For me, diabetes is personal. I have family members who are diabetic, and two uncles as well as one of my cousins died from diabetic-related complications. I wrote a book about complementary treatments for diabetes,1 and I am always looking for new strategies to treat diabetes. This article is about such a strategy that I find to be quite compelling, involving a fig fruit extract.

About Diabetes

Diabetes is characterized by high glucose (blood sugar) levels resulting from an inability to make or use sufficient insulin. Diabetic symptoms may include frequent urination, dehydration, blurred vision, increased infections, and increased appetite. In some
cases constant fatigue is the only overt symptom.

Prevalence of Diabetes

According to the American Diabetes Association, in 2018, 34.2 million Americans, or 10.5 percent of the population, had diabetes. Most cases were type 2 diabetes, but nearly 1.6 million Americans have type 1 diabetes, including about 187,000 children and adolescents. Of the 34.2 million adults with diabetes, 26.8 million were diagnosed, and 7.3 million were undiagnosed. The percentage of Americans age 65 and older remains high, at 26.8 percent, or 14.3 million seniors (diagnosed and undiagnosed). Furthermore, the incidence of diabetes doesn’t show signs of slowing with 1.5 million cases diagnosed every year, and about 88 million Americans age 18 and older with prediabetes (metabolic syndrome).2

Ramifications of Uncontrolled Diabetes

The diagnosis of diabetes is based primarily upon blood glucose levels. Typically, this is done by means of a blood test that measures these levels. When high blood glucose levels remain high and largely uncontrolled for a long period of time, the result can be a variety of serious complications. These complications include, but are not limited to, neuropathy (pain in the hands and feet), nephropathy (kidney disease), high blood pressure, cholesterol and triglyceride levels, peripheral vascular disease (including pain when walking and foot ulcers), retinopathy (the leading cause of blindness worldwide), and weight gain and/or obesity.3

Treatment of Diabetes

What you eat and how much you eat of it make all the difference in the world regarding the stability of blood glucose levels. Consequently, it is no surprise that diet is the primary means for helping to control blood glucose levels and diabetes. Other strategies include an exercise program and various medications. This may include oral medications and/or insulin injections. While frequently necessary, such medications are not without potential side effects, so it is often desirable to limit the amount of these medications whenever possible. The use of certain nutraceuticals may help to achieve this and may help in the control of blood glucose levels. One such nutraceutical is fig fruit extract-derived abscisic acid—and its effects are unlike any other glucose control-related nutraceutical I’ve ever researched.

Abscisic Acid

Abscisic acid (ABA) is an isoprenoid molecule (i.e. a class of organic compound composed of two or more units of hydrocarbons, with each unit consisting of five carbon atoms arranged in a specific pattern). In addition to its presence in foodstuffs like fruits and vegetables, ABA is produced and released by several human cell types and through the carotenoid biogenesis pathway. In fact, ABA is an intermediate in human carotenoid synthesis. ABA has also been shown to have multiple physiological effects in mammals’ adaptation to stress, including regulation of carbohydrate metabolism.4

ABA’s Mechanism of Action

One thing that makes ABA so unique is its mechanism of action. ABA upregulates genes that are involved in carbohydrate metabolism. The precise mechanism of action relates to an innovative pathway: ABA binds to the lanthionine synthetase C-like receptor 2 peptide (LANCL2) and initiates cellular signaling and an enzyme cascade.5-7 This ultimately increases the expression of a glucose transporter (GLUT-4), and modulates inflammatory markers. This means that ABA actually promotes positive benefits at the genetic or nutrigenomic level. Likewise, ABA increases the activity of the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR γ) in 3T3-L1 preadipocytes (i.e. pre-fat cells) and that its full antidiabetic effects are dependent on the presence of PPAR γ in immune cells. Collectively, these physiological activities improve blood carbohydrate homeostasis and response to stress,8-10 suggesting adaptogen-like functions. Of course, maintaining healthy blood sugar levels is important for optimal metabolic and neurological functions, and initial research in animals demonstrated efficacy.

