Abstract
BackgroundElevated 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.MethodsC57/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.ResultsA 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.ConclusionHFD-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.
Highlights
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with insulinotropic effects, where its release in response to food intake stimulates insulin secretion in a glucosedependent manner [1]
Considering the link between obesity and T2D, reduced GLP-1 secretion in T2D, progressively diminished GLP-1 secretory response with increasing Body mass index (BMI) [12], as well as the fact that high levels of free fatty acids (FFAs) induce apoptosis in a number of different cell types, we investigated if hyperlipidemia could result in increased apoptosis, and reduced GLP1-positive cell number and GLP-1 secretory capacity - using an in vitro model
Since we aimed to determine the effects of a high fat diet (HFD), and if such effects could be counteracted by metformin treatment, the animals receiving a HFD were divided into two groups - where eight animals received oral gavage administration of 300 mg/kg/day metformin and the remaining eight animals received oral administration of saline
Summary
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with insulinotropic effects, where its release in response to food intake stimulates insulin secretion in a glucosedependent manner [1]. This incretin response has been suggested to be impaired in type 2 diabetes (T2D), characterized by hyperglycemia resulting from impaired insulin. Situated on the villi lining the intestine, the L-cells have apical microvilli facing the gut lumen and secretory vesicles located adjacent to the basolateral membrane This morphology enables the L-cells to be regulated by neuronal factors and hormones, as well as by direct nutrient stimulation [4,5]. 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
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