Insulin action in the double incretin receptor knockout mouse.
OBJECTIVE
The incretins glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide have been postulated to play a role in regulating insulin action, although the mechanisms behind this relationship remain obscure. We used the hyperinsulinemic-euglycemic clamp to determine sites where insulin action may be modulated in double incretin receptor knockout (DIRKO) mice, which lack endogenous incretin action.


METHODS
DIRKO and wild-type mice were fed regular chow or high-fat diet for 4 months. Clamps were performed on 5-h-fasted, conscious, unrestrained mice using an arterial catheter for sampling.


RESULTS
Compared with wild-type mice, chow and high fat-fed DIRKO mice exhibited decreased fat and muscle mass associated with increased energy expenditure and ambulatory activity. Clamp rates of glucose infusion (GIR), endogenous glucose production (endoR(a)), and disappearance (R(d)) were not different in chow-fed wild-type and DIRKO mice, although insulin levels were lower in DIRKO mice. Liver Akt expression was decreased but Akt activation was increased in chow-fed DIRKO compared with wild-type mice. High-fat feeding resulted in fasting hyperinsulinemia and hyperglycemia in wild-type but not in DIRKO mice. GIR, suppression of endoR(a), and stimulation of R(d) were inhibited in high fat-fed wild-type mice but not in DIRKO mice. High-fat feeding resulted in impaired tissue glucose uptake (R(g)) in skeletal muscle of wild-type mice but not of DIRKO mice. Liver and muscle Akt activation was enhanced in high fat-fed DIRKO compared with wild-type mice.


CONCLUSIONS
In summary, DIRKO mice exhibit enhanced insulin action compared with wild-type mice when fed a regular chow diet and are protected from high-fat diet-induced obesity and insulin resistance.
Ayala
Julio E
JE
Vanderbilt University Medical Center, 2200 Pierce Ave., 702 Light Hall, Nashville, TN 37232, USA. julio.ayala@vanderbilt.edu
Bracy
Deanna P
DP
Hansotia
Tanya
T
Flock
Grace
G
Seino
Yutaka
Y
Wasserman
David H
DH
Drucker
Daniel J
DJ
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D003433:Crosses, Genetic; D004041:Dietary Fats; D004734:Energy Metabolism; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000033:anatomy & histology; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics*; D011964:Receptors, Gastrointestinal Hormone / Q000172:deficiency* / Q000235:genetics*; D018027:Receptors, Glucagon / Q000172:deficiency* / Q000235:genetics*
D004041:Dietary Fats; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011956:Receptors, Cell Surface; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C041086:gastric inhibitory polypeptide receptor