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1 Department of Medicine, Lund University, SE-205 02 Malmö, Sweden; 2 Institute of Systems Science and Biomedical Engineering (LADSEB-Consiglio Nazionale delle Ricerche), I-35127 Padua, Italy; and 3 Department of Animal Physiology, University of Groningen, 9750 Haren, The Netherlands
Although pituitary
adenylate cyclase-activating polypeptide (PACAP) stimulates insulin
secretion, its net influence on glucose homeostasis in vivo has not
been established. We therefore examined the action of PACAP-27 and
PACAP-38 on insulin secretion, insulin sensitivity, and glucose
disposal as derived from the minimal model of glucose disappearance
during an intravenous glucose tolerance test in anesthetized mice.
PACAP-27 and PACAP-38 markedly and equipotently potentiated
glucose-stimulated 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 (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after
glucose alone (P < 0.001), and the total area under the curve for insulin
(AUCinsulin) was potentiated by
60% (P < 0.001). In contrast,
PACAP-27 and PACAP-38 reduced the insulin sensitivity index
(SI) [0.23 ± 0.04 10
4
min1/(pmol/l) for PACAP-27
and 0.29 ± 0.06 104
min1/(pmol/l) for PACAP-38
vs. 0.46 ± 0.02 104
min1/(pmol/l) for controls
(P < 0.01)].
Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination
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
(AUCinsulin times
SI) were not affected by
PACAP-27 or PACAP-38. Finally, when given together with glucose,
PACAP-27 did not alter plasma glucagon or norepinephrine levels but
significantly increased plasma epinephrine levels. We conclude that
PACAP, besides its marked stimulation of insulin secretion, also
inhibits insulin sensitivity in mice, the latter possibly explained by
increased epinephrine. This complex action explains why the peptide
does not enhance glucose disposal.
pituitary adenylate cyclase-activating polypeptide; glucose effectiveness; minimal model
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