Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome.
Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Cushing's syndrome suggested that adrenal expression of ectopic, overexpressed, or mutated GIP receptor (GIPR) underlies this syndrome. The expression of GIPR was studied by RT-PCR in human adrenal tissues from two patients with GIP-dependent Cushing's syndrome (adenoma, bilateral hyperplasia), five fetal or adult controls, one patient with Cushing's disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplasias and compared to that in normal pancreas. Hybridization of the RT-PCR-amplified ribonucleic acids with the human GIPR complementary DNA showed an overexpression of GIPR in the adrenals of the two GIP-dependent Cushing's syndrome patients compared to that in normal adrenal tissues (2-3 orders of magnitude) or pancreas (10-fold); no signal could be seen in adrenal adenomas or macronodular hyperplasia from cases of non-food-dependent Cushing's syndrome. No mutation of the GIPR was identified by sequencing the full-length receptor in GIP-dependent adrenal tissue. New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues. Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-dependent, but not in normal fetal, adult, or non-food-dependent Cushing's syndrome, adrenals. We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome.
N'Diaye
N
N
Department of Medicine, Research Center, Campus Hôtel-Dieu, Centre Hospitalier de l'Université de Montréal, Quebec, Canada.
Tremblay
J
J
Hamet
P
P
De Herder
W W
WW
Lacroix
A
A
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D003480:Cushing Syndrome / Q000235:genetics*; D018076:DNA, Complementary / Q000737:chemistry; D005260:Female; D005502:Food; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*
D018076:DNA, Complementary; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D012194:RNA-Directed DNA Polymerase; D006854:Hydrocortisone