population of individuals with DMT2. Although new insights are continuously incorporated into guidelines, our study shows that implementation in practice lags.

Sodium-glucose cotransporter 2 inhibitor attenuates left ventricular dysfunction in post-myocardial infarction in rats via reducing cardiac mitochondrial impairment

Abstract Background Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a class of antidiabetic drugs that has demonstrated cardiovascular benefits in heart failure patients, regardless of diabetic status. Although current evidence regarding the role of SGLT2i in myocardial infarction (MI) is still limited, a recent randomized study reported the favorable effects of dapagliflozin on cardiometabolic outcomes in post-MI patients. Nevertheless, the evidence of the underlying mechanism of SGLT2i in post-MI is still unclear. Purpose We aimed to investigate the cardioprotective effects and cellular mechanisms of SGLT2i in post-MI rats. Methods 72 male Wistar rats were divided into two groups: the MI group, which underwent surgery involving permanent ligation of the left anterior descending coronary artery to induce MI (n=58), and the sham group, which underwent a sham operation (n=14). One-week post-surgery, echocardiography was performed. For inclusion in the MI group, only rats exhibiting anterior wall akinesia and a left ventricular ejection fraction (LVEF) < 50% were considered. Subsequently, MI rats were stratified into three groups to receive different interventions: 1) MI+VEH (distilled water, PO, n=13), 2) MI+DAPA (dapagliflozin, 1 mg/kg, PO, n=11), and 3) MI+ENA (enalapril, 10 mg/kg, PO, n=14). After 8 weeks of treatment, echocardiography was performed again. Then, the rats were sacrificed, and heart tissues were used to determine mitochondrial function and protein expressions. Results After 8 weeks of treatment, the MI+VEH group exhibited a decrease in LVEF compared to the sham group (Fig. 1A). The MI+VEH group was associated with cardiac mitochondrial dysfunction, as indicated by increased mitochondrial oxidative stress, mitochondrial membrane depolarization, and mitochondrial swelling, and impaired mitochondrial biogenesis, as indicated by decreasing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions (Fig. 1B-F). Treatment with dapagliflozin and enalapril effectively attenuated left ventricular (LV) systolic dysfunction, reversed mitochondrial dysfunction, and restored mitochondrial biogenesis induced by MI (Fig. 1A-F). Conclusion SGLT2i could attenuate LV dysfunction and restore mitochondrial dysfunction in post-MI rats. These findings demonstrate SGLT2i as a novel cardioprotection against post-MI complications.

Incidence of type 2 diabetes by occupation – 10-year follow-up of the Gutenberg Health Study

Abstract Background In order to implement targeted type 2 diabetes (T2D) prevention measures for the workplace, it is important to identify high-risk occupations. Most previous studies examine the association between T2D and occupation cross-sectionally, but longitudinal studies are missing. This study aims to investigate the 10-year incidence of T2D in the working population of a German cohort and identify occupations with an increased risk. Methods Data from the population-based Gutenberg Health Study (GHS) were used to examine occupation at baseline (2007-2012) and T2D incidence at the 10-year follow-up. Occupational phases were coded into categories according to the KldB 2010. T2D was defined as either a physician-diagnosed T2D, HbA1c-level ≥6.5% or use of antidiabetic drugs. Age- and sex-standardised incidence and 95% confidence intervals (CI) were calculated for occupational groups based on the age- and sex-distribution of the German population. Standardised incidence ratios (SIR) and 95% CI were calculated using the incidence in the total GHS working population as the reference. Results Of 8130 workers at baseline, 45.2% were female, the mean age was 48.4 years and 4.5% had prevalent T2D. 388 cases occurred between baseline and the 10-year follow-up within the subgroup of persons without prevalent T2D at baseline and with follow-up data (n = 5954). The standardised incidence was 6.9%. “Food production and processing” (20.7%), “cleaners” (16.5%) and “drivers and mobile plant operators” (14.8%) had the highest standardised incidences. Compared to the total working population, we observed a threefold increased SIR for employees in “food production and processing” (3.0, 95% CI 1.8-4.7) and a two times higher SIR for “cleaners” (2.2, 95% CI 1.0-4.7) and “drivers and mobile plant operators” (2.2, 95% CI 1.3-3.3). Conclusions We identified occupations with an increased risk of T2D. Preventive measures and etiological research on work-related risks should focus on these occupations. Key messages • The highest standardised incidence was observed in the occupational groups “food production and processing”, “cleaners” and “drivers and mobile plant operators”. • Targeted prevention measures for type 2 diabetes in the workplace should focus on these occupational groups with increased incidence.

