We examined
glucose metabolism after I1-imidazoline (I1R) and alpha2-adrenergic receptor (alpha2AR) activation in an animal model of
metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I1R/alpha2AR agonists
moxonidine and
rilmenidine or the alpha2AR agonist
guanabenz. Because of the dual specificity of
moxonidine, its actions were split into
adrenergic and nonadrenergic components by using selective antagonists:
rauwolscine (alpha2AR)
efaroxan (I1R/alpha2AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]
heptane (
AGN 192403) (I1R).
Hyperglycemia induced by
moxonidine,
rilmenidine, and
guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates.
Glucagon was reduced by the I1R agonists (
moxonidine, 32 +/- 5%;
rilmenidine, 24 +/- 7%) but elevated by
guanabenz (71 +/- 32%). The hyperglycemic and hypoinsulinemic responses to
moxonidine were blocked by
rauwolscine. In contrast,
rauwolscine potentiated the reduction in
glucagon (39 +/- 6%). AGN 193402 blocked the
glucagon response without affecting
hyperglycemia and hypoinsulinemia.
Efaroxan blocked all responses to
moxonidine. When SHROB rats were treated with
moxonidine 15 min before an oral
glucose tolerance test, the
glucose area under the curve (AUC) was increased. Antagonizing the alpha2AR component of
moxonidine's action with
rauwolscine improved
glucose AUC 3-fold and facilitated the
insulin secretory response and reduced
glucagon secretion. Testing fasting
glucose and
insulin during 3 weeks of oral
moxonidine revealed early
hyperglycemia that later faded, and a progressive drop in fasting
insulin. The acute
hyperglycemia and hypoinsulinemia elicited by
moxonidine and
rilmenidine was mediated by alpha2AR, whereas I1R may reduce
glucagon and increase
insulin, particularly after a
glucose load.