Somatostatin infusion corrects hyperghrelinemia without reducing appetite in adults with Prader-Willi syndrome

Anthony P. Goldstone^1,2, Mike Patterson³, Mark Vanderpump⁵, Nila Kalingag², Bernard Khoo², Audrey E. Brynes⁴, Mohammad A. Ghatei³, Stephen R. Bloom³, Ashley B. Grossman², Márta Korbonits² & Tricia M-M. Tan⁵

¹Division of Pediatric Genetics, University of Florida College of Medicine, Gainesville, USA; ²Dept. of Endocrinology, St. Bartholomew’s Hospital, London, UK; ³Depts. of Metabolic Medicine and ⁴Dietetics, Imperial College School of Medicine, Hammersmith Hospital, London, UK; ⁵Dept. of Endocrinology, Royal Free and University College Hospital Medical School, London, UK.

Prader-Willi syndrome (PWS) is characterized by severe childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone, which has been postulated as contributing to their hyperphagia. We have found that fasting ghrelin levels are 2.0- to 2.2-fold higher, and post-prandial ghrelin levels 1.8-fold higher, in PWS (n=10-27) than non-PWS adults (n=17-32), adjusting for % body fat. At least part of the hyperghrelinemia in PWS may be explicable by their relative hypoinsulinemia, since insulin lowers plasma ghrelin. Fasting ghrelin levels were 1.3- to 1.8-fold higher, and post-prandial ghrelin levels 1.2- to 1.5-fold higher in PWS than non-PWS adults, adjusting for insulin levels or insulin sensitivity. Hyperghrelinemia is not seen in patients with hypothalamic obesity from craniopharyngioma.

Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 µg/hr) or saline for 300min, and had blood samples taken every 30min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60min free food access period from +120min. Despite somatostatin lowering fasting plasma ghrelin by 60 ± 2% (p=0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 ± 9% of food intake during saline infusion, p=0.6). Somatostatin also lowered plasma PYY levels by 45 ± 16% (p=0.04), and produced post-prandial hyperglycemia (p=0.04). In a separate study, there was no reduction in fasting or post-prandial plasma levels of somatostatin or PYY in PWS adults, but pancreatic polypeptide secretion was impaired.

We conclude that either (i) hyperghrelinemia may not contribute to hyperphagia in PWS adults; (ii) the persistent orexigenic effect of underlying hypothalamic or other hormonal abnormalities in PWS, which impair satiety, override changes in ghrelin; or (iii) concomitant reductions in anorexigenic gastrointestinal hormones, such as PYY, by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for hyperphagia in PWS. However larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.

June 2004