Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP-1 and the relative number of intestinal L-cells

Camilla Kappe; Qimin Zhang; Thomas Nyström; Ake Sjöholm

doi:10.1186/1758-5996-6-70

Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP-1 and the relative number of intestinal L-cells

Diabetol Metab Syndr. 2014 Jun 2:6:70. doi: 10.1186/1758-5996-6-70. eCollection 2014.

Authors

Camilla Kappe¹, Qimin Zhang², Thomas Nyström², Ake Sjöholm³

Affiliations

¹ Department of Clinical Science and Education, Karolinska Institutet, Unit for Diabetes Research, Södersjukhuset, SE-118 83 Stockholm, Sweden ; Department of Medical Cell Biology, Uppsala University, BMC, SE-751 23 Uppsala, Sweden.
² Department of Clinical Science and Education, Karolinska Institutet, Unit for Diabetes Research, Södersjukhuset, SE-118 83 Stockholm, Sweden.
³ Department of Clinical Science and Education, Karolinska Institutet, Unit for Diabetes Research, Södersjukhuset, SE-118 83 Stockholm, Sweden ; Department of Internal Medicine, Södertälje Hospital, SE-152 86 Södertälje, Sweden ; Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, Mobile, AL 36688-0002, USA.

Abstract

Background: Elevated serum free fatty acids (FFAs) contribute to the pathogenesis of type-2-diabetes (T2D), and lipotoxicity is observed in many cell types. We recently showed that simulated hyperlipidemia induces lipoapoptosis also in GLP-1-secreting L-cells in vitro, while metformin confers lipoprotection. The aim of this study was to determine if a high fat diet (HFD) reduces the number of enteroendocrine L-cells and/or GLP-1 plasma levels in a rodent model, and potential effects thereupon of metformin treatment.

Methods: C57/Bl6 mice received control/HFD for 12-weeks, and oral administration of metformin/saline for the last 14 days. Blood glucose, glycosylated hemoglobin and plasma insulin and GLP-1 were determined before and after treatment with metformin using ELISAs. GLP-1-immunopositive cells in intestinal tissue sections were quantified using immunohistochemistry.

Results: A HFD increased blood glucose, glycosylated hemoglobin, and fasting plasma insulin (33%, 15% and 70% increase, respectively), in conjunction with reduced oral glucose tolerance, indicating the manifestation of insulin resistance. Metformin counteracted these adverse effects, while also reducing prandial plasma FFAs. The number of GLP-1-positive cells was indicated to be reduced (55% reduction of the number of GLP-1-positive cells, p = 0.134), while there was a trend toward increased prandial plasma GLP-1 despite reduced food intake following a HFD.

Conclusion: HFD-fed mice rapidly develop insulin resistance. Metformin exerts beneficial glucose lowering effects, and is indicated to improve the incretin response. Albeit no significant effect, a HFD tends to reduce the number of GLP-1-positive cells. However, considering concurrent normal or increased plasma GLP-1, any reduction in the number of GLP-1-positive cells, probably does not contribute to development of the glucose intolerance, but may contribute to progression of the diabetic state through eventual loss of a functional incretin response.

Keywords: Glucagon-like peptide-1; Insulinotropic; L-cell; Lipotoxicity; Metformin.