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Loss of pancreatic Mig6 improves glucose homeostasis during diet‐induced obesity
Author(s) -
Olivos Naomie,
Fueger Patrick T
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.734.3
Subject(s) - insulin resistance , medicine , endocrinology , glucose homeostasis , beta cell , homeostasis , type 2 diabetes , insulin , insulin receptor , biology , diabetes mellitus , chemistry , islet
In response to nutritional overload, functional beta cell mass normally expands to compensate for diet‐induced insulin resistance, thereby preserving glucose homeostasis. In the pathogenesis of type 2 diabetes (T2D), however, the compensation is insufficient, as beta cell dysfunction and destruction develop, leading to a mismatch between functional beta cell mass and insulin sensitivity. Thus, targeting beta cell proliferation as well as beta cell secretory capacity (i.e., function) and survival could prevent the onset of the disease. We have been investigating the impact of the elevated levels of mitogen inducible gene 6 (Mig6) in beta cells during glucolipotoxicity, as this milieu is thought to contribute to T2D. Mig6 is an adaptor protein that impairs EGFR signaling, a critical cell survival and proliferation pathway. Thus, we hypothesized that ablating Mig6 would fortify functional beta cell mass and preserve glucose homeostasis during diet‐induced obesity and insulin resistance. To this end, we compared mice lacking pancreatic Mig6 (PKO) and their wild‐type (WT) littermates fed either a low fat or high fat diet. No observable phenotypic differences were observed between either genotype fed the low fat diet. High fat feeding increased body mass and decreased glucose tolerance in WT mice, despite a robust increase in beta cell cross‐sectional area (as an index of beta cell mass). In contrast, high fat‐fed PKO mice had improved glucose tolerance compared to WT littermates, despite no increase in beta cell cross‐sectional area. These data suggest that either PKO mice are protected from diet‐induced insulin resistance or their beta cell function is enhanced to the extent to be able to compensate for systemic insulin resistance. Therefore, blocking the actions of Mig6 and thereby enhancing EGFR signaling could represent a novel strategy for preventing or delaying the progression to T2D. Support or Funding Information NIH grant DK099311 (PTF)