Leptin does not directly regulate the pancreatic hormones amylin and pancreatic polypeptide: interventional studies in humans.

OBJECTIVE Leptin and the pancreatic hormones amylin and pancreatic polypeptide are being evaluated alone or in combination for the treatment of obesity, but their physiological regulation has not yet been fully elucidated. Thus, we examined whether amylin and pancreatic polypeptide are regulated by caloric intake and/or short- and long-term energy deprivation and whether any potential regulation is mediated by changes in leptin levels. RESEARCH DESIGN AND METHODS We measured circulating levels of amylin and pancreatic polypeptide after 1) a 75-g glucose load in 28 healthy, normal-weight women, 2) 72-h complete energy deficiency (severe hypoleptinemia) with administration of either placebo or replacement-dose recombinant methionyl human leptin (r-metHuLeptin) in normal-weight men (n = 6) and women (n = 7), and 3) chronic mild energy deficiency (mild hypoleptinemia) in 7 women with hypothalamic amenorrhea before and after r-metHuLeptin administration for 3 months. RESULTS Amylin and pancreatic polypeptide levels increased 15 min after a 75-g glucose load and remained elevated at 60 and 120 min (P < 0.0001). Fasting for 72 h decreased leptin (to 21%) and amylin (to 67%) of baseline but not pancreatic polypeptide levels. Normalizing leptin levels with r-metHuLeptin did not alter the fasting-induced decrease in amylin and had no effect on pancreatic polypeptide levels. Neither amylin nor pancreatic polypeptide levels were different in leptin-deficient women with hypothalamic amenorrhea compared with weight-matched control subjects, and normalization of leptin levels with r-metHuLeptin treatment did not alter amylin or pancreatic polypeptide levels. CONCLUSIONS Circulating amylin levels increase after a glucose load and decrease in response to short-term complete fasting, but these changes are not mediated by leptin.