Loss-of-function mutation of the galanin gene is associated with perturbed islet function in mice.
The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1-5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P < 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P < 0.001) and in isolated islets (P < 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P < 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.
Ahrén
Bo
B
Department of Medicine, Lund University, B11 Biomedical Centre, SE-221 84 Lund, Sweden. Bo.Ahren@med.lu.se.
Pacini
Giovanni
G
Wynick
David
D
Wierup
Nils
N
Sundler
Frank
F
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001835:Body Weight; D003847:Deoxyglucose / Q000494:pharmacology; D019004:Galanin / Q000235:genetics* / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013564:Sympathetic Nervous System / Q000502:physiology
D000963:Antimetabolites; D007004:Hypoglycemic Agents; D007328:Insulin; D019004:Galanin; D005934:Glucagon; D003847:Deoxyglucose; D005947:Glucose