{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:30:17Z","timestamp":1789587017334,"version":"build-2803163510"},"reference-count":59,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Diabetes is a metabolic disorder with an increasing global prevalence. Somatostatin (SST), a peptide hormone, regulates hormone secretion via five SST receptor (SSTR) subtypes (SSTR1\u20135) in a tissue\u2010specific manner. As SSTR5 is expressed in pancreatic \u03b2\u2010cells and intestinal L\u2010cells, studies have suggested that SSTR5 regulates glucose tolerance through insulin and incretin secretion, thereby having a prominent role in diabetes. Moreover, SSTR5 knockout (KO) mice display enhanced insulin sensitivity; however, the underlying mechanism has not been clarified. Therefore, in this study, we investigate the effect of SSTR5 blockade on insulin resistance and the target organ using SSTR5 KO mice and a selective SSTR5 antagonist (compound\u20101). High\u2010fat diet (HFD)\u2010fed SSTR5 KO mice exhibited significantly lower homeostasis model assessment of insulin resistance (HOMA\u2010IR) than HFD\u2010fed wild\u2010type mice. Two\u2010week oral administration of compound\u20101 dose\u2010dependently and significantly reduced changes in the levels of glycosylated hemoglobin (GHb), plasma glucose, plasma insulin, and HOMA\u2010IR in male KK\u2010A<jats:sup>y<\/jats:sup>\/Ta Jcl mice (KK\u2010A<jats:sup>y<\/jats:sup> mice), a model of obese type 2 diabetes with severe insulin resistance. Additionally, compound\u20101 significantly increased the glucose infusion rate while decreasing hepatic glucose production in male KK\u2010A<jats:sup>y<\/jats:sup> mice, as evidenced by hyperinsulinemic\u2010euglycemic clamp analyses. In addition, compound\u20101 ameliorated the insulin\u2010induced Akt phosphorylation suppression by octreotide in the liver of male C57BL\/6J mice. Collectively, our results demonstrate that selective SSTR5 inhibition can improve insulin sensitivity by enhancing liver insulin action; thus, selective SSTR5 antagonists represent potentially novel therapeutic agents for type 2 diabetes.<\/jats:p>","DOI":"10.1002\/prp2.1043","type":"journal-article","created":{"date-parts":[[2022,12,31]],"date-time":"2022-12-31T06:38:44Z","timestamp":1672468724000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Selective somatostatin receptor 5 inhibition improves hepatic insulin sensitivity"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7127-6106","authenticated-orcid":false,"given":"Yumiko Okano","family":"Tamura","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Drug Discovery Unit Takeda Pharmaceutical Company Limited  Fujisawa 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