Effects of SGLT-2i and GLP-1RA in vascular function parameters: the impact of the weight loss

Abstract Background Arterial stiffness and endothelial function markers flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness and endothelial function as well as the metabolic parameters of HbA1c and Weight in T2DM patients. Patients and Methods: We enrolled 99 consecutive patients under stable antidiabetic therapy who did not reach therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Glycosylated hemoglobin (Hba1c) and weight expressed through Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) and flow-mediated dilatation (FMD), as biomarkers of arterial stiffness and endothelial function accordingly, were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups in traditional risk factors of age and sex or baseline HbA1c, BMI, PWV, and FMD levels (ps=NS for all). In both groups PWV values displayed a statistically significant improvement from 11.2±2.5 to 9.3±2.2 m/sec (p<0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group, as presented in Figure 1 through the differences in the values of PWV. FMD values were also significantly improve in both groups from baseline to follow-up; from 6.04±1.22 to 6.50±1.26% (p<0,001) for the GLP-1RA group and from 6.38±1.21 to 6.81±1.29% (p<0.001) for the SGLT-2i group. Moreover, both groups achieved better weight management goals in terms of BMI values between baseline and follow-up; from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group (p<0.001) and from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p<0.001), in addition to achieving better glycemic control in terms of HbA1c values, as seen in their paired differences: for GLP-1RA: 1.3±0.7% and for SGLT-2i: 0.8±0.5%. Interestingly, in the SGLT-2i group the magnitude of the PWV improvement was correlated with the weight loss (r=0.368, p=0.007). Conclusion These data provide evidence that the newer antidiabetic drugs, both GLP1-RA and SGLT-2i, have actions that benefit both vascular function, endothelium as well as metabolic parameters. Interestingly, in the patients receiving SGLT-2i the magnitude of the PWV improvement was correlated with the weight loss.delta PWV for SGLT-2i & GLP-1RA groupsCorrelation of deltaWeight & deltaPWV

Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.

Novel Phenoxyalkanoic Acid Derivatives as Free Fatty Acid Receptor 4 Agonists for Treating Type 2 Diabetes Mellitus

Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure–activity relationship and pharmacological studies for the development of antidiabetic drugs.

Combination therapy of systemic and local metformin improves imiquimod-induced psoriasis-like lesions with type 2 diabetes: the role of AMPK/KGF/STAT3 axis.

Insulin resistance and a disturbed lipid profile are common associations with type 2 diabetes mellitus (T2DM) and different skin diseases, particularly psoriasis (PsO). We investigated potential therapeutic mechanisms of metformin in a murine animal model of psoriasiform lesions in T2DM. Forty-two rats were randomly divided into control, PsO, and type II DM (T2DM) groups. After confirmation of DM, the type II diabetic rats were allocated into T2DM+ PsO, T2DM+ PsO+ systemic metformin (S. met), T2DM+ PsO+ topical metformin (T. met)), and T2DM+ PsO + combined metformin (C. met). PsO was induced by topical imiquimod. Systemic administration of the cornerstone antidiabetic drug, metformin, was able to improve insulin resistance and lipid profile. At molecular levels, both topical and systemic metformin significantly increased AMP-activated protein kinase (AMPK), and lowered keratinocyte growth factor (KGF) / "Signal transducer and activator of transcription" (STAT)3 protein levels, and the IL-17RA and IL-17RC gene expression. Although its glucose-controlling effect was not optimum, T.met gel served anti-psoriatic and anti-inflammatory effects.

Analysis of antidiabetic drug utilization patterns in type 2 diabetes patients: a perspective on real-time prescribing practices

