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

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.

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…Therefore, GLP2 could be responsible for glycaemic improvement after bariatric surgery and can be considered as a key signal to drive intestinal reprogramming of glucose metabolism (Saeidi et al 2013). In addition, animal studies have shown that GLP2 secretion from ileal tissue is decreased in diabetic conditions (Shan et al 2013), and reduced numbers of L-cells have been detected in the intestinal tissue from HFD-fed mice compared with intestinal tissue from mice receiving a control diet (Kappe et al 2014). Therefore, GLP2-decreased production might lead to T2D.…”

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

“…Recent investigations together with our unpublished observations have revealed that disturbances in the intestinal L-cell population may contribute to the loss-of-functional incretin response in diabetes (Kappe et al 2014). In the context of type 1 diabetes pathogenesis, such disturbances may contribute to the observed metabolic abnormalities.…”

The regulation of function, growth and survival of GLP-1-producing L-cells

“…Finally, in support of deleterious effects of the saturated fatty acid palmitate and lipotoxicity, studies using a dietinduced obesity mouse model and murine GLUTag cells indicated that intake of excess saturated fatty acids induces ER stress in the intestine and decreases GLP-1 production [187], and studies of L-cell mass in mice fed a high fat or control diet for 10 weeks, suggested reduced L-cell mass [188].…”