title: Assessment of insulin sensitivity in adults with permanent neonatal diabetes mellitus due to mutations in the KCNJ11 gene encoding Kir6.2.
abstract: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Klupa
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wanic
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gach
authors.forename: Iwona
authors.initials: I
authors.lastname: Solecka
authors.forename: Jacek
authors.initials: J
authors.lastname: Sieradzki