A Look at Several Evidence-Based Nutrients Aimed at Regulating Glucose Levels, Improving Insulin Function, and Lowering HbA1c Levels
The prevalence of metabolic dysregulation, namely type 2 diabetes mellitus (T2DM), is increasing at alarming rates, particularly for younger persons. Prior to 2020, the U.S. and the UK were seeing a decline in new cases of T2DM, but that trend is now beginning to reverse. Some researchers hypothesise that these increases are related to challenges that the COVID-19 pandemic has presented. Patients may joke about their lab results, claiming that their less-optimal levels are due to quarantine weight or lifestyle changes. Even when attempting to share a laugh, there can be much truth in those statements. The pandemic has led to many people consuming less-nutritious foods and decreasing their activity levels, which can both disrupt metabolic health.
These lifestyle choices are far from the sole aetiology of increasing blood sugar levels across the U.S. and the UK. Recent years have also caused many people unprecedented and unrelenting stress. Chronic stress is a known risk factor for cardiovascular disease and T2DM. Stress can potentially influence someone’s lifestyle factors, including diet and exercise habits, which can account for some of the dysregulation. Additionally, stress leads directly to glucose dysregulation and increased inflammation in response to chronically elevated cortisol levels.
Markers of metabolic health and signs of early metabolic syndrome should be at the forefront of every integrative practitioner’s mind right now. Healthy glucose metabolism is a significant predictor of overall health and mortality; additionally, we know that COVID-19 infections may have more devastating effects in people with elevated blood glucose levels. Researchers are also observing a curious trend in patients who have previously been diagnosed with COVID-19, particularly in those who were hospitalised. It is estimated that almost half of the patients admitted to the hospital for COVID-19 are seeing new-onset hyperglycaemia. Blood sugar elevations frequently last for months after the infection has subsided, with as many as 35% of cases lasting six months or more. This data leaves many physicians wondering if there will be a new wave of diabetic patients as this pandemic subsides.
Given the link between T2DM and the current health landscape, it’s now even more important to intervene when a patient presents with markers indicating early or advanced glycaemic dysregulation. Many of these patients may be resistant to medications or may present in the early, prediabetic stage, yet may be in desperate need of intervention beyond diet and lifestyle management for effective results. In these cases, it’s essential to look to alternative options, such as botanicals and nutraceuticals, that may offer better results than diet and exercise alone.
Chromium is a trace mineral that’s often overlooked but of utmost importance for proper blood sugar regulation. Low chromium levels are associated with impaired glucose and insulin function, and, subsequently, T2DM. Physicians first noticed the importance of chromium for glucose tolerance with patients receiving long-term total parenteral nutrition (TPN). TPN patients developed symptoms of diabetes, yet their symptoms would not respond to insulin administration. However, they improved when supplemented with chromium, suggesting that the chromium deficiency may be a source of symptoms of glucose dysregulation; this spurred on a much-needed area of study for diabetic patients.2
More recent research has shed light on chromium’s mechanisms as an integral part of blood sugar regulation. Chromium increases insulin receptor numbers and affinity, allowing for increased insulin binding to cells. Chromium also activates intracellular signaling pathways involved in glucose transporter 4 (GLUT4) translocation, increasing glucose transport and enhancing insulin sensitivity. Long-term chromium supplementation leads to improved glucose tolerance because it potentiates insulin in the cell.
Chromium has also been shown to have acute effects clinically, with multiple studies documenting improved postprandial glucose levels when supplemental chromium was ingested with the meal.3 Clinical trials have shown that chromium supplementation levels above 200 mcg daily are effective for improving glucose profiles and that chromium picolinate or polynicotinate are the most efficacious forms.2
Biotin can be an important adjunct vitamin to chromium in blood sugar regulation. It has been shown to increase the efficacy of chromium when used to address blood glucose levels.3 In clinical trials, pairing biotin with chromium has improved haemoglobin A1c (HbA1c) and fasting glucose levels and has led to decreases in current prescription medications for diabetic patients.3 These results may be due to biotin’s essential role in carbohydrate metabolism.3
Biotin functions as a gene modulator, as it alters gene expression. Proposed mechanisms for biotin’s hypoglycaemic qualities include upregulation of hepatic and pancreatic glucokinase expression. Glucokinase is a critical enzyme that regulates glucose uptake by the liver and regulates insulin secretion in response to changes in blood glucose concentration. Biotin upregulates insulin production through these mechanisms in the presence of elevated glucose.7
Biotin deficiencies have been linked to impaired glucose tolerance tests and decreased glucose utilisation, while supplemental biotin, particularly when paired with chromium, is linked to better glucose regulation. In one randomised controlled trial, 447 subjects with poorly controlled T2DM were given 600 mcg of chromium picolinate paired with 2 mg of biotin, or a placebo. Improvements in HbA1c and fasting glucose levels were significantly higher in the treatment group vs. placebo. Multiple studies have revealed similar results, suggesting that biotin and chromium can be used in concert to enhance their properties of glucose regulation.
Fraxinus excelsior L. (Ash; European Ash)
Many practitioners might not readily recognise this botanical. Still, ash has a long history of traditional use as a hypoglycaemic agent, particularly in the tree’s native North Africa. Locals know of the seeds as a health-promoting food and consume them regularly in their diets. While the exact mechanisms of ash remain unknown, some researchers suggest that the glycoside flavonoids present in it partially inhibit intestinal glucose uptake.
