Betagenin: New intestine‐derived hormone which ameliorates diabetes

Type 2 diabetes is characterized by an insufficient compensatory response of pancreatic β cells to overcome peripheral insulin resistance. Effective β-cell compensation in response to insulin resistance can prevent the progression to type 2 diabetes1. The recent success of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors in treating diabetes underscores the critical role of the intestine as an endocrine organ. However, these conventional therapies fail to restore the reduced functional β-cell mass2. Incretins are gut-derived hormones that enhance insulin secretion following food intake in a glucose-dependent manner. The two most extensively studied incretins, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, promote insulin release through distinct G-protein-coupled receptors abundantly expressed on pancreatic β cells. These receptors are also widely distributed in non-islet tissues, where they contribute to additional metabolic effects. Consequently, there is significant interest in understanding the extra pancreatic roles of incretin hormones. Therapeutic approaches for type 2 diabetes have focused on enhancing incretin receptor signaling through two main strategies3. GLP-1 not only enhances insulin synthesis but also restores glucose responsiveness in glucose-resistant β cells, promotes β cell proliferation and neogenesis, and protects against β cell apoptosis. The mechanisms by which GLP-1 suppresses glucagon secretion from α cells remain debated4. Yokoo et al5. first identified the complementary DNA (cDNA) clone identified in C57BL/6J (BL6) mice through the oligo-cap SST strategy, and quantitative real-time PCR (qPCR) analysis was found to encode a gene with intestine-specific expression. The gene sequence matched that of transmembrane 4 L6 family member 20 (Tm4sf20), which encodes a 25-kDa membrane protein of unknown function. Database analysis (Ensembl Genome Browser) showed that the predicted amino acid sequence of human betagenin shares 75% similarity with the product of murine Tm4sf20, which is specifically expressed in the small intestine5. The authors named it as betagenin. Also, the betagenin gene was found to be highly conserved across mammalian species and an intestine-specific secretory protein. Then they found that betagenin stimulates glucose-dependent insulin secretion. They were evaluated the therapeutic potential of betagenin in vivo using a streptozotocin (STZ) induced diabetes model. Interestingly, in mice with STZ-induced diabetes, adenovirus-mediated overexpression of betagenin normalized blood glucose levels. However, their β-cell areas remained smaller compared to those of wild-type mice. These results suggest that betagenin enhances glycemic control in diabetic mice by promoting insulin secretion and increasing β-cell mass. Furthermore, they generated betagenin transgenic (BL6 and KK strain) and knockout (KO) mice. They questioned whether betagenin expression is essential for maintaining normal pancreatic morphology. The two transgenic strains (BL6 and KK) exhibited normal body size and weight, yet their β-cell mass and islet number were three times greater than those of their wild-type littermates. However, although KO mice appeared normal in size, their β-cell-to-pancreatic area ratios were over four times lower than those of their wild-type littermates, and they also had significantly fewer islets. They synthesized a betagenin peptide with 60 amino acid residues. Notably, the amino acid sequence of this peptide is highly conserved across species. Betagenin peptide stimulated ERK1/2 phosphorylation in MIN6 cells, an effect that was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126. They also determined that synthetic betagenin has similar effects in both mouse and human pancreatic islets using EdU incorporation experiments in vivo. The betagenin via intravenous injection induced the beta cell proliferation. They found the effect of betagenin peptide both in vitro (MIN6 cell line) and ex vivo (human and mouse islets). Betagenin peptide reduced the apoptosis through the activation of MAPK pathways. Therefore, they found that betagenin peptide enhances insulin secretion in a glucose-dependent manner in pancreatic islets from both mice and humans. This result is mediated through the ERK1/2 pathway and confirmed with U0126 MEK, an ERK1/2 inhibitor. They investigated the long-term therapeutic effects of betagenin peptide on diabetes using an STZ-induced diabetic mouse model. Mice were treated with betagenin peptide (10 μg/mouse, IV) for 51 days. Interestingly, oral glucose tolerance tests (OGTT) revealed improved glucose tolerance as well as reduced baseline blood glucose levels. Unexpectedly, HbA1c levels did not change significantly, even when blood glucose levels were lower than those of control mice. Also, a significant increase in β-cell mass was observed following betagenin peptide administration. Yokoo et al5. first identified the betagenin as a putative intestinal secreted protein1. Betagenin stimulates pancreatic islet insulin secretion in a glucose-dependent manner while increasing β-cell number and islet mass. These results suggest exciting opportunities for further research. However, here are some unsolved limitations remain, and it would be great to do more investigation to verify the role of the betagenin (Figure 1). According to the results, betagenin induces β-cell proliferation and reduces apoptosis, showing promising potential for preserving β-cell mass. If these findings are confirmed, betagenin could lead to a new class of β-cell–preserving therapies for diabetes. A critical question, however, is how to determine the optimal direction for therapeutic development. These findings highlight exciting opportunities for further research. Betagenin's unique effect on β-cell regeneration holds promise for the creation of new, more effective diabetes therapies. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.