Polyherbal dietary supplementation for prediabetic adults: study protocol for a randomized controlled trial

Prediabetes, a disorder for which global prevalence is rapidly increasing [1], affects 38% of people in the United States [2]. People with prediabetes present with slightly elevated glucose levels (i.e., fasting plasma glucose between 100 and 125 mg/dL, glycated hemoglobin/A1c (HbA_1c) between 5.7 and 6.4%, or postprandial glucose between 140 and 199 mg/dL), but not high enough to be considered type 2 diabetes (T2D) [3]. People with prediabetes often do not display physical symptoms; however, prediabetes perpetuates pancreatic β-cell dysfunction [4] and nearly always precedes diagnosis of T2D [3], a disease affecting approximately 9% of adults in the United States [5]. Prediabetes and T2D is often accompanied by comorbid low HDL (high-density lipoprotein) cholesterol and high triglycerides, and is responsible for increased risk of macrovascular disease such as heart disease and stroke. T2D further increases risk for microvascular disease such as retinopathy (which may lead to blindness and other visual problems), nephropathy (which may lead to kidney failure), neuropathy (a leading cause of amputation), and death [2, 6, 5].

Current recommendations for managing prediabetes and preventing progression to T2D remain limited due to very few pharmacological options with favorable safety profiles [7, 8] and the challenges posed in successful implementation and maintenance of certain lifestyle modifications (i.e., increased physical activity, diet, and weight loss) [3, 9].

A number of herbs have been used to manage symptoms related to deleterious changes in glucose metabolism [10‐17]. A number of clinical studies of herbal interventions (i.e., cinnamon, fenugreek, banaba, curcumin, and others) conducted among adult populations with prediabetes have demonstrated improved glycemic control, particularly with regard to reducing fasting blood glucose [18‐25] and postprandial glucose [18, 22, 26‐29], HbA_1c [25, 30, 31], fasting insulin levels [9, 26, 28‐31], homeostatic model of Insulin Resistance (HOMA-IR) [20, 28, 30, 32, 33], and increasing homeostatic model of β-cell function (HOMA-β) [27, 32]. Substantial changes in glycemic parameters typically occur within 12 weeks [34, 35]. Likewise, each of these outcomes have demonstrated significant changes over a 12-week duration in previous trials [19, 20, 22, 28, 29, 33, 36].

Several herbs have also demonstrated benefit in glycemic control in clinical trials among T2D populations. These herbs and herbal extracts include berberine [37‐39], ginseng [40, 41], gymnema [42, 43], banaba [44], cinnamon [24, 45], fenugreek [46], and kudzu [47]. Of these, some have also demonstrated potential benefit for promoting positive changes in lipid markers [37, 48‐60].

Each of these seven plant ingredients may improve glycemic control, and all have a wide history of ethnobotanical use in raw unprocessed, crudely processed, or other preparations [15, 17, 61]. Approximately 80% of the total content of free amino acids in fenugreek seeds is represented by 4-hydroxyisoleucine, and appears to directly stimulate insulin in a glucose-dependent manner [62‐65]. Likewise, in vitro research suggests that some active constituents of the banaba leaf have an insulin-like effect [66, 67]. Lagerstroemin, an ellagitannin present in banaba, may activate insulin receptors [44, 65, 66, 68]. In addition, kudzu likely increases glucose utilization [69] and activates alpha-1 adrenoceptors in the adrenal gland to enhance the secretion of beta-endorphin, resulting in decreased plasma glucose [70]. Gymnema leaves contain oleanane triterpene saponins, which include gymnemic acids [71]. Gymnemic acids appear to reduce intestinal absorption of glucose and may stimulate pancreatic β-cell growth [72, 73]. Gymnema may also have a direct effect on β-cell function, thus resulting in the release of insulin [74]. Further, gymnema may also increase serum C-peptide levels, indicative of a potential increase in endogenous insulin secretion [43].

Other plant ingredients in GlucoSupreme™ Herbal, a commercially available polyherbal dietary supplement, may be responsible for similar mechanisms of action. Polyphenolic polymers, found in cinnamon, appear to potentiate insulin action by increasing phosphorylation of the insulin receptor, thereby increasing insulin sensitivity, which may lead to improvements in blood glucose control and lipid levels. Cinnamon extracts also appear to activate glycogen synthetase and increase glucose uptake [75‐77]. Berberine, another ingredient present in the study treatment, stimulates glucose transport through a mechanism distinct from insulin via increasing GLUT1 activity [78], and improves glucose metabolism through induction of glycolysis related to the inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondrial inhibition that increases the AMP/ATP ratio [38]. Thus, at least some of berberine’s potential effects in the treatment of diabetes derive from stimulation of AMPK activity [79]. Berberine also enhances signaling, notably through increased glucose transporter-4 translocation into the plasma membrane via the enhancement of insulin signaling pathways and insulin receptor substrate-1-phosphoinositide 3-kinase-Akt. In addition, berberine appears to increase glucose-stimulated insulin secretion and proliferation in Min6 cells via an enhanced insulin/insulin-like growth factor-1 signaling cascade. Berberine likely decreases glucose absorption through the intestinal epithelium in part due to its ability to inhibit alpha-glucosidase [80], and may act as an effective insulin-sensitizing and insulinotropic treatment [81]. The chemical structure of berberine and related isoquinoline alkoloids differs from other commonly used hypoglycemic agents, such as sulfonylureas, biguanides, thiazolidinediones (TZDs), and acarbose [38].

