A lot of dietary compounds impact insulin resistance and glucose regulation directly. Many supplements have been proven to work as a "sugar mimetic" by binding to enzymes such as alpha-glucosidase or amylase. These enzymes create sugar from starch, and their inhibition can blunt blood sugar spikes that are detrimental to health. But now, alternate ways to impact blood sugar on a more profound level are being discovered. These ways are independent and possibly superior to simple intestinal starch-to-sugar conversion. Proteins and hormones such as FGF21, GSK-3, GLP-1, GLUT-1, AMPK and SIRT1 are some of the emerging markers we see in the new generation of research on blood sugar management. Interestingly, natural and food-based compounds are being used to address these markers in some recent strong clinical trials.

Fibroblast growth factor 21 (FGF21) is considered a “novel master regulator of the metabolic profile" that controls both lipid and glucose metabolism.¹ FGF21 has been called a “starvation hormone," and behaves dose-dependently in a “U" shape with respect to calorie consumption versus expression. That is, FGF21 is elevated when we are both starving and overfed, but not when we are healthy. FGF21 is also localized in the liver and regulates lipolysis (burning of fat) and GLUT-1, a glucose transporter that promotes glucose uptake into cells that is independent of insulin activity.²

This dual action on both sugar and fat makes FGF21 unique. In short, when we are overfed, our bodies want to store all of the calories we consume as fat because, in the old days, this calorie storage was our key to survival. But in our current overfed state, we want to reduce FGF21 expression in the liver where calories are either burned or stored. This tips the balance of metabolism toward fat and sugar burning—and away from storage. This is a good thing. FGF21 is such an interesting and new target that drug companies such as Eli Lilly have recently performed clinical studies that administered FGF21 directly to humans and found it effective.³

While drug treatments for diabetes are years away, natural compounds found in our diet are already known to impact FGF21 in in-vivo models. For example, a vegetable often used in Asian stir-fry dishes called bitter melon is also a key part of Ayurveda in India. Known as karela, this cucumber cousin is supported by a relatively strong body of literature for blood sugar reduction. But now we are learning bitter melon’s benefits may go beyond blood sugar support and have effects on a central regulator of energy metabolism.

For example, recent data published by researchers from the renowned Pennington Biomedical Research Center in the journal Scientific Reports found mice fed a high-fat diet with a standardized bitter melon (Momordica charantia) extract experienced reduced FGF21 levels in liver and blood along with improved blood glucose and insulin levels.⁴ The subjects consuming the extract did not gain as much weight as the control groups, and they also showed increased liver levels of AMPK and SIRT1. These are both markers associated with calorie restriction and longevity in trials using resveratrol.⁵ It has been suggested by some researchers that effects on markers such as FGF21 may also relate to longevity due to their connection with sirtuins.

In other research, scientists looked at what goes on in the brain during blood sugar regulation. The brain is often overlooked as a target for blood sugar control, but emerging evidence suggests the body’s command center is critical to the ultimate control of blood sugar and insulin regulation in multiple ways. The brain controls feelings of hunger that we measure as satiety, but the brain also helps control energy metabolism from sugars and fat in peripheral organs, such as the liver and stomach.

For example, new research on an under-represented form of cinnamon has renewed interest in the brain as a target for blood sugar management. While a strong body of research supports the use of Chinese or cassia cinnamon bark extracts for reducing blood sugar, new research suggested use of its sister cinnamon, considered the "true" cinnamon or Cinnamomum zeylanicum may be useful for regulation of blood sugar from within the command center of the brain.

This new research suggested insulin resistance in the brain may actually dictate what is going on in the rest of the body. In a study published by researchers in Germany in the March 2014 issue of PLoS One, essential oil components eugenol and cinnemaldehyde from true cinnamon, in addition to an alcohol extract of C. zeylanicum, appeared to improve the marker GSK-3 and reduce insulin sensitivity in the brains of obese mice.⁶ The subjects in this study were bred to be obese and were fed a high-fat diet, a model that closely mimics the genetic and lifestyle predispositions of many Americans. Most interesting, the effects by the true cinnamon extract were accompanied by increases in brain activity that, according to the authors, “let obese mice move more and made them more awake."  Alcohol-soluble cinnamon extractives were therefore credited in this study to improve blood sugar regulation from a new pathway—by controlling insulin resistance and GSK-3 from inside the brain. 

Speaking of the brain, glucagon-like peptide 1 (GLP-1) is another central hormone that controls nearly all of the relevant physiological functions after eating a meal, including feelings of hunger (satiety) in the brain. GLP-1 also resides in fat cells and the liver where it signals to calorie burning pathways, and helps in cardiovascular and blood pressure support.⁷ In a 2013 study on a combination of thermogenic nutrients such as red pepper, green tea and L-carnitine, both GLP-1 and satiety increased versus placebo following a standardized meal.⁸ Ingredients that are often considered to exert completely different effects from each other, such as curcumin, barley and polyunsaturated fatty acids like omega-3s have each improved GLP-1 in powerful and relevant studies.^9,10 This research suggests that there are different types of compounds which can address the same endpoint of GLP-1.

We have all of these profound markers now, whose roles continue to be uncovered, and whose activities in clinical trials continue to be evaluated. We are truly in a golden age of nutrition research, and we are fortunate that many are increasingly recognizing dietary compounds to have the same potential as many drugs. While we stand on the shoulders of giants, we hope and anticipate that the last decades of nutritional research are only an indicator of the future.

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