This paper reports a young female patient who carried KCNJ11 R136C mutation. She was considered as KCNJ11-MODY and prescribed by metformin, acarbose and glimepiride. Blood sugar control improved significantly.
KCNJ11-MODY is an autosomal dominant diabetes mellitus caused by mutations in KCNJ11 gene, first reported by Bonnefond et al. in 2012. KCNJ11 gene is located at 11p15.1, contains only one exon and encodes Kir6.2 subunit. Kir6.2 contains the binding sites of ATP and phosphatidylinositol 4,5-diphosphate, which can inhibit and activate the channel, respectively.[3, 4] KATP channel on pancreatic β cells couples energy metabolism and electrical activity and plays an important role in the process of insulin secretion. Under sub-stimulus glucose concentration, the membrane potential of β cell is affected by the conductance of the KATP channel, maintaining the cell member potential at a hyperpolarized level. When blood glucose rises, glucose is quickly taken up and metabolized into ATP. ATP binds to KATP channel, closing the channel, depolarizing cell membrane, opening voltage-gated calcium channels, calcium ion influx and triggering insulin vesicles release.
Mutations in KCNJ11 gene affect the activity of KATP channels, causing abnormal insulin secretion in pancreatic β-cells. Activating mutation can cause a decrease in the affinity of ATP to the channel in pancreatic β cells. KATP channel can’t be closed normally under the stimulation of glucose and cell membrane continues to be in a hyperpolarized state. Extracellular Ca2+ can’t inflow and insulin can’t be secreted normally, which leads to a series of continuous and varying degrees of glucose metabolism abnormalities, including neonatal diabetes mellitus, impaired fasting glucose, impaired glucose tolerance and KCNJ11-MODY. Inactivation mutation in KCNJ11 gene can lead to continuous closure of KATP channel, continuous depolarization of β cell membrane, continuous inflow of extracellular Ca2+, excessive secretion and release of insulin, resulting in congenital hyperinsulinism hypoglycemia.
Bonnefond et al. reported among a four-generation family of thirty-seven members, twelve members carried KCNJ11 E227K mutation: three members (aged 11–40 years old) with normal glucose metabolism, and nine members with abnormal glucose metabolism. They were diagnosed with diabetes at the age of 13–59 years old. This mutation can cause a decrease in the sensitivity of ATP to KATP channel. Before that, there were two reports about KCNJ11 mutation causing diabetes. Some patients might also be diagnosed as KCNJ11-MODY. Four members in a three-generation Japanese family carried KCNJ11 C42R and were diagnosed as diabetes, three cases of which were 3, 22 and 26 years old. Functional identification showed that the mutation channel is less sensitive to ATP.  An Italian family carrying KCNJ11 c.679G > C and c.680A > T(p.E227L) was reported, two of which can be considered as KCNJ11-MODY.
Ang et al., Ren et al., Li et al. and He et al. reported MODY13 family trees in Chinese, KCNJ11 c.392T＞C (p.I137T)、c.679G＞A（E227K）、c.602G＞A（p.R201H）and c.142A＞G（p.N48D），but none of mutation channels have been identified functionally. Liu et al. reported three new KCNJ11 heterozygous mutations in three MODY diabetic families: two activating mutations R27H and R192H, one inactivating mutation S116F117del. In vitro studies showed that the sensitivity of KATP channel to ATP carrying R27H or R129H is significantly reduced. The authors also pointed out that KNCJ11 mutation was measured in 3.2% of 96 Chinese families with early-onset type 2 diabetes mellitus.
Most of the reported KCNJ11-MODY patients had successfully converted from insulin to sulfonylureas, which can not only improve blood glucose, reduce medical costs, but also improve the quality of life. The key point lies in the accurate screening and effective identification of KCNJ11-MODY.
It was reported that the mutation of KCNJ11 R136 to other amino acids, such as Arg136His, Arg136Leu, can cause congenital hyperinsulinemia,[14, 15] and the authors didn’t conduct functional studies on related mutations. More surprisingly, Bellann ́e-Chantelot et al. reported that an infant with congenital hyperinsulinemia carried KCNJ11 R136C mutation. Park et al. also reported a Korean infant with congenital hyperinsulinemia carried Arg136Cys and Ala187Val compound heterozygous mutations, but the authors didn’t describe the above two cases in detail. The function of the mutation channel wasn’t been studied. The same mutation in the same site of the same gene cause contrary clinical phenotype, which also reflects the clinical heterogeneity of KCNJ11 gene mutation.
Further studies are required to carry out the functional identification and related research of KCNJ11 R136C to gain a deeper understanding of the clinical heterogeneity.