*Article*

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

**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. Cox 10, 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 and Michelle E. Kimple 1,2,3,4,\***


**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 *Leptinob/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., gu<sup>t</sup> microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

**Keywords:** obesity; type 2 diabetes; insulin resistance; inflammation; gu<sup>t</sup> microbiome; untargeted plasma metabolomics; polyunsaturated fatty acids; prostaglandins; insulin secretion; beta-cell function


**Citation:** Schaid, M.D.; Zhu, Y.; Richardson, N.E.; Patibandla, C.; Ong, I.M.; Fenske, R.J.; Neuman, J.C.; Guthery, E.; Reuter, A.; Sandhu, H.K.; et al. 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**, *11*, 58. https://doi.org/ 10.3390/metabo11010058

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Received: 1 November 2020 Accepted: 7 January 2021 Published: 16 January 2021

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