Diabetes Regulates Fructose Absorption through Thioredoxin-Interacting Protein

On October 11, a study published in eLife revealed the effects of thioredoxin-interacting protein (Txnip) on fructose absorption and metabolic disease progression in mice models. It has been established Txnip overexpression impairs glucose uptake in peripheral tissues whereas Txnip ablation results in increased glucose uptake.  Txnip is thought to regulate glucose uptake through increased expression of glucose transporter 1 (GLUT1).

Txnip interacts with fructose transporters GLUT2 and GLUT5 and promotes fructose uptake

To determine if Txnip is involved in fructose metabolism, researchers assessed Txnip interactions with GLUT2 and GLUT5 independent of thioredoxin binding and report that simultaneous expression of Txnip and GLUT2 or GLUT5 increased fructose absorption in enterocytes by 16.1% and 16.2%, respectively. Interestingly, overexpression of GLUT2 or GLUT5 alone was not enough to elicit increased fructose absorption.

Based on studies from studies from wild type (WT) or Txnip ablated (Txnip-KO) mice researchers suggest that Txnip expression promotes fructose intake in the small intestines and that the transport of fructose from intestine to the blood stream is reduced when Txnip is not present. Interestingly, researchers found that ablation of Txnip doesn’t affect fructose absorption and availability to other organs and that the small intestine is the primary regulator.

Txnip is necessary for fructose-associated metabolic disorders

Next, researchers sought to determine if knocking out Txnip would result in diminished fructose-associated metabolic disturbances. Both WT and Txnip-KO mice were fed a moderate fat diet (containing .16% fructose) with 30% w/v fructose in their water (FSD). Interestingly, WT mice on the FSD had significantly higher body weight than WT mice on a regular diet. Txnip-KO mice had similar weights regardless of diet. Txnip-KO mice had lower baseline blood glucose (BG) levels. A prolonged FSD resulted in glucose intolerance and insulin resistance in WT mice; Txnip-KO mice fed a FSD demonstrated no such metabolic changes.

Studies to determine risk for liver injury suggest that Txnip-KO mice had “reduced severity of adverse metabolic outcomes associated with a high fructose diet relative to their WT counterparts.”

Fructose induces Txnip expression and interaction with fructose transporters in the small intestine

Next, researchers investigated whether or not a high fructose diet could affect the expression of GLUT2, GLUT5 or Txnip. Both GLUT2 and GLUT5 expression was significantly elevated in the jejunum of WT mice fed a FSD compare to WT mice fed a RD. Similarly, WT mice fed a FSD had higher expression of Txnip. Researchers also found “that the Txnip interaction with the fructose transporters responds to fructose loads…that both fructose transporters are involved in Txnip-mediated fructose transport.”

Insulin-deficient diabetes induced by streptozotocin increased Txnip expression and fructose absorption

It has previously been demonstrated that Txnip expression is greater in people with glucose intolerance or type 2 diabetes (T2DM). Researchers induced type 1 diabetes (T1DM) in both WT and Txnip-KO mice and assessed levels of Txnip expression in the jejunum. T1DM Txnip-KO mice had higher blood glucose levels compared to their non-diabetic Txnip-KO mice. WT T1DM mice had greater levels of Txnip expression than WT non-diabetic mice.  When given radiolabeled fructose, the T1DM WT mice demonstrated increased fructose absorption. There were no observed differences in absorption of radiolabeled fructose between T1DM Txnip-KO and non-diabetic Txnip-KO mice.

Researchers conclude “Our data in combination with other studies suggests that Txnip links glucose homeostasis with fructose transport, as diabetes induce Txnip expression, which promotes fructose absorption. Because excess absorption of fructose contributes to liver fat accumulation and hypertension, our experiments suggest that the diabetic state may contribute to these components of metabolic disease at least in part through Txnip and increased fructose transport.”