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The goal of our laboratory research is to find ways to generate regulated insulin secretion in cells or tissues for pancreatic β-cell replacement therapy in diabetes. Specifically, we predict that understanding the factors underlying the β-cell gene expression program could enable the induction of β-cell functions in other cell types from patients, thereby circumventing problems such as limited tissue supply and immune rejection. To this end, we demonstrated that β-cell selective ablation of the MODY5 gene (for maturity onset diabetes of the young, form 5; encoding the HNF1β transcription factor) compromised glucose-stimulated insulin secretion (1). We further examined the complex regulation of HNF4α, encoded by the MODY1 gene, a target of MODY3 gene product HNF1α (2, 3). Current efforts are directed toward expressing these factors from their native gene promoters as safer alternatives to unregulated viral promoters. To this end, we developed a strategy to substantially boost native promoter activities for use in gene therapy vectors (4).
In related research on mammalian carbohydrate absorption and disposal, our laboratory discovered a robust, anticipatory diurnal rhythmicity in intestinal expression of genes for hydrolytic and absorptive functions, an observation highlighting an important adaptive pathway in intestinal physiology (5). In collaboration with a bariatric surgeon at Brigham and Women’s Hospital, we extended these findings to the effects of disrupted eating rhythms (6), diurnal rhythmicity in drug transport capacity (7), and the identification of a signaling pathway regulating intestinal glucose absorption (8). These studies are relevant to shift work, chronotherapy (timing of chemotherapy), and appetite control. Our current focus is an NIH-funded study to identify the mechanisms by which bariatric surgery rapidly resolves obesity-associated diabetes independent of weight loss, a project designed to find less invasive strategies to manage obesity and glucose intolerance.
- Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, and Rhoads DB, Selective deletion of the Hnf1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology 145(8):3941-9, 2004.
- Huang J, Karakucuk V, Levitsky LL, and Rhoads DB, Expression of HNF4a variants in pancreatic islets and Ins-1 b cells. Diabetes Metab Res Rev, 2008. 24(7): p. 533-543.
- Huang J, Levitsky LL, and Rhoads DB, Novel P2 promoter-derived HNF4a isoforms with different N-terminus generated by alternate exon insertion. Exp Cell Res, 2009. 315(7): p. 1200-11.
- Huang J, Levitsky LL, and Rhoads DB, Boosting native promoter activities with non-adjacent response-element multimers. J Biotechnol, 2010. 150(2): p. 259-67.
- Rhoads DB, Rosenbaum DH, Unsal H, Isselbacher KJ, and Levitsky LL, Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is transcriptionally regulated. J Biol Chem, 1998. 273(16): p. 9510-6.
- Balakrishnan A, Stearns AT, Ashley SW, Tavakkolizadeh A, and Rhoads DB, Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats. J Nutr, 2010. 140(5): p. 908-14.
- Stearns AT, Balakrishnan A, Rhoads DB, Ashley SW, and Tavakkolizadeh A, Diurnal rhythmicity in the transcription of jejunal drug transporters. J Pharmacol Sci, 2008. 108(1): p. 144-8.
- Stearns AT, Balakrishnan A, Rhoads DB, and Tavakkolizadeh A, Rapid upregulation of sodium-glucose transporter SGLT1 in response to intestinal sweet taste stimulation. Ann Surg, 2010. 251(5): p. 865-71.