Type 2 Diabetes Mellitus Therapy Research Articles

Effect of active static stretching on glycemia in type 2 diabetes

Background: Type 2 diabetes Mellitus (T2DM) is a chronic disease whose prevalence is increasing worldwide. It is characterized by insulin resistance in insulin-dependent tissues (e.g. skeletal muscle, adipose tissue). Despite new evidence that stretching may aid in glycemic control, this form of physical exercise remains underutilized in the therapy of T2DM. Objective: The objective of this study was to evaluate the effects of active static stretching on the glycemia of individuals with T2DM. Methods: Twenty-nine volunteers participated in the study, divided into 3 randomly assigned groups: 30-second stretching group (GA30) with 10 participants; 45-second stretching group (GA45) with 10 participants; control group (CG) with 9 participants. Results: Analysis of the intervention groups versus the control group showed that the intervention groups GA30 and GA45 had a significant milligrams per deciliter (mg/dl) reduction in glycemia compared to the control group (control Δ-7.9mg/dl, GA30 Δ12.7mg/dl and GA45 Δ18.5mg/dl >0.001) and between intervention groups (GA30 and control Δ 20.5mg/dl, P 0.002), GA45 and control (Δ 26.4mg/dl, P 0.001). There was no difference between the intervention groups. The results suggest that, regardless of the application time, active static stretching reduces glycemia in individuals with T2DM. In an analysis divided into 4 stages (1st and 2nd weeks, 3rd and 4th weeks, 5th and 6th weeks, and 7th and 8th weeks), the results obtained from the glycemic difference before and after each two weeks were as follows: GA30 pre and post (1st ≠ 17.4 mg/dl, 2nd ≠ 5.8 mg/dl, 3rd ≠ 14.5 mg/dl, and 4th ≠ 8.9 mg/dl), GA45 pre and post (1st ≠ 18.1 mg/dl, 2nd ≠ 17.0 mg/dl, 3rd ≠ 19.2 mg/dl, and 4th ≠ 20.0 mg/dl), and CG pre and post (1st ≠ -10.4 mg/dl, 2nd ≠ -3.7 mg/dl, 3rd ≠ -11.4 mg/dl, and 4th ≠ -11.7 mg/dl). Conclusion: This interaction between the two-factor period (Group and Period) did not have a significant effect. Finally, a descriptive analysis of pre- and post-intervention glucose behavior showed the variability of glycemia during the period. Thus, active static stretching significantly reduces acute and chronic glycemia in individuals with T2DM compared to control.

Pharmacoinformatics approach for type 2 diabetes mellitus therapeutics using phytocompounds from Costus genus: an in-silico investigation

Type 2 Diabetes Mellitus (T2DM), as a significant health concern globally, particularly in India, underscoring the vital need for effective therapeutics. Current drug therapies for T2DM may have limitations, leading researchers to explore natural products as alternatives. In this study. We have investigated the anti-diabetic compounds from the Costus genus, known as the insulin plant, which is abundant in southern India. The bioinformatics tools and software used for in-silico analysis to identify potential therapeutic compounds and hub genes associated with T2DM in the Indian population that could cut short the in-vitro and in-vivo experimental approaches in near future. The systematic review and combinatorial in-silico analysis revealed IGF2BP2, INS and TCF as the key targets that are associated with T2DM. The compounds stigmasterol, cycloartenol, and diosgenone were explored to be potent among all the 38 phytocompounds from genus Costus with binding energies −8.48, −10.07, and −10.31 kcal/mol against IGF2BP2, INS and TCF. The molecular dynamics (MD) simulation studies of these complexes demonstrated stable and consistent dynamic behavior, particularly in the INS-cycloartenol, IGF2BP2-stigmasterol and TCF7L2-diosgenone complexes. The identified compounds and associated targets represent potential candidates for T2DM therapeutics in the Indian population. The pharmacoinformatics approach presented in the study could streamline the drug discovery process by prioritizing compounds for further experimental validation. Communicated by Ramaswamy H. Sarma

