Betagenin and the Gut–Pancreas Axis: A Candidate Intestine-Derived Signal for β-Cell Function and Survival in Diabetes Mellitus

Pancreatic β-cell dysfunction and progressive loss of functional β-cell mass are central features of both type 1 and type 2 diabetes mellitus, although the mechanisms driving β-cell failure differ between these disorders. Current glucose-lowering therapies improve glycemic control and reduce cardiometabolic risk but do not consistently restore endogenous β-cell mass in established diabetes mellitus. The gut–pancreas axis has traditionally been defined by the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, the intestine produces additional signals that may influence β-cell function, survival, and regenerative capacity. Betagenin is a recently identified intestine-derived peptide generated from the Tm4sf20 gene product. An approximately 10-kDa betagenin-immunoreactive peptide was detected in the circulation of wild-type mice. The initial study reported that betagenin enhanced glucose-stimulated insulin secretion (GSIS), increased cell-cycle-associated responses in β-cell models and islet preparations, and reduced β-cell apoptosis. Pharmacological evidence implicated MEK–ERK1/2 signaling in selected responses. In isolated human islets, betagenin enhanced GSIS and increased 5-ethynyl-2′-deoxyuridine (EdU) incorporation, although the identity and fate of EdU-positive cells remain unresolved. In streptozotocin-induced diabetic mice, administration of synthetic betagenin and adenovirus-mediated betagenin expression improved hyperglycemia and were associated with recovery of estimated β-cell mass. These findings are preclinical; responses in isolated human islets do not establish clinical efficacy in patients or durable regeneration of functional human β-cells. This review examines betagenin as a candidate circulating component of the gut–pancreas axis and discusses its potential to influence β-cell function, survival, and recovery after injury. We also address key questions concerning physiological regulation of endogenous betagenin, receptor identification, β-cell specificity in human islets, pharmacokinetics, long-term safety, and therapeutic relevance in progressive type 2 diabetes mellitus.