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Aims: To evaluate the impact of a dual glucose‐dependent insulinotropic peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist tirzepatide (TZP), and its potential dose‐response effect, on heart rate. Methods: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP‐1 receptor agonists [GLP‐1RAs], insulin, placebo). The GLP‐1RA and non‐GLP‐1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta‐analyses and network meta‐analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). Results: Eight articles were included in this systematic review and meta‐analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta‐analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP‐1RAs and non‐GLP‐1RAs (GLP‐1 RAs: MD 2.29, 95% CI 1.00, 3.59; non‐GLP‐1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD −0.97, 95% CI −1.79, −0.14; TZP 15 mg: MD −2.57, 95% CI −3.79, −1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD −1.5, 95% CI −2.38, −0.82). Network meta‐analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP‐1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). Conclusions: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP‐1RA and non‐GLP‐1RA groups, but also that the 15‐mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose‐response impact on heart rate. Further research on the effects of TZP treatment‐related increases in heart rate is required. [ABSTRACT FROM AUTHOR]

Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus and also has hepatoprotective effects. However, the role of liraglutide treatment on liver injury in a mouse model of type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ) and its underlying mechanisms remain to be elucidated. In the present study, diabetes was initiated in experimental animals by single-dose intraperitoneal inoculation of STZ. Forty female C57BL/6J mice were equally assigned into five groups: diabetic group, insulin+diabetic group, liraglutide+diabetic group, insulin+liraglutide+diabetic group, and control group for eight weeks. Diabetic mice exhibited a significantly elevated blood glucose level and decreased body weight, and morphological changes of increased steatosis and apoptosis were observed in the liver compared with the control. Furthermore, a significant increase in the levels of malondialdehyde and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β) and the proapoptotic proteins caspase-3 and Bax were observed in the livers of diabetic mice, together with marked increases in antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as antiapoptotic protein Bcl-2, all of which were significantly mitigated by treatment with liraglutide, insulin, and their combinations. Interestingly, liraglutide monotherapy showed better efficacy in ameliorating liver injury in T1DM mice than insulin monotherapy, similar to the combined drug therapy. Furthermore, the expression of Wnt/β-catenin signaling pathway-associated molecules was upregulated in the liver of mice treated with liraglutide or insulin. The results of the present study suggested that liraglutide improves T1DM-induced liver injury and may have important implications for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with T1DM. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD. Methods: We retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD. Results: A total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e-0.07776X, R2 = 0.4154). Treatment regimens in MD patients were varied, with no metformin users and a weak correlation between insulin dosage and body weight. Conclusions: The increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Diabetic cardiovascular autonomic neuropathy (DCAN) seriously threatens the prognosis and quality of life of patients with type 2 diabetes mellitus, associated with increased mortality. The present study aimed to investigate the relevant risk factors of DCAN. Materials and Methods: The present study enrolled a total of 109 patients with type 2 diabetes mellitus. DCAN was defined as a score of at least 2 points in Ewing tests. The updated homeostasis model assessment of insulin resistance (HOMA2‐IR) based on fasting C‐peptide was calculated to reflect insulin resistance. Logistic regression analysis, interaction and stratified analyses were used to investigate the relationship between HOMA2‐IR or other indicators and DCAN. Receiver operating characteristic analysis was carried out to estimate the discriminative value of the variables independently associated with DCAN and to determine