Endo Case Challenge: A Cannabis User With Excessive Sweating and Syncope at Work

Marwa Saleem, MD; Ahmad Al Maradni, MD; Mahmoud Alsayed, MD; Ricardo Correa, MD, EdD


June 13, 2022


Endogenous insulin is synthesized as a precursor — a proinsulin — which undergoes enzymatic cleavage to produce insulin and C-peptide in equimolar amounts. Therefore, factitious hypoglycemia produced by exogenous insulin administration results in suppressed C-peptide. Factitious hypoglycemia produced by sulfonylurea consumption often produces high levels of C-peptide and insulin.

An insulinoma and a non–islet cell insulin-producing neuroendocrine tumor have a similar biochemical picture; however, the latter usually causes postprandial hypoglycemia. Fasting hypoglycemia, which is a characteristic feature of an insulinoma, is rare in this disorder. Moreover, a non–islet cell insulin-producing neuroendocrine tumor is typically associated with abnormally high IGF-2 levels.

An insulinoma is a type of functional neuroendocrine tumor that manifests with hypoglycemia caused by inappropriately high secretion of insulin. The incidence is approximately one to four patients per million per year.[1,2] Insulinomas typically occur in persons aged between 40 and 60 years but are not uncommon in older patients.[2] Usually, an insulinoma is a single benign tumor; it is malignant in only 5.8% of patients.

Insulinomas generally have a variable and nonspecific clinical picture that could be attributable to the episodic insulin secretion from the tumor. Patients may develop vague symptoms early in the disease course or they may present with life-threatening symptoms, such as syncope, arrhythmia, and hypoglycemic coma. The median duration of symptoms varies and can range from months to even years from the onset of the symptoms until diagnosis. Owing to the wide range of symptoms and varying severity, insulinomas can remain undiagnosed and carry significant mortality and morbidity.

The pathogenesis of insulinomas remains unclear. In patients with insulinomas, insulin secretion continues despite a low glucose level for a substantial period. Minn and colleagues identified an insulin splice variant in isolated human pancreatic islets of nondiabetic donors that retains 26 bp of intron 1 and thereby changes the 5' untranslated region. The splice variant has increased translational activities compared with native insulin mRNA.[3] The mammalian target of rapamycin (mTOR) functions downstream of phosphatidylinositol 3–kinase and AKT (also known as protein kinase B) and could be abnormally activated in several cancers, including insulinomas. Inhibitors of the mTOR could stabilize blood glucose in patients with insulinomas.[3]

Insulinomas can occur sporadically or in conjunction with multiple endocrine neoplasia type 1 (MEN1) syndrome, which is an autosomal dominant disorder associated with mutations in the MEN1 gene mapped to chromosome 11q13.[4] MEN1 syndrome is characterized by parathyroid hyperplasia, anterior pituitary adenomas, and tumors of the endocrine pancreas and duodenum. In addition, a variety of sporadic endocrine tumors, such as parathyroid adenomas, pancreatic insulinomas, and pituitary prolactinomas, have expressed somatic mutations and loss of heterozygosity of the MEN1 alleles. Thus, the MEN1 gene may play the same role in nonhereditary endocrine tumors.[5,6]


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