LEPTIN LEVELS IN PROTRACTED CRITICAL ILLNESS - EFFECTS OF GROWTH HORMONE-SECRETAGOGUES AND THYROTROPIN-RELEASING-HORMONE

Prolonged critical illness is characterized by feeding-resistant wasti ng of protein, whereas reesterification, instead of oxidation of fatty acids, allows fat stores to accrue and associate with a low-activity status of the somatotropic and thyrotropic axis, which seems to be par tly of hypothalamic origin. To further unravel this paradoxical metabo lic condition, and in search of potential therapeutic strategies, we m easured serum concentrations of leptin; studied the relationship with body mass index, insulin, cortisol, thyroid hormones, and somatomedins ; and documented the effects of hypothalamic releasing factors, in par ticular, GH-secretagogues and TRH. Twenty adults, critically ill for s everal weeks and supported with normocaloric, continuously administere d parenteral and/or enteral feeding, were studied for 45 h. They had b een randomized to receive one of three combinations of peptide infusio ns, in random order: TRH tone day) and placebo (other day); TRH + GH-r eleasing peptide (GHRP)-2 and GHRP-2; TRH + GHRH + GHRP-2 and GHRH + G HRP-2. Peptide infusions were started after a 1-mu g/kg bolus at 0900 h and infused (1 mu g/kg.h) until 0600 h the next morning. Serum conce ntrations of leptin, insulin, cortisol, T-4, T-3, insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the acid-labile subunit (ALS ) were measured at 0900 h, 2100 h, and 0600 h on each of the 2 study d ays. Baseline leptin levels (mean +/- SEM: 12.4 +/- 2.1 mu g/L) were i ndependent of body mass index (25 +/- 1 kg/m(2)), insulin (18.6 +/- 2. 9 mu IU/mL), cortisol (504 +/- 43 mmol/L), and thyroid hormones (T-4: 63 +/- 5 nmol/L, T-3: 0.72 +/- 0;08 nmol/L) but correlated positively with circulating levels of IGF-I [86 +/- 6 mu g/L, determination coeff icient (R-2) = 0.25] and ALS (7.2 +/- 0.6 mg/L, R-2 = 0.32). Infusion of placebo or TRH had no effect on leptin. In contrast, GH-secretagoue s elevated leptin levels within 12 h. Infusion of GHRP-2 alone induced a maximal leptin increase of +87% after 24 h, whereas GHRH + GHRP-2 e levated leptin by up to +157% after 36 h. The increase in leptin withi n 12 h was related (R-2 = 0.58) to the substantial rise in insulin. Af ter 45 h, and having reached a plateau, leptin was related to the incr eased IGF-I (R-2 = 0.37). In conclusion, circulating leptin levels dur ing protracted critical illness were linked to the activity state of t he GH/IGF-I axis. Stimulating the GH/IGF-I axis with GH-secretagogues increased leptin levels within 12 h. Because leptin may stimulate oxid ation of fatty acids, and because GH, IGF-I, and insulin have a protei n-sparing effect, GH-secretagogue administration may be expected to re sult in increased utilization of fat as preferential substrate and to restore protein content in vital tissues and, consequently, has potent ial as a strategy to reverse the paradoxical metabolic condition of pr otracted critical illness.