Insulinoma Associated with a Case of Multiple Endocrine Neoplasia Type I: Functional Somatostatin Receptors and Abnormal Glucose-Induced Insulin Secretion

Abstract

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low K_m glucose transporter GLUT1 but no transcript for the high K_m glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.

Ectopic ACTH Cushing’s Syndrome: V3 Vasopressin Receptor But Not CRH Receptor Gene Expression in a Pulmonary Carcinoid Tumor

“…Plain chest X-ray films were normal. During octreotide receptor scintigraphy ( 111 In-OctreoScan) [8], no abnormal tracer uptake was observed. An abdominal CT scan and a transduodenal pancreatic echography also failed to reveal any abnormality.…”

Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro

“…The abnormal sensitivity of insulinomas to low glucose concentrations with poor further response to higher glucose concentrations can result in hypoglycemic episodes in the fasting state and not after meals. Two insulinomas resembling our case patients 5 and 6 have previously been studied in vitro (18,20). Compared with a glucose-free medium, 1 mmol/L glucose induced an ;10-fold increase in insulin secretion, which was not larger at higher glucose concentrations.…”

“…In previous in vitro investigations of human insulinoma cells, insulin secretion was unaffected by high glucose concentrations in five case patients from three studies (11,12,16) and was variably augmented in seven single case patients (9,10,14,(17)(18)(19)(20). Other agents were rarely tested: insulin secretion was increased by a sulfonylurea in two insulinomas (18,19) and leucine was ineffective in one of one insulinoma (11).…”

“…Compared with a glucose-free medium, 1 mmol/L glucose induced an ;10-fold increase in insulin secretion, which was not larger at higher glucose concentrations. This excessive sensitivity to a low glucose concentration remained unexplained (18) or was tentatively ascribed to the strong expression of the highaffinity GLUT-1 in the tumor cells (20). However, it is now established that GLUT-1 and GLUT-3 are the major glucose transporters in normal human b-cells (33,34).…”

“…Minced pieces of the tumor were incubated either immediately (9,10) or after culture for several days or weeks (11)(12)(13). In other studies, pieces of the tumor were digested with collagenase before the measurement of insulin secretion either immediately (14,15) or after 1-8 weeks of culture (16)(17)(18)(19)(20). Second, only a few, dissimilar protocols of stimulation or inhibition were usually tested in static incubations.…”