Background: Type 2 diabetes is a most common health problem associated with significant morbidity and mortality worldwide, evaluation of drug utilization pattern is very crucial and significant in order to promote the rational use of drugs in treatment of diabetes, and offer insights in to the actual patterns of drug use. The objective is to evaluate drug utilization pattern of antidiabetic drugs among type 2 diabetic patients at Integral Institute of Medical Science & Research. Methods: This is a prospective observational study involving 100 subjects conducted for a period of 6 months after approval by Institutional Ethics Committee (IEC) of Integral University at IIMS and R Hospital. Informed consent was obtained from all the participants. Data gathered was examined using descriptive statistics and compared to the standard guidelines. Drug utilization pattern was studied and evaluated to analyse the pattern of drug therapy among type 2 diabetics. Results: Antidiabetic drugs were given 198 times among the 100 participants, averaging 2 antidiabetic drugs per prescription, Insulin therapy (58.58%) and Metformin (20.20%) were the most prescribed medications, combination therapy was common, with 66% of patients particularly with Glimepiride (DPP4 Inhibitor) at 10.61%. Most prescriptions were given by generic name (55%) and 90% of the drugs prescribed were from the WHO essential medicines. Most patients were aged 51-60 years, with a nearly equal gender distribution. Conclusion: The study highlights the prescribing patterns and characteristic use of antidiabetic medications. These findings provide valuable insights into the current prescribing practices in type-2 DM treatment and can contribute to optimizing treatment strategies for better patient outcomes.

SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes.

Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes. This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD. From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results. In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.

Intravitreal Metformin Protects Against Choroidal Neovascularization and Light-Induced Retinal Degeneration

Neovascular age-related macular degeneration (nAMD), a leading cause of blindness in older adults, presents a challenging pathophysiology involving choroidal neovascularization (CNV) and retinal degeneration. Current treatments relying on intravitreal (IVT) administration of anti-angiogenic agents are costly and of moderate effectiveness. Metformin, the common anti-diabetic drug, has been associated with decreased odds of developing AMD. Studies have shown that metformin can mitigate cellular aging, neoangiogenesis, and inflammation across multiple diseases. This preclinical study assessed metformin’s impact on vessel growth using choroidal explants before exploring IVT metformin’s effects on laser-induced CNV and light-induced retinal degeneration in C57BL/6J and BALB/cJ mice, respectively. Metformin reduced new vessel growth in choroidal explants in a dose-dependent relationship. Following laser induction, IVT metformin suppressed CNV and decreased peripheral infiltration of IBA1+ macrophages/microglia. Furthermore, IVT metformin protected against retinal thinning in response to light-induced degeneration. IVT metformin downregulated genes in the choroid and retinal pigment epithelium which are associated with angiogenesis and inflammation, two key processes that drive nAMD progression. These findings underscore metformin’s capacity as an anti-angiogenic and neuroprotective agent, demonstrating this drug’s potential as an accessible option to help manage nAMD.

Elucidation of potent mammalian enzymes inhibitors targeting anti-diabetes drug from Castanea mollissima blume, 1851: an edible herbal collected in Vietnam via experimental and computation approaching

Elucidation of potent mammalian enzymes inhibitors targeting anti-diabetes drug from Castanea mollissima blume, 1851: an edible herbal collected in Vietnam via experimental and computation approaching

Semaglutide and smoking cessation in individuals with type 2 diabetes mellitus: there is no smoke without fire!

Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials.

Mechanisms of action of fungal polysaccharides and their therapeutic effect.

The purpose of this article is to discuss the relationship between the therapeutic bioactivity of basidial fungal polysaccharides (BFPs) BFPs and their structural characteristics and conformational features, as well as to characterize the mechanisms of action of BFPs in diseases of various origins. The review was conducted using the PubMed (Medline), Scopus, Web of Science and the Russian Science Citation Index databases. 8645 records were identified, of which 5250 were studies (86 were randomized controlled trials). The period covered is from 1960 to the present. The most significant studies conducted mainly in Southeast Asian countries were selected for the review. Based on clinical studies, as well as the results obtained on in vivo, in vitro and ex vivo models, it has been proven that BFPs have diverse and highly effective biological activity in the human body in various diseases. The production of BFPs-based vaccines is an innovative strategy from a clinical and biochemical point of view, since as potential immunoprotective and low-toxic biopolymers they have innate immune receptors in the body. Promising results have been obtained in the development of antidiabetic drugs, probiotic, renoprotective and neurodegenerative dietary supplements. The biological activity, mechanism of action and specific therapeutic effect of BFPs largely depend on their structural and physicochemical characteristics. BFPs as multifunctional macromolecular complexes with low toxicity and high safety are ideal as new powerful pharmaceuticals for the treatment and prevention of many diseases.

Recent Advances in the Drugs and Glucose-Responsive Drug Delivery Systems for the Treatment of Diabetes: A Systematic Review.

