Tumor‐like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin‐induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat

AIMS/INTRODUCTION: Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non‐large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin‐induced insulin secretion (IIIS) in these islets. MATERIALS AND METHODS: Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks‐of‐age were isolated. The islets of fa/fa rats at 12 weeks‐of‐age were separated into non‐large islets (≤200 μm in diameter) and enlarged islets (>300 μm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets. RESULTS: The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for β‐cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets. CONCLUSIONS: The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell‐like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age‐dependent increase in such islets could contribute to the pathophysiology of obese diabetes.