glucagon-like-peptide-1 and Acromegaly

To study the effect of octreotide on glucagon-like peptide (7-36) amide (GLP-1) and insulin secretion in patients with pituitary tumors during preoperative treatment and in healthy subjects.. Open design prospective clinical study.. Eighteen patients with pituitary macroadenomas (13 clinically nonfunctioning (NFA; 11/13 had GH insufficiency), 5 GH secreting (GHA)) received preoperative octreotide treatment: 3x100 microg/day s. c. for 3 months, and 3x500 microg/day s.c. for an additional 3 months. Seven healthy subjects received (for ethical reasons) only 3x100 microg/day for 10 days. A standardized meal (St-M) test, oral glucose test (oGTT) and i.v. glucose test (ivGTT) were done before octreotide therapy, on days 1, 2 and 3 (D1,2,3), after 3 months (M3) and 6 months (M6) of octreotide treatment in the patients, and before treatment, on D1,2,3 and on D8,9,10 of octreotide treatment in the healthy subjects. Serum GLP-1, insulin and GH as well as plasma glucose were determined for 180 min (oGTT, St-M) or 120 min (ivGTT).. Pretreatment fasting GLP-1 concentrations as well as integrated responses (area under the curve 0-180 min) to oGTT and St-M were not significantly different between NFA, GHA and healthy subjects. During the oGTT, octreotide initially almost abolished the early (0-60 min) and diminished the late (60-180 min) GLP-1 and insulin responses in patients and healthy subjects. At M6 integrated insulin responses had significantly recovered, while the increase in GLP-1 response failed to reach significance (GLP-1: 56.5% of pretreatment at D2 versus 93.5% at M6 and 41.2 versus 63.1% in NFA and GHA respectively; insulin: 50.2 versus 71.2% and 35.5 versus 70. 4%). An escape of GLP-1 and insulin in healthy subjects (D2 versus D9) was not significant. Intestinal glucose absorption was apparently not reduced, since the early glucose rise was similar before and during octreotide treatment. During the St-M the GLP-1 and insulin responses were similarly suppressed by octreotide and recovered during ongoing treatment (GLP-1: 49.6% of pretreatment at D1 versus 79.0% at M6 in NFA and 46.9 versus 52.9% in GHA. Insulin: 27.6 versus 83.9% and 23.5 versus 54.4%). The escape was significant in NFA but not in GHA. In the healthy subjects the escape was already significant on D8 (GLP-1: 39.5% of pretreatment at D1 versus 68.3% at D8; insulin: 36.6 versus 53.8%). During the ivGTT GLP-1 did not increase. The early insulin response (0-30 min) was abolished by octreotide, followed by a reduced peak at 60 min. The reduction of the integrated insulin response during ivGTT was similar to that during oGTT. An insulin escape reached significance only for NFA (52. 6% of pretreatment at D3 versus 66.7% at M6). Glucose tolerance (KG value) deteriorated and did not improve during ongoing treatment. Octreotide suppressed the median GH concentration (8h profile) of the GHA patients from 10.3 microg/l (pretreatment) to 5.8, 6.3 and 3. 7 microg/l at D4, M3 and M6 with no escape. GH was 1.5 microg/l postoperatively.. Octreotide abolishes the early and diminishes the late GLP-1 and insulin responses to oGTT and St-M in NFA and GHA patients and in healthy subjects. In contrast to GH, both hormones partially escape from suppression during ongoing therapy. During treatment with our conventional octreotide doses suppression of insulin secretion is maximal. Under these conditions an effect of the additional loss of GLP-1 is not apparent. Basal GLP-1 concentrations and integrated responses to oGTT and St-M were similar in healthy subjects and in patients with GH excess or GH insufficiency.

Topics: Acromegaly; Adenoma; Adult; Antineoplastic Agents, Hormonal; Blood Glucose; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Hormones; Human Growth Hormone; Humans; Insulin; Male; Middle Aged; Octreotide; Peptide Fragments; Pituitary Neoplasms; Prospective Studies; Protein Precursors

Impaired insulin sensitivity (IS) and β-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, β-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised β-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of β-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of β-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

Topics: Acromegaly; Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Prospective Studies; Receptors, Gastrointestinal Hormone