Individuals Diagnosed With Type 2 Diabetes Mellitus and the Status of Vitamin B12 Deficiency: A Review.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder with a multifactorial etiology and a significant global burden. In recent years, emerging evidence has suggested a potential link between T2DM and vitamin B12 deficiency, raising concerns about its impact on disease progression, management, and associated complications. This comprehensive review critically examines the current understanding of the prevalence, risk factors, clinical implications, and management strategies related to vitamin B12 deficiency in individuals diagnosed with T2DM. The review begins by providing an overview of the epidemiology of T2DM and its associated complications, underscoring the need for comprehensive management approaches. Subsequently, it delves into the physiology of vitamin B12, including its sources, absorption mechanisms, and biological functions, laying the groundwork for understanding the potential implications of deficiency in T2DM. A thorough analysis of the literature is conducted to elucidate the prevalence and risk factors of vitamin B12 deficiency in individuals with T2DM, considering factors such as age, duration of diabetes, medication use (e.g., metformin), dietary patterns, and comorbidities. Special attention is given to the role of metformin, the first-line therapy for T2DM, in precipitating or exacerbating vitamin B12 deficiency through mechanisms involving alterations in the gut microbiota and intestinal absorption. The review further explores the clinical manifestations and diagnostic challenges associated with vitamin B12 deficiency in the context of T2DM, emphasizing the importance of recognizing subtle symptoms and implementing appropriate screening protocols. It discusses the potential implications of vitamin B12 deficiency on glycemic control, diabetic neuropathy, cognitive function, cardiovascular health, and overall quality of life in individuals with T2DM. In addressing the management of vitamin B12 deficiency in T2DM, the review examines various therapeutic strategies, including oral and parenteral supplementation, dietary modifications, and lifestyle interventions. It critically evaluates the evidence supporting routine screening for vitamin B12 deficiency in individuals with T2DM and discusses controversies surrounding optimal supplementation protocols, dosing regimens, and monitoring strategies. Furthermore, the review highlights gaps in current knowledge and identifies areas for future research, such as the long-term effects of vitamin B12 supplementation on clinical outcomes in T2DM, the impact of genetic factors on vitamin B12 metabolism, and the potential role of personalized interventions. Overall, this review consolidates existing evidence and provides insights into the complex relationship between T2DM and vitamin B12 deficiency, aiming to inform clinical practice, enhance patient care, and guide future research endeavors in this important area of metabolic medicine.

The cross talk between type II diabetic microenvironment and the regenerative capacities of human adipose tissue-derived pericytes: a promising cell therapy

BackgroundPericytes (PCs) are multipotent contractile cells that wrap around the endothelial cells (ECs) to maintain the blood vessel's functionality and integrity. The hyperglycemia associated with Type 2 diabetes mellitus (T2DM) was shown to impair the function of PCs and increase the risk of diabetes complications. In this study, we aimed to investigate the deleterious effect of the diabetic microenvironment on the regenerative capacities of human PCs.MethodsPCs isolated from human adipose tissue were cultured in the presence or absence of serum collected from diabetic patients. The functionality of PCs was analyzed after 6, 14, and 30 days.ResultsMicroscopic examination of PCs cultured in DS (DS-PCs) showed increased aggregate formation and altered surface topography with hyperbolic invaginations. Compared to PCs cultured in normal serum (NS-PCs), DS-PCs showed more fragmented mitochondria and thicker nuclear membrane. DS caused impaired angiogenic differentiation of PCs as confirmed by tube formation, decreased VEGF-A and IGF-1 gene expression, upregulated TSP1, PF4, actin-related protein 2/3 complex, and downregulated COL21A1 protein expression. These cells suffered more pronounced apoptosis and showed higher expression of Clic4, apoptosis facilitator BCl-2-like protein, serine/threonine protein phosphatase, and caspase-7 proteins. DS-PCs showed dysregulated DNA repair genes CDKN1A, SIRT1, XRCC5 TERF2, and upregulation of the pro-inflammatory genes ICAM1, IL-6, and TNF-α. Further, DS-treated cells also showed disruption in the expression of the focal adhesion and binding proteins TSP1, TGF-β, fibronectin, and PCDH7. Interestingly, DS-PCs showed resistance mechanisms upon exposure to diabetic microenvironment by maintaining the intracellular reactive oxygen species (ROS) level and upregulation of extracellular matrix (ECM) organizing proteins as vinculin, IQGAP1, and tubulin beta chain.ConclusionThese data showed that the diabetic microenvironment exert a deleterious effect on the regenerative capacities of human adipose tissue-derived PCs, and may thus have possible implications on the vascular complications of T2DM. Nevertheless, PCs have shown remarkable protective mechanisms when initially exposed to DS and thus they could provide a promising cellular therapy for T2DM.Graphical abstract

Could the Propionic Acid Treatment in Combination with Metformin be Safe for the Small Intestine of Diabetic Rats?

