Journal of Diabetes最新文献

β-cell dedifferentiation in humans is considered as a mechanism underlying β-cell failure, which is characterized by the loss of their differentiated identity and reversion to a fetal-like state. In humans, significant increases in the hormones-negative/Chromogranin A-positive endocrine cells were detected in islets from T2D individuals, which were accompanied by decreased expressions of the β-cell identity transcription factors (NKX6.1, MAFA, etc.) and reactivation of the progenitor marker, NEUROGENIN 3, and dramatic inductions of the dedifferentiation marker, ALDH1A3 and BACH2. The observation of increased dysfunctional dedifferentiated β-cells in non-diabetic patients with chronic pancreatitis or pancreatic ductal adenocarcinoma as well as in non-diabetic aged subjects proposed that β-cell dedifferentiation is not only a major mechanism of pancreatogenic diabetes and age-related diabetes but also an initial trigger for human β-cell failure before hyperglycemia occurs. Indeed, the finding that the ratio of dedifferentiated β-cells is inversely related to HOMA-β and 2h-C Peptide in subjects without a diabetes history further supports the contribution of β-cell dedifferentiation to β-cell failure in humans. Considerable efforts have been made and are still required to identify targets and pathways (in)dependent of hyperglycemia that trigger dedifferentiation in human β-cells. These findings hold promise for the development of effective therapeutic strategies aimed at preventing or reversing this process, thereby maintaining or restoring functional β-cell mass.

The figure shows the market share of prescriptions filled from 2008 to 2023. Over this period, the GLP-1 prescription market shifted from predominantly Byetta to a broader distribution across Victoza, Trulicity, and Ozempic, with smaller shares of Rybelsus and Mounjaro by 2023.

We thank the authors for their thoughtful comments on our randomized controlled trial of glycated albumin (GA)-guided therapy in newly diagnosed type 2 diabetes mellitus (T2DM) [1]. We appreciate the opportunity to clarify several key points.

First, we fully agree that the primary endpoint—achievement of HbA1c<7% at 12 weeks—was neutral, and we explicitly reported and discussed this negative result. We had acknowledged that secondary analyses were exploratory and hypothesis-generating, and we have interpreted them with appropriate caution, as stated in the manuscript.

Second, regarding the HbA1c<6.5% result, we agree that intention-to-treat inference is primary. The difference was marginal in the full analysis set (35.7% vs. 23.8%, p = 0.065) and nominally significant in the per-protocol set (40.5% vs. 25.3%, p = 0.034). We reported both transparently and did not base our main conclusion on the per-protocol finding; rather, we view the consistent direction of effect as a signal warranting further investigation.

Third, we agree that the greater improvements in HbA1c reduction, HOMA-β, HOMA-IR, and anthropometric parameters in the GA-guided group may partly reflect earlier and more intensive combination therapy. However, this is precisely the intended clinical utility of GA: to provide a timely, actionable trigger for treatment intensification when HbA1c remains insensitive to short-term changes. In addition, according to the protocol, in the standard therapy group, apart from withholding the GA measurement data, we did not impose any additional restrictions on blood glucose monitoring; capillary blood glucose testing was permitted as per routine clinical practice. So, the relevant question is not whether GA has intrinsic therapeutic effects, but whether GA measurement facilitates earlier and more effective treatment decisions compared with routine clinical practice. Our trial provides preliminary evidence.

Finally, we agree that short-term changes in HOMA-β and HOMA-IR should not be equated with durable β-cell recovery or sustained improvement in insulin sensitivity. We interpreted these as short-term metabolic improvements rather than evidence of long-term disease modification.

We thank the authors for their insightful comments.

Q.R. wrote the manuscript. L.J. reviewed and edited the manuscript. Q.R. and L.J. contributed significantly and in keeping with the latest guidelines of the International Committee of Medical Journal Editors.

This work was supported by Asahi Kasei Pharma Corporation and National Clinical Key Specialty Construction Program of China (Department of Endocrinology, Peking University People's Hospital) with support from the central government budget.

The authors declare no conflicts of interest.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.