Mutations in the Kir6.2 subunit of the K_ATPchannel and permanent neonatal diabetes: New insights and new treatment

Abstract

Permanent neonatal diabetes (PNDM) is diagnosed in the first three months of life and is a major management problem as patients require lifelong insulin injections. Recently, activating mutations in the KCNJ11 gene which encodes the Kir6.2 subunit of the KATP channels in the pancreatic beta-cells were found to be an important cause of PNDM. The mutated KATP channels do not close in the presence of adenosine triphosphate (ATP) so the beta-cell membrane is hyperpolarized and insulin secretion does not occur. Some patients have DEND syndrome (developmental delay, epilepsy and neonatal diabetes) with the neurological features arising from mutated KATP channels in muscle, nerve and brain. Defining a genetic aetiology has not only given insights into clinical classification and disease mechanism, but has also influenced treatment. Sulphonylureas, by binding the sulphonylurea receptor, can close the KATP channel. This has led to patients who were insulin-dependent being able to discontinue insulin injections and achieve excellent control with sulphonylurea tablets. In this article we discuss the work that established Kir6.2 mutations as a common cause of neonatal diabetes, the clinical features, the underlying mechanism and the impact on patient treatment.

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

“…The majority of patients have permanent neonatal diabetes mellitus but transient neonatal diabetes mellitus has also been described [2]. Onethird of patients also have neurological features arising from mutated K ATP channels in muscle, nerve and brain [1,3]. The most severe manifestation has been described as DEND syndrome (developmental delay, early-onset generalised epilepsy and neonatal diabetes) [3,4].…”

“…Onethird of patients also have neurological features arising from mutated K ATP channels in muscle, nerve and brain [1,3]. The most severe manifestation has been described as DEND syndrome (developmental delay, early-onset generalised epilepsy and neonatal diabetes) [3,4]. A more common, but less severe presentation is intermediate DEND syndrome, when patients do not have epilepsy; in most cases this is associated with the V59M mutation [4].…”

Insulin gene mutations as a cause of permanent neonatal diabetes

“…Genetic factors play an important role in the development of diabetes with some forms resulting from mutations in a single gene. Although monogenic forms of diabetes are collectively relatively uncommon, the identification of the underlying genetic defects has provided important insights into pancreatic development and the control of pancreatic ␤ cell function and improvements in diagnosis and treatment (1)(2)(3). Moreover, common variation in the same genes that can cause monogenic forms of diabetes can affect the risk of developing the common polygenic forms (4,5).…”

Farmacogenética Do Tratamento De Diabete Melito

“…As sulfoniluréias têm maior capacidade de ligar-se ao SUR1 e fechar o IKATP por uma via independente de ATP 41 . Portadores de variantes do gene KCNJ1 tiveram o tratamento insulínico descontinuado utilizando glibenclamida ou outras sulfoniluréias, alguns dos quais apresentaram melhor controle glicêmico 42,43 . Estes foram alguns dos primeiros casos em que pacientes dependentes de insulina puderam ser tratados eficientemente com sulfoniluréias.…”