Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

Michael D Schaid; Yanlong Zhu; Nicole E Richardson; Chinmai Patibandla; Irene M Ong; Rachel J Fenske; Joshua C Neuman; Erin Guthery; Austin Reuter; Harpreet K Sandhu; Miles H Fuller; Elizabeth D Cox; Dawn B Davis; Brian T Layden; Allan R Brasier; Dudley W Lamming; Ying Ge; Michelle E Kimple

doi:10.3390/metabo11010058

Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E₂ Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

Metabolites. 2021 Jan 16;11(1):58. doi: 10.3390/metabo11010058.

Authors

Michael D Schaid^{1

2

3}, Yanlong Zhu^{4

5}, Nicole E Richardson^{1

3}, Chinmai Patibandla^{1

3}, Irene M Ong^{6

7}, Rachel J Fenske^{2

3}, Joshua C Neuman^{2

3}, Erin Guthery^{1

3}, Austin Reuter^{1

3}, Harpreet K Sandhu^{1

3}, Miles H Fuller^{8

9}, Elizabeth D Cox¹⁰, Dawn B Davis^{1

2

3}, Brian T Layden^{8

9}, Allan R Brasier^{1

11}, Dudley W Lamming^{1

2

3}, Ying Ge^{4

5

12}, Michelle E Kimple^{1

2

3

4}

Affiliations

¹ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
³ Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
⁴ Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Human Proteomics Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁶ Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁷ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁸ Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁹ Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
¹⁰ Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53792, USA.
¹¹ Institute for Clinical and Translational Research, University of Wisconsin-Madison, Madison, WI 53705, USA.
¹² Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

Abstract

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E₂ (PGE₂). Expression of the pancreatic islet EP3 and PGE₂ synthetic enzymes and/or PGE₂ excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptin^ob/ob mutation-a strong genetic model of T2D-were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

Keywords: beta-cell function; gut microbiome; inflammation; insulin resistance; insulin secretion; obesity; polyunsaturated fatty acids; prostaglandins; type 2 diabetes; untargeted plasma metabolomics.

Abstract

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