Improved beta-cell survival and reduced insulitis in a type 1 diabetic rat model after treatment with a beta-cell-selective K(ATP) channel opener.
Treatment with ATP-sensitive K(+) channel openers (KCOs) leads to inhibition of insulin secretion and metabolic "rest" in beta-cells. It is hypothesized that in type 1 diabetes this may reduce beta-cell death resulting from metabolic stress as well as reduce the immunogenicity of the beta-cells during autoimmune beta-cell destruction. We have investigated whether the beta-cell-selective KCO compound, NN414, can be used to improve beta-cell survival in DR-BB rats rendered diabetic by modulation of their immune system. The rats were treated three times daily on days 1-19 with NN414, diazoxide, or vehicle. On day 21, an intravenous glucose tolerance test was conducted to assess beta-cell function. Postmortem histological analysis of rats' pancreata assessed the degree of insulitis and beta-cell volume. Among NN414-treated rats, 46% (16 of 35) were found to have a beta-cell mass similar to that of nondiabetic controls and significant glucose-stimulated C-peptide values, whereas only 11% (4 of 36) of vehicle-treated rats possessed a normal beta-cell mass and function (P < 0.002, by chi(2) test). Furthermore, responsive NN414-treated rats were almost free of insulitis. Thus, this study demonstrated that treatment with KCO compounds can indeed lead to preservation of beta-cell function and reduction of insulitis in a rat diabetes model.
Skak
Kresten
K
Department of Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
Gotfredsen
Carsten F
CF
Lundsgaard
Dorthe
D
Hansen
John Bondo
JB
Sturis
Jeppe
J
Markholst
Helle
H
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D003499:Cyclic S-Oxides / Q000097:blood / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011913:Rats, Inbred BB
D001786:Blood Glucose; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D007004:Hypoglycemic Agents; D007328:Insulin; C475618:NN 414