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Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells.

ABSTRACT: As a potential druggable nuclear receptor, steroidogenic factor 1 (SF1) regulates obesity and insulin resistance in the ventromedial hypothalamic nucleus. Herein, we sought to demonstrate its expression and functions in islets in the development of obesity-induced diabetes. SF1 was barely detected in the beta cells of lean mice but highly expressed in those of non-diabetic obese mice, while decreased in diabetic ones. Conditional deletion of SF1 in beta cells predisposed diet-induced obese (DIO) mice to glucose intolerance by perturbing glucose-stimulated insulin secretion (GSIS). Consistently, forced expression of SF1 restored favorable glucose homeostasis in DIO and db/db mice by improving GSIS. In isolated islets and MIN6, overexpression of SF1 also potentiated GSIS, mediated by improvement of mitochondrial ATP production. The underlying mechanisms may involve oxidative phosphorylation and lipid metabolism. Collectively, SF1 in beta cell preserves GSIS to promote beta-cell adaptation to obesity and hence is a potential therapeutic target for obesity-induced diabetes.

SUBMITTER: Guo Y

PROVIDER: S-EPMC10068556 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells.

Guo Yan Y Liu Liehua L Cheng Yanglei Y Li Hai H Wan Xuesi X Ma Jiajing J Liu Juan J Liang Weiwei W Zhang Pengyuan P Chen Jie J Cao Xiaopei X Guan Hongyu H Xiao Haipeng H Li Yanbing Y

iScience 20230320 4

As a potential druggable nuclear receptor, steroidogenic factor 1 (SF1) regulates obesity and insulin resistance in the ventromedial hypothalamic nucleus. Herein, we sought to demonstrate its expression and functions in islets in the development of obesity-induced diabetes. SF1 was barely detected in the beta cells of lean mice but highly expressed in those of non-diabetic obese mice, while decreased in diabetic ones. Conditional deletion of SF1 in beta cells predisposed diet-induced obese (DIO) ...[more]

PMID: 37020955

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Project description:The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic β-cell is the main mechanism for reducing elevated plasma glucose. Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). Steps include retrieval of information from databases, curation of experimental and clinical data for model calibration and validation, integration of heterogeneous data including absolute and relative measurements, unit normalization, data normalization, and model annotation. An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools. The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic β-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and β-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio). Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the β-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion. The observed glucose-dependent increase in glycolytic intermediates and the resulting change in ATP/ADP ratios and insulin secretion is a robust phenomenon observed across data sets, experimental systems and species. Model predictions of the glucose-dependent response of glycolytic intermediates and biphasic insulin secretion are in good agreement with experimental measurements. Our model predicts that factors affecting ATP consumption, ATP formation, hexokinase, phosphofructokinase, and ATP/ADP-dependent insulin secretion have a major effect on GSIS. In conclusion, we have developed and applied a systematic modeling workflow for pathway models that allowed us to gain insight into key mechanisms in GSIS in the pancreatic β-cell.

Dataset Information

Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells.

Publications

Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells.

Similar Datasets

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