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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]

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]

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]

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]

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]

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]

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]

Background The aim of the randomized present study was to compare the therapeutic efficacy and safety of a combination of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, plus insulin glargine (GL + sita) with that of premixed insulin aspart 30 (NOV) for type 2 diabetes (T2D) patients controlled with oral hypoglycemic drugs (HbA1c 7 %-9 %). Methods Sixty-five patients were randomized (1: 1) to the GL + sita (n = 33) and NOV (n = 32) groups and were treated with the combination regimen or premixed insulin twice a day for 16 weeks. The primary endpoint was mean change in HbA1c. Secondary endpoints included fasting blood glucose, blood glucose profiles (seven time points), rate of achieving target HbA1c (<7 % or ≤6.5 %), insulin dose, incidence of hypoglycemia, and body weight. Results After 16 weeks, there was no significant difference in HbA1c between the two groups, although more patients achieved HbA1c <7.0 % in the GL + sita group. There was a significant difference in body weight changes between the GL + sita and NOV groups (−0.45 vs 1.52 kg, respectively; P < 0.001). Mean plasma glucose and the mean amplitude of glycemic excursion were significantly lower in the GL + sita than NOV group ( P < 0.005), as was the incidence of symptomatic hypoglycemia (2.85 % vs. 13.3 %, respectively; P < 0.001). Conclusion The combination of GL + sita greatly improved HbA1c in T2D patients (HbA1c 7 %-9 %) with an efficacy that was equal to that of premixed insulin. Thus, GL + sita treatment is a viable option for patients who fail to achieve glycemic control using oral hypoglycemic drugs. [ABSTRACT FROM AUTHOR]