Human pancreatic α‐ to β‐cell area ratio increases after type 2 diabetes onset

AIMS/INTRODUCTION: Pancreatic α‐cell area and the α‐ to β‐cell area ratio (α/β) might be associated with glucose tolerance. The aim was to clarify how these histological parameters change as glucose tolerance deteriorates. MATERIALS AND METHODS: We analyzed pancreatic tissues obtained from pancreatectomies of 43 patients. We evaluated the relationships between α‐cell area or the α/β and various clinical parameters. Additionally, we analyzed α‐cell proliferation and the expression patterns of various pancreatic transcription factors. RESULTS: The α/β in individuals with longstanding (previously diagnosed) type 2 diabetes (0.36 ± 0.12) was higher than that in those with normal glucose tolerance (0.18 ± 0.10; P < 0.01), impaired glucose tolerance (0.17 ± 0.12; P < 0.05) and newly diagnosed diabetes (0.17 ± 0.12; P < 0.05). In all participants, glycated hemoglobin (HbA1c) correlated with relative α‐cell area (P = 0.010). Diabetes duration (P = 0.004), HbA1c (P < 0.001) and plasma glucose levels (P = 0.008) were significantly correlated with the α/β in single regression analyses, and diabetes duration was the only independent and significant determinant in stepwise multiple regression analyses (P = 0.006). The α‐cell Ki67‐positive ratio in patients with HbA1c ≥6.5% was significantly higher than that in patients with HbA1c <6.5% (P = 0.022). We identified β‐cells that expressed aristaless‐related homeobox and α‐cells that did not express aristaless‐related homeobox at all glucose tolerance stages. Aristaless‐related homeobox and NK homeobox 6.1 expression patterns varied in insulin and glucagon double‐positive cells. CONCLUSIONS: The pancreatic α/β increases after type 2 diabetes onset and correlates with diabetes duration. This change might occur through α‐cell proliferation and phenotypic changes in pancreatic endocrine cells.