PACAP STIMULATES INSULIN-SECRETION BUT INHIBITS INSULIN SENSITIVITY IN MICE

Although pituitary adenylate cyclase-activating polypeptide (PACAP) st imulates insulin secretion, its net influence on glucose homeostasis i n vivo has not been established. We therefore examined the action of P ACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and gl ucose disposal as derived from the minimal model of glucose disappeara nce during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-s timulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1-5 min) insulin response was 3.8 +/- 0.4 nmol/l (PACAP-27) and 3.3 +/- 0.3 nmol/l (PA CAP-38), respectively, vs. 1.4 +/- 0.1 nmol/l, after glucose alone (P < 0.001), and the total area under the curve for insulin (AUC(insulin) ) was potentiated by 60% (P < 0.001). In contrast, PACAP-27 and PACAP- 38 reduced the insulin sensitivity index (S-I) [0.23 +/- 0.04 10(-4) m in(-1)/(pmol/l) for PACAP-27 and 0.29 +/- 0.06 10(-4) min(-1)/(pmol/l) for PACAP-38 vs. 0.46 +/- 0.02 10(-4) min(-1)/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose e limination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUC( insulin) times S-I) were not affected by PACAP-27 or PACAP-38. Finally , when given together with glucose, PACAP-27 did not alter plasma gluc agon or norepinephrine levels but significantly increased plasma epine phrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the l atter possibly explained by increased epinephrine. This complex:action explains why the peptide does not enhance glucose disposal.