title: Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1.
abstract: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome characterized by multiple tumors in the parathyroid glands, endocrine pancreas and anterior pituitary. Recent clinical studies have revealed a strong association between MEN1 syndrome and the risk of developing diabetes mellitus; however, the underlying mechanisms remain unknown. In this study, heterozygous Men1 knockout (Men1(+/-)) mice were used as MEN1 models to investigate MEN1-associated glucose metabolic phenotypes and mechanisms. Heterozygous deficiency of Men1 in 12-month-old male mice induced fasting hyperglycemia, along with increased serum insulin levels. However, male Men1(+/-) mice did not show insulin resistance, as evidenced by Akt activation in hepatic tissues and an insulin tolerance test. Increased glucose levels following pyruvate challenge and expression of key gluconeogenic genes suggested increased hepatic glucose output in the male Men1(+/-) mice. This effect could be partly due to higher basal serum glucagon levels, which resulted from pancreatic islet cell proliferation induced by heterozygous loss of Men1 Taken together, our results indicate that fasted male Men1(+/-) mice, in the early stage of development of MEN1, display glucose metabolic disorders. These disorders are caused not by direct induction of insulin resistance, but via increased glucagon secretion and the consequent stimulation of hepatic glucose production.
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Zhongxiuzi
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Houjian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China.
authors.forename: Zeen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China ghjin@xmu.edu.cn xmq8887@xmu.edu.cn.
authors.forename: Maoqiang
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Basic Medical SciencesMedical College, Xiamen University, Xiamen, China ghjin@xmu.edu.cn xmq8887@xmu.edu.cn.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Jin
mesh_terms: D000818:Animals; D005215:Fasting / Q000097:blood*; D005934:Glucagon / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology; D006579:Heterozygote; D006943:Hyperglycemia / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005934:Glucagon
keywords: Men1; glucagon; gluconeogenesis; hepatic glucose output; insulin resistance