Osteocalcin protects islet identity in low-density lipoprotein receptor knockout mice on high-fat diet

Author:

Beamish Christine A1ORCID,Lee Yoon K1,Gaber A Osama1,Chanana Priyanka1,Graviss Edward A12,Kloc Malgorzata134,Gaber M Waleed56,Hsueh Willa A7,Sabek Omaima M13ORCID

Affiliation:

1. Department of Surgery, Houston Methodist Research Institute, Houston, Texas, USA

2. Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, Texas, USA

3. Department of Cell and Microbiology, Weill Cornell Medical College, New York, New York, USA

4. Department of Genetics, The University of Texas Anderson Cancer Center, Houston, Texas, USA

5. Department of Pediatrics, Hematology-Oncology Section, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA

6. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, USA

7. Department of Internal Medicine, The Ohio State University Diabetes and Metabolism Research Center, Columbus, Ohio, USA

Abstract

Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic β-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr−/−) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to β-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on β-cell identity and function. LDLr−/− mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin–glucagon colocalization, islet size and %β-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %β and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin–glucagon colocalization, and reduction in β-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to β-cell identity in LDLr−/− mice and offers intriguing clinical implications for countering metabolic syndrome.

Publisher

Bioscientifica

Reference61 articles.

1. Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion;Ackermann,2007

2. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients;Anello,2005

3. Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet auto-transplantation;Beamish,2019

4. Pretransplant HOMA-β is predictive of insulin independence in 7 patients with chronic pancreatitis undergoing islet autotransplantation;Beamish,2022

5. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose;Brereton,2014

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3