What is the mechanism of action of non-insulinoma neuroendocrine tumors?

Insulin hypersecretion from pancreatic neuroendocrine tumors is the principle cause of spontaneous hypoglycemia in adults after excluding iatrogenic causes. In occasional cases, patients with type 2 diabetes can subsequently develop fasting hypoglycemia due to the development of a pNET, and there is one case reported of an insulinoma in a patient with type 1 diabetes.

Hypoglycemia in association with hyperinsulinemia, but in the absence of insulinoma, is termed noninsulinoma pancreatogenous hypoglycemia. Pancreatic histological features include β-cell hyperplasia and increased periductular islets, morphological findings similar to those seen in persistent hyperinsulinemic hypoglycemia of infancy or childhood. Hypoglycemia due to islet cell hyperplasia occurring in adults against a background of diabetes has been described, but is extremely rare with only four cases reported. More recently, noninsulinoma pancreatogenous hypoglycemia has been identified in patients after Roux-en-Y gastric bypass surgery associated with islet cell hyperplasia. In these Roux-en-Y gastric bypass subjects, excess insulin has been associated with increased glucagon-like peptide-1; hypoglycemic symptoms typically emerge years after their surgery, suggesting an islet cell adaptation to prolonged stimulus.

Roberts, Rachel E, et al. “GLP-1 and glucagon secretion from a pancreatic neuroendocrine tumor causing diabetes and hyperinsulinemic hypoglycemia.” The Journal of clinical endocrinology and metabolism 97.9 (2012):3039-3045.

GLP-1 has trophic effects on pancreatic β-cells, stimulating β-cell proliferation and neogenesis. Although we cannot define the duration of GLP-1 excess, it is likely that for several years the patient had increased GLP-1 levels that potentially exerted a chronic trophic stimulus. Increased GLP-1 secretion is thought to be the mechanism for the development of islet cell hyperplasia and nesidioblastosis years after gastric bypass. GLP-1 acts as an incretin-stimulating glucose-dependent insulin secretion underlying the use of GLP-1 agonists in the treatment of T2DM. GLP-1 analogs are not known to cause hypoglycemia. Nevertheless, it remains likely that the fasting hypoglycemia in our case was caused by the long-term trophic effects leading initially to islet cell hyperplasia and subsequently to the development of autonomous function. The mechanism for this remains unclear, although prolonged hormone stimulation resulting in autonomous behavior can occur in endocrine tissues—for example, in tertiary hyperparathyroidism.

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