Endocrine Pancreas

Insulin

Insulin is an anabolic hormone that promotes glucose transport into all cells except B cells, hepatocytes, and central nervous system cells. Insulin is a 56–amino acid polypeptide with a molecular weight of 6 kDa, which is synthesized as proinsulin, its precursor peptide. In response to pancreatic B cell stimulation by glucose, proinsulin is synthesized in the endoplasmic reticulum and transported to the Golgi complex, where it is cleaved into insulin and the residual C-peptide ( Fig. 39.2 ). The resulting insulin molecule consists of two polypeptide chains (A and B) joined by two disulfide bridges. C-peptide and insulin are secreted in equimolar amounts. After cleavage of C-peptide, insulin is moved via microtubules into secretory granules, where it is released directly into the bloodstream via exocytosis.

The B cell is highly sensitive to changes in glucose concentration and is maximally stimulated at concentrations of 400 to 500 mg/dL. In response to glucose, the islets of Langerhans immediately react with a short burst of stored insulin (4–6 minutes), followed by a sustained secretion of insulin, which requires active synthesis of the hormone within the islet cell. Insulin binds to a specific 300-kDa glycoprotein cell surface receptor, and stimulation of this insulin receptor is dependent on insulin concentration. After insulin receptor stimulation, glucose is actively transported across cell membranes throughout the body by membrane-bound glucose transporters. There are several classes of glucose transporters, with varying affinities for glucose. Insulin resistance, present in type 2 diabetes, can be the result of decreased numbers of receptors or a decreased affinity of receptors for insulin.

Glucagon

Glucagon is a 29–amino acid, straight chain polypeptide with a molecular weight of 3.5 kDa. Secreted by A cells within islets, the primary function of glucagon is to elevate blood glucose levels through stimulation of glycogenolysis and gluconeogenesis in the hepatocytes. Islet A and B cells respond primarily to serum glucose concentration, but in a reciprocal fashion. Like epinephrine, cortisol, and growth hormone, glucagon is considered a stress hormone because it increases metabolic fuel in the form of glucose during stress. Glucose has a strong suppressive effect on glucagon secretion. Excess glucagon can lead to hyperglycemia, whereas insufficient glucagon can lead to profound hypoglycemia. Dysfunctional secretion of glucagon may play a role in the elevation of blood glucose levels in diabetes.

Other Influences on Glucose Homeostasis

Enteric peptide hormones released from the proximal gastrointestinal tract also influence glucose homeostasis through the enteroinsular axis. Therefore, orally administered glucose has a greater effect on insulin secretion than an equivalent amount of glucose administered intravenously, even though blood glucose levels might be similar. Insulinotropic factors, called incretins, act directly on the B cells to stimulate insulin release. Incretins such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 are intestinal hormones that are released in response to ingestion of nutrients, particularly carbohydrates. They have a number of important biological effects, which include release of insulin, inhibition of glucagon and somatostatin, maintenance of beta-cell mass, delay of gastric emptying, and inhibition of feeding. In comparison to incretins’ stimulation of insulin, humoral inhibitors of insulin secretion include somatostatin, amylin, leptin, and pancreastatin.

Ghrelin is a 28–amino acid peptide hormone produced by ghrelin cells of the gastrointestinal tract. Discovered in 1999, ghrelin was found to exert a series of metabolic effects, including the regulation of glucose metabolism. Ghrelin primarily inhibits insulin release from the pancreas, increases hepatic glucose production, and prevents glucose disposal in muscle and adipose tissues, which collectively leads to hyperglycemia and impaired glucose tolerance. In diet-induced obesity, ghrelin exacerbates hyperglycemia; in starvation or severe calorie restriction, ghrelin increases blood glucose concentrations in order to maintain glucose homeostasis.

Leptin is a peptide hormone produced in adipose cells. Leptin is released into the circulatory system based on energy stores and functions as a feedback mechanism that signals to regulatory centers in the brain to inhibit food intake and to regulate body weight. In response to adequate fat stores, leptin inhibits insulin secretion. In obese humans, leptin levels are increased, exacerbating hyperglycemia. In the obese state, there is thought to be leptin resistance, with lack of inhibition of food intake.

