2 research outputs found
Targeted Ablation of Glucose-dependent Insulinotropic Polypeptide-producing Cells in Transgenic Mice Reduces Obesity and Insulin Resistance Induced by a High Fat Diet*
The K cell is a specific sub-type of enteroendocrine cell located in the
proximal small intestine that produces glucose-dependent insulinotropic
polypeptide (GIP), xenin, and potentially other unknown hormones. Because GIP
promotes weight gain and insulin resistance, reducing hormone release from K
cells could lead to weight loss and increased insulin sensitivity. However,
the consequences of coordinately reducing circulating levels of all K
cell-derived hormones are unknown. To reduce the number of functioning K
cells, regulatory elements from the rat GIP promoter/gene were used to express
an attenuated diphtheria toxin A chain in transgenic mice. K cell number, GIP
transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT
transgenic mice. Other enteroendocrine cell types were not ablated. Food
intake, body weight, and blood glucose levels in response to insulin or
intraperitoneal glucose were similar in control and GIP/DT mice fed standard
chow. In contrast to single or double incretin receptor knock-out mice, the
incretin response was absent in GIP/DT animals suggesting K cells produce GIP
plus an additional incretin hormone. Following high fat feeding for 21-35
weeks, the incretin response was partially restored in GIP/DT mice. Transgenic
versus wild-type mice demonstrated significantly reduced body weight
(25%), plasma leptin levels (77%), and daily food intake (16%) plus enhanced
energy expenditure (10%) and insulin sensitivity. Regardless of diet, long
term glucose homeostasis was not grossly perturbed in the transgenic animals.
In conclusion, studies using GIP/DT mice demonstrate an important role for K
cells in the regulation of body weight and insulin sensitivity