Effects of propionic acid (PA) on the cellular and molecular processes in the small intestine under type 2 diabetes mellitus (T2DM)-induced endoplasmic reticulum (ER) stress remain incompletely studied. The aim of the study was to assess the state of unfolded protein response (UPR) system in the small intestine of diabetic rats and to explore PA's influence on metformin treatment. Male Wistar rats were divided into 1) control and 2) T2DM groups, and groups receiving (14 days, orally) 3) metformin (60 mg/kg), 4) PA (60 mg/kg), and 5) PA+metformin. Western blotting, RT-PCR, and transmission electron microscopy were performed. We found that T2DM induced elevation of ER intermembrane space and UPR overactivation based on increased GRP78, ATF6 and PERK levels in small intestine. Metformin treatment led to a further UPR activation. PA supplementation partially restored enterocytes functioning via normalization of ATF6 and PERK content, while IRE1 level reached the maximum value, compared to all groups. The most pronounced effect of adaptation to the T2DMinduced ER stress was observed after combined metformin and PA action. In particular, decreased ER intermembrane space in enterocytes was detected compared to separate metformin and PA administration, which was accompanied by restored GRP78, PERK and IRE1 levels. Our study proves the safety of additional therapy with propionic acid in combination with metformin for the functional state of small intestine. Due to its ability to modulate UPR signaling, PA may be considered a safe and perspective candidate for supportive therapy in T2DM, especially for neuroprotection.

Gut-targeted therapies for type 2 diabetes mellitus: A review.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance. The global prevalence of T2DM has reached epidemic proportions, affecting approximately 463 million adults worldwide in 2019. Current treatments for T2DM include lifestyle modifications, oral antidiabetic agents, and insulin therapy. However, these therapies may carry side effects and fail to achieve optimal glycemic control in some patients. Therefore, there is a growing interest in the role of gut microbiota and more gut-targeted therapies in the management of T2DM. The gut microbiota, which refers to the community of microorganisms that inhabit the human gut, has been shown to play a crucial role in the regulation of glucose metabolism and insulin sensitivity. Alterations in gut microbiota composition and diversity have been observed in T2DM patients, with a reduction in beneficial bacteria and an increase in pathogenic bacteria. This dysbiosis may contribute to the pathogenesis of the disease by promoting inflammation and impairing gut barrier function. Several gut-targeted therapies have been developed to modulate the gut microbiota and improve glycemic control in T2DM. One potential approach is the use of probiotics, which are live microorganisms that confer health benefits to the host when administered in adequate amounts. Several randomized controlled trials have demonstrated that certain probiotics, such as Lactobacillus and Bifidobacterium species, can improve glycemic control and insulin sensitivity in T2DM patients. Mechanisms may include the production of short-chain fatty acids, the improvement of gut barrier function, and the reduction of inflammation. Another gut-targeted therapy is fecal microbiota transplantation (FMT), which involves the transfer of fecal material from a healthy donor to a recipient. FMT has been used successfully in the treatment of Clostridioides difficile infection and is now being investigated as a potential therapy for T2DM. A recent randomized controlled trial showed that FMT from lean donors improved glucose metabolism and insulin sensitivity in T2DM patients with obesity. However, FMT carries potential risks, including transmission of infectious agents and alterations in the recipient's gut microbiota that may be undesirable. In addition to probiotics and FMT, other gut-targeted therapies are being investigated for the management of T2DM, such as prebiotics, synbiotics, and postbiotics. Prebiotics are dietary fibers that promote the growth of beneficial gut bacteria, while synbiotics combine probiotics and prebiotics. Postbiotics refer to the metabolic products of probiotics that may have beneficial effects on the host. The NIH SPARC program, or the Stimulating Peripheral Activity to Relieve Conditions, is a research initiative aimed at developing new therapies for a variety of health conditions, including T2DM. The SPARC program focuses on using electrical stimulation to activate peripheral nerves and organs, in order to regulate glucose levels in the body. The goal of this approach is to develop targeted, non-invasive therapies that can help patients better manage their diabetes. One promising area of research within the SPARC program is the use of electrical stimulation to activate the vagus nerve, which plays an important role in regulating glucose metabolism. Studies have shown that vagus nerve stimulation can improve insulin sensitivity and lower blood glucose levels in patients with T2DM. Gut-targeted therapies, such as probiotics and FMT, have shown potential for improving glycemic control and insulin sensitivity in T2DM patients. However, further research is needed to determine the optimal dose, duration, and safety of these therapies.

Computational Approaches for Clinical, Genomic and Proteomic Markers of Response to GLP-1 Therapy in Type-2 Diabetes Mellitus: An Exploratory Analysis With Machine Learning Algorithms.

