Document Detail


NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat.
MedLine Citation:
PMID:  14514634     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A novel potassium channel opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive potassium channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 +/- 82 mmol. l(-1). min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol.l(-1).min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.
Authors:
Richard D Carr; Christian L Brand; Thora B Bodvarsdottir; John B Hansen; Jeppe Sturis
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Diabetes     Volume:  52     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-09-29     Completed Date:  2003-12-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2513-8     Citation Subset:  AIM; IM    
Affiliation:
Department of Pharmacological Research I, Novo Nordisk, Bagsvaerd, Denmark. rdc@novonordisk.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Bicyclo Compounds, Heterocyclic / administration & dosage,  pharmacology*
Blood Glucose / metabolism*
Body Weight / drug effects
Cyclic S-Oxides / administration & dosage,  pharmacology*
Diabetes Mellitus, Type 2 / physiopathology*
Drug Administration Schedule
Fasting / blood
Glucose / metabolism*
Glucose Tolerance Test
Insulin / blood,  physiology,  secretion
Islets of Langerhans / physiopathology*
Male
Pancreas / secretion
Perfusion
Potassium Channels, Inwardly Rectifying / drug effects*,  metabolism*
Rats
Rats, Zucker
Chemical
Reg. No./Substance:
0/Bicyclo Compounds, Heterocyclic; 0/Blood Glucose; 0/Cyclic S-Oxides; 0/NN 414; 0/Potassium Channels, Inwardly Rectifying; 11061-68-0/Insulin; 50-99-7/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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