Daily Endocrinology Research Analysis

In diabetes, pancreatic β cells degenerate from their mature differentiated state to a dedifferentiated state. BRD4 plays a pivotal role during embryogenesis and cancer development, but its function in modulating β-cell differentiation remains unknown. In this study, multiple models including calorie restriction db/db mouse, long-term and acute conditional knockout mouse, and human islet organoids are adopted to assess BRD4 function in β cells. Two hundred twenty-two young patients with diabetes are also recruited for whole exome sequencing (WES) to screen for BRD4 mutations. This study shows that BRD4 expression is significantly reduced in human diabetic β cells while significantly increased after calorie restriction in the diabetic mouse. β cell differentiation is impaired after long-term and acute Brd4 knockout. BRD4 knockdown in human islet organoids results in the loss of differentiation and reduction of insulin synthesis. It is found that p.R749C can significantly affect BRD4 signaling and might play roles in diabetes development in patients. This study also shows that ATF5 is a direct target of the BRD4 pathway in β cells. Targeting BRD4-mediated regulatory networks may hold promise for developing novel therapeutic strategies to maintain the differentiated state of β cells.

AIMS: This indirect treatment comparison (ITC) compared the efficacy and safety of tirzepatide with semaglutide for managing obesity or overweight in participants with type 2 diabetes (T2D), informed by the pivotal trials SURMOUNT-2 and STEP 2. MATERIALS AND METHODS: Participants had body mass index (BMI) ≥ 27 kg/m RESULTS: Tirzepatide 10 and 15 mg were associated with statistically significant greater reductions in weight, BMI and HbA1c versus semaglutide. Tirzepatide 15 mg was associated with statistically significant greater odds versus semaglutide of ≥5% and ≥15% weight reduction and statistically significant improvements in several cardiometabolic risk factors, including waist circumference, fasting plasma glucose and triglycerides. Both tirzepatide doses showed non-significant trends of greater improvements in high-density lipoprotein, low-density lipoprotein, systolic blood pressure and diastolic blood pressure versus semaglutide as well as a generally comparable safety profile to semaglutide. CONCLUSIONS: In this ITC versus semaglutide 2.4 mg, tirzepatide 10 and 15 mg were associated with statistically significant greater weight, BMI and HbA1c reduction and tirzepatide 15 mg with statistically significant improvements in multiple cardiometabolic risk factors crucial in managing obesity or overweight among patients with T2D. Both tirzepatide doses also had a generally similar safety profile to semaglutide. PLAIN LANGUAGE SUMMARY: What is the context and purpose of this research study? Excess weight and type 2 diabetes (T2D) are strongly connected, where most patients with T2D have obesity or overweight. Weight management is crucial for improving T2D outcomes and preventing its progression. Weight management comprises behavioural interventions, psychological support, dietary changes and physical activity programmes. Medications may also be prescribed or surgical options may also be considered. Two such medications for weight management are tirzepatide (up to 15 mg) and semaglutide (up to 2.4 mg), which are injected subcutaneously once per week to help control appetite by prolonging patients' feeling of fullness. These medications are also used at different doses to treat T2D. Because there were no clinical trials directly comparing tirzepatide and semaglutide, particularly in patients with both T2D and either obesity or overweight, this study aimed to indirectly compare the effectiveness and safety of tirzepatide and semaglutide for weight management in patients with overweight or obesity and T2D. What was done? We indirectly compared the efficacy and safety of two doses of tirzepatide (10 and 15 mg per week) versus semaglutide 2.4 mg per week for weight management in adults with both T2D and either obesity or overweight. We used data from two large clinical trials, SURMOUNT-2 and STEP 2, which tested tirzepatide and semaglutide, respectively, against a placebo, all adjunct to diet and exercise. An indirect treatment comparison of tirzepatide and semaglutide was then possible via the placebo arm acting as the common comparator. The similarity of study design and patient populations in the two trials was evaluated and found to be sufficiently close to allow meaningful comparisons. Appropriate statistical methodology was used to facilitate comparisons of the two trials. What were the main results? Compared to semaglutide 2.4 mg, the higher dose of tirzepatide (15 mg) was associated with a statistically significant improvement in several outcomes such as weight reduction, glycaemic outcomes and triglycerides, while the lower dose of tirzepatide (10 mg) was associated with some statistically significant improvements (e.g., weight reduction and HbA1c) and had otherwise comparable outcomes to semaglutide. However, both doses of tirzepatide were associated with statistically significant greater reductions in glycated haemoglobin A1c (HbA1c) compared to semaglutide, which is a key target of T2D treatment. Both doses of tirzepatide had a generally similar safety profile compared to semaglutide. What is the originality and relevance of this study? Currently, there are no clinical trials that compare tirzepatide and semaglutide directly for the management of obesity and overweight in patients with T2D. Previous studies have compared tirzepatide and semaglutide results from different clinical trials for weight management in patients without T2D, not specifically focusing on patients with T2D. This is the first study to indirectly compare tirzepatide and semaglutide for weight management in people with T2D who also have obesity or overweight. The findings of this study suggest that higher doses of tirzepatide may be more effective than semaglutide for weight reduction and improving other health-related outcomes in these patients.

A subpopulation of kisspeptin neurons in the arcuate nucleus (ARN) of the hypothalamus functions as the GnRH pulse generator, driving the pulsatile secretion of LH from the anterior pituitary. Recent advances in in vivo GCaMP fiber photometry have allowed the direct measurement of ARN kisspeptin (ARNKISS) neuronal population activity in mice. In both sexes, ARNKISS neurons display large, brief calcium activity episodes, termed synchronization episodes, each corresponding to a correlated LH pulse. Here we present quantitative and comparative analyses of calcium activity in these neurons and LH profiles in male and female mice, based on a combination of previously published and unpublished data. Our findings reveal a significant sex difference in pulse generator frequency in intact mice, with males exhibiting slower and more stochastic synchronization episodes compared to females. Additional sex differences were noted in the profile of synchronization episodes. In gonadectomized mice, the synchronization frequency and the episode profiles became similar across sexes, indicating that gonadal steroids largely drive sex differences in the intact state. However, sex-specific differences in pulse frequency distributions persisted after gonadectomy, suggesting possible steroid-independent differences in the GnRH pulse generator. Sex differences in the LH pulse frequency and amplitude were observed in intact mice and were abolished following gonadectomy, highlighting the correlation between synchronization episodes and downstream hormonal signaling.