Donald McClain
Professor of Medicine and of Biochemistry
B.A. Harverford College
Ph.D. Rockefeller University
M.D. Cornell University Medical College
Research
Our laboratory studies the molecular basis for type 2 diabetes mellitus and its complications that result from elevated levels of blood glucose. We focus upon the pathways by which glucose normally regulates transcription and protein function through the hexosamine pathway of glucose metabolism. By artificially increasing hexosamine flux, we were able to induce changes in the tissues responsible for fuel homeostasis that were identical to those induced by excess nutrients. Furthermore, the animals also developed the central phenotypic characteristics of type 2 diabetes as they aged. These include obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia, and elevations of leptin. We have shown that the basis for these effects is the modification of cytosolic and nuclear proteins by O-linked GlcNAc. This occurs in many cases on sites otherwise used for phosphorylation. Thus, the hexosamine pathway acts as a "damper" on acute phosphorylation-mediated signaling, minimizing rapid fluctuations in metabolic fluxes in cases of chronic nutrient excess.
We are currently engaged in work to more fully characterize the biochemical basis for these changes, concentrating on the transcriptional regulation, activation and subcellular partitioning of key enzymes of fuel homeostasis such as glycogen synthase.We have demonstrated that the O-GlcNAc modification on glycogen synthase occurs in a dynamic fashion and mimics phosphorylation, thus inactivating glycogen synthase. Insulin, however, which normally stimulates glycogen synthase by dephosphorylating the enzyme, does not stimulate deglycosylation. Thus, the enzyme is inactivated in an insulin-resistant manner, possibly accounting for insulin resistance in type 2 diabetes. We are currently mapping the sites of this modification on glycogen synthase, and studying the modification of other key proteins in metabolic regulation such as AMP-dependent kinase. We are also investigating the effects of changes in hexosamine flux in other tissues such as insulin-secreting beta cells.
Our laboratory also studies the mechanisms by which oxidant stress adversely affects cells in diabetes. Our model is the human disease hemochromatosis wherein iron overload occurs due to unregulated iron absorption in the gut. We are studying the mechanisms of diabetes in these individuals and in a knockout mouse model. Mitochondrial dysfunction occurs, and its mechanism is under investigation.
References
1. McClain DA, Abraham D, Rogers J, Brady R, Gault P, Ajioka R, Kushner JP (2006) High Prevalence of Abnormal Glucose Homeostasis Secondary to Decreased Insulin Secretion in Individuals with Hereditary Hemochromatosis. Diabetologia 49:1661-9
2. Cooksey RC, Pusuluri S, Hazel M, McClain DA (2006) Hexosamines Regulate Sensitivity of Glucose-Stimulated Insulin Secretion in Beta Cells. Am J Physiol (Endocr and Metab) 290:E334-340
3. McClain DA, Hazel M, Parker G, Cooksey RC (2005) Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid. Am J Physiol (Endocr and Metab)288:E973-979
4. Cooksey RC, Jouihan HA, Ajioka RS, Hazel MW, Jones DL, Kushner JP, McClain DA (2004) Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology 145:5305-12
5. Hazel M, Cooksey RC, Jones D, Parker G, Neidigh JL, Witherbee B, Gulve EA, McClain DA (2004) Activation of the hexosamine signaling pathway in adipose tissue results in decreased serum adiponectin and skeletal muscle insulin resistance. Endocrinology145:2118-28
6. Parker GJ, Lund KC, Taylor RP, McClain DA (2003) Insulin resistance of glycogen synthase mediated by o-linked N-acetylglucosamine. J Biol Chem 278:10022-7
7. McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA (2002) Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci USA 99:10695-9
8. Tang J, Neidigh JL, Cooksey RC, McClain DA (2000) Transgenic mice with increased hexosamine flux specifically targeted to beta-cells exhibit hyperinsulinemia and peripheral insulin resistance. Diabetes 49:1492-9
9. Veerababu G, Tang J, Hoffman RT, Daniels MC, Hebert LF Jr, Crook ED, Cooksey RC, McClain DA (2000) Overexpression of glutamine: fructose-6-phosphate amidotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance.Diabetes 49:2070-8