ABA in Animal Research

A study11 was conducted in obese diabetic mice to assess the efficacy of ABA in improving glucose homeostasis and suppressing inflammation when administered in combination with rosiglitazone (Ros), an antidiabetic drug that works as an insulin sensitizer by binding to the PPAR in fat cells and making the cells more responsive to insulin. The mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at six and eight weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined. Gene expression was examined on white adipose tissue (WAT) cultured with ABA, Ros or an ABA/Ros combination. The results were that both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. ABA and Ros synergistically increased PPAR γ activity. In conclusion, ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity.

Likewise, other in-vitro and animal research12 also showed beneficial results with ABA. In-vitro experiments in adipocytes (fat cells) demonstrated that ABA- and insulin-stimulated glucose uptake. As compared with insulin, ABA treatment of adipocytes induced lower triglyceride accumulation, CO2 production and glucose-derived fatty acid synthesis. ABA increased mitochondrial content, enhanced O2 consumption and increased the replication of brown adipose tissue (BAT) genes—which is valuable since BAT activation improves glucose homeostasis and insulin sensitivity in humans. A single dose of oral ABA (1μg/kg body weight) increased BAT glucose uptake twofold in treated rats compared with untreated controls. One-month-long ABA treatment at the same daily dose significantly upregulated expression of BAT markers from treated mice compared with untreated controls. These results suggest a role for ABA in the induction and maintenance of BAT activity.

Moreover, in obese mice, ABA treatment improved insulin sensitivity, decreased adipocyte hypertrophy, reduced macrophage infiltration into the white adipose tissue and downregulated pro-inflammatory markers.13,14

Researchers hypothesized that chronic ABA administration might exert a protective effect in a model of neuroinflammation induced by high-fat diet (HFD). This could have value since inhibiting neuroinflammation might also be efficacious in the prevention and/or treatment of neurological disorders of inflammatory etiology such as overweight, obesity and type 2 diabetes. In this study,15 male Wistar rats were fed with standard diet or HFD with or without ABA in the drinking water for 12 weeks. Glucose tolerance test and behavioral paradigms were performed to evaluate the peripheral and central effects of treatments. Results were that the HFD-induced insulin resistance peripherally and increased the levels of proinflammatory markers in in the brain. ABA administration, however, restored glucose tolerance in HFD-fed rats. In addition, chronic ABA treatment rescued cognitive performance in these animals, while not affecting control diet fed animals. The researchers concluded that ABA might become a new therapeutic molecule improving the neuroinflammatory status and insulin resistance.

ABA in Human Research

Research has shown that plasma ABA increases in normal human subjects, but not in diabetic patients, after a glucose load for an oral glucose tolerance test (OGTT).16 This adds arguments to ABA modulation of the physiological response to glucose intake, similarly to insulin and the incretin glucagon-like peptide-1 (GLP-1).The presence of ABA in fruits prompted researchers to conduct a study17 exploring the bioavailability of dietary ABA and the effect of ABA-rich fruit extracts on glucose tolerance in rats and humans. Rats underwent an OGTT, with or without 1 µg/kg ABA, either synthetic or present in a fruit extract. Human volunteers (n=14) also underwent an OGTT or a standard breakfast and lunch, with or without a fruit extract, yielding an ABA dose of 0.85 or 0.5 µg/kg, respectively. Plasma glucose, insulin, and ABA were measured at different time points. Oral ABA was well absorbed and, at 0.5-1 µg/kg, significantly lowered glucose levels and insulinemia in rats and in humans. Thus, the glucose-lowering effect of low-dose ABA in vivo does not depend on an increased insulin release. Researchers concluded that low-dose ABA intake may be proposed as an aid to improving glucose tolerance in patients with diabetes who are deficient in or resistant to insulin.

