The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

Objective Recently, our first clinical study with the novel multiligand somatostatin (SRIF) analogue SOM230 in acromegalic patients showed that SOM230, due to its beneficial inhibitory effects on GH levels compared with octreotide (OCT), might increase the number of patients that can be biochemically controlled. Since SRIF analogues are also known to interact with other metabolic pathways, IGF-I, IGFBP-1, glucose and insulin concentrations on the control day (CD) and on treatment days following a single s.c. injection SOM230 100 and 250 mu g, were compared to those following OCT 100 mu g. Design and patients Randomized, cross-over, double-blinded proof-of-concept trial in 12 patients with active acromegaly. Results Free IGF-I levels were suppressed after 24 h by OCT, SOM230 250 and 100 mu g, whereas at 48 h only both SOM230 dosages still induced these inhibitory effects. Circulating IGFBP-1 levels (AUC; 0830-1430 h) compared with CD, increased sharply after OCT (from 48 to 237 mu g/l/h; P < 0.001 vs. CD), while SOM230 250 and 100 mu g elicited a lower and dose-dependent effect (163 and 90 mu g/l/h, respectively, P < 0.05 vs. CD and OCT). Neither insulin nor GH levels showed statistically significant correlation with IGFBP-1 levels either after SOM230 or OCT. An early rise in glucose levels 1 h postinjection with SOM230 250 mu g compared with OCT and CD was observed 8.3 +/- 0.8, 4.4 +/- 0.5 and 4.9 +/- 0.4 mmol/l, respectively: P < 0.05). SOM230 250 mu g (19 +/- 4 vs. 46 +/- 3 mU/l on CD: P < 0.05), although clearly less potent than OCT (5.4 +/- 0.4 mU/l: P < 0.01 vs. CD), inhibited insulin release. Since these corresponding absolute insulin levels cannot entirely explain this hyperglycaemic effect of SOM230, other mechanisms seem involved in this glucose rise. If SOM230 would influence glucose homeostasis in peripheral target tissues of insulin action, expression of SS-receptors (sst) seems a logical necessity. In normal human liver tissues, analysed by quantitative polymerase chain reaction (PCR), the average sst(1) mRNA expression level appeared significantly higher compared with sst(2) (n = 6, relative copy number 161 +/- 46 vs. 57 +/- 6; P < 0.05). Fat tissue expressed both sst(1) and sst(2) mRNA, whereas in muscle only sst(2) mRNA was found. Conclusion Both dosages of SOM230 inhibit free IGF-I in a more sustained fashion compared to OCT, implying longer duration of action. The superior action of OCT compared with SOM230 in stimulating IGFBP-1 levels, suggests direct regulation of IGFBP-1 by SRIF analogues via sst(2). Finally, expression of only sst(1) and sst(2) in target tissues of insulin action, might point towards additional modulatory effects by SOM230 on glucose homeostasis.