Gene expression profiles associated with stimulus-responsive insulin secretion in insulinoma

Insulinoma is a functional pancreatic neuroendocrine tumor that usually causes fasting hypoglycemia through inappropriate autonomous insulin secretion. However, some insulinomas show postprandial or stimulus-induced hypoglycemia, suggesting that some tumors retain the ability to respond to physiological stimuli. We examined four patients with confirmed insulinoma who showed different clinical patterns of hypoglycemia and integrated clinical stimulation tests with DNA microarray analysis. Insulin secretory dynamics were assessed using an oral glucose tolerance test, meal tolerance test, and glucagon stimulation test, as clinically indicated. Among the four cases, Case 1 showed no clear fasting hypoglycemia but developed hypoglycemia after meals and oral glucose loading, accompanied by marked insulin secretion. In this case, insulin or C-peptide increased markedly after glucose, meal, and glucagon stimulation. In contrast, the other three cases showed relatively weak insulin secretory responses to stimulation. During the fasting test, Cases 3 and 4 developed hypoglycemia early, whereas Case 2 showed a prolonged time to hypoglycemia. Transcriptomic analysis showed that, by hierarchical clustering, Case 1 was clearly separated from Cases 3 and 4, whereas Case 2 was relatively close to Case 1. Case 1 showed relatively preserved expression of genes involved in glucose sensing, ATP-sensitive potassium channel function, incretin/cAMP signaling, exocytosis, and β-cell differentiation. In contrast, cases with predominant fasting hypoglycemia showed higher expression of hexokinase 1 and stress-response genes. These findings suggest that clinical heterogeneity in insulinoma may reflect differences in β-cell-like stimulus-response mechanisms, glucose sensing, stress responses, and differentiation status.