GLUCOSE TRANSPORT REGULATION IN SMALL INTESTINE

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Intestinal expression of the high-affinity Na+/glucose cotransporter (SGLT1), which is responsible for the absorption of dietary glucose and galactose, exhibits both circadian periodicity in its activity and induction by dietary carbohydrate. Because the daily variation in SGLT1 activity is established by the feeding schedule (whether ad libitum or imposed) and persists in the absence of food, this variation has been described as anticipatory. We provide evidence indicating a genetic basis for this anticipatory rhythm. The normal daily periodicity in SGLT1 expression has been examined in rats maintained in a 12-h photoperiod and allowed free access to chow. SGLT1 mRNA levels varied up to 10-fold, with the maximum abundance occurring near the beginning of the dark phase of the photoperiod and the minimum near the onset of light. SGLT1 transcription also changes, with the rate estimated densitometrically (relative to -tubulin) 6.4 q 1.0 times greater between 1000 h and 1100 h than between 1600 h and 1700 h (n=4; p<.007, 2-tailed t-Test). We cloned the rat SGLT1 proximal promoter region and identified an element for hepatocyte nuclear factor 1 (HNF-1) conserved between rat and human. A probe generated from this element formed different complexes with small intestinal nuclear extracts, depending on when the source animal was killed. Serological tests indicated that HNF-1a was present in all complexes, while HNF-1b was present at 1600 h and 2200 h but not at 0400 h or 1000 h. We propose that exchange of HNF-1 dimerization partners contributes to circadian changes in SGLT1 transcription. This expanded role for HNF-1 implicates this homeoprotein in temporal pattern formation in addition to its canonical role in spatial pattern formation. because we have also observed differential SGLT1 mRNA levels in rhesus monkeys (off-set by approximately one-half day from rats), we suggest that a similar mechanism is present in primates. This study has been accepted for publication by the Journal of Biological Chemistry. An RO1 grant is pending to extend these studies (NIDDK).