Both insulin and glucagon secretions are also under neuronal control. Vagal (cholinergic) stimulation leads to the release of insulin. Insulin release is stimulated by the autonomic peptidergic nerve release of gastrin-releasing peptide, cholecystokinin (CCK), gastrin, enkephalin, and VIP, as well as β-sympathetic nerve stimulation. On the other hand, insulin release is inhibited by neurotensin, substance P, somatostatin, and α-sympathetic nerve stimulation. In comparison, glucagon secretion is stimulated by sympathetic neural transmitters, epinephrine, and the amino acids arginine and alanine.

Molecular Genetics of PNETs

Although most PNETs occur sporadically, others can be associated with genetic syndromes. The most common genetic syndrome associated with PNETs is multiple endocrine neoplasia type 1 (MEN1), characterized by PNETs, parathyroid adenomas or hyperplasia, and pituitary adenomas. MEN1 is caused by mutations or allelic deletions in the tumor suppressor gene, menin, on chromosome 11q13 and is inherited in an autosomal dominant fashion. Menin is a component of the histone methyltransferase complex and is involved in control of G1 to S phase cell cycle progression. Mutation or allelic deletion causes loss of tumor suppressor function and predisposes patients to neoplastic growth in the parathyroid, pituitary, and pancreatic endocrine tissue.

Von Hippel-Lindau (VHL) syndrome is also associated with PNETs. Patients with inherited mutations of the VHL gene are at risk for the development of renal cell carcinoma, pheochromocytoma, benign tumors of the central nervous system, retina, epididymis, and inner ear and pancreatic lesions, including NETs, microcystic adenomas, and simple cysts. Similar to MEN1, the management of PNETs can be challenging, since they are often multifocal and associated with tumors in other locations. PNETs associated with VHL generally behave in an indolent fashion, and it has been suggested that these tumors can be observed until they reach at least 2 3 cm in size. However, specific germline mutations in exon 3 of the VHL gene may be associated with a more aggressive phenotype and warrant earlier treatment and closer surveillance.

Most PNETs, however, are not associated with a known genetic syndrome and occur sporadically. Other than family history, risk factors for PNETs are not well defined. As in other neoplastic processes, tumorigenesis of PNETs involves an accumulation of a number of genetic events. The common genetic mutations and impacted signal transduction pathways in PNETs is shown in Fig. 39.3 . Complete exomic sequencing of a discovery set of 10 sporadic PNETs revealed mutations in 149 genes, of which 6 were selected for further analysis in a validation set of 58 PNETs. Inactivating mutations in MEN1 were seen in 44% of sporadic tumors. Mutations in death-domain associated protein (DAXX) and alpha thalassemia-mental retardation syndrome X-linked (ATRX), whose protein products are involved in p53-mediated DNA damage repair, were seen in 25% and 18%, respectively. Patients with mutations in MEN1 or DAXX/ATRX had prolonged survival compared to those who did not. Previous expression analyses had suggested dysregulation of the mammalian target of rapamycin (mTOR) pathway in a large proportion of tumors. ^, The mTOR protein is serine/threonine kinase and a key component of a cellular pathway playing an important role in the regulation of cell growth and proliferation. mTOR is upregulated in several tumors, including PNETs. This has potential clinical implications since the mTOR inhibitor everolimus has been U.S. Food and Drug Administration (FDA) approved for advanced NETs. Potentially, mutational testing will allow selection of patients most likely to benefit from this targeted therapy. Overall, the mutational analysis was most remarkable for how distinct the genetic abnormalities were from those observed in a similar study of pancreatic adenocarcinoma ( Table 39.4 ). Mutations in KRAS were not seen in PNETs and mutations in P53 were seen only rarely, at least not in these well-differentiated tumors.

In a separate study comparing well- and poorly differentiated PNETs, MEN1 and DAXX/ATRX expression by immunohistochemistry was abnormal in approximately half of well-differentiated tumors. In contrast, staining of DAXX/ATRX was normal in poorly differentiated tumors, but there was a high incidence of abnormal p53 and retinoblastoma expression as well as overexpression of the antiapoptotic protein Bcl2, implicating it as a target for therapy in these tumors.