Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro

Abstract

Insulinomas are β-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma β-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients.

Concurrent insulinoma and impaired glucose tolerance suspected as owing to obesity

“…Moreover, some reports contended that insulin resistance was found in insulinoma due to the defect in peripheral glucose utilisation 20 21. Some reported that human insulinomas in vitro show distinct defects in insulin secretion 22. Therefore, the concurrent insulinoma and impaired glucose tolerance might not be as rare as once thought.…”

Case Report: Hypoglycemia Due to Metastatic Insulinoma in Insulin-Dependent Type 2 Diabetes Successfully Treated With 177 Lu-DOTATATE

“…However, in the presence of an insulinoma, this glucose-insulin coupling becomes dysregulated. Small-scale in vitro studies have shown that cultured human insulinoma cells can have near maximal glucose responsiveness at blood glucose levels of 1.0–3.0 mmol/L ( 19 ) with no significant increase in insulin release with rise in glucose concentration from 2.8 to 8.3 mmol/L in one study ( 20 ) and plateau at 10.0–15.0 mmol/L in two other studies ( 19 , 21 ). The autonomous insulin secretion despite low glucose concentrations and the blunted insulin response to higher glucose concentrations can give rise to fasting hypoglycemia and postprandial hyperglycemia, respectively.…”

Is the Size of Insulinoma Predictive for its Endocrine Behavior? An Endoscopic Ultrasound Study

“…Insulinomas represent a heterogenous group of tumors that show a different secretory behavior, for example, due to changes in the growth behavior of beta cells, abnormalities in the somatostatin receptor expression, or the exocytosis of the insulin granules [27]. In addition, the presence of hexokinase I enables the secretion of insulin at low blood sugar levels in some insulinomas [28]. Boden et al put forward the theory that insulinomas mainly show glucose transporter type 1 (GLUT1) expression and healthy beta cells, mainly GLUT2 [29].…”