the optimal cut‐off point of these models to screen DCAN. Results: The HOMA2‐IR levels were significantly higher in patients with DCAN, and tended to be worsened with the progression of the DCAN. Logistic regression analysis showed an independent association between HOMA2‐IR (odds ratio 39.30, 95% confidence interval 7.17–215.47) and DCAN. HOMA2‐IR (area under the curve 0.878, 95% confidence interval 0.810–0.946; cut‐off value 1.735) individually predicted DCAN significantly higher than the other independent risk factors individually used, whereas models combining HOMA2‐IR and other risk factors did not significantly boost the diagnostic power. Conclusions: Insulin resistance is independently associated with DCAN. HOMA2‐IR presents to be a highly accurate and parsimonious indicator for DCAN screening. Patients with HOMA2‐IR >1.735 are at a high risk of DCAN; thus, priority diagnostic tests should be carried out for these patients for timely integrated intervention. [ABSTRACT FROM AUTHOR]

Introduction: The cardiovascular efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) are well documented; however, the differences in cardiovascular efficacy among subpopulations remain unknown. This systematic review and meta-analysis aimed to explore the differences in cardiovascular efficacy of long-acting GLP-1RAs among subpopulations of patients with T2DM and to assess the drug safety. Methods: Relevant studies up to March 31, 2020 were searched for in six electronic databases, namely PubMed, Cochrane Library, Embase, Clinical Trials, Science Direct, and Web of Science. The primary outcome was three-point major adverse cardiovascular events (including cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke). Subpopulations were defined using ten selected influential factors, and the differences in cardiovascular efficacy in subpopulations stratified by different influential factors were accessed by synthesizing studies with random-effects models one by one. Results: A total of six cardiovascular outcome trials of long-acting GLP-1RAs, comprising 49,936 participants, were included. Among stratified subpopulations, no significant differences in the cardiovascular efficacy of long-acting GLP-1RAs were observed across the ten characteristics of subjects (all P for interaction > 0.05). Favorable trends were observed in the subpopulation with established cardiovascular disease (CVD) compared to that without (P = 0.171). With regards to safety, long-acting GLP-1RAs did not significantly increase the risk of retinopathy (OR 1.09; 95% CI 0.92–1.29; P = 0.316), but increase the risk of serious gastrointestinal events (OR 1.37; 95% CI 1.02–1.83; P = 0.037). Long-acting GLP-1RAs did not significantly increase the risk of serious adverse events (OR 0.92; 95% CI 0.85–1.00; P = 0.039). Conclusions: Our analysis suggested no subpopulation differences in the cardiovascular efficacy of long-acting GLP-1RAs among stratified subpopulations, and favorable trends were only observed in the subpopulation with established CVD. These findings may have implications for the management of long-acting GLP-1RAs across subpopulations of patients with T2DM. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the safety of insulin lispro Mix 25 and 50 (LM25 and LM50) in hypoglycemia in patients with type 2 diabetes mellitus (T2DM). Methods: This was a post hoc analysis of a phase IV, randomized, crossover clinical trial in Chinese patients with T2DM switching from premixed human insulin 70/30 (PHI70/30) to LM25 or LM50. Eighty-one subjects received a two-stage crossover protocol of either LM25 or LM50 twice daily for 16 weeks. Habitual diet was taken, and self-monitoring of blood glucose (SMBG) was performed throughout the study period. High-carbohydrate diet (HCD), high-fat diet (HFD) and habitual diet patterns were taken, and 72 h continuous glucose monitoring (CGM) was performed at the last 3 days of each treatment stage. Results: The frequencies of nocturnal hypoglycemia in LM50 were lower than those in LM25 under a Chinese habitual diet pattern. The related factors of hypoglycemia in patients with T2DM treated with a LM25 or LM50 regimen were the weight-based daily mean insulin dose and the type of combined oral hypoglycemic agents. Under both HCD and habitual diet patterns, the optimal cut point values of bedtime glucose predicting nocturnal hypoglycemia in LM50 were lower than those in LM25. Conclusions: The risk of nocturnal hypoglycemia in the LM50 regimen was lower than that in the LM25 regimen under the HCD pattern, and the safety range of bedtime glucose for the LM50 regimen was wider than that of the LM25 regimen in Chinese T2DM patients. Premixed insulin analogs combined with acarbose were more helpful to reduce the incidence of hypoglycemia. Trial Registration: http://www.chictr.org.cn #ChiCTR-TTRCC-12002516. [ABSTRACT FROM AUTHOR]

