Biomedical subjects

F Ashcroft

Publications and source records attributed to F Ashcroft.

3 recordsLinked to original sources

PubMed2001

ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis.

Glucose-responsive (GR) neurons in the hypothalamus are thought to be critical in glucose homeostasis, but it is not known how they function in this context. Kir6.2 is the pore-forming subunit of K(ATP) channels in many cell types, including pancreatic beta-cells and heart. Here we show the complete absence of both functional ATP-sensitive K+ (K(ATP)) channels and glucose responsiveness in the neurons of the ventromedial hypothalamus (VMH) in Kir6.2-/- mice. Although pancreatic alpha-cells were functional in Kir6.2-/-, the mice exhibited a severe defect in glucagon secretion in response to systemic hypoglycemia. In addition, they showed a complete loss of glucagon secretion, together with reduced food intake in response to neuroglycopenia. Thus, our results demonstrate that KATP channels are important in glucose sensing in VMH GR neurons, and are essential for the maintenance of glucose homeostasis.

ATP-Binding Cassette Transporters↗

PubMed2000

Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K(ATP) channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.

ATP-Binding Cassette Transporters↗

PubMed1995

AA group dynamics and 12-step activity.

OBJECTIVE: AA groups may differ in perceived social dynamics but little is known about diversity in other potentially curative processes within AA. This study examined how three AA groups differed in perceived social dynamics, group emphasis on the 12 steps of AA, and completion of the 12 steps. METHOD: Questionnaires were completed by AA members affiliated with three mainstream AA groups. Surveys were done after investigators paid several visits to meetings as an aid to identifying group members. A majority of the AA members were male (64%) and had, on average, 45 months of continuous sobriety. RESULTS: Profile analyses showed that the three AA groups differed in perceived group cohesiveness, independence, aggressiveness and expressiveness. The AA groups also differed in how frequently members reported that the 12 steps were discussed in meetings. Step discussion was lowest in the group with highest aggressiveness. Differences were also found in the reported frequency of completing AA steps, such that members in the group with highest cohesiveness and step discussion reported having completed the fewest surrender (1-3) steps. CONCLUSIONS: AA groups appear to differ not only in perceived social environment (fellowship) characteristics, but in AA program implementation as reflected in discussion and completion of the 12 steps. Such differences may be stable within groups across time. These findings further caution against regarding AA as a homogeneous entity. Clearer understanding of the heterogeneity among AA groups may provide bases for initial matching of individuals to AA experiences.

Adult↗