Roux-en-Y gastric bypass is highly successful in reducing body weight, improving metabolic status and normalising hyperglycaemia in patients with type 2 diabetes . One increasingly recognised, albeit uncommon long-term complication of this surgery is hyperinsulinaemic hypoglycaemia. In a very small subset of patients, hypoglycaemia may be very severe and unresponsive to medical and nutritional management; in some cases, partial pancreatectomy has been performed for patient safety . Pancreases from these patients demonstrate islet cell hyperplasia, with enlarged and/or more numerous islets, some of them adjacent to and budding from ducts, consistent with so-called nesidioblastosis . Metabolic studies have demonstrated dysregulation of insulin secretion following oral liquid meals, potentially linked to increased incretin secretion resulting from early nutrient exposure to the intestinal Roux limb . Increased incretin sensitivity could also contribute to the syndrome. Furthermore, insulinoma has also been reported in some individuals following gastric bypass surgery. An important, but unanswered question is whether there are any molecular parallels between insulinoma and the excessive insulin secretion and potential islet cell hyperplasia observed in this subgroup of post-gastric bypass patients.
GLP-1 receptors mediate GLP-1 effects to stimulate insulin secretion . In gastric bypass patients, GLP-1 levels are increased in response to standard liquid meals , suggesting a potential role for GLP-1 in mediating insulin secretion and, potentially, islet expansion and/or protection against apoptosis. It was previously unknown whether differences in GLP-1 receptor levels could make an additional contribution to the pathophysiology. Our studies demonstrate that GLP-1 receptor content does not differ in islet or acinar tissue in the post-gastric bypass hypoglycaemia setting. Moreover, the normal content of GLP-1 receptors is in sharp contrast to the robust overexpression of GLP-1 receptors in human insulinoma. Our data thus suggest that different pathophysiological mechanisms contribute to increased insulin secretion in these two hyperinsulinaemic hypoglycaemic conditions.
Our results are based on in vitro receptor autoradiography, a method that has a number of advantages [2, 3]. First, morphology permits distinction of islets from acini, which is important as both compartments normally express GLP-1 receptors. Second, autoradiography is quantitative and, in contrast to immunohistochemistry, permits precise evaluation of GLP-1 receptor density in specific compartments . Third, it is a highly specific method that allows assessment of ligand binding through direct pharmacological characterisation of the binding sites.
What, if any, immediate clinical consequences could result from the present study? We had previously considered the possible use of 111In-labelled DOTA-exendin-4 for in vivo imaging of post-gastric bypass hypoglycaemia patients, with a view to ruling out insulinoma and assessing possible increases in islet mass. Our results do not support the rationale behind such an approach at the present time, as neither islet nor acinar GLP-1 receptor levels differed in post-gastric bypass patients with hypoglycaemia compared with control pancreas.