Computational Approaches for Clinical, Genomic and Proteomic Markers of Response to GLP-1 Therapy in Type-2 Diabetes Mellitus: An Exploratory Analysis With Machine Learning Algorithms.

Waste to Medicine: Evidence from Computational Studies on the Modulatory Role of Corn Silk on the Therapeutic Targets Implicated in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and/or defective insulin production in the human body. Although the antidiabetic action of corn silk (CS) is well-established, the understanding of the mechanism of action (MoA) behind this potential is lacking. Hence, this study aimed to elucidate the MoA in different samples (raw and three extracts: aqueous, hydro-ethanolic, and ethanolic) as a therapeutic agent for the management of T2DM using metabolomic profiling and computational techniques. Ultra-performance liquid chromatography-mass spectrometry (UP-LCMS), in silico techniques, and density functional theory were used for compound identification and to predict the MoA. A total of 110 out of the 128 identified secondary metabolites passed the Lipinski's rule of five. The Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis revealed the cAMP pathway as the hub signaling pathway, in which ADORA1, HCAR2, and GABBR1 were identified as the key target genes implicated in the pathway. Since gallicynoic acid (-48.74 kcal/mol), dodecanedioc acid (-34.53 kcal/mol), and tetradecanedioc acid (-36.80 kcal/mol) interacted well with ADORA1, HCAR2, and GABBR1, respectively, and are thermodynamically stable in their formed compatible complexes, according to the post-molecular dynamics simulation results, they are suggested as potential drug candidates for T2DM therapy via the maintenance of normal glucose homeostasis and pancreatic β-cell function.

Assessing medication adherence and their associated factors amongst type-2 diabetes mellitus patients of Jazan Province, Saudi Arabia: A single-center, cross-sectional study.

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) globally is reaching epidemic proportions. By 2035, it is projected to increase to 417 million, which is of significant concern as T2DM represents the most oversized budget item in many healthcare systems, primarily due to the high rates of morbidity and mortality associated with the disease. The worldwide cost burden of T2DM has been inexorably growing. A key contributor to the remarkably high morbidity and mortality rates is poor glycemic control potentially associated with medication non-adherence. AimThe present research’s main objective included assessing medication adherence among patients with T2DM in a single center in Jazan Province. MethodsThree hundred nine patients with T2DM participated in a cross-sectional survey over three months (September to November 2022). The study participants comprised 50.8 % (females) and 49.2 % (males), with a mean age of 44.12 years (SD ± 12.70). A 31-item self-report questionnaire was used for data collection. ResultsSixty-six percent of the sample were found to be adherent to their T2DM therapy. A positive association was noticed between the GMAS score and the participant’s age (r = 0.24; p < 0.01). The participants’ medication adherence was significantly associated with having age above 50 years (χ2 = 13.62; p = 0.001), residing in urban localities (χ2 = 21.37; p < 0.001), being married (χ2 = 12.80; p = 0.002), having glycated hemoglobin level more than 8 % (χ2 = 6.99; p = 0.03) and taking between one to three medications per day (χ2 = 17.63; p < 0.001). ConclusionThe majority of T2DM patients in the present study were found adherent to their anti-diabetic medications, particularly older patients. Future studies should focus on exploring the reasons for the reported high adherence among older patients and non-adherence among younger patients, as this could facilitate the development of a strategy to enhance adherence.

Tetrazoles and Related Heterocycles as Promising Synthetic Antidiabetic Agents.

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders.

Status of lipid control in Bangladeshi subjects with type 2 diabetes mellitus on lipid-lowering drugs: a multicenter, facility-based, cross-sectional study

