The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice.
To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high-fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUC(insulin)) was augmented from 4.0+/-0.8 to 8.0+/-1.8 nmol/lx60 min by the oral glucose, i.e. by a factor of 2 (P=0.023), whereas in the high-fat fed mice, AUC(insulin) was augmented from 0.70+/-0.4 to 12.4+/-2.5 nmol/lx60 min, i.e. by a factor of 17 (P<0.001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by approximately 50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1.
Ahrén
Bo
B
Department of Clinical Sciences, Lund University, BMC B11, SE-221 84 Lund, Sweden Metabolic Unit, Institute of Biomedical Engineering (ISIB-CNR), Padova, Italy. bo.ahren@med.lu.se
Winzell
Maria Sörhede
MS
Pacini
Giovanni
G
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004041:Dietary Fats / Q000008:administration & dosage*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000097:blood; D005947:Glucose / Q000008:administration & dosage*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008810:Mice, Inbred C57BL
D004041:Dietary Fats; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose