The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice.

Yutaka Seino,Yuichiro Yamada,Bo Ahrén

doi:10.3389/fendo.2021.665537

Abstract

A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.

Highlights

Following its first conductancy in 1917, the oral glucose tolerance test (OGTT) has been a standard technique in experimental and clinical medicine and has since 1980 been a key tool for diagnosis and screening of impaired glucose tolerance and type 2 diabetes [1]
By dividing the studies into different study arms depending on gender, glucose-dependent insulinotropic polypeptide (GIP) receptor KO and glucagon-like peptide-1 (GLP-1) receptor KO animals, a total of thirteen different study arms were reported in these six publications (Table 2)
We reviewed the literature on glucose and insulin responses to oral glucose in GIP and GLP-1 receptor KO mice and found that glucose intolerance is not as robustly demonstrated as is generally assumed

Summary

Introduction

Following its first conductancy in 1917, the oral glucose tolerance test (OGTT) has been a standard technique in experimental and clinical medicine and has since 1980 been a key tool for diagnosis and screening of impaired glucose tolerance and type 2 diabetes [1]. To study the reported impact on glucose and insulin responses to oral glucose in these mice, we reviewed the literature in which studies on oral glucose challenges in GIP receptor KO or GLP-1 receptor KO mice have been performed. A glucose dependent nature of the impact of genetic deletion of GIP and GLP-1 receptors on glucose and insulin responses to oral glucose may exist, which may explain the partial inconsistency in the literature. To test this hypothesis we have, in the present study, undertaken a study on the glucose and insulin responses to stepwise oral glucose administration over a wide range in GIP receptor KO and GLP-1 receptor KO mice

Methods

Results

Conclusion