BackgroundAchievement of lipid targets is crucial in patients with type 2 diabetes mellitus (T2DM) to mitigate the risk of cardiovascular diseases (CVD). Data on lipid-control status among patients with T2DM in Bangladesh are scarce. This study was conducted to determine the lipid-control status among patients with T2DM who were on lipid-lowering drugs in the country.MethodsThis cross-sectional study was conducted in the diabetes outpatient departments of several tertiary hospitals in Bangladesh from January 2022 to December 2022. Adults of both sexes diagnosed with T2DM for at least one year and were on the lipid-lowering drug(s) for a minimum of 3 months were included in the study by consecutive sampling. Patients’ data were collected by face-to-face interviews, and blood samples were collected for fasting lipid profile. The lipid target was set at < 200 mg/dL for total cholesterol (TC), < 150 mg/dL for triglyceride (TG), < 100 mg/dL for low-density lipoprotein cholesterol (LDL-C), > 40 mg/dL for high-density lipoprotein cholesterol (HDL-C), and < 160 mg/dL for non-HDL cholesterol (non-HDL-C).ResultThree thousand sixty patients (age 44.7 ± 13.3 years, female 57%) with T2DM were evaluated. Overall, almost 81% of the study subjects achieved the LDL-C target. Besides, TC, TG, HDL-C, and non-HDL-C targets were achieved by 40.8, 21.6, 66.3, and 44.1% of patients, respectively. However, all the lipid parameters were under control in only 8.8% of patients. Almost 77.6% of the patients with ischemic heart disease, 81.5% of patients with stroke, and 65% of patients with CKD had LDL levels < 70 mg/dL. Only 10.03% achieved the HbA1c target of < 7%. 7.4% of patients achieved both HbA1c < 7% and LDL < 100 mg/dL and 5% achieved both HbA1c < 7% and LDL < 70 mg/dL. Advanced age (aOR 0.97, 95% CI 0.96, 0.98, p < 0.001), longstanding T2DM (aOR 0.53, 95% CI 0.39, 0.72, p < 0.001), and non-statin therapy (aOR 0.25, 95% CI 0.16, 0.37, p < 0.001) were negatively associated with lipid control (LDL < 100 mg/dL) while using oral hypoglycemic drugs or insulin (aOR 2.01, 95% CI 1.45, 2.77, p < 0.001) and having cardiovascular comorbidity (aOR 3.92, 95% CI 3.00, 5.12, p < 0.001) were positively associated with lipid control.ConclusionThough most patients with T2DM achieved their target LDL level, the prevalence of both glycemic and overall lipid control was low in our study despite lipid-lowering therapy.

Oral Multidrug Co‐Delivery System Targeting Differential Sites for Diabetes Mellitus Treatment

AbstractAlthough regulation of the blood glucose level is a common therapy for Type 2 diabetes mellitus (T2DM), the root cause of this disease (such as the damage of pancreatic β cells) cannot be solved. Remodeling the pancreatic microenvironment and gut microbial homeostasis to improve β cells dysfunction become a potential strategy but remains challenging. Herein, a curcumin (CUR) and bifidobacterial (BI) co‐delivery system based on the self‐emulsifying technology (CUR‐BI‐SEDDS), which can generate a protective and self‐assembled coating on BI surface to achieve the above strategy is designed. CUR‐loaded oil phase coating endows BI with resistance against gastric invasion and helps BI colonize to positively regulate the abundance of gut microbiota. Following oral ingestion, the CUR‐loaded oil phase is self‐emulsified into nano‐emulsion, separated from BI, and delivers CUR to pancreas via the chylomicron pathway to remodel the inflammatory pancreatic microenvironment. As a result, CUR‐BI‐SEDDS showed excellent efficacy in restoring the islet β cell function, thus maintaining the systemic glucose homeostasis via only once administration every day. This study not only provides a promising regimen for thorough T2DM therapy but also explores a versatile oral co‐delivery platform for combination of chemo‐drugs and living biotherapeutics, which can exert potency at diverse target sites.

A high-throughput structural dynamics approach for identification of potential agonists of FFAR4 for type 2 diabetes mellitus therapy

Diabetes mellitus is a metabolic disorder that persists as a global threat to the world. A G-protein coupled receptor (GPCR), free fatty acid receptor 4 (FFAR4), has emerged as a potential target for type 2 diabetes mellitus (T2DM) and obesity-related disorders. The current study has investigated the FFAR4, deploying 3-dimensional structure modeling, molecular docking, machine learning, and high-throughput virtual screening methods to unravel the receptor’s crucial and non-crucial binding site residues. We screened four lakh compounds and shortlisted them based on binding energy, stereochemical considerations, non-bonded interactions, and pharmacokinetic profiling. Out of the screened compounds, four compounds were selected for ligand-bound simulations. The molecular dynamic simulations were carried out for 1µs for native FFAR4 and 500 ns each for complexes of FFAR4 with compound 1, compound 2, compound 3, and compound 4. Our findings showed that in addition to reported binding site residues ARG99, ARG183, and VAL98 in known agonists like TUG-891, the amino acids ARG22, ARG24, THR23, TRP305, and GLU43 were also critical binding site residues. These amino acids impart stability to the FFAR4 complexes and contribute to the stronger binding affinity of the compounds. The study also indicated that aromatic residues like PHE211 are crucial for recognizing the active site’s pi-pi and C-C double bonds. Since FFAR4 is a membrane protein, the simulation studies give an insight into the mechanisms of the crucial protein-lipid and lipid-water interactions. The analysis of the molecular dynamics trajectories showed all four compounds as potential hit molecules that can be developed further into potential agonists for T2DM therapy. Amongst the four compounds, compound 4 showed relatively better binding affinity, stronger non-bonded interactions, and a stable complex. Communicated by Ramaswamy H. Sarma

