Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and β-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 β cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on β-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.

Over the past two decades, diabetes pharmacopoeia has flourished, with new drugs that, on top of their glucose-lowering efficacy, have been shown to protect the heart and the kidney. Despite these new opportunities, metformin retains a pivotal role among glucose-lowering agents. As one of the few available insulin sensitizers, metformin is an effective, safe, and overall well-tolerated drug backed by over 60 years of clinical experience, including evidence for potential benefits beyond glucose reduction across different ages, sexes, genetic backgrounds, geographical areas, and stages of disease. Although there is some discussion of whether metformin offers the most effective front-line option in newly diagnosed type 2 diabetes (T2D), it remains a natural companion to all other glucose-lowering agents. Furthermore, metformin comes at a very low cost and, as such, it has extremely high cost-effectiveness, particularly given the serious economic burden associated with diabetes complications. This financial advantage is particularly relevant in resource-constrained healthcare systems, where the affordability of metformin may be instrumental in implementing an effective treatment in an evergrowing number of individuals. We present here compelling real-world evidence in support of the clinical efficacy and cost-effectiveness of metformin across different patient populations, highlighting areas where more population-based studies are needed to further incorporate and consolidate its use in the pharmacological management of T2D.

Young adulthood can be a challenging time for individuals with diabetes mellitus (DM) as they experience increasing independence and life transitions, which can make it difficult to engage in DM self care. Compared to older adults, young adults are more likely to have higher glycated hemoglobin A1c (HbA1c). They also often have lower adherence to standards of care in DM, and higher utilization of emergency department (ED) visits and hospitalizations for diabetic ketoacidosis. This review describes health-care utilization and explores factors that may contribute to high HbA1c among young adults with DM. In addition, it discusses the unique health-care needs of young adults with DM, examines the role of technology in their DM care, and analyzes the effects of social determinants of health on their health-care utilization.

UNASSIGNED: Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction.
UNASSIGNED: The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes.
UNASSIGNED: Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications.
UNASSIGNED: The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%).
UNASSIGNED: ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.

UNASSIGNED: High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are cardiac biomarkers commonly detected in adults with type 2 diabetes (T2D) and are associated with heart failure risk.
UNASSIGNED: The purpose of this study was to evaluate the effects of exercise training (ET) on hs-cTnT and NT-proBNP and evaluate the associations of these biomarkers with cardiorespiratory fitness among adults with T2D.
UNASSIGNED: Participants of the HART-D (Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes) trial who were randomly assigned to one of 3 ET groups or a non-exercise control group were included. Cardiac biomarkers and cardiorespiratory fitness (evaluated by peak oxygen uptake [VO2peak]) were assessed at baseline and after 9 months. The effects of ET (3 ET groups pooled) vs non-exercise control on hs-cTnT and NT-proBNP were assessed using separate analysis of covariance models. Multivariable-adjusted linear regression was performed to identify factors associated with follow-up biomarkers and ΔVO2peak.
UNASSIGNED: The present study included 166 participants randomized to the ET (n = 135) and non-exercise control (n = 31) groups. Compared with the non-exercise control, ET did not significantly change hs-cTnT or NT-proBNP. In adjusted analysis, each ET group and ΔVO2peak were not significantly associated with hs-cTnT or NT-proBNP levels on follow-up. Among individuals in the ET group, baseline hs-cTnT was inversely associated with ΔVO2peak [per 1 SD higher log (hs-cTnT): β = -0.08 (95% CI = -0.15 to -0.01)].
UNASSIGNED: Among individuals with T2D, ET did not modify cardiac biomarkers. Higher baseline hs-cTnT was associated with blunted cardiorespiratory fitness improvement in response to exercise.

Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly conducted in European populations, while Middle Eastern populations remain largely underrepresented. We conducted a GWAS on the indices of IR (HOMA2-IR) and beta cell function (HOMA2-%B) in 6,217 non-diabetic individuals from the Qatar Biobank (QBB; Discovery cohort; n = 2170, Replication cohort; n = 4047) with and without body mass index (BMI) adjustment. We also developed polygenic scores (PGS) for HOMA2-IR and compared their performance with a previously derived PGS for HOMA-IR (PGS003470). We replicated 11 loci that have been previously associated with HOMA-IR and 24 loci that have been associated with HOMA-%B, at nominal statistical significance. We also identified a novel locus associated with beta cell function near VEGFC gene, tagged by rs61552983 (P = 4.38 × 10-8). Moreover, our best performing PGS (Q-PGS4; Adj R2 = 0.233 ± 0.014; P = 1.55 x 10-3) performed better than PGS003470 (Adj R2 = 0.194 ± 0.014; P = 5.45 x 10-2) in predicting HOMA2-IR in our dataset. This is the first GWAS on HOMA2 and the first GWAS conducted in the Middle East focusing on IR and beta cell function. Herein, we report a novel locus in VEGFC that is implicated in beta cell dysfunction. Inclusion of under-represented populations in GWAS has potentials to provide important insights into the genetic architecture of IR and beta cell function.

