Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice

Abstract

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.

Figures

Figure 1

Disruption of the GIPR gene by homologous recombination. (A) Schematic drawings of the wild-type GIPR locus, the targeting vector, and the mutant allele generated after homologous recombination. Exons 4 and 5 of GIPR are indicated by closed boxes. The 5′ and 3′ probes for DNA blotting are indicated. Restriction enzymes: B, BglII; H, HindIII; RI, EcoRI; RV, EcoRV. PGK-neo, phosphoglycerate kinase-neomycin; HSV-TK, herpes simplex virus thymidine kinase. (B) EcoRI-digested genomic DNA from a litter derived from a GIPR+/− intercross was hybridized with a 3′ probe. The sizes of wild-type (7 kb) and targeted (3 kb) alleles are indicated. (C) Insulin secretion from isolated pancreatic islets was examined in response to the indicated concentrations of glucose with or without 100 nM GIP. Data were obtained from 12-week-old mice. Values are expressed as mean ± SE. ***, P < 0.001 for GIPR−/− mice vs. GIPR+/+.

Figure 2

Body weight and fasting blood glucose levels in GIPR−/− and GIPR+/+ mice. (A) Growth curve. ○, GIPR+/+; ■, GIPR−/−. Body weight was measured in g at 1, 2, 4, 8, 12, and 20 weeks. (B) Fasting plasma glucose levels were measured after a 16-hr fast. Open bars, GIPR+/+; filled bars, GIPR−/−.

Figure 3

Glucose tolerance test. (A) Intraperitoneal glucose tolerance test in age-matched GIPR+/+ mice (○, n = 4) and GIPR−/− (■, n = 6). (B) Oral glucose tolerance test in age-matched GIPR+/+ mice (○, n = 4) and GIPR−/− (■, n = 6). (C) Plasma insulin levels after oral glucose loading for age-matched GIPR+/+ mice (open bars, n = 4) and GIPR−/− (filled bars, n = 6). Statistical significance was assessed by using the unpaired t test. Values are indicated as mean ± SE. *, P < 0.05; **, P < 0.01; ***, P < 0.001 for GIPR−/− mice vs. GIPR+/+.

Figure 4

Effects of diet on blood glucose levels and plasma insulin levels after meal ingestion. GIPR+/+ mice (A and B) and GIPR−/− mice (C and D) were fed control diet (open symbols) or high fat diet (closed symbols). Blood glucose levels (A and C) and plasma insulin levels (B and D) were measured after meal ingestion. Values are indicated as mean ± SE. *, P < 0.05; **, P < 0.01.

Figure 5

Schematic models for insulin resistance and insulin secretion induced by high-fat feeding. (Left) The model in normal subjects. Both insulin resistance and compensatory insulin secretion are induced by high-fat feeding. Blood glucose levels are kept normal. (Right) The model if the GIP/GIPR axis is disturbed. The insulin secretion is insufficient and glucose intolerance develops.