Effect of sodium-glucose co-transporter inhibitors on arterial stiffness in patients with type 2 diabetes mellitus

Abstract Introduction Selective sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduce cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In addition to glucose homeostasis the impaired arterial stiffness may participate in this morbidity and mortality. Purpose The aim of this study was to investigate the effect of administration of SGLT2i therapy on arterial stiffness parameters, including aortic pulse wave velocity (PWV) and central systolic blood pressure (SBPao), which have significant prognostic value for predicting cardiovascular events. Methods Our prospective, observational study included 40 patients with T2DM (mean age: 60.3±9.9 years, 24 males). Biochemical and arterial stiffness parameters were analysed before starting SGLT2i therapy (14 patients on dapagliflozin, 25 patients on empagliflozin, 1 patient on ertugliflozin), at 3, 6 months and an average of 3.3±1.3 years follow-up period. Arterial stiffness parameters were determined using an invasively validated oscillometric based Arteriograph (AG) method. Changes in the variables and their interrelation was analysed by repeated data ANOVA and multivariate linear regression. Results Significant decrease in PWV and HgbA1c were observed 3 months after the initiation of SGLT2i therapy (PWV: 10.68±1.35 m/s vs. 10.05±1.40 m/s and HgbA1c: 7.86±0.55 vs. 6.83±0.66 %, p&amp;lt;0,05) and this long-term effect continued during the 3.3-years follow-up period (PWV: 9.96±1.25 m/s and HgbA1c: 7.19±0.81 %, p&amp;lt;0,005, Figure 1). Pearson's correlation analysis and multivariate linear regression analysis showed no association between decreased PWV and BMI, brachial diastolic blood pressure (DBPb) while significant, but weak correlation was observed with HgbA1c and brachial systolic blood pressure (SBPb) (r=0.22-0.26, p&amp;lt;0.05, Figure 2). SBPao results showed non-significant decrease and a subsequent non-significant long-term increase comparing to baseline during the 3.3 years follow-up. Conclusion Short and long-term SGLT2i therapy in T2DM significantly improved PWV values and this effect is independent of changes in SBPao. All these findings emphasize the clinical relevance of arterial stiffness as a biomarker in the SGLT2i induced beneficial effect on the vasculature, however further clarification, long-term evaluation needed to define the role of PWV in the prediction of cardiovascular events.Figure 1Figure 2

Time to act: the challenge of high incidence of diabetes and prediabetes in patients admitted with different cardiovascular diseases phenotypes

Abstract Background Limited studies have focused on diagnosing type 2 diabetes mellitus (T2DM) and prediabetes in hospitalized patients with cardiovascular diseases (CVD) with their different phenotypes. In addition, HbA1c levels in patients admitted for cardiovascular reasons may be lower than in patients with symptoms of hyperglycemia. Purpose To assess the incidence of newly and previously diagnosed T2DM and prediabetes among patients hospitalized with CVD, depending on the reasons for admission. Methods In the single-center prospective study (registry) we enrolled 773 patients ≥40 years with established CVD and arterial hypertension (HTN) without type 1 diabetes mellitus, except for previously diagnosed T2DM and prediabetes who were admitted to the City Clinical hospital. We also assessed the reasons for admission. From 06.01.2018 to 03.01.2020 275 (35.6%) patients hospitalized with acute coronary syndrome (ACS), 163 (21.1%) with acute decompensated heart failure (ADHF), 157 (20.3%) with HTN, 75 (9.7%) with atrial fibrillation or flutter (AF), 67 (8.7%) with chronic coronary syndrome (CCS) and 36 (4.7%) with newly diagnosed T2DM. All of them screened for T2DM and prediabetes using HbA1c and fasting plasma glucose by ADA Guidelines. Results Screening results are shown in Picture 1. The overall incidence of T2DM or prediabetes in hospitalized patients with CVD was 55.9%, and before the screening, only 25.7% were diagnosed with T2DM or prediabetes. The highest incidence of T2DM or prediabetes, including previously diagnosed, was among patients admitted with ADHF – 71.2%, and the lowest, 46.2%, in those hospitalized with ACS. Picture 2 presents mean levels of HbA1c in patients with newly and previously diagnosed T2DM, depending on the reasons for admission. The highest HbA1c levels were identified in patients with CVD who were hospitalized with symptoms of hyperglycemia and in whom the diagnosis of T2DM was confirmed (р&amp;lt;0,001). However, patients hospitalized with ADHF, AF and CCS had a HbA1c level almost twice lower than in patients hospitalized with newly diagnosed T2DM and lower than in those hospitalized with ACS and HTN (р&amp;lt;0,001). At the same time, HbA1c levels in previously diagnosed T2DM did not differ significantly between groups. Conclusion Thus, about 1 out of 2 patients hospitalized with CVD have a T2DM or prediabetes, and more than a third of patients without a T2DM or prediabetes (41%) were previously undiagnosed. In addition, patients admitted with ADHF, AF, and CCS with newly diagnosed T2DM had lower levels of baseline HbA1c than patients with overt symptoms of hyperglycemia, ACS, and HTN. All this has a potential impact on the target groups of screening and initial therapy of T2DM, including new classes of drugs.Picture 1Picture 2

Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes Mellitus Management: Pharmacophore Virtual Screening, Molecular Docking, Pharmacokinetic Evaluations, and Conceptual DFT Analysis

Dipeptidyl Peptidase 4 (DPP-4) expressed on the surface of many different cells is a promising target to develop new candidates for Type 2 diabetes mellitus (T2DM) management. In this light, we performed a computer-aided simulation involving 3-D pharmacophore screening, molecular docking, and drug-likeness assessment to identify novel potential DPP-4 inhibitors with an improved physicochemical profile to treat T2DM. In addition, global reactivity descriptors, including HOMO and LUMO energies, HOMO-LUMO gaps, and Fukui indices, were computed to confirm the essential structural features to achieve DPP-4 activity. The gathered outcomes recommend that eight out of 240 million compounds collected from eight pre-built databases (Molport, Chembl30, ChemDiv, ChemSpace, Mcule, Mcule-ultimate, LabNetwork, and ZINC) are drug-like and nontoxic, and may serve as starting points for designing novel, selective, and potent DPP-4 inhibitors. Furthermore, the success of the current workflow to identify DPP-4-potential inhibitors strengthens its potential efficiency to also predict natural compounds as novel adjutants or main therapy for T2DM or discover hit compounds of other targets.

FRI649 ADMIRE: Assessing Dapagliflozin And Metformin As An Initial Regimen In Diabetes Mellitus For Enhanced Glucose Control

Abstract Disclosure: D. Phadke: None. D. Gopal: None. D. Biswas: None. D. Birla: None. A. Prasad: None. P. Joshi: None. Introduction: Early aggressive glucose lowering in type 2 diabetes mellitus (T2DM) has shown improved outcomes, and combination oral antidiabetic agents (OAAs) on top of lifestyle therapy are necessary. In India, most T2DM patients receive combination therapy with two or more OAAs to achieve glycemic targets more rapidly. The fixed dose combination (FDC) of dapagliflozin and metformin is widely used in India, as it improves glycemia, reduces weight and blood pressure (BP), and has good tolerability. This study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as initial therapy for T2DM patients in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled 481 T2DM patients across 49 clinical units for a period of 6 months. The study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as the initial choice FDC in T2DM. The study was conducted in compliance with the principles of the Declaration of Helsinki, good clinical practice, and regulatory guidelines. Ethical approval for the study was obtained on August 6, 2022, and the study was conducted from August 15, 2022, to January 20, 2023. Results: The study demonstrated that dapagliflozin and metformin FDC significantly reduced weight by 4.2 kg (p &amp;lt; 0.0001), fasting plasma glucose by 21.4 mg/dL (p &amp;lt; 0.0001), and improved estimated glomerular filtration rate (eGFR) by 1.9 m²/1.73 ml/min (p &amp;lt; 0.0001). Additionally, systolic BP was reduced by 10.7 mmHg (p &amp;lt; 0.0001), and diastolic BP was reduced by 6.6 mmHg (p &amp;lt; 0.0001), which is in combination with the concomitant medications. Incidence of genito-urinary tract infection was 8.9%. Conclusion: In a real-world setting, dapagliflozin and metformin FDC can be used as initial therapy for T2DM with good efficacy, tolerability, and safety. Physicians preferred this combination due to its ability to promote weight loss, reduce cardiovascular events, and decline in renal function. The excellent safety and efficacy reported by physicians for this FDC of dapagliflozin and metformin has contributed to improved compliance with the treatment. Thus, in the Indian population, dapagliflozin and metformin FDC is effective, safe, and has good tolerability as an initial therapy for T2DM. Presentation: Friday, June 16, 2023

Physical Activity and Type 2 Diabetes: In Search of a Personalized Approach to Improving β-Cell Function.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual β-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and β-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on β-cell function.

