David Rhoads, Ph.D.

Modulating beta cell function: Transcriptional approaches and impact of bariatric surgery

Our two research projects focus on the metabolic disorders of type 2 diabetes and obesity. First, the ability to engineer tissues capable of regulated insulin secretion would be a major advance toward management of T2D. The beta-cell phenotype is established by its unique transcription factor (TF) network, maintained by multiple reciprocal interactions. We postulate that exploiting these interactions can produce enhanced or sustained expression of key beta-cell TFs to improve beta-function or, ideally, to generate regulated insulin secretion in non-beta cells. To this end, we have been constructing gene transfer vectors for beta-cell TFs using their cognate gene promoters. This strategy is envisioned to retain native control mechanism as well as to avoid potentially toxic constitutive or viral promoters. Because native promoters typically have limited activity in gene transfer vectors, boosting their activity was a necessary prerequisite. To date, we have boosted activities of the promoters for hepatocyte nuclear factors HNF1alpha and HNF4alpha, prototypic for pancreatic islet lineage specification and essential for beta-cell differentiation and function, by >500-fold while retaining inducer responsiveness. Efforts are underway to incorporate these features into additional beta-cell TF expression vectors for use in engineering non-beta cells to perform regulated insulin secretion. Our ultimate goal is to achieve sustained transgene expression using native promoters that recapitulate inherent beta-cell regulation.

Bariatric surgery, in particular Roux-en-Y gastric bypass (RYGB), is remarkably effective at resolving T2D associated with morbid obesity. However, the underlying mechanisms for this benefit are not fully known. A better understanding could lead to less invasive or even non-surgical options to achieve similar metabolic benefits, thereby extending a valuable therapeutic option to a wider patient population. To this end, we have been examining the effects on nutrient absorption and neuroendocrine signaling in a rodent model of vagus-sparing RYGB. Recently, we have extended our analyses to the hepatic portal vein, a potential site for nutrient sensing in metabolic control. Ultimately, we hope to identify targets amenable to pharmaceutical control of nutrient absorption in conditions such as obesity and diabetes.

References.

1. Stearns AT, Balakrishnan A, Rounds J, Rhoads DB, Ashley SW, and Tavakkolizadeh A, Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na+/glucose cotransporter SGLT1. Am J Physiol Gastrointest Liver Physiol, 2008. 294(4): p. G1078-83.

2. Stearns AT, Balakrishnan A, Rhoads DB, Ashley SW, and Tavakkolizadeh A, Diurnal expression of the rat intestinal sodium-glucose cotransporter 1 (SGLT1) is independent of local luminal factors. Surgery, 2009. 145(3): p. 294-302. PMCID:PMC2749303

3. 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. PMCID:PMC2855260

4. Balakrishnan A, Stearns AT, Park PJ, Dreyfuss JM, Ashley SW, Rhoads DB, and Tavakkolizadeh A, MicroRNA mir-16 is anti-proliferative in enterocytes and exhibits diurnal rhythmicity in intestinal crypts. Exp Cell Res, 2010. 316(20): p. 3512-21. PMCID:PMC2976799

5. Balakrishnan A, Tavakkolizadeh A, and Rhoads DB, Circadian clock genes and implications for intestinal nutrient uptake. J Nutr Biochem, 2012. 23(5): p. 417-22. PMCID:PMC3331921

6. Bhutta HY, Deelman TE, Ashley SW, Rhoads DB, and Tavakkoli A, Disrupted circadian rhythmicity of the intestinal glucose transporter SGLT1 in Zucker diabetic fatty rats. Dig Dis Sci, 2013. 58(6): p. 1537-45. PMCID: PMC3691300 [Available on 2014/6/1]



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