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.