Kir6.2

The ATP-sensitive potassium (K_ATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life.

A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type K_ATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays.

Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the K_ATP channel by 40%, categorising this as a loss-of-function mutation.

Our data support the increasing evidence that individuals with mild loss-of-function K_ATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of K_ATP channel mutations in cases of atypical diabetes.

Post-transplant diabetes mellitus (PTDM) is a common complication after transplantation. We aim to explore potential risk factors of PTDM and its association with outcomes after lung transplantation (LTx).

A retrospective study was conducted in 100 patients who underwent LTx at our institution from 2017 to 2021. Patients' information was collected, and genotyping for single nucleotide polymorphisms known to potentially increase the risk of Type 2 DM was performed. Univariate and multivariate analyses were conducted to identify risk factors for PTDM. The primary outcome was the incidence of PTDM. Secondary outcomes were associations between PTDM and clinical outcomes following LTx.

Thirty-nine patients (39.0%) developed PTDM, while 10 patients (25.6%) recovered subsequently. The incidence of PTDM was associated with age > 45 (HR: 2.919, 95% CI [1.021-8.348]), pre-transplant HbA1c > 5.7% (HR: 2.344, 95% CI [1.201-4.573]), KCNJ11 rs5215 (HR: 2.090, 95% CI [1.050-4.162]) and tacrolimus concentration > 8 ng/mL in the first month (HR: 2.090, 95% CI [1.050-4.162]). Patients with PTDM experienced elevated fasting blood glucose levels (FBG) during the first month post-transplantation (p < 0.001), and required a longer duration for FBG to return to normal levels (p < 0.001). However, the presence of PTDM did not significantly impact renal function, incidence of infection episodes, chronic lung allograft dysfunction or mortality following LTx.

Advanced age, elevated HbA1c levels, KCNJ11 gene polymorphism, and early exposure to tacrolimus are all significant risk factors for PTDM following LTx. The clinical implications of these factors warrant attention.

Vascular smooth muscle K_ATP channels critically regulate blood flow and blood pressure by modulating vascular tone, and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular K_ATP) over Kir6.2/SUR1 (pancreatic K_ATP) has alluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N-aryl-N'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC₅₀ of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus (DA) vessels, VU0542270 induced DA constriction in a dose-dependent manner similar to that of the non-specific K_ATP channel inhibitor, glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific K_ATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. Significance Statement Small-molecule inhibitors of vascular smooth muscle K_ATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis, however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, we describe the discovery and characterization of the first vascular-specific K_ATP channel inhibitor, VU0542270.