Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

L Ahlkvist,K Brown,B Ahrén

doi:10.1530/ec-12-0079

Abstract

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

Highlights

In fully compensated insulin resistance, there is a sufficient upregulation of insulin secretion whereas in glucose intolerance and type 2 diabetes this upregulation is inadequate (1)
The insulin secretion due to G-protein-coupled receptor 119 (GPR119) activation in insulin resistance was accompanied by significantly increased plasma levels of intact glucagon-like peptide-1 (GLP1) already after 5 min (8.6G1.2 vs 3.7 G0.9 pg/ml, PZ0.004) and levels stayed significantly elevated after 20 min (1.2G0.2 vs 0.6G0.2 pg/ml, PZ0.05) (Fig. 1G)
The glucose elimination rate was significantly higher after GPR119 activation compared with vehicle (PZ0.014) (Table 1), not sufficient to significantly reduce individual glucose levels or areas under the curve (AUC) glucose (Fig. 1E). b-Cell function was significantly improved after GPR119 activation in high-fat diet (HFD) mice compared with vehicle (60-min AUCINS/GLU; PZ0.002) (Table 1)

Summary

Introduction

In fully compensated insulin resistance, there is a sufficient upregulation of insulin secretion whereas in glucose intolerance and type 2 diabetes this upregulation is inadequate (1). We previously suggested that the incretin hormones may contribute by demonstrating in model experiments that the incretin effect, i.e., the augmented insulin secretion seen after oral vs i.v. glucose, is increased in insulin-resistant mice (3) and that the b-cell responsiveness to intravenous glucagon-like peptide-1 (GLP1) is augmented (3, 4). One approach to test this hypothesis would be to activate G-protein-coupled receptor 119 (GPR119). This receptor is expressed in gut enteroendocrine cells (5), whereby activation has been shown to result in increased release of GLP1 (6, 7). GPR119 protein is localized to islet b-cells (6), and GPR119 activation may regulate glycemia both directly by activating islet b-cell insulin secretion (8) and indirectly through release of intestinal incretin hormones

Methods

Results

Conclusion