UNASSIGNED: Previous studies have confirmed that the triglyceride glucose (TyG) index, recognized as a reliable marker of insulin resistance, is an important risk factor for diabetic kidney disease (DKD). However, it is still unclear whether the DKD risk continues to increase linearly with the elevation of TyG index. This study aimed to thoroughly investigated the intrinsic relationship between TyG index and DKD risk in type 2 diabetes (T2D).
UNASSIGNED: This cross-sectional study included 933 patients with T2D in China, who were categorized into DKD and non-DKD groups and stratified by TyG index levels. Logistic regression analysis identified the independent risk factors for DKD. The association between DKD risk and TyG index was evaluated using the restricted cubic spline (RCS) curves analysis. The R package \'CatPredi\' was utilized to determine the optimal cut-off point for the relationship between DKD risk and TyG index, followed by threshold effect analysis.
UNASSIGNED: The prevalence of DKD was 33.01%. After adjusting for confounding factors, TyG index was identified as a prominent clinical risk factor for DKD, showing the highest odds ratio (OR 1.57 (1.26 - 1.94), P<0.001). RCS analysis revealed a non-linear relationship with a threshold interval effect between the TyG index and DKD risk. When TyG index ≤ 9.35, DKD risk plateaued at a low level; however, when TyG index > 9.35, DKD risk increased gradually with rising TyG index. Among patients with TyG index > 9.35, each 1-unit increase was associated with a 1.94-fold increased DKD risk (OR=1.94 (1.10 - 3.43), P=0.022).
UNASSIGNED: The DKD risk presented a threshold effect with the increase of TyG index, initially stable at a low level, and then gradually rising when the TyG index is above 9.35.

Dyslipidemia is a disorder where abnormally lipid concentrations circulate in the bloodstream. The disorder is common in type 2 diabetics (T2D) and is linked with T2D comorbidities, particularly cardiovascular disease. Dyslipidemia in T2D is typically characterized by elevated plasma triglyceride and low high-density lipoprotein cholesterol (HDL-C) levels. There is a significant gap in the literature regarding dyslipidemia in rural parts of Africa, where lipid profiles may not be captured through routine surveillance. This study aimed to characterize the prevalence and demo-graphic profile of dyslipidemia in T2D in the rural community of Ganadougou, Mali. We performed a cross-sectional study of 104 subjects with T2D in Ganadougou between November 2021 and March 2022. Demographic and lipid profiles were collected through cross-sectional surveys and serological analyses. The overall prevalence of dyslipidemia in T2D patients was 87.5% (91/104), which did not differ by sex (P = .368). High low-density lipoprotein cholesterol (LDL-C) was the most common lipid abnormality (78.9%, [82/104]). Dyslipidemia was associated with age and hypertension status (P = .013 and.036, respectively). High total and high LDL-C parameters were significantly associated with hypertension (P = .029 and .006, respectively). In low-resource settings such as rural Mali, there is a critical need to improve infrastructure for routine dyslipidemia screening to guide its prevention and intervention approaches. The high rates of dyslipidemia observed in Gandadougou, consistent with concomitant increases in cardiovascular diseases in Africa suggest that lipid profile assessments should be incorporated into routine medical care for T2D patients in African rural settings.

UNASSIGNED: In recent decades, adults living with congenital heart disease (ACHD) have improved their survival, thus increasing their predisposition to the onset of cardiometabolic risk factors and chronic health conditions.
UNASSIGNED: The purpose of this study was to describe cardiometabolic risk profiles in the ACHD population and their relationship to congenital heart disease (CHD) lesion complexity.
UNASSIGNED: We performed a cross-sectional study from ACHD in a third-tier referral center in Mexico City. The association between cardiometabolic risk factors and CHD complexity was estimated using logistic regression models.
UNASSIGNED: Our study cohort included 1,171 ACHD patients (median age: 31 [IQR: 23.2-42.7] years, male 63.6%). Cardiac diagnosis was classified as mild (44.9%), moderate (37.8%), and severe (17.2%) CHD complexity. Low high-density lipoprotein cholesterol (55%) was the most common cardiometabolic risk factor; followed by insulin resistance (54.5%) and prediabetes (52.4%). Patients with mild and moderate CHD had a higher prevalence of obesity and metabolic syndrome, while patients with severe CHD had a higher prevalence of hyperuricemia and subclinical hypothyroidism. In the logistic regression analysis, the severity of CHD was associated with higher odds of hyperuricemia (moderate CHD, OR: 1.87; 95% CI: 1.20-2.93; P = 0.010; severe CHD, OR: 2.75; 95% CI: 1.64-4.62; P < 0.001) and lower risks of metabolic syndrome (OR: 0.61; 95% CI: 0.41-0.91; P = 0.010), prediabetes (OR: 0.58; 95% CI: 0.42-0.81; P < 0.001), and arterial hypertension (OR: 0.49; 95% CI: 0.33-0.74; P < 0.001) compared with mild CHD complexity.
UNASSIGNED: We observed high rates of cardiometabolic risk factors in Mexican ACHD patients and these risk profiles varied by CHD lesion complexity. These results highlight the need for ongoing metabolic health surveillance in the ACHD population.

BACKGROUND: The purpose of this study is to investigate the impact of social media-based microlearning (SMBM) on enhancing the knowledge, self-care, and self-efficacy behaviors of patients with type 2 diabetes (T2D) receiving care at a hospital-based diabetes clinic in Zahedan, Iran.
METHODS: This intervention study was conducted from September 2021 to the end of 2022, with an intervention group (SMBM) and a control group (conventional-based training) consisting of patients with T2D. A total of 80 eligible patients were selected using a convenience sampling method and randomly assigned to either the intervention group (n = 40) or the control group (n = 40). The knowledge level, self-care, and self-efficacy of the samples were assessed before and two weeks after the educational intervention. Data analysis was conducted using SPSS version 24, and independent and paired T-tests were used for analysis.
RESULTS: The results of the study revealed that after the intervention, the levels of knowledge, self-care, and self-efficacy in the intervention group were significantly higher than those in the control group (p-value < 0.001).
CONCLUSIONS: In conclusion, the SMBM appears to be an effective tool for improving self-efficacy, self-care, and knowledge among patients with type 2 diabetes.