Diabetes is a common chronic metabolic disease. Different types of drugs play important roles in controlling diabetes and its complications, but there are some limitations. The glucose-responsive drug delivery system is a novel technology with potential in diabetes treatment. It could automatically release drugs in response to changes in glucose levels in the body to maintain blood glucose within a normal range. The emergence of a glucose-sensitive drug delivery system provides a more intelligent and precise way to treat diabetes. The review is carried out according to the Preferred Reporting Items for Systematic Reviews (PRISMA 2020) guidelines This review focuses on the recent advances in the drugs and different systems of glucose-sensitive drug delivery, including glucose oxidase, phenylboronic acid, Concanavalin A, and other glucose-reactive systems. Furthermore, the glucose-responsive drug delivery system combined with the application applied in hydrogels, microneedles, and nanoparticles is also explored and summarized. The new platforms to sustain the release of anti-diabetic drugs could be desirable for patients. It could lead to increased adherence and glycemic outcomes for the detection and treatment of diabetes. Furthermore, given the limitations of glucose-responsive drug delivery systems, solutions and perspectives are proposed to help the understanding and application of these systems. This review will be helpful for drug discovery and treatment of diabetes from a new perspective.

Serum interleukin-10 level is increased and correlated positively with disease severity in patients with dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with a linear deposit of autoantibodies at the epidermal basement membrane zone. It was reported that diabetes patients who took a dipeptidyl peptidase-4 inhibitor (DPP4i), an oral antidiabetic drug, had an increased incidence of BP. However, data on DPP4i-related BP are limited. In our study, we measured serum levels of various cytokines using LEGENDplex and assessed correlations of these serum levels with clinical severity and laboratory data. Serum samples obtained from BP patients who visited our hospital from June 2016 to February 2023 were collected in this study. Patients' background, characteristics, and clinical data were retrospectively collected from their charts. Serum samples from 27 patients with DPP4i-unrelated BP, 17 patients with DPP4i-related BP, and 13 healthy controls were analyzed. Patients with DPP4i-related BP had lower score of Bullous Pemphigoid Disease Area Index (BPDAI)-erythema/urticaria, lower number of circulating eosinophils, and lower titer of anti-BP180 antibody than patients with DPP4i-unrelated BP. The serum interleukin (IL)-6 level was significantly higher in patients with DPP4i-related BP than in healthy controls (P = 0.0037). The serum IL-10 level was significantly higher in patients with DPP4i-related BP than in patients with DPP4i-unrelated BP and in healthy controls (P = 0.0006, P = 0.0448), and was positively correlated with the BPDAI-blister/erosions score (r = 0.757, P = 0.001), BPDAI-erythema/urticaria score (r = 0.616, P = 0.013), and BPDAI-total score (r = 0.833, P < 0.001) in patients with DPP4i-related BP. In conclusion, patients with DPP4i-related BP had increased serum levels of IL-6 and IL-10 compared with healthy controls and positive correlations between the serum IL-10 level and BPDAI scores reflecting clinical severity, indicating that the serum IL-10 level is a potential objective biomarker of disease severity in patients with DPP4i-related BP.

Multifunctional mesoporous nanoselenium delivery of metformin breaks the vicious cycle of neuroinflammation and ROS, promotes microglia regulation and alleviates Alzheimer's disease

Clinical trials based on a single molecular target continue to fail, and the adverse effects of Aβ protein aggregation and neuroinflammation need to be solved and treatment of Alzheimer's disease. Herein, by designed a nano-sized flower mesoporous selenium transport carrier (Met@MSe@Tf) with high enzyme-like activity, metformin (Met) was loaded, and transferrin (Tf) was modified to bind to transferrin receptor to promote receptor-mediated transport across the BBB. In the AD lesion environment, with the acidic environment response dissociation, promote the release of metformin by nanoflower to achieve therapeutic effect in the brain lesion site. Metformin, a major anti-diabetic drug in diabetic metabolism, has been found to be a promising new therapeutic target in neurodegenerative diseases. Further studies showed that the metformin drug release from the designed and synthesized transport nanoparticles showed high intrinsic activity and the ability to degrade the substrate involved, especially the degradation of Aβ deposition in the cortex and hippocampus, increased the phagocytosis of microglia, thus relieving neuroinflammation simultaneously. Collectively, in vivo experiments demonstrated that Met@MSe@Tf significantly increased the number of NeuN-positive neurons in the hippocampus of AD mice, promoted neurovascular normalization in the brain, and improved cognitive dysfunction in AD transgenic AD mice. Thus, it provides a preclinical proof of concept for the construction of a highly modular accurate drug delivery platform for Alzheimer's disease.

