title: The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients.
abstract: 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 microg, were compared to those following OCT 100 microg.
  
  
  METHODS
  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 microg, 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 microg/l/h; P < 0.001 vs. CD), while SOM230 250 and 100 microg elicited a lower and dose-dependent effect (163 and 90 microg/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 microg 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 microg (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 sst1 mRNA expression level appeared significantly higher compared with sst2 (n = 6, relative copy number 161 +/- 46 vs. 57 +/- 6; P < 0.05). Fat tissue expressed both sst1 and sst2 mRNA, whereas in muscle only sst2 mRNA was found.
  
  
  CONCLUSIONS
  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 sst2. Finally, expression of only sst1 and sst2 in target tissues of insulin action, might point towards additional modulatory effects by SOM230 on glucose homeostasis.
authors.affiliation: Department of Internal Medicine, Section Endocrinology, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. j.vanderhoek@erasmusmc.nl
authors.forename: Joost
authors.initials: J
authors.lastname: van der Hoek
authors.forename: Aart-Jan
authors.initials: AJ
authors.lastname: van der Lelij
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Piet
authors.initials: P
authors.lastname: Uitterlinden
authors.forename: Kwai W
authors.initials: KW
authors.lastname: Poon
authors.forename: Viktor
authors.initials: V
authors.lastname: Boerlin
authors.forename: Ian
authors.initials: I
authors.lastname: Lewis
authors.forename: Tillmann
authors.initials: T
authors.lastname: Krahnke
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lamberts
mesh_terms: D000172:Acromegaly / Q000188:drug therapy*; D000273:Adipose Tissue / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D050260:Carbohydrate Metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008099:Liver / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D015282:Octreotide / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; C517782:pasireotide; D015282:Octreotide