Differentiated approach to glycemic management in type 2 diabetic patients during inpatient treatment of acute myocardial infarction: glycemic control and long-term prognosis

BACKGROUND: The risk of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) is 2 times higher than without DM. Previously an association between the time in the target range of glycemia during hospitalization of AMI in patients with T2DM (hTIR — «hospital time in range») and long-term prognosis was found. It is supposed that a differentiated approach to glycemic management will help to achieve a higher level of hTIR and will lead to an improved prognosis.AIM: To evaluate the effectiveness of differentiated approach to glycemic management in patients with T2DM during inpatient treatment of AMI and impact on long-term prognosis.MATERIALS AND METHODS: The study included patients with T2DM who were hospitalized with AMI with ST-segment elevation and underwent percutaneous coronary intervention. A total amount of patients was 161; 102 were in the main group, 59 in the control group. There was a differentiated approach to glycemia management based on phenotype determination in the main group. Insulin therapy was prescribed to patients with the 1st phenotype during the entire inpatient treatment. Patients with the second phenotype received insulin therapy followed by switching oral antidiabetic drugs (OAD). Patients of the 3rd phenotype were prescribed only OAD. In the control group, therapy of T2DM was prescribed according to the standard hospital procedures based on current clinical recommendations.RESULTS: In the main group, 22 patients (22%) were in the 1st phenotype, 54 (53%) –in the 2nd, 26 (25%) –in the 3rd. The average glycemia during hospitalization in the main group was lower than in the control group: 9.4±1.7 mmol/l vs 10.3±2.3 mmol/l (p=0.006). The hTIR in the main group was 58 [53; 71]% vs 46 [33; 63]% in the control group (p&lt;0.001). It was shown that when hTIR &gt; 55% is reached, the risk of cardiovascular death within a year after hospitalization is reduced by 80%.CONCLUSION: The differentiated approach to glycemic management in patients with T2DM leads to an improvement in glycemic control during inpatient treatment of AMI and is accompanied by a tendency to a lower incidence of cardiovascular death within a year after hospitalization. Achieving hTIR &gt; 55% is associated with a multifold reduction of the risk of cardiovascular death in a year. About 25% of patients with DM2 during inpatient treatment of AMI do not need the insulin therapy.

Proteomic Profiling Identifies Distinct Regulation of Proteins in Obese Diabetic Patients Treated with Metformin.

Background: Obesity and type 2 diabetes mellitus (T2DM) are characterized by underlying low-grade chronic inflammation. Metformin has been used as the first line of therapy in T2DM as it decreases hepatic glucose production and glucose intestinal absorption, enhances insulin sensitivity and weight loss, and is known to ameliorate inflammation. The mechanisms through which metformin exerts its effect remain unclear. Proteomics has emerged as a unique approach to explore the biological changes associated with diseases, including T2DM. It provides insight into the circulating biomarkers/mediators which could be utilized for disease screening, diagnosis, and prognosis. Methods: This study evaluated the proteomic changes in obese (Ob), obese diabetics (OD), and obese diabetic patients on metformin (ODM) using a 2D DIGE MALDI-TOF mass spectrometric approach. Results: Significant changes in sixteen plasma proteins (15 up and 1 down, ANOVA, p ≤ 0.05; fold change ≥ 1.5) were observed in the ODM group when compared to the Ob and OD groups. Bioinformatic network pathway analysis revealed that the majority of these altered plasma proteins are involved in distinct pathways involving acute-phase response, inflammation, and oxidative response and were centered around HNF4A, ERK, JNK, and insulin signaling pathways. Conclusions: Our study provides important information about the possible biomarkers altered by metformin treatment in obese patients with and without T2DM. These altered plasma proteins are involved in distinct pathways involving acute-phase response, inflammation, and oxidative response and were centered around HNF4A, ERK, JNK, and insulin signaling pathways. The presented proteomic profiling approach may help in identifying potential biomarkers/mediators affected by metformin treatment in T2DM and inform the understanding of metformin's mechanisms of action.