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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]

Insufficient decompensated insulin secretion and insulin resistance caused by pancreatic β-cell dysfunction are the pathological bases of type 2 diabetes mellitus (T2DM). Glucolipotoxicity in pancreatic β-cells is an important factor leading to their dysfunction, closely related to inflammatory signals, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress (ERs). However, there may be other unproven regulatory mechanisms that govern pancreatic β-cell dysfunction. Therefore, further elucidation of the underlying mechanisms that lead to pancreatic β-cells dysfunction will provide a sufficient theoretical basis for the more effective prevention and treatment of T2DM. As a stress protein with pro-inflammatory properties, Serum Amyloid 1 (SAA1) promotes the progression of metabolic syndrome-related diseases by activating immune cells and damaging endothelial cells. In the development of T2DM, the activation of nuclear factor-kappa B (NF-κB) signaling aggravates pancreatic β-cells dysfunction under the stimulation of free fatty acids (FFAs), inflammatory factors, and chemokines. Moreover, the facilitating effect of SAA1 on the activation of the NF-κB signaling pathway has been demonstrated in other studies. In the present study, we demonstrated that SAA1 inhibits insulin secretion and promotes apoptotic molecular expression in pancreatic cells and islets and that NF-κB signaling inhibitors could reduce this effect of SAA1. SAA1 deficiency improved high-fat diet (HFD)-induced pancreatic β-cell dysfunction and decreased expression of NF-κB signaling molecules. Our findings suggested that HFD-induced SAA1 might exacerbate T2DM by enhancing pancreatic β-cell dysfunction; such a function of SAA1 might depend on NF-κB signaling activation. • SAA1 levels of liver and serum are increased in HFD-induced T2DM mice. • SAA1 inhibits insulin secretion and promotes apoptotic molecular expression in pancreatic β-cells and islets. • SAA1 induces pancreatic β-cells dysfunction via NF-kB signaling. • SAA1 deficiency alleviates HFD-induced T2DM. [ABSTRACT FROM AUTHOR]

Islet β-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet β-cell function is beneficial to better management of T2DM. Protecting islet β-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet β-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the " Clinical expert consensus on the assessment and protection of pancreatic islet β-cell function in type 2 diabetes mellitus." This consensus suggests that β-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet β-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet β-cell function, independent of glycemic control. [ABSTRACT FROM AUTHOR]