Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP

1 Diabetes Section, Laboratory of Clinical Investigation and 3 Research Resources Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; 2 Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital; and 4 Hippokration Hospital, Athens, Greece Submitted 23 July 2004 ; accepted in final form 3 October 2005 Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance ( n = 14) had as many L cells (15 ± 1), expressed per 1,000 gut epithelial cells, as K cells (13 ± 1), with some containing both hormones (L/K cells, 5 ± 1). In type 2 diabetes, the number of L and L/K cells was increased (26 ± 2; P < 0.001 and 9 ± 1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype. duodenum; euglycemia; type 2 diabetes; glucagon-like peptide-1; gastric inhibitory polypeptide Address for reprint requests and other correspondence: M. J. Theodorakis, M.D., Diabetes Section, NIA/NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224