ABSTRACT
Among all serious diseases globally, diabetes (type 1 and type 2) still poses a major challenge to the world population. Several target proteins have been identified, and the etiology causing diabetes has been reasonably well studied. But, there is still a gap in deciding on the choice of a drug, especially when the target is mutated. Mutations in the KCNJ11 gene, encoding the kir6.2 channel, are reported to be associated with congenital hyperinsulinism, having a major impact in causing type 1 diabetes, and due to the lack of its 3D structure, an attempt has been made to predict the structure of kir6.2, applying fold recognition methods. The current work is intended to investigate the affinity of four phytochemicals namely, curcumin (Curcuma longa), genistein (Genista tinctoria), piperine (Piper nigrum), and pterostilbene (Vitis vinifera) in a normal as well as in a mutant kir6.2 model by adopting a molecular docking methodology. The phytochemicals were docked in both wild and mutated kir6.2 models in two rounds: blind docking followed by ATP-binding pocket-specific docking. From the binding pockets, the common interacting amino acid residues participating strongly within the binding pocket were identified and compared. From the study, we conclude that these phytochemicals have strong affinity in both the normal and mutant kir6.2 model. This work would be helpful for further study of the phytochemicals above for the treatment of type 1 diabetes by targeting the kir6.2 channel.
Subject(s)
Congenital Hyperinsulinism , Curcumin , Diabetes Mellitus , Genistein , Molecular Docking Simulation , PhytochemicalsABSTRACT
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.