Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects

Abstract

Objective: 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. Design: Open design prospective clinical study. Methods: Eighteen patients with pituitary macroadenomas (13 clinically nonfunctioning (NFA; 11/13 had GH insufficiency), 5 GH secreting (GHA)) received preoperative octreotide treatment: 3×100 mg/day s.c. for 3 months, and 3×500 mg/day s.c. for an additional 3 months. Seven healthy subjects received (for ethical reasons) only 3×100 mg/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).Results: 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 (K G value) deteriorated and did not improve during ongoing treatment. Octreotide suppressed the median GH concentration (8 h profile) of the GHA patients from 10.3 mg/l (pretreatment) to 5.8, 6.3 and 3.7 mg/l at D4, M3 and M6 with no escape. GH was 1.5 mg/l postoperatively. Conclusions:...

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

“…However, SSA therapy results in suppression of the GH concentration to !2.5 mg/l in only 48-58% of the patients (4) with suppression of insulin as an unwanted side effect (5,6).…”

“…The clinically available SSA, Octreotide and Lanreotide respectively, significantly suppress GH secretion in up to 50-70% of acromegalic patients (2,3,4) while strict biochemical control (GH !1 mg/l) is achieved in up to 33% (3). However, these SSA also suppress insulin secretion and thus negatively affect glucose homoeostasis in a significant number of patients (3,5,6,7,8).…”

Pegvisomant increases intra-abdominal fat in patients with acromegaly: a pilot study.

“…In these studies, the comparison was made between GT during OCT and PEG therapies respectively rather than after an OCT washout and PEG therapy. OCT suppresses insulin secretion (2,25). Therefore, GT will be poor even in the presence of normalized GH concentrations.…”

“…Due to the excess GH, untreated acromegaly is associated with increased lipolysis, decreased fat mass, insulin resistance (IR), and deterioration of glucose tolerance (GT). During SSA therapy, insulin that facilitates lipolysis is suppressed by the drug (2). Hence, patients on SSA still have a decreased fat mass and glucose intolerance even if GH is normalized.…”

Medical Therapy of Acromegaly

“…However, the integrated insulin concentration is only slightly reduced [92]. Depending on the individual situation (obesity, metabolic syndrome, age) SRL can nevertheless induce diabetes mellitus.…”