In similar research18 with humans and mice, the effects of low-dose ABA were tested on the metabolic parameters that are dysregulated in prediabetes and metabolic syndrome (MS). Ten healthy human subjects received 1 µg ABA/Kg body weight (BW)/day as an ABA-rich dietary supplement (55 µg ABA/tablet). The following parameters were examined: 1) the glycemia profile after a carbohydrate-rich meal, with or without supplement, was compared, and 2) fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), and body mass index (BMI) after 75 days of daily supplementation of a habitual Mediterranean diet were compared with starting values. Mice were fed a high-glucose diet with or without synthetic ABA (1 µg/Kg BW) for four months and the same parameters investigated in the human study were compared. Results were that the ABA-rich dietary supplement significantly reduced the area under the curve of glycemia after a carbohydrate-rich meal and FBG, HbA1c, TC and BMI after chronic treatment in humans (see table). ABA-treated mice also showed a significant reduction of HbA1c, TC and body weight gain compared with untreated controls. The combined results led researchers to conclude that the observed improvement of the metabolic parameters can be attributed to ABA. Further, they advocate the use of ABA-rich dietary supplement in prediabetes and/or MS.

After these first two studies, a third randomized, double-blind crossover study19 was conducted.

This study examined the effects of two ABA-containing fig fruit extracts (ABAlife), on glycemic index (GI) and insulinemic index (II) to a standard glucose drink. Ten healthy adults consumed four test beverages containing ABAlife with postprandial glucose and insulin assessed at regular intervals over two hours to determine GI and II responses. Test beverages containing 200 mg ABAlife-50× and 1200 mg ABAlife-10× significantly reduced GI values by -25 percent (P = 0.001) and -24 percent (P = 0.002), respectively. Two lower doses of ABAlife also reduced GI values compared with the reference drink (by approximately -14 percent), but the differences did not reach statistical significance. Addition of ABAlife to the glucose solution significantly reduced II values at all dosages and displayed a clear dose-response reduction: ABAlife-50× at 100 mg and 200 mg (-14 percent (P < 0.05) and -24 percent (P = 0.01), respectively) and ABAlife-10× at 600 mg and 1200 mg (-16 percent (P < 0.05) and -24 percent (P = 0.01), respectively). The two lower doses of ABAlife contained 40 µg ABA, and the two higher doses of ABAlife contained 80 µg ABA. The researchers concluded that ABAlife supplementation is a promising nutritional intervention for the management of acute postprandial glucose and insulin homeostasis, and it should be investigated as adjunctive treatment for glucose management of chronic metabolic disorders such as prediabetes and type 2 diabetes mellitus.

It should be noted that ABAlife is a standardized extract of Spanish dried fig fruit, Ficus carica L., containing one of the highest concentrations of ABA found in nature. Figs are GRAS (generally recognized as safe); ABA is self-affirmed GRAS and was evaluated as a safe substance by the U.S. Environmental Protection Agency (EPA), posing no dietary risks to humans. Ficus carica L. fructus is a permitted plant part in the Belfrit list (i.e. a list of plants eligible for use in food supplements as part of a cooperative project between Belgium, France and Italy).

Conclusion

Diabetes and metabolic syndrome are prevalent in our society, and the ramifications of uncontrolled high blood glucose levels can be devastating. While diet, exercise and prescription medications are part of the standard of care for treating these disorders, the complementary use of ABA can be an extremely valuable and strategic addition to an overall diabetes/metabolic syndrome management program. ABA promotes positive benefits at the genetic or nutrigenomic level, and both animal and human research has demonstrated its efficacy in managing blood glucose levels, insulin response and other healthy metabolic parameters. In particular, ABAlife, a standardized extract of Spanish fig fruit provides a rich source of ABA and has been shown to offer a meaningful adjunct treatment for glucose management of chronic metabolic disorders such as metabolic syndrome (prediabetes) and type 2 diabetes mellitus. VR

References

1 Bruno G. A Guide to Complementary Treatments for Diabetes. Garden City Park, NY: Square One Publishers; 2010.

2 American Diabetes Association. Statistics about diabetes. Retrieved June 19, 2020 from www.diabetes.org/resources/statistics/statistics-about-diabetes#:~:text=Prevalence percent3A percent20In percent202018 percent2C percent2034.2 percent20million,of percent20the percent20population percent2C percent20had percent20diabetes.&text=Undiagnosed percent3A percent20Of percent20the percent2034.2 percent20million,and percent207.3 percent20million percent20were percent20undiagnosed.

