Pathophysiology

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The clinical manifestations of insulinomas are based on the excessive secretion of insulin with the resultant hypoglycemia.

An understanding of the physiology of insulin secretion from the beta cells is required for the appreciation of modern diagnostic tests for insulinoma. The beta cells synthesize a large polypeptide molecule, proinsulin, which undergoes proteolytic division into active insulin and a connecting peptide (C peptide) (Figure 13-1). Both C peptide and the double-chain polypeptide insulin are secreted from beta-cell granules and should rise together during pancreatic islet secretion, as occurs during hyper-glycemia. Because of neoplastic transformation (insulinoma) or diffuse hyperplasia, the beta islet cells escape from the usual glucose feedback inhibition. Because C-peptide fragments are increased in patients with insulinoma they can be used as a marker of overproduction of the beta islet cells. Thus, C peptide and proinsulin are both usually increased in patients with endogenous insulin over-secretion. In patients with factitious hyperinsulin-

Figure 13-1. Secretion of insulin from the pancreatic islet beta cells. Schema of rough endoplasmic reticulum (ER), where proinsulin is synthesized, and secretion granules, where proinsulin is cleaved into insulin and C peptide. Reproduced with permission from Rubenstein AH, Kuzuva H. Horowitz DL. Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemia disorders. Arch Intern Med 1977;137:625. Copyright 1977 American Medical Association.

Figure 13-1. Secretion of insulin from the pancreatic islet beta cells. Schema of rough endoplasmic reticulum (ER), where proinsulin is synthesized, and secretion granules, where proinsulin is cleaved into insulin and C peptide. Reproduced with permission from Rubenstein AH, Kuzuva H. Horowitz DL. Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemia disorders. Arch Intern Med 1977;137:625. Copyright 1977 American Medical Association.

ism, C-peptide levels are usually low and therefore help make the correct diagnosis. In normal individuals, exogenous insulin should suppress beta-cell secretion and C-peptide levels, as should hypo-glycemia, whereas in persons with persistent insulin secretion, C-peptide levels will be increased.

Most patients with insulinoma have sporadic disease, but about 10% are associated with other hormone-secreting tumors (parathyroid, other pancreatic, pituitary, adrenal carcinoid, and thyroid) or multiple endocrine neoplasia (MEN) type I. The gene for MEN type I has been identified on chromosome 11. Making the diagnosis of MEN type I is important in patients with insulinoma because the effective surgical therapy is different for patients with MEN type I and for most of those with sporadic islet cell tumors. The primitive APUD (amine precursor uptake and decarboxylation) neural crest cells, as reported by Pearse,3 were initially thought to migrate to colonize various parts of the developing gut. The cells then differentiated to form the endocrine glands of the APUD series but, at the same time, retained their pluripotential endocrine characteristics, which may be displayed in conditions of neoplasia or hyperplasia. The glands in the APUD series include the thyroid, parathyroids, adrenals, pancreas, pituitary, and others. Pearse3 and Pearse and Polak4 defined the cytochemical and ultrastructural characteristics of these cells. Although this theory is no longer entirely valid, it provides a useful concept to understand the tumors involved in patients with MEN type I.

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