Comparative Analysis of ARIMA, SARIMA and Prophet Model in Forecasting

Machine learning has become a powerful tool in forecasting, offering greater accuracy than traditional human predictions in today’s data-driven world. The capability of machine learning to predict future trends has significant implications for key sectors such as finance, healthcare, and supply chain management. In this study, ARIMA/SARIMA (AutoRegressive Integrated Moving Average/Seasonal AutoRegressive Integrated Moving Average), alongside Prophet, a scalable forecasting tool developed by Facebook based on a generalized additive model, are considered. These models are applied to predict the demand for antidiabetic drugs. The records were collected by the Australian Health Insurance Commission. This dataset was sourced from Medicare Australia. The study evaluates the performance of these models based on their Mean Absolute Error (MAE), a key metric for assessing forecast accuracy. Root Mean Squared Error (RMSE) and Mean Absolute Percentage Error (MAPE) are also considered. The outcome of the comparative analysis shows that the Prophet model outperformed both ARIMA and SARIMA models, achieving an MAE of 0.74, which is significantly lower than the MAE values of 2.18 and 3.02 obtained by SARIMA and ARIMA, respectively. Prophet&amp;apos;s superior performance shows its effectiveness in handling complex, non-linear trends and seasonal patterns often observed in real-world time series data. This research contributes to the growing knowledge of machine learning-based forecasting and shows the importance of advanced models like Prophet in optimizing business operations and driving innovation. The findings from this research offer valuable guidance for data experts, analysts, and researchers in selecting the best forecasting methods for reliable predictions.

Exploring the 3,5-Dibromo-4,6-dimethoxychalcones and Their Flavone Derivatives as Dual α-Glucosidase and α-Amylase Inhibitors with Antioxidant and Anticancer Potential.

The rising levels of type 2 diabetes mellitus (T2DM) and the poor medical effects of the commercially available antidiabetic drugs necessitate the development of potent analogs to treat this multifactorial metabolic disorder. It has been demonstrated that targeting two or more biochemical targets associated with the onset and progression of diabetes along with oxidative stress and/or cancer could be a significant strategy for treating complications related to this metabolic disorder. The 3,5-dibromo-4,6-dimethoxychalcones (2a-f) and the corresponding flavone derivatives (3a-f) were synthesized and characterized using spectroscopic (NMR, HR-MS and FT-IR) techniques. The inhibitory effect of both series of compounds against α-glucosidase and α-amylase was evaluated in vitro through enzymatic assays. Selected compounds were also evaluated for potential to activate or inhibit superoxide dismutase. Compound 3c was selected as a representative model for the flavone series and evaluated spectrophotometrically for potential to coordinate Cu(II) and/or Zn(II) ions implicated in the metal-catalyzed free radical generation. A plausible mechanism for metal-chelation of the test compounds is presented. Furthermore, the most active compounds from each series against the test carbohydrate-hydrolyzing enzymes were selected and evaluated for their antigrowth effect on the human breast (MCF-7) and lung (A549) cancer cell lines and for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The parent chalcone 2a and flavone derivatives 3a, 3c and 3e exhibited relatively high inhibitory activity against the MCF-7 cells with IC50 values of 4.12 ± 0.55, 8.50 ± 0.82, 5.10 ± 0.61 and 6.96 ± 0.66 μM, respectively. The chalcones 2a and 2c exhibited significant cytotoxicity against the A549 cells with IC50 values of 7.40 ± 0.67 and 9.68 ± 0.80 μM, respectively. Only flavone 3c exhibited relatively strong and comparable cytotoxicity against the MCF-7 and A549 cell lines with IC50 values of 6.96 ± 0.66 and 6.42 ± 0.79 μM, respectively. Both series of compounds exhibited strong activity against the MCF-7 and A549 cell lines compared to the analogous quercetin (IC50 = 35.40 ± 1.78 and 35.38 ± 1.78 μM, respectively) though moderate compared to nintedanib (IC50 = 0.53 ± 0.11 and 0.74 ± 0.15 μM, respectively). The test compounds generally exhibited reduced cytotoxicity against the Vero cells compared to this anticancer drug. Molecular docking revealed strong alignment of the test compounds with the enzyme backbone to engage in hydrogen bonding interaction/s and hydrophobic contacts with the residues in the active sites of α-glucosidase and α-amylase. The test compounds possess favorable drug-likeness properties, supporting their potential as therapeutic candidates against T2DM.