Objective. Previous studies have revealed dysregulated circulating microRNAs (miRNAs) in patients with type 1 diabetes (T1D). Here, we explored the serum levels of miR-21, miR-25, miR-146a, and miR-181a in patients with autoimmune diabetes (T1D and latent autoimmune diabetes of adults (LADA)) compared with type 2 diabetes (T2D) and nondiabetic individuals. Design, patients, and measurements. The serum levels of miR-21, miR-25, miR-146a, and miR-181a in patients with T1D (n = 29), LADA (n = 16), and T2D (n = 31) and in nondiabetic individuals (n = 19) were determined by quantitative real-time polymerase chain reaction, and receiver-operating characteristic (ROC) curves were evaluated to determine the discriminatory performances of these four miRNAs. Furthermore, target genes and pathways potentially modulated by these four miRNAs were predicted by bioinformatics analysis to investigate the possible functions of these miRNAs in autoimmune diabetes. Subsequently, multiple logistic regression analysis was performed to identify independent predictors for autoimmune diabetes, and a nomogram was established. Results. miR-21, miR-25, miR-146a, and miR-181a were significantly downregulated in the serum of patients with autoimmune diabetes compared with those in T2D patients and nondiabetic individuals (p<0.001). The areas under the ROC curves of these four miRNAs were greater than 0.80 (p<0.001). Bioinformatics analysis suggested that miR-21, miR-25, miR-146a, and miR-181a regulated multiple genes in pathways associated with immunity, inflammatory responses, hyperglycemia, and metabolism, which are involved in the pathogenesis of autoimmune diabetes. Multiple logistic regression analysis identified miR-25 (odds ratio (OR): 0.001, p<0.05), miR-146a (OR: 0.136, p<0.05), and fasting C-peptide levels (OR: 0.064, p<0.05) as independent predictors of autoimmune diabetes. Conclusions. miR-25 and miR-146a may serve as potential circulating biomarkers and provide insights into the pathogenesis of autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to explore the association between serum UA and cellular aging markers. Design: The current cross-sectional analysis was based on data collected within a type 2 diabetes project. Settings: Serum uric acid (UA), which has both antioxidant and pro-oxidant properties, is thought to be involved in cellular aging processes. Participants: There are 536 participants included in total, 65.3% of which are women. The average serum UA in women was 267.8 umol/l, lower than in men of 337.7 umol/l (P<0.001). Measurements: Serum UA, blood lipid profile, HbA1c, plasma glucose and insulin were determined. The peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) were assessed using a real-time PCR assay. Logistic regressions were used to analyze the associations between serum UA and cellular aging markers. Results: In Spearman's correlation analysis, there were significantly negative correlations between serum UA and LTL in both women and men (r=−0.162, P=0.006; and r=−0.232, P=0.004, respectively). The logistic regression adjusted for age, BMI, WC, daily energy intake, HbA1c, TG, and LDL-C revealed that the ORs of shorter LTL comparing the extreme serum UA quintiles was 5.52 (95% CI 1.69–18.02; P for trend =0.025) in women and 6.49 (95% CI 1.38–30.45; P for trend =0.108) in men. Furthermore, the OR (95% CI) for shorter LTL per 1 SD increment in serum UA was 1.51(1.10–2.07) in women and 1.64(1.01–2.65) in men. In regard to mtDNAcn, the association between elevated serum UA and lower mtDNAcn only reached significance in men when comparing the second and fifth quintiles with reference quintile (OR=3.73(1.07–13.04) and 3.76(1.01–14.09), separately, and P for trend=0.066). Conclusions: Our results indicate a significant negative association between serum UA and peripheral blood cellular aging markers. Serum UA might play a role in promoting cellular aging. [ABSTRACT FROM AUTHOR]