Ginsenosides are triterpenoid saponins and the major active constituents of ginseng [82], and target different types of tissues, producing metabolic and other pharmacological responses [40, 83]. Antidiabetic effects demonstrated by ginsenosides present in American ginseng root, including Rb₁ [40, 83, 84], are likely related to their ability to activate peroxisome PPAR-γ, which is responsible for regulation of expression of key genes involved in lipid and glucose metabolism and adipocyte differentiation [83, 85, 86]. The activation of PPAR-γ causes body-wide lipid repartitioning by increasing the triglyceride content in adipose tissue and lowering free fatty acids in circulation, liver, and muscle, thus leading to improvements in insulin sensitivity [40, 83, 87]. Likewise, the transcriptional response of PPAR-γ may result in the recruitment of cofactors which increase insulin-stimulated glucose uptake, and positively regulate glucose metabolism and energy expenditure [83, 88, 89].

TZDs are full PPAR-γ agonists [90] often prescribed in the clinical treatment of T2D, but often result in undesirable side effects [83, 91, 92]. Alternately, the potential antidiabetic effects of the partial PPAR-γ agonist ginsenoside Rb₁ is exemplified through the promotion of adipocyte differentiation via PPAR-γ activation and increased activation of glucose transporter 4 (GLUT4) associated with insulin sensitivity in adipocyte tissue [83, 84, 87]. Therefore, American ginseng may improve insulin resistance by reducing lipotoxicity in muscle and liver through increasing the ability to store lipids in adipocytes, and enhance insulin sensitivity through increase of adipocyte GLUT4 expression [83].

While many of these herbs appear to be promising when used in isolation, the practice of herbal medicine most often utilizes polyherbal combinations for purported synergistic effects [82]. Although a handful of polyherbal dietary supplement formulations [9, 20, 21, 33, 93, 94] have been examined for the improvement of glycemic control among prediabetic populations, no study has yet examined the potential impacts of berberine, ginseng, gymnema, banaba, cinnamon, fenugreek, and kudzu as a polyherbal formulation using a comprehensive panel of validated markers of lipid status and glycemic control (i.e., short-term, medium-term, and longer-term) utilized in both research and clinical practice.

In light of the vast number of commercially available, polyherbal formulas that have not yet been studied, rigorous clinical trials are needed to evaluate the efficacy of commercially available, polyherbal dietary supplements. This remains an especially important research gap since the dosages and ingredients in these formulas are highly heterogeneous and have not been well-examined.

Over 50% of American adults take a dietary supplement for a variety of health-related goals [123]. Glycemic control is a common goal of dietary supplementation, since prediabetes is an increasingly common risk factor for T2D and pharmacological agents are currently limited in the treatment of prediabetes. There is a pressing need to provide evidence-based options to improve glycemic control so as to prevent the burden of T2D, for which costs have increased 41% between 2007 and 2012 in the United States [124]. The Diabetes Prevention Lifestyle Change Program (DPP) delayed T2D incidence in a multicenter randomized controlled trial in the United States. by 58% compared to metformin (31%) over a 4-year period [125]. Further, 15-year follow-up demonstrated DPP participants continued to delay the T2D development by 27% compared to placebo, superior to metformin (18% delay) [126]. Additional beneficial approaches to delay or prevent T2D are needed for people unable to implement broad lifestyle interventions, such as the DPP, or to perhaps supplement these lifestyle changes. Rigorous evaluation of the safety and efficacy of commercially available, polyherbal dietary supplements appears warranted, as these supplements are popular and may be more representative of traditional and modern herbal medicine practice than single herbs in isolation [82, 127]. In light of the evidence supporting the use of some herbal dietary supplement formulations to improve glycemic parameters, the study investigators hypothesize that the polyherbal dietary supplement under study may restore glycemic parameters to normal ranges, irrespective of broad changes in diet or physical activity. Thus, this polyherbal formulation may ultimately be helpful in deterring the incidence of T2D by preventing glycemic parameters from reaching ranges associated with this costly disease. The randomized, double-blinded design is utilized in this study to gain an understanding of the safety and efficacy of this polyherbal dietary supplement on 12-week changes in short-term, medium-term, and comparatively longer-term markers of glycemic function, as measured by validated laboratory assessment of fasting blood glucose and fasting insulin (short-term), fructosamine (medium-term), and HbA_1c (longer-term). In addition, we measure a number of clinically relevant outcomes that capture peak glycemic dysfunction (GlycoMark), insulin resistance, β-cell function, insulin sensitivity (QUICKI), lipid profile (total cholesterol, low-density lipoprotein (LDL), HDL, and triglycerides), inflammation (high-sensitivity C-reactive protein (hs-CRP)), and progression to T2D.

Although the study design is optimized by the selection of a study treatment containing only plant ingredients with demonstrated mechanisms of action (i.e., enzymatic, signal enhancement, etc.) [40, 43, 44, 62‐92, 128], the generalizability of this study cannot be extended to smokers since they were excluded for potential safety concerns. In addition, the small sample size of this proof-of-concept and exploratory study confers a limited scope to examine potential adverse effects, and the possibility remains that investigators may find smaller than anticipated effects regarding outcomes. This may pose a potential limitation in drawing conclusions regarding outcomes. However, the study is designed to detect considerable between-group differences, determined a priori through power analyses and the accommodation of an optional use of adaptive sample size re-estimation. If the planned trial shows beneficial effects on the outcomes, subsequent trials should ideally utilize a larger sample and examine potential longer-term (> 12-week) effects of the study treatment on glycemic control.