Fisetin limits the complications of diabetes

The complications of diabetes are the major cause of both morbidity and mortality in patients with the disease. Abnormally high blood glucose (hyperglycemia) level are thought to be a major cause of these complications. The consequences of hyperglycemia include protein glycation which is implicated in many age-related chronic diseases such as cardiovascular diseases and Alzheimer’s disease. It also causes reactive oxygen species (ROS) production and inflammation.

A team lead by Pamela Maher from the Salk Institute, who also identified and characterized the flavonoid fisetin as an orally active neuroprotective and cognition-enhancing molecule, explored in this study whether fisetin can protect in-vivo against hyperglycemia. In vitro testing has shown that fisetin increases the level of the major intracellular antioxidant, glutathione (GSH). In the context of diabetic complications, GSH is an essential co-factor (helper molecule) for glyoxalase 1, the enzyme which is part of the system removing methylglyoxal (MG). MG has negative effects on insulin secretion from pancreatic beta-cells and is a major precursor of advanced glycation endproducts (AGE) as well as other negative consequences. Fisetin can also induce the transcription factor Nrf2 that is associated with the up-regulation of GSH metabolism and the protection of cells from toxic stress.

Maher and team tested the hypothesis that fisetin can prevent the complications of diabetes in vivo in the Akita mouse model of type 1 diabetes. Specifically they looked at the effects of fisetin on the development of diabetic nephropathy (kidney disease) and anxiety symptoms. Worth to note is that other research indicated that diabetic kidney disease is a marker of brain dysfunction in patients with type 1 diabetes.

In the experiments Fisetin was fed to Akita mice between the ages of 6 and 24 weeks in their food at 0.05%, resulting in a daily dose of approximately 25–40 mg/kg.

Based on the analyses and measurements the researchers concluded that oral administration of fisetin increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces at least two major complications of diabetes in Akita mice: reduced kidney hypertrophy and albuminuria (the presence of albumin in the urine, typically a symptom of kidney disease). It also maintained normal levels of locomotion in the open field test.

These findings correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals. The expression of the receptor for advanced glycation end products (RAGE) and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the MG-protein glycation which is associated with diabetes and therefore likely ameliorates multiple complications of the disease.

Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.

Finally to create more perspective we translate the fisetin dosing in the mice to human equivalent doses. The FDA has specified guidelines for this conversion to Human Equivalent Dose (HED).  So starting from the 25-40mg/kg/day dose in the Akita mice we calculate a HED of 2 – 3.3mg/kg/day. For a person weighing 70kg that would result in a daily dosing of 140-230mg. Typical supplements on the market contain 100mg fisetin per serving.

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