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Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist.
Endocrinology. 2006 Oct; 147(10):4664-73.E

Abstract

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.

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Authors+Show Affiliations

Strowski MZ
Medizinische Klinik m. S. Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. mathias.strowski@charite.de
Cashen DE
No affiliation info available
Birzin ET
No affiliation info available
Yang L
No affiliation info available
Singh V
No affiliation info available
Jacks TM
No affiliation info available
Nowak KW
No affiliation info available
Rohrer SP
No affiliation info available
Patchett AA
No affiliation info available
Smith RG
No affiliation info available
Schaeffer JM
No affiliation info available

MeSH

AnimalsBlood GlucoseDiabetes Mellitus, Type 2DogsGlucagonGrowth HormoneHypoglycemic AgentsIn Vitro TechniquesInsulinIslets of LangerhansMaleMiceMice, Inbred C57BLMice, KnockoutMice, ObeseRatsReceptors, Somatostatin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16857751

Citation

Strowski, Mathias Z., et al. "Antidiabetic Activity of a Highly Potent and Selective Nonpeptide Somatostatin Receptor Subtype-2 Agonist." Endocrinology, vol. 147, no. 10, 2006, pp. 4664-73.
Strowski MZ, Cashen DE, Birzin ET, et al. Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist. Endocrinology. 2006;147(10):4664-73.
Strowski, M. Z., Cashen, D. E., Birzin, E. T., Yang, L., Singh, V., Jacks, T. M., Nowak, K. W., Rohrer, S. P., Patchett, A. A., Smith, R. G., & Schaeffer, J. M. (2006). Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist. Endocrinology, 147(10), 4664-73.
Strowski MZ, et al. Antidiabetic Activity of a Highly Potent and Selective Nonpeptide Somatostatin Receptor Subtype-2 Agonist. Endocrinology. 2006;147(10):4664-73. PubMed PMID: 16857751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist. AU - Strowski,Mathias Z, AU - Cashen,Doreen E, AU - Birzin,Elizabeth T, AU - Yang,Lihu, AU - Singh,Vandana, AU - Jacks,Thomas M, AU - Nowak,Krzysztof W, AU - Rohrer,Susan P, AU - Patchett,Arthur A, AU - Smith,Roy G, AU - Schaeffer,James M, Y1 - 2006/07/20/ PY - 2006/7/22/pubmed PY - 2006/10/25/medline PY - 2006/7/22/entrez SP - 4664 EP - 73 JF - Endocrinology JO - Endocrinology VL - 147 IS - 10 N2 - Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes. SN - 0013-7227 UR - https://www.unboundmedicine.com/medline/citation/16857751/Antidiabetic_activity_of_a_highly_potent_and_selective_nonpeptide_somatostatin_receptor_subtype_2_agonist_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2006-0274 DB - PRIME DP - Unbound Medicine ER -