Maria Sara Remedi
Research Instructor
Address:
Department of Cell Biology and Physiology
Washington University School of Medicine
Box 8228
660 South Euclid Avenue
St. Louis, MO 63110, U.S.A.
Telephone: 314-362-6636
FAX No.: 314-362-7463
E-mail: mremedi@wustl.edu
Research
KATP channels are the critical link between glucose metabolism and insulin secretion in pancreatic b-cells. In humans, activating mutations in the b-cell KATP channel underlie Neonatal Diabetes Mellitus (NDM), disease characterized by persistent hyperglycemia presenting in the first six months of life. By contrast, loss-of-function mutations of b-cell KATP channel subunits (SUR1, Kir6.2) causes congenital Hyperinsulinism of Infancy (HI), a rare disease characterized by high insulin levels in parallel with low blood glucose.
The manipulation by gene transfer of ion channels in pancreatic β-cells or the use of transgenic animals models that we have generated in our laboratory (mice which overexpress, underexpress or have mutations in the KATP channel) give me the exciting possibility to explore in more detail the consequences of KATP channel alterations in the development of type-2 diabetes, NDM or HI. Hyperinsulinemia can precede the development of diabetes and, interestingly, many HI patients can cross-over to a diabetic phenotype in later life. Type-2 diabetes requires interaction of genetic and environmental factors for its development. Since one of the major causal factors in the development of hyperinsulinemia and insulin resistance is the high-fat diet and the consequent obesity, which precede type-2 diabetes in genetically predisposed individuals, I am also interested in the consequences of high-fat feeding on diabetic or hyperinsulinemic transgenic mice. Thus, by feeding transgenic mice with a high-fat diet I can directly examine the temporal progression of β-cell function and the contribution of genetic and environmental factors in the development of these diseases.I am also interested in study KATP channel mutations causing NDM, thus by using a mouse model of KATP-induced NDM I can study not only factor/s involved in the development of the disease, but also the mechanism/s underlying long-term secondary consequences of diabetes.
Better identifying of factors and understanding of how them are involved in the signaling cascade that connects glucose metabolism and insulin secretion could have significant implications in diabetes and HI therapy.
Figure 1. Mice with overactive KATP channel in the pancreas develop severe diabetes, thus reiterating KATP-induced human neonatal diabetes mellitus (NDM). Severe diabetes was accompanied by loss of β-cell mass and insulin content in these mice. Maintenance of normoglycemia by synergic islet transplantation not only prevents the development of diabetes, but also completely avoids the secondary consequences of the disease (see Remedi et al. 2009 Cell Metabolism 9, 140–151) [Abstract].
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