title: Functional rest through intensive treatment with insulin and potassium channel openers preserves residual beta-cell function and mass in acutely diabetic BB rats.
abstract: Diazoxide and the diazoxide-analogue, NNC 55-0118, are potassium channel openers that interfere with insulin secretion from beta-cells. In vitro, we show that these two drugs inhibit insulin release from diabetes-resistant BB rat islets cultured at either low or high glucose concentration and cause an intracellular accumulation of insulin with high glucose. Preservation of beta-cells was investigated in newly diabetic BB rats treated with insulin implants from day 0-8 under oral diazoxide, NNC 55-0118 or solvent gavage once a day from day 0-7. Three of eight rats (37.5%) treated with diazoxide and three of ten (30%) treated with NNC 55-0118 retained near normal C-peptide responses when challenged with glucose/arginine on day 9, whereas none of eight (0%) solvent-treated rats showed a C-peptide response. Immunohistochemical staining for insulin and glucagon showed that all the C-peptide responding rats had insulin-positive cells in their islets. In contrast, islets from non-responding rats displayed marked inflammation or end-stage lesions. Furthermore, rats with C-peptide response and treated with NNC 55-0118 exhibited only minimal signs of islet inflammation, whereas C-peptide responding diazoxide-treated rats had low level islet inflammation. These results imply that it is conceivable to preserve residual beta-cells at diabetes onset by induction of target cell rest with potassium channel openers and continuous insulin treatment.
authors.affiliation: Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: S B
authors.initials: SB
authors.lastname: Rasmussen
authors.forename: T S
authors.initials: TS
authors.lastname: Sørensen
authors.forename: J B
authors.initials: JB
authors.lastname: Hansen
authors.forename: T
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: L
authors.initials: L
authors.lastname: Hornum
authors.forename: H
authors.initials: H
authors.lastname: Markholst
mesh_terms: D000818:Animals; D001120:Arginine; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000032:analysis; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003981:Diazoxide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005934:Glucagon / Q000032:analysis; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis / Q000378:metabolism / Q000627:therapeutic use*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology*; D007700:Kinetics; D015221:Potassium Channels / Q000819:agonists* / Q000187:drug effects; D051381:Rats; D011913:Rats, Inbred BB; D011920:Rats, Inbred WF
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D015221:Potassium Channels; D005934:Glucagon; D001120:Arginine; C411625:NNC 55-0118; D003981:Diazoxide