Disrupted Circadian Rhythmicity of the Intestinal Glucose Transporter SGLT1 in Zucker Diabetic Fatty Rats
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Intestinal absorptive capacity shows a circadian rhythm synchronized with eating patterns. Disrupting these coordinated rhythms, e.g., with shift work, may contribute to metabolic disease. Circadian expression of nutrient transporters has not been studied in metabolic disease. We studied the circadian rhythm of intestinal transporter sodium glucose co-transporter type 1 (SGLT1) in an obese diabetic rat.
We compared obese Zucker diabetic fatty (ZDF) rats to lean ZDF littermates. Temporal feeding patterns were assessed, then rats were harvested at Zeitgeber (ZT, ZT0 = 7:00 a.m.) 3, 9, or 15 to measure insulin resistance, SGLT1 expression and intestinal glucose absorption capacity. Regulators of SGLT1 (sweet taste receptor T1R2/3; clock genes) were measured to elucidate underlying mechanisms.
Both groups exhibited altered circadian food intake. Obese ZDF rats lost circadian rhythmicity of SGLT1 mRNA expression and functional activity. Lean ZDF rats maintained rhythmicity of SGLT1 mRNA expression but that of functional glucose absorption was blunted. Circadian rhythms of intestinal clock genes were maintained in both groups. Neither group had discernible rhythms of intestinal GLUT2 (glucose transporter) or T1R2 (sweet taste receptor component) mRNA expression. In summary, lean and obese ZDF rats exhibited similar disruptions in circadian feeding. Glucose intolerance was evident in lean rats, but only obese rats further developed diabetes and exhibited disrupted circadian rhythmicity of both SGLT1 mRNA expression and function.
Our findings suggest that disrupted circadian feeding rhythms contribute to glucose intolerance, but additional factors (genetics, changes in nutrient sensing/transport) are needed to lead to full diabetes.
KeywordsCircadian Intestinal glucose sensing Metabolic disease SGLT1
We thank Jan Rounds for invaluable managerial support, and Dr. Carel Le Roux at Imperial College, London, UK for his role as co-educational supervisor to HB. The manuscript has been presented as an oral presentation at the Society of Academic and Research Surgery, Nottingham UK (Jan 2012) and the Academic Surgical Congress, Las Vegas (Feb 2012). It was published in abstract form only in a supplementary issue of Journal of Surgical Research as related to this meeting. This study was funded by National Institute of Health Grant 1 R01 DK084064 (AT) and Harvard Clinical and Translational Science Center 5 KL2 RR025757 (AT).
Conflict of interest
HY Bhutta, TE Deelman, SW Ashley, and DB Rhoads have no conflicts of interest. A Tavakkoli has an equity interest in Avaxia Biologics, a company that is developing oral antibodies for treatment of intestinal disorders, with potential applications for treatment of diabetes and obesity. AT’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies.
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