Food as medicine: can we use flavonoids to manage diabetes?

 Michael Houghton & Elizabeth Barber

According to Diabetes Australia, one Australian develops diabetes every 5 minutes, with a total annual impact to the economy estimated to be at least $14.6 billion AUD. Type 2 diabetes is a disease in which the pancreas fails to make enough insulin to maintain steady glucose levels in the body. As a result, blood glucose levels become chronically elevated and spike erratically following a meal. Type 2 diabetes is managed through diet, exercise and medication; otherwise, poor management can lead to complications of diabetes, such as progressive damage in the heart and blood vessels, kidneys, eyes and nerves, and eventually death. 

Whilst there are a number of effective drugs to treat diabetes, their use is controversial due to unclear benefits outweighed by uncomfortable side effects. Acarbose is a FDΑ-approved drug that works by inhibiting carbohydrate digestive enzymes, particularly alpha-glucosidases in the small intestines. Alpha-glucosidase works by breaking down disaccharides into monosaccharides (absorbable sugar units). As seen in Figure 1, by inhibiting alpha-glucosidase, acarbose can slow down the rate of carbohydrate digestion and glucose absorption, improving the management of diabetes. This drug, however, comes with some unpleasant side effects due to over-inhibition of the enzymes and an excess of undigested carbohydrates reaching the bowel, resulting in bloating, cramping, flatulence and abdominal pain.

A number of plant-derived bioactive compounds, called polyphenols, have been shown to improve biomarkers of diabetes, among the most promising of which are flavonoids, with mean intake worldwide in the range of 150 - 600 mg/day. Food-derived flavonoids not only show extremely low toxicity but also possess no evident side effects and so these compounds are a promising alternative to drugs such as acarbose. Several flavonoids, found in tea, cocoa and various fruits and vegetables, have been shown to inhibit alpha-glucosidases of various non-human sources. Limited studies have been conducted using human enzymes due to ethical issues in obtaining biopsies of the intestine, with enzymes sourced from rodents and microbes used instead. However, these data can be inaccurate when translating the effects of potential inhibitors to humans in vivo.

Since enzyme inhibition varied between species and substrates used, our study aimed to evaluate the inhibition of three types of human alpha-glucosidases by several flavonols (a sub-class of flavonoids), compared with acarbose and EGCG (a tea flavonoid known for its inhibitory potential on sucrase and maltase). The flavonols used were quercetagetin, kaempferol, galangin and quercetin and these can be found in spinach, kale, berries, beans, tea, broccoli, onions, herbs and spices.

The three types of human alpha-glucosidases investigated individually in our study were isomaltase, sucrase and maltase (see Figure 2). Isomaltose is a rare disaccharide in nature and so isomaltase has been less studied than sucrase and maltase. However, isomaltose is often added to foods as a low-caloric sweetener during industrial-scale production, so assessing the inhibitory potential of flavonoids and acarbose on all three enzymes is of particular interest. 

Figure 2. 

In our study, we extracted alpha-glucosidase enzymes from human gut cells grown in the lab. In a controlled environment, we measured the ability of these enzymes to break down sucrose, maltose or isomaltose in the presence of the tested flavonoids (including EGCG) and acarbose. A high-performance ion chromatography system was used to measure the sugars present, especially glucose, for the experiments. The inhibitory potentials of flavonoids were calculated based on the rate of glucose produced when measuring the activity of the alpha-glucosidase enzymes.

Our results found:

-        All compounds inhibited human sucrase, maltase and isomaltase to varying degrees in a dose-dependent manner, at concentrations that may be found in the human intestinal lumen.

-        Quercetagetin is a strong human alpha-glucosidase inhibitor, similar to acarbose, followed by kaempferol and galangin, which are more potent than quercetin and EGCG (acarbose ≥ quercetagetin > galangin ≥ kaempferol > quercetin ≥ EGCG).

-        We established that certain structural properties of flavonoids (i.e. an additional hydroxyl group in quercetagetin) enhance their inhibitory potential.  

-        Our experimental approach using human intestinal cells and advanced and sensitive technology is superior to previous studies assessing the inhibitory potentials of flavonoids and provides more accurate outcomes.

This study highlighted that flavonoids are inhibitors of human sucrase, maltase and, notably, isomaltase, providing a rational basis for using flavonoids from dietary sources as antidiabetic compounds. 

We plan to screen more polyphenols for their inhibitory potential of human alpha-glucosidases and alpha-amylases (starch digestive enzymes) using this superior approach, either individually or synergistically. From here, we will perform human intervention studies with combinations of flavonoids or flavonoid-rich foods representing increased intake of fruit and vegetables (> 500 mg/day), to evaluate the translation of our in vitro results to the clinical setting for the management of blood glucose levels following a meal. 

 

Publication information - You can find more about this research here.

Barber, E.; Houghton, M.J.; Williamson, G. Flavonoids as Human Intestinal α-Glucosidase Inhibitors. Foods 2021, 10, 1939. https://doi.org/10.3390/foods10081939

Dr Michael Houghton is a Research Fellow in the Department of Nutrition, Dietetics and Food at Monash University with a background in cell metabolism, biochemistry and molecular nutrition. His research, under the supervision of Prof Gary Williamson, is focused on the association between biologically active dietary components, metabolism, the gut microbiome and chronic disease risk factors, specifically in metabolic diseases and, more recently, in COVID-19. He is the Departmental expert in cell culture, ion chromatography, droplet digital PCR, automated Westerns, advanced plate reader assays and cell respirometry. In addition to his research, Michael has guest lectured for several BSc and MSc units, is currently co-supervising two PhD students and he chairs the multi-institutional, interdisciplinary Monash Health Translation Precinct ECR Committee.

 

Dr Elizabeth Barber is a Registered Nutritionist and lecturer in the Department of Nutrition, Dietetics and Food at Monash University. She explores the mechanisms by which functional foods improve metabolic dysfunction and inflammation using advanced molecular nutrition and food science research. Her expertise lies in cell culture, analytical chemistry, molecular and serological assays, clinical study and food and recipe modifications. 

 

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