BACKGROUND/AIMS: beta-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic beta-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB). METHODS: Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured. RESULTS: Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions. CONCLUSIONS: Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions.
Animals ; Apoptosis/*drug effects ; Biological Markers/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Diabetes Mellitus/drug therapy ; Endoplasmic Reticulum Stress/*drug effects ; Glyburide/*pharmacology/therapeutic use ; Hypoglycemic Agents/*pharmacology/therapeutic use ; Rats

Permanent neonatal diabetes (PND) is a rare form of diabetes characterized by insulin-requiring hyperglycemia diagnosed within the first three months of life. In most cases, the causes are not known. Recently, mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive K(+) channel have been described in patients with PND. We report the first two Korean cases with PND due to a lysineto- arginine substitution at position 170 (K179R) and a valine-to-methionine substitution at position 59 (V59M) mutations of KCNJ11 encoding Kir6.2, respectively. After several years of insulin therapy, these patients were managed by oral glibenclamide therapy at a daily dose of 0.8-0.9 mg/kg. Their basal c-peptide levels increased after one week of glibenclamide therapy, and one month later, the insulin and c-peptide levels were in the normal ranges without any episodes of hyper- or hypoglycemia. These cases demonstrate that oral sulfonylurea may be the treatment of choice in PND patients with KCNJ11 mutations even at a young age.
Base Sequence ; C-Peptide/blood ; DNA Mutational Analysis ; Diabetes Mellitus/blood/*drug therapy/genetics ; Female ; Glyburide/*therapeutic use ; Hemoglobin A, Glycosylated/metabolism ; Heterozygote ; Humans ; Hypoglycemic Agents/therapeutic use ; Infant ; Infant, Newborn ; Insulin/blood/*therapeutic use ; Korea ; *Mutation ; Potassium Channels, Inwardly Rectifying/*genetics ; Sulfonylurea Compounds/therapeutic use ; Treatment Outcome

BACKGROUNDIt has been found that the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is closely related to allergic rhinitis (AR). In the previous study, we have demonstrated that antiallergic herbal agents (AHA) can obviously inhibit the allergic reaction of AR. The aim of this study was to explore the expression of CFTR and the effects of AHA on CFTR to improve the allergic reaction of AR.

METHODSAn animal model of an AR rabbit was established using ovalbumin (OVA). The rhinitis rabbits were randomly assigned to three groups: AHA treating group (AHATG), modeling group (MG) and healthy controlling group (HCG). The expressions of CFTR protein were examined by immunohistochemical method. The mucosal epithelial cells of all the rabbits were primarily cultured with tissue culture method in vitro and treated with or without glibenclamide for 24 hours. The levels of monocyte chemotactic factor-1 (MCP-1) and RANTES protein in supernatants of culture were measured by ELISA, and the expressions of CFTR mRNA were detected by real-time PCR.

RESULTSThe expressions of CFTR mRNA and protein greatly increased in mucosal epithelial cells of MG. The protein concentrations of MCP-1, RANTES in culture supernatants of MG were significantly higher than those in the other two groups (P < 0.01), and they reached much higher level than those at the start points in the MG (P < 0.05) and were significantly different compared with those in the AHATG after being cultured for 24 hours (P < 0.01). CFTR mRNA in MG + glibenclamide were much lower than those in MG (P < 0.05). RANTES and CFTR mRNA treated with glibenclamide in AHATG were significantly lower than those in the AHATG (P < 0.01). Minimal changes in the secretions of MCP-1 in the epithelial cells were detected between AHATG and AHATG + glibenclamide (P > 0.05).

CONCLUSIONSAHA can inhibit the secretions of CFTR, RANTES and MCP-1 in mucosal epithelia and improve inflammatory reaction of AR. CFTR may play an important role in the secretion of RANTES and mucosal inflammatory response in AR. Glibenclamide can inhibit the CFTR secretion in mucosal epithelial cells, in particular during AR process. These effects of glibenclamide on secretion of RANTES can be effectively strengthened by AHA.

Animals ; Cells, Cultured ; Chemokine CCL2 ; genetics ; metabolism ; Chemokine CCL5 ; genetics ; metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator ; genetics ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Enzyme-Linked Immunosorbent Assay ; Glyburide ; pharmacology ; therapeutic use ; Immunohistochemistry ; Male ; Mucous Membrane ; drug effects ; metabolism ; Nasal Mucosa ; drug effects ; metabolism ; Polymerase Chain Reaction ; RNA, Messenger ; genetics ; Rabbits ; Random Allocation ; Rhinitis, Allergic, Seasonal ; drug therapy ; metabolism