glucagon-like-peptide-1 and Cushing-Syndrome

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Topics: Adipokines; Adrenal Glands; Adult; Androgens; Cushing Syndrome; Diabetes Mellitus, Type 2; Endocrine System; Estrogens; Fatty Liver; Female; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypothalamus; Hypothyroidism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Pancreas; Pituitary Gland; Polycystic Ovary Syndrome; Postmenopause; Thyroid Gland

We studied a patient with food-induced, ACTH-independent, Cushing's syndrome and a unilateral adrenocortical adenoma. In vivo cortisol secretion was stimulated by mixed, glucidic, lipidic, or proteic meals. Plasma ACTH levels were undetectable, but iv injection of ACTH stimulated cortisol secretion. Unilateral adrenalectomy was followed by hypocortisolism with loss of steroidogenic responses to both food and ACTH. In vitro, cortisol secretion by isolated tumor cells was stimulated by the gut hormone gastric inhibitory polypeptide (GIP) and ACTH, but not by another gut hormone, glucagon-like peptide-1 (GLP-1). Both peptides stimulated the production of cAMP but not of inositol 1,4,5-trisphosphate. In quiescent cells, GIP and ACTH stimulated [3H]thymidine incorporation and p42-p44 mitogen-activated protein kinase activity. GIP receptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highly expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food-independent Cushing's syndrome, and in two hyperplastic adrenals associated with ACTH hypersecretion. In situ hybridization demonstrated that expression of GIP receptor RNA was confined to the adrenocortical tumor cells. Low levels of ACTH receptor messenger RNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase in cAMP that may participate in the stimulation of both cortisol secretion and proliferation of the tumor cells.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocorticotropic Hormone; Adult; Calcium-Calmodulin-Dependent Protein Kinases; Cushing Syndrome; DNA; Female; Gastric Inhibitory Polypeptide; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Humans; Hydrocortisone; Peptide Fragments; Polymerase Chain Reaction; Protein Precursors; Receptors, Corticotropin; Receptors, Gastrointestinal Hormone; RNA, Messenger; Tumor Cells, Cultured