Mary Lynn Formanack, Ph.D.

Research

      Polymorphisms in the two genes encoding the ATP-sensitive potassium channel KATP channel subunits, SUR1 and Kir6.2, cause neonatal diabetes. Normal pancreatic beta-cells, secrete insulin when ATP-binds to and closes KATP channels. Genetic variations which produce gain-of-function amino acid changes in channel proteins prevent proper channel closing and, thus, normal insulin secretion. I have identified several single nucleotide polymorphisms (SNPs) in these two genes which are associated with risk for type 2 diabetes and with reduced insulin secretion in Pima Indians. While none of these SNPs cause diabetes, I am interested in understanding the mechanism by which they increase risk for disease.

     Two SNPs encode amino acid changes in functionally significant domains in SUR1 protein. One of these is located in Nucleotide Binding Fold 1 (NBF1). NBF1 and NBF2 function together, bind and hydrolyze nucleotides, and transmit this signal to Kir6.2. I am examining the mutation’s effects on channel response to ATP and ADP binding. Another missense mutation is located in the C-terminus of SUR1. The C-terminus interacts with Kir6.2. I am investigating this interaction to determine if the mutation has functional consequences.

     Additionally, since environmental factors, for instance, diet and obesity, are known to increase risk for diabetes, I plan to examine these mutated channels for altered response to lipids.