The impact of ANG II and IV on INS-1 cells and on blood glucose and plasma insulin.
The impact of angiotensin (ANG) for peripheral, global effects is well known. Local ANG systems including that of the insulin-releasing beta cell are not well investigated. In insulin-secreting cell line (INS-1), AT(1) and AT(4) receptors for ANG II and IV were demonstrated by Western blots. Only small amounts of ANG II-binding sites of low affinity were observed. ANG II and SARILE displaced binding of (125)I-ANG II. ANG II and IV as well as their non-degradable analogs SARILE and Nle-ANG IV increased the glucose-induced insulin release in a bell-shaped way; the maximum effect was at approximately 1 nM. The increase was antagonized by 1 microM losartan or 10 microM divalinal (AT(1) and AT(4) receptor antagonists, respectively). The insulin release was accompanied by a (45)Ca(2+) uptake in the case of ANG II and ANG IV. Divalinal abolished the effect of ANG IV and Nle-ANG IV on this parameter. ANG IV reduced the increase in blood glucose during a glucose tolerance test with corresponding, albeit smaller effects on plasma insulin. Using confocal laser scanning microscopy, transfected insulin-regulated aminopeptidase (IRAP) with AT(4) receptors was shown to be accumulated close to the nucleus and the cytosolic membrane, whereas GLUT4 was not detectable. IRAP was inhibited by ANG IV. In conclusion, AT(1) and AT(4) receptors may be involved in diabetic homeostasis. Effects are mediated by insulin release, which is accompanied by an influx of extracellular Ca(2+). The impact of ANG IV/IRAP agonists may be worth being used as antidiabetics.
Department of Pharmacology, Institute of Medicinal Chemistry, University of Muenster, Münster, Germany.
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M
Siebelmann
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J
Wensing
E J
EJ
Verspohl
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D019808:Losartan / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D014162:Transfection
D001786:Blood Glucose; D007328:Insulin; D018942:Macrolides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C040929:bafilomycin A1; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D005947:Glucose; D019808:Losartan