Evidence for paracrine/autocrine regulation of GLP-1-producing cells

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Kappe, CKarolinska Institutet (author)

Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Article/chapterEnglish2013

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American Physiological Society,2013

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LIBRIS-ID:oai:prod.swepub.kib.ki.se:127929382
http://kipublications.ki.se/Default.aspx?queryparsed=id:127929382URI
https://doi.org/10.1152/ajpcell.00227.2013DOI

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Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9–39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

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Zhang, QM (author)
Holst, JJ (author)
Nystrom, TKarolinska Institutet (author)
Sjoholm, A (author)
Karolinska Institutet (creator_code:org_t)

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In:American journal of physiology. Cell physiology: American Physiological Society305:10, s. C1041-C10491522-15630363-6143

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By the author/editor: Kappe, C; Zhang, QM; Holst, JJ; Nystrom, T; Sjoholm, A

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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