3 Bruno G. A Guide to Complementary Treatments for Diabetes. Garden City Park, NY: Square One Publishers; 2010.

4 Zocchi E, Hontecillas R, Leber A, et al. Abscisic Acid: A Novel Nutraceutical for Glycemic Control. Front Nutr. 2017; 4: 24.

5 Bassaganya-Riera J, Skoneczka J, Kingston DGJ, et al. Mechanisms of Action and Medicinal Applications of Abscisic Acid. Curr Med Chem. 2010; 17(5): 467-478.

6 Bassaganya-Riera J, Guri AJ, Lu P, et al. Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ. J Biol Chem. 2011; 286 (4): 2504-2516.

7 Malara A, et al. The Plant Hormone Abscisic Acid Is a Prosurvival Factor in Human and Murine Megakaryocytes. BiolChem. 2017 Feb24; 292(8):3239-3251.

8 Zocchi E, Hontecillas R, Leber A, et al. Abscisic Acid: A Novel Nutraceutical for Glycemic Control. Front Nutr. 2017; 4: 24.

9 Bassaganya-Riera J, Skoneczka J, Kingston DGJ, et al. Mechanisms of Action and Medicinal Applications of Abscisic Acid. Curr Med Chem. 2010; 17(5): 467-478.

10 Bassaganya-Riera J, Guri AJ, Lu P, et al. Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ. J Biol Chem. 2011; 286 (4): 2504-2516.

11 Guri AJ, Hontecillas R, Bassaganya-Riera J. Abscisic Acid Synergizes With Rosiglitazone to Improve Glucose Tolerance and Down-Modulate Macrophage Accumulation in Adipose Tissue: Possible Action of the cAMP/PKA/PPAR γ Axis. Clin Nutr. 2010 Oct;29(5):646-53.

12 Sturla L, Mannio E, Scarfì S, et al. Abscisic Acid Enhances Glucose Disposal and Induces Brown Fat Activity in Adipocytes in Vitro and in Vivo. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Feb;1862(2):131-144.

13 (Guri AJ, Hontecillas R, Si H, Liu D, Bassaganya-Rivera J. Dietary abscisic acid ameliorates glucose tolerance and obesity-related inflammation in db/db mice fed high-fat diets. Clin Nutr (2007) 26(1):107–16.

14 Guri AJ, Hontecillas R, Ferrer G, Casagran O, Wankhade U, Noble AM, et al. Loss of PPAR gamma in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue. J Nutr Biochem (2008) 19(4):216–28).

15 Sánchez-Sarasúa S, Moustafa S, lvaro García-Avilés Á, et al. The Effect of Abscisic Acid Chronic Treatment on Neuroinflammatory Markers and Memory in a Rat Model of High-Fat Diet Induced Neuroinflammation. Nutr Metab (Lond). 2016 Oct 26;13:73.

16 Ameri P, Burzzone S, Mannino E, et al. Impaired Increase of Plasma Abscisic Acid in Response to Oral Glucose Load in Type 2 Diabetes and in Gestational Diabetes. PLoS One. 2015 Feb 27;10(2):e0115992.

17 Magnone M, Ameri P, Salis A, et al. Microgram Amounts of Abscisic Acid in Fruit Extracts Improve Glucose Tolerance and Reduce Insulinemia in Rats and in Humans. FASEB J. 2015 Dec;29(12):4783-93.

18 Magnone M, Leoncini G, Vigliarolo T, et al. Chronic Intake of Micrograms of Abscisic Acid Improves Glycemia and Lipidemia in a Human Study and in High-Glucose Fed Mice. Nutrients. 2018 Oct 12;10(10):1495.

19 Atkinson FS, Villar A, Mulà A, et al. Abscisic Acid Standardized Fig (Ficus carica) Extracts Ameliorate Postprandial Glycemic and Insulinemic Responses in Healthy Adults. Nutrients. 2019 Jul 31;11(8):1757.

Gene Bruno, MS, MHS, the dean of academics for Huntington University of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at [email protected].