1233-P: Metabolic Consequences of GCK Mutations—Does the Source of Inheritance—Mother or Father—Matter?

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-06-13 DOI:10.2337/db25-1233-p

YANG LIU, YIFAN ZHANG, SHUHUI JI, WENLI FENG, YADI HUANG, JINYANG ZHEN, QIANNAN MA, MING LIU

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Abstract

Introduction and Objective: Mutations in the glucokinase (GCK) gene are the primary cause of maturity-onset diabetes of the young (MODY), and the source of inheritance—whether maternal or paternal—may influence metabolic outcomes in offspring. However, this area has not been fully explored. To address this, we employed a novel GCK heterozygous inactivating mutation model (GCKmut), characterized by mild, non-progressive fasting hyperglycemia without dyslipidemia, to investigate the differential metabolic effects of maternal and paternal inheritance on offspring metabolism. Methods: The GCKmut inherited from the father is referred to as GCKmut (paternal), abbreviated as GCKmut (P), while the mutation inherited from the mother is termed GCKmut (maternal), abbreviated as GCKmut (M). Blood glucose and body weight of GCKmut offspring were monitored every one or two weeks from postnatal day 1 (P1) to 16 weeks. At 4 weeks, glucose tolerance was evaluated by intraperitoneal injection glucose tolerance test (IPGTT), and serum insulin content was detected by ELISA. Intracellular insulin content was assessed by Western blotting. At 16 weeks, insulin sensitivity was evaluated using an intraperitoneal insulin tolerance test (IPITT). Both male and female mice were included. Results: Compared to GCKmut (M), GCKmut (P) exhibited lower birth weight and serum insulin on P1, with slightly elevated blood glucose. By the first week, their blood glucose changes disappeared, and by the third week, their weight had caught up. At 16 weeks, GCKmut (P) showed impaired glucose tolerance and reduced serum insulin compared to GCKmut (M). Nevertheless, there were no significant differences in insulin and proinsulin levels or insulin sensitivity among the groups. Results were consistent for both male and female mice. Conclusion: Paternal inheritance of the GCKmut leads to reduced birth weight in newborns and disrupts glucose homeostasis in adulthood. Disclosure Y. Liu: None. Y. Zhang: None. S. Ji: None. W. Feng: None. Y. Huang: None. J. Zhen: None. Q. Ma: None. M. Liu: None. Funding National Key R&D Program (2022YFE0131400 and 2019YFA0802502), National Natural Science Foundation of China (82220108014), Tianjin Municipal Health Commission (TJWJ2021ZD001), Tianjin Medical University General Hospital Clinical Research Program (22ZYYLCZD02), Tianjin Municipal Science and Technology Commission (23JCQNJC00680), Discipline Research Special Project of Tianjin Medical University (2024XKNFM13), Discipline Research Special Project of Tianjin Medical University (2024XKNFM09).

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1233-P: GCK突变的代谢后果——遗传来源——母亲还是父亲重要？

简介和目的：葡萄糖激酶（GCK）基因突变是年轻人成熟型糖尿病（MODY）的主要原因，遗传来源——无论是母系还是父系——都可能影响后代的代谢结果。然而，这一领域尚未得到充分探索。为了解决这个问题，我们采用了一种新的GCK杂合失活突变模型（GCKmut），其特征是轻度，非进行性空腹高血糖，无血脂异常，来研究母体和父亲遗传对后代代谢的差异影响。方法：从父亲遗传的GCKmut称为GCKmut（父系），缩写为GCKmut (P)，而从母亲遗传的突变称为GCKmut（母体），缩写为GCKmut (M)。从出生后第1天（P1）至第16周，每隔1周或2周监测GCKmut子代的血糖和体重。4周时，采用腹腔注射糖耐量试验（IPGTT）评估糖耐量，ELISA检测血清胰岛素含量。细胞内胰岛素含量采用免疫印迹法测定。16周时，使用腹腔胰岛素耐量试验（IPITT）评估胰岛素敏感性。研究对象包括雄性和雌性小鼠。结果：与GCKmut (M)相比，GCKmut (P)在P1时表现出较低的出生体重和血清胰岛素，血糖轻度升高。到第一周，他们的血糖变化消失了，到第三周，他们的体重也赶上了。在16周时，与GCKmut (M)相比，GCKmut (P)表现出葡萄糖耐量受损和血清胰岛素降低。然而，两组之间的胰岛素和胰岛素原水平或胰岛素敏感性没有显著差异。结果在雄性和雌性小鼠中都是一致的。结论：父系遗传GCKmut导致新生儿出生体重降低，并破坏成年后的葡萄糖稳态。刘宇晨：没有。张：没有。季：没有。冯伟：没有。黄：没有。甄：没有。马：没有。刘先生：没有。国家重点研发计划项目（2022YFE0131400和2019YFA0802502），国家自然科学基金项目（82220108014），天津市卫生健康委员会项目（TJWJ2021ZD001），天津医科大学总医院临床研究项目（22ZYYLCZD02），天津市科委项目（23JCQNJC00680），天津医科大学学科研究专项项目（2024XKNFM13），天津医科大学学科研究专项（2024XKNFM09）。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.