Role of nitric oxide synthase isoforms in glucose-stimulated insulin release.

• The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of L-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

Nyckelord

Isoenzymes : antagonists & inhibitors

Islets of Langerhans : enzymology

Insulin : secretion

Indazoles : pharmacology

In Vitro

Glucose : pharmacology

Female

Enzyme Inhibitors : pharmacology

Diazoxide : pharmacology

Animal

Adenosine Triphosphate : physiology

Nitric-Oxide Synthase : antagonists & inhibitors

Nitric-Oxide Synthase : physiology

Potassium Channels : drug effects

Rats

omega-N-Methylarginine : pharmacology

Non-U.S. Gov't

Support

Sprague-Dawley

Isoenzymes : physiology

Mice

Inbred Strains

NG-Nitroarginine Methyl Ester : pharmacology

Nitric Oxide Donors : pharmacology

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)