There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors (NETs). Key phase 3 studies include the CLARINET trial, which evaluated lanreotide in patients with nonfunctioning enteropancreatic NETs; the RADIANT-2 and RADIANT-4 studies, which evaluated everolimus in functioning and nonfunctioning NETs of the gastrointestinal tract and lungs; the TELESTAR study, which evaluated telotristat ethyl in patients with refractory carcinoid syndrome; and the NETTER-1 trial, which evaluated ¹⁷⁷Lu-DOTATATE in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and postoperative surveillance) are summarized in this article. Surgical guidelines are described in a companion article.

The adrenal steroid dehydroepiandrosterone (DHEA) has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on previous data from our laboratory, we hypothesized that DHEA binds to specific cell-surface receptors to activate intracellular G-proteins and endothelial nitric-oxide synthase (eNOS). We now pharmacologically characterize a putative plasma membrane DHEA receptor and define its associated G-proteins. The [³H]DHEA binding to isolated plasma membranes from bovine aortic endothelial cells was of high affinity (K _d = 48.7 pm) and saturable (B _max = 500 fmol/mg protein). Structurally related steroids failed to compete with DHEA for binding. The putative DHEA receptor was functionally coupled to G-proteins, because guanosine 5′-O-(3-thio)triphosphate (GTPγS) inhibited [³H]DHEA binding to plasma membranes by 69%, and DHEA increased [³⁵S]GTPγS binding by 157%. DHEA stimulated [³⁵S]GTPγS binding to Gα_i2 and Gα_i3, but not to Gα_i1 or Gα_o. Pretreatment of plasma membranes with antibody to Gα_i2 or Gα_i3, but not to Gα_i1, inhibited the DHEA activation of eNOS. Thus, DHEA receptors are expressed on endothelial cell plasma membranes and are coupled to eNOS activity through Gα_i2 and Gα_i3. These novel findings should allow us to isolate the putative receptor and reevaluate the physiological role of DHEA activity.

In man, glucagon-like peptide-I-(7-37) [GLP-I-(7-37)] is the most potent endogenous insulin-stimulating hormone. Although GLP-I-(7-37)-stimulated insulin secretion from the beta-cell is associated with an increase in cAMP accumulation, little is known about the signal transduction pathways used by this peptide. Using a cDNA encoding a high affinity rat GLP-I-(7-37) receptor [Kd = 4.1 nM for GLP-I-(7-37); Kd = 1 microM for GLP-I-(1-36) amide] expressed in a monkey kidney cell line (COS-7), we have demonstrated that the receptor is not only coupled to adenylyl cyclase, but is associated with an increase in the free cytosolic calcium level ([Ca2+]i). GLP-I-(7-37) increased both cAMP and [Ca2+]i in a dose-dependent manner and with equal potency (ED50 = 2.0 nM). The major source of the increased [Ca2+]i was found to be through the release of intracellular pools of Ca2+ associated with an increase in phosphoinositol turnover. Northern blot hybridization studies demonstrated that the GLP-I-(7-37) receptor gene was expressed in relatively high abundance in pancreatic islets and lung, but was also expressed at lower levels in the brain, liver, kidney, and skeletal muscle. This study establishes that a single GLP-I receptor species can mediate the effects of GLP-I-(7-37) through multiple G-protein-coupled signaling pathways, including the adenylyl cyclase system, phospholipase-C, and changes in [Ca2+]i.

Truncated forms of glucagon-like peptide-1 are the most potent endogenous stimuli of insulin secretion and have powerful antidiabetogenic effects. To determine the structure and coupling mechanisms of the human GLP-1 receptor we have isolated two pancreatic islet cDNAs, encoding the 463 amino acid receptor and differing mainly in their 3' untranslated regions. The deduced amino acid sequence is 90% homologous with the rat GLP-1 receptor. Northern blot analysis shows expression of a single 2.7 kb transcript in pancreatic tissue. When expressed in COS-7 cells the recombinant receptor conferred specific, high affinity GLP-1(7-37) binding. GLP-1(7-37) increased intracellular cAMP in a concentration dependent manner and caused an increase in the free cytosolic calcium ([Ca2+]i) from an intracellular pool, characteristic of phospholipase C (PLC) activation. Thus, like the structurally related glucagon and parathyroid hormone receptors, the human GLP-1 receptor can activate multiple intracellular signaling pathways including adenylyl cyclase and PLC. Knowledge of the GLP-1 receptor structure will facilitate the development of receptor agonists and elucidation of the important role of GLP-1 in normal physiology and disease states.