In clinical studies, ash has performed quite remarkably. One study looked at the effects of a liquid extract of ash seed on glucose-induced postprandial hyperglycaemia in healthy, nondiabetic volunteers. The glycaemic curve for the treatment group showed a gradual improvement over the first two hours following glucose ingestion compared to the placebo group.9 Another randomised, crossover, double-blind, placebo-controlled study utilised a branded standardised extract of ash to observe its effects on insulin sensitivity and glycaemic homeostasis for overweight individuals aged 50 to 80 years old, a cohort with a high risk of diabetes development. Researchers observed that it resulted in a remarkable reduction (28%) in glucose area under the curve (AUC) values compared to the placebo group. There were no changes to insulin levels in any of the studies mentioned above, suggesting that ash inhibits glucose uptake without impacting insulin sensitivity. Likely due to this mechanism of action, ash has a very high safety profile while effectively moderating postprandial glucose levels, positioning it as both a preventative and an interventional agent.
Berberine is well known as a metabolic gem in integrative medicine. It is an alkaloid, bright yellow in colour, with a bitter taste that is a constituent of European barberry, goldenseal, Oregon grape, phellodendron, and other commonly used herbs. Berberine’s mechanism for lowering blood glucose rests in its ability to increase insulin receptor expression. Research also suggests that berberine increases adenosine monophosphate (AMP)–activated protein kinase activity, stimulating glucose uptake in the muscles and reducing glucose reproduction in the liver. There is also some evidence that berberine increases glucagon-like peptide 1 secretion in animal models.
Berberine’s multiple mechanisms of glycaemic control are consistent with its results in clinical trials. Form is important when it comes to berberine’s mechanisms. Berberine HCL possesses more profound metabolic effects, while berberine sulfate produces a stronger antimicrobial response commonly achieved through some berberine containing botanicals. One clinical trial found supplementing 500mg of berberine three times daily comparable to metformin in individuals with newly diagnosed T2DM. Each of the measured parameters—which included HbA1c, fasting blood glucose, postprandial blood glucose, and plasma triglycerides—were found to significantly improve in both the berberine group and the metformin group. Multiple clinical studies have repeated these results, with berberine consistently showing a reduction in both blood glucose and lipid profiles. Berberine is certainly worth considering as a supplemental agent for patients struggling with impaired blood glucose regulation.
Insulin resistance and blood sugar dysregulation can be dangerous and deadly, possibly even more now than before. Unfortunately, we often see these conditions progress rather than regress unless interventions are made. It is well documented that diet and lifestyle play a significant part in the onset and progression of diabetes and metabolic syndrome. Those interventions should always be discussed and implemented, as they are of utmost importance, particularly for the truly integrative approach. However, some patients might find these challenging and might need supportive options while incorporating new lifestyle changes that may take time to become second nature. When working with a patient who desires a natural approach to diabetes or blood sugar dysregulation but could use some speedy results, consider integrating one or all of these options. In doing so, you could support healthy insulin levels, postprandial glucose levels, and fasting glucose levels, and an improved HbA1c.
 Centers for Disease Control and Prevention. Diabetes Report Card 2019. Atlanta, GA: Centers for Disease Control and Prevention, U S Department of Health and Human Services; 2020. Available from: https://www.cdc.gov/diabetes/pdfs/library/Diabetes-Report-Card-2019-508.pdf
 Hackett RA, Steptoe A. Psychosocial Factors in Diabetes and Cardiovascular Risk. Curr Cardiol Rep. 2016;18(10):95.
 Tudpor K, et al. Psychological Stress Is a Risk Factor for Type 2 Diabetes Mellitus in College Students. Stud Health Technol Inform. 2021;285:296-99.
 Lima-Martínez MM, et al. COVID-19 and diabetes: A bidirectional relationship. Clin Investig Arterioscler. 2021;33(3):151-7.
 Negahdaripour M. Post-COVID-19 Hyperglycemia: A Concern in Selection of Therapeutic Regimens. Iran J Med Sci. 2021;46(4):235-6.
 Montefusco L, et al. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection. Nat Metab. 2021;3(6):774-85.
 Sirtori CR, et al. Nutraceutical approaches to metabolic syndrome. Ann Med. 2017;49(8):678-97.
 A scientific review: the role of chromium in insulin resistance. Diabetes Educ. 2004;Suppl:2-14.
 Anderson RA, et al. Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia. Metabolism. 1987;36(4):351-5.
 Paiva AN, et al. Beneficial effects of oral chromium picolinate supplementation on glycemic control in patients with type 2 diabetes: A randomized clinical study. J Trace Elem Med Biol. 2015;32:66-72.
 Fernandez-Mejia C. Pharmacological effects of biotin. J Nutr Biochem. 2005;16(7):424-7.
 Albarracin CA, et al. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev. 2008;24(1):41-51.
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 Visen P, et al. Acute effects of Fraxinus excelsior L. seed extract on postprandial glycemia and insulin secretion on healthy volunteers. J Ethnopharmacol. 2009;126(2):226-32.
 Montó F, et al. Action of an extract from the seeds of Fraxinus excelsior L. on metabolic disorders in hypertensive and obese animal models. Food Funct. 2014;5(4):786-96.
 Zulet MA, et al. A Fraxinus excelsior L. seeds/fruits extract benefits glucose homeostasis and adiposity related markers in elderly overweight/obese subjects: a longitudinal, randomized, crossover, double-blind, placebo-controlled nutritional intervention study. Phytomedicine. 2014;21(10):1162-9.
 Zhang H, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59(2):285-92.
 Coughlan KA, et al. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014;7:241-53.
 Lu SS, et al. Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats. J Endocrinol. 2009;200(2):159-65.
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