Aim To investigate the correlation between serum uric acid (SUA) and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. Methods Two hundred T2DM patients were divided into four groups at the cut-off points of 5, 7, and 9 mg/dL of SUA levels. Nerve conduction studies (NCS), Semmes-Weinstein monofilament testing (SWMT), and vibration perception threshold (VPT) tests were performed on these patients. Results Significant differences in motor/sensory nerve amplitude and conduction velocity (CV) parameters among different SUA level groups were observed (all P < 0.05). SUA levels were negatively correlated with the means of motor/sensory nerve amplitude and CV (all P < 0.05). Duration of T2DM > 10 years, SUA > 9 mg/dL and total cholesterol (TC) > 5.2 mmol/L were found to be significantly associated with DPN (all P < 0.05). Receiver-operating characteristic (ROC) analysis revealed that the cut-off points of T2DM duration combined with SUA and TC were 9 years, 7.8 mg/dL, and 4.97 mmol/L, respectively (AUC = 0.65; 95% CI: 0.53–0.77; sensitivity, 70.6%; specificity, 65.2%, P = 0.009). Conclusion There is a significant association between elevated SUA levels and DPN, and T2DM duration, SUA, and TC may be valuable indicators to predict the occurrence of DPN in T2DM patients. [ABSTRACT FROM AUTHOR]

Aim We measured the levels of bone turnover markers (BTMs) in patients with early diabetic nephropathy from type 2 diabetes mellitus (T2DM), and investigated the associations of BTMs with adipokines, serum fibroblast growth factor-21 (FGF21) and osteonectin. Methods We included 159 males and 300 females with T2DM in this cross-sectional study. Clinical characteristics, BTMs and adipokines levels were measured. Results One-hundred and ninety-two (41.8%) patients presented with albuminuria. Patients with albuminuria had significantly higher levels of serum osteonectin ( P < 0.0001) and FGF21 ( P = 0.0125) than those with normoalbuminuria. Serum levels of P1NP were slightly lower among patients with albuminuria ( P = 0.031), but the difference disappeared after adjusting for FBG, PBG, and HbA1c. Serum FGF21 levels were independently and negatively related to eGFR (overall β = − 0.161, P = 0.001; albuminuria group β = − 0.240, P = 0.001) but not related to uACR. While Osteonectin was independently and positively related to uACR (overall β = 0.209, P = 0.001; albuminuria group β = 0.170, P = 0.021). The levels of serum FGF21 were independently inversely related with P1NP (overall β = − 0.192, P < 0.0001; albuminuria group β = − 0.195, P = 0.031). Conclusions Our results suggest that persistent hyperglycemia may inhibit bone formation. Both osteonectin and FGF21 were associated with early nephropathy in T2DM patients, albeit with different patterns. [ABSTRACT FROM AUTHOR]

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Visceral fat (VF) influences left ventricular (LV) structure and diastolic function in type 2 diabetes (T2DM). However, there are limited data on the association among them based on different BMI levels as well as accounting for arterial stiffness. This study investigated the association of fat distribution, arterial stiffness, left ventricular (LV) structure and diastolic function in T2DM patients. This cross-sectional study comprised 905 patients. VF area (VFA) and subcutaneous fat area (SFA) were assessed by a dual bioelectrical impedance analyzer. Brachial-ankle pulse wave velocity (baPWV) was measured by a volume-plethysmographic apparatus and LV structure and diastolic function were echocardiography. Patients were divided into three groups based on BMI levels. Linear and logistic regression analysis were used to investigate the association. In multivariate linear regression, relative wall thickness (RWT) was negatively correlated with E/A in obese patients (β = −0.203, p = 0.004). LV mass/height2.7 was positively correlated with E/E' in normal weight (β = 0.232, p = 0.002) and obese patients (β = 0.232, p = 0.008). In multivariate logistic regression, baPWV was an independent determinant of LV remodeling (LVRM) in normal weight (OR = 1.001; 95% CI, 1.000, 1.002; P = 0.006), overweight (OR = 1.001; 95% CI, 1.000, 1.002; P = 0.008) and obese groups (OR = 1.003; 95% CI, 1.001, 1.004; P = 0.001), while VFA was correlated with arterial stiffness in normal weight (OR = 1.032; 95% CI, 1.017, 1.047; P < 0.001) and overweight groups (OR = 1.011; 95% CI, 1.002, 1.021; P = 0.015). VF might impact LVRM through changes in baPWV in T2DM patients, thus influencing diastolic function. • Visceral fat area (VFA), but not subcutaneous fat area or BMI, was positively correlated with baPWV. • Both VFA and baPWV were associated with left ventricular structure. • BaPWV has a stronger correlation with left ventricular remodeling (LVRM) than VFA. • VFA might impact LVRM through changes in baPWV. [ABSTRACT FROM AUTHOR]