Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene.
OBJECTIVE
Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified.


METHODS
We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic-hyperinsulinaemic clamp.


RESULTS
Impaired clearance of exogenous insulin caused four-fold higher clamp insulin levels in Arg1174Gln carriers compared with control subjects (p<0.05). In Arg1174Gln carriers insulin increased glucose disposal and non-oxidative glucose metabolism (p<0.05), but to a lower extent than in controls (p<0.05). Insulin increased Akt phosphorylation at Ser473 and Thr308, inhibited glycogen synthase kinase-3alpha activity, reduced phosphorylation of glycogen synthase at sites 3a+3b, and increased glycogen synthase activity in Arg1174Gln carriers (all p<0.05). In the insulin-stimulated state, Akt phosphorylation at Thr308 and glycogen synthase activity were reduced in Arg1174Gln carriers compared with controls (p<0.05), whereas glycogen synthase kinase-3alpha activity and phosphorylation of glycogen synthase at sites 3a+3b were similar in the two groups.


CONCLUSIONS
In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin-stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance. Our data suggest that impaired insulin clearance in part rescues in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors.
Højlund
K
K
Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
Wojtaszewski
J F P
JF
Birk
J
J
Hansen
B F
BF
Vestergaard
H
H
Beck-Nielsen
H
H
D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D006580:Genetic Carrier Screening; D005973:Glutamine; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000502:physiology*; D009154:Mutation; D011972:Receptor, Insulin / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D001786:Blood Glucose; D007328:Insulin; D005973:Glutamine; D001120:Arginine; D011972:Receptor, Insulin