Phlorizin was extracted from the bark of the apple tree in 1835 as part of the quest for active drugs in tree bark, previous examples being the salicylates and quinine. In 1886 von Mering showed that the drug produced glycosuria, polyuria and weight loss in dogs, thus imitating diabetes. Although intensively investigated at the time, its mode of action remained mysterious until the elucidation of sodium/glucose cotransporter mechanisms in the 1960s. Phlorizin is poorly absorbed when taken by mouth, but is well tolerated in humans by injection, and has been used as a research tool to demonstrate the existence of glucose toxicity. In 1997 Japanese investigators developed the first SGLT inhibitor to be well absorbed by mouth, with the initial aim of inhibiting intestinal absorption of glucose. This, in turn,led to development of the modern range of SGLT inhibitors.
Phlorizin is a natural constituent present in the root bark, leaves and shoots of apple trees, and (to a lesser extent) in the fruit itself. It is also found in other fruit trees including the pear. It may be considered a normal constituent of the human diet, and is partly responsible for the colour and flavour of apple juice and cider.
Chemically, it belongs to the flavonoid family, polyphenolic compounds produced by many plants which act as antioxidants. Phlorizin contains a glucose moiety which binds to SGLT1 and SGLT2 with 2000-3000 times the affinity of glucose itself.
Phlorizin was extracted from the bark of the apple tree in 1835 as part of the quest to identify active drugs in tree bark, previous examples being the salicylates and quinine. It was actively investigated as a potential antimalarial.
In 1886 von Mering demonstrated that doses > 1 gram daily produced glycosuria, and showed that the drug produced glycosuria, polyuria and weight loss in dogs, thus imitating diabetes. Although this generated much interest at the time as a potential insight into the mechanism of diabetes, it soon became apparent that the drug acted only on the renal tract. Nor was there much enthusiasm for the possible therapeutic utility for diabetes of an agent that promoted glycosuria and weight loss.
Elucidation of Countertransport Mechanisms
The currently accepted mechanism (minus a few details) was first proposed by Robert K Crane, who sketched the mechanism on a napkin at dinner. The concept was essentially one of simultaneous transport of two solutes, one of which (sodium) diffuses "downhill" along a concentration gradient, and the other (glucose) "uphill" against a steep gradient via an energy-requiring process. This applied both to the uptake of glucose (and galactose) by SGLT1 in the brush border of the intestine, and to reuptake of glucose by SGLT2 and SGLT1 in the renal tubule.
Phlorizin found a use as a research tool capable of lowering circulating glucose by a non-insulin dependent mechanism. This included the first demonstration of glucose toxicity in 1987, which showed that insulin sensitivity could be restored by simply by lowering elevated glucose levels.
It was also tested as a possible means of disrupting glucose metabolism in cancer cells, based on the hypothesis that it might compete with glucose for entry into such cells.
In 1997 Japanese investigators suggested that inhibiting glucose absorption from the gut might be useful as a means of glucose control in a manner analogous to that of acarbose. Since phlorizin is poorly absorbed by mouth, a range of other compounds were developed and tested, leading up to the modern range of SGLT2 inhibitors.
Safety of Phlorizin
Injected phlorizin is well tolerated in humans, and is in general less toxic than its reputation would suggest. There are however concerns about possible off-target effects. It appears to have unexpected effects upon some tissues in the central nervous system, including glucose-sensing cells in the hypothalamus. Paradoxically, these and other effects upon nervous tissue have been produced in the absence of SGLT2 receptors, suggesting the possibility that other types of glucose transporter might be present.
^ Wikipedia. Sodium-Glucose Transport proteins. http://en.wikipedia.org/wiki/Sodium-glucose_transport_proteins (accessed 13th Nov 2014)
^ Rosetti L et al. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 1987; 79:1510–1515
^ Ehrenkrantz J et al. Phlorizin: a review. Diabetes Metabolism Research and Reviews 2005;21:31-8