Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP.
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.
Theodorakis
Michael J
MJ
Diabetes Section, Laboratory of Clinical Investigation, National Institute of Health, Baltimore, MD 21224, USA.
Carlson
Olga
O
Michopoulos
Spyros
S
Doyle
Máire E
ME
Juhaszova
Magdalena
M
Petraki
Kalliopi
K
Egan
Josephine M
JM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004386:Duodenum / Q000166:cytology / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007328:Insulin; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose