A review on comparative study between metformin and hesperidin in the management of diabetic complications

Rohit Chettri¹, Sushil Gurung¹, Sairashmi Samanta¹, Royan Chhettri¹

Introduction

Diabetes mellitus (DM), an endocrinological disorder that stems from altered glucose metabolism and poorly managed hyperglycemic state over prolonged period of time. The branching of this typical endocrinological disorder is divided mainly into two types Type I DM (IDDM) resulting in inadequate release of insulin in response to glucose & Type II DM (NIDDM) resulting in insulin resistance where the insulin becomes unresponsive [1]. In developing countries like India, the prevalence of type-2 DM is flaring and is expected to rise from 25.2 million to 35.7 million cases by the year 2045 [2]. Insulin Resistance with improper glycemic control comes with a wide range of complications in the vasculature system categorized as micro (nephropathy, neuropathy & retinopathy) & macro (coronary heart failure, peripheral artery disease and stroke) vascular complications [3]. These complications moreover minimize the life quality and hastens the occurrence of disability & discomfort [4]. Sedentary lifestyle and obesity have been the major risk associated with the development of DM more common in developed and developing nations [5]. Still the etiopathological mechanism has not been well established for understanding the development of DM as is thought to be occurring from multiple factors [6-8]. Research studies has successfully demonstrated the effectiveness of use of oral hypoglycemic drugs in conjugation with lifestyle modulation in reversing type 2 DM associated complications by controlling hyperglycemic state in diabetic patients [9, 10]. But the use of oral hypoglycemic agents comes with a greater disadvantage of inducing hypoglycaemia that may be fatal in some cases thus in the present field of endocrinological research much

(RAGE) that signals downstream cascade to promote the development of diabetic complications [Source data:

greater emphasis is being laid on discovering plant based bioactive compounds for delaying or preventing diabetes associated complications. For example, regular consumption of food rich in flavonoids like Emblica officinalis gaertn fruit can effectively delay the occurrence of diabetic complications as proven recently at our very own institute [11]. Flavonoids are plant-based phytochemical found at a diverse range in pant and its product such as tea, coffee, fruits, vegetables etc. and are well acknowledged for their antineoplastic, antibacterial, antifungal, antihyperglycemic, antiparasitic, neuron preserving, cardio-protective & antiinflammatory activity [12]. Hesperidin (PubChem CID:10621) a bioflavonoid found abundantly in citrus fruits and peels is found to effectively improve plasma glucose levels & insulin levels moreover their anti-oxidative properties enhance its therapeutic importance in ameliorating diabetes-associated complications when used as a dietary supplement [13]. Metformin a well-known st insulin sensitizer is used as 1 drug of choice in management of type 2 DM which has an effective control over high blood glucose levels and also gives a prominent fall in HbA1c levels which are the major precursors for development of advanced glycosylated end products (AGEs) that triggers the synthesis of free radicles as well as activates downstream signaling pathways for development of diabetic complications (Figure 1) [14, 15]. In this review article we went through a systematic review with a series of literatures

MA et al. 2022] [14].

on comparing the effectiveness of plant based flavonoid hesperidin for DM associated secondary complications in contrast to metformin a standard oral hypoglycemic agent used in type-2 DM.

Hesperidin, metformin & secondary complications of diabetes mellitus

Insulin Resistance/Type 2 DM is a complex metabolic condition caused by prolonged high blood sugar levels, leading to changes in how the body processes glucose and fats, as well as dysfunction of the beta cells in the pancreas that contribute to the development of diabetes-related complications [16]. Based upon preclinical and human studies polyphenols such as flavonoids impart an important role in regulating metabolic alteration related to an effective management of diabetic complications [17]. Flavonoids are polyphenolic natural products produced by plant commonly found in fruits, herbs, vegetables, flowers and seeds [18]. Till date more than ten thousand different flavonoids have been discovered and have been well acknowledged for their therapeutic properties [19]. The biosynthesis of flavonoids are known to be brought from phenylpropanoid pathway in plants [20]. Flavonoids (Figure 2) are classified into 7 subtypes structure as anthoxanthins, flavanones, flavanonols, flavans, chalchones, anthocyanidins, and isoflavonoids are the different subgroups of flavonoids [21].

Mengstie

reduced blood glucose and normalized serum insulin function, activated p38 MAPK & inhibited reduced infiltration of inflammatory polymorphonuclear angiogenesis and vasculogenesis.

Among the diverse group of flavonoids hesperidin (hesperetin 7-rutinoside) is a flavanone (Figure 3) found abundantly in citrus fruits such as in peels of Citrus sinensis (orange), Citrus limon (lemon), Citrus paradise (Grapefruit) etc [22].

(GK), levels.

Diabetic Retinopathy- Retinal anti-apoptotic agent (Bax ganglion cell 5 (RGC-5) cell caspase-9 and caspaseculture phosphorylation of JNK.

STZ induced diabetic foot ulcers up-regulation of VEGF in rats cells, ↑ Hesperidin as an anti-diabetic agent acts positively by regulating plasma glucose levels, glucose uptake and insulin secretion moreover also has an important role in diminishing the actions of AGEs which are proteins that undergo glycosylation in the systemic circulation during hyperglycemic state [23-25]. Many preclinical studies with positive results have been established with the use of Hesperidin a flavone glycoside in diabetic complications as discussed (Table 1). Hesperidin is generally considered safe, but one might experience side effects. Gastrointestinal issues like nausea or diarrhoea can occur, and allergic reactions such as skin rashes or itching are possible. It can also affect blood pressure, which may be a concern for those with cardiovascular conditions. Additionally, hesperidin might interact with medications like blood thinners or anticoagulants, potentially increasing bleeding risks [26]. Its bioavailability is relatively low due to poor water solubility and limited absorption in the digestive tract. Factors such as food intake, dosage, and individual gut microbiota can impact its absorption. Researchers are exploring various formulation techniques, including nano-carriers, to enhance hesperidin's absorption and effectiveness [27]. Genetic polymorphisms in enzymes like CYP3A4, UGT1A1, SULT1A1 and variations in drug transporters, such as P- glycoprotein (encoded by the ABCB1 gene) may influence hesperidin’s bioavailability and clearance [28].

& ↓ Bcl-2), down regulation of Wayne 2017 [34] 3, restoration of mitochondrial -c, Ang-1, Tie-2, TGF-β, Smad 2/3, Li 2018 [35] endothelial growth factor & activation of AMPK/SIRT1 forkhead box O (FOXO)

Metformin (Figure 4) (1,1-dimethyl biguanide hydrochloride), a biguanide is a plant based anti-diabetic drug sourced from Galega officinalis (also known as goat's rue) (Figure 5) [36] the use of this oral hypoglycemic drug either as a monotherapy or in combination has been well known for effective management of DM, prior literatures have highlighted the potential benefits of both metformin and hesperidin in managing diabetic complications, with metformin primarily improving insulin sensitivity and hesperidin exhibiting antioxidant and anti-inflammatory properties [37, 38].

STZ induced Neuropathic ↓ TNF-α, reduction in Intraepidermal nerve fiber density rats (IENFD) is preserved.

STZ induced Retinopathic ↓ malondialdehyde, glutamate, tumor necrosis factor rats and vascular retinal mRNA expression factor-α and TLR4.

AKT-knockout mice- ↓ Bax/Bcl-2 ratio, ↑ PK2, PKR1, and PKR2 expression Cardiacmyopathy Wound in STZ induced ↑ PI3K/Akt, ↓ diabetic rats The anti-diabetic action behind this drug is mainly by increasing the sensitivity of insulin in response to glucose & by concealing hepatic glucose breakdown through AMPK mediated pathway [39]. On a molecular basis it supresses the genes that codes for enzymes involved in gluconeogenic pathway, such as glucose 6 phosphatase, phosphoenolpyruvate carboxykinase and pyruvate carboxylase resulting in suppression of gluconeogenesis [40], apart from regulating hepatic glucose production it also lowers blood glucose levels by up-regulating GLUT 4 transporters in the skeletal muscles, causing fall in glucose absorption from the intestines and stimulating glucagonlike-peptide-1 (GLP-1) thereby enhancing insulin action and lowering blood glucose levels [41-43]. The mechanistic role of metformin in diabetic complication is tabulated below. Use of metformin may occasionally lead to hypoglycemia, especially when combined with other glucose-lowering medications its rare but serious complications include lactic acidosis, particularly with potential long-term vitamin B12 deficiency [44]. It is contraindicated in individuals with severe renal impairment, liver disease, unstable heart failure, alcohol abuse, or those experiencing severe infections or dehydration [45].

Diabetic nephropathy

One of the primary reasons for end-stage kidney failure is the onset of diabetes with poorly managed blood sugar levels resulting in diabetic nephropathy (DN), a prevalent complication of diabetes [52]. Diabetic nephropathy (DN) typically begins with hyperfiltration and albuminuria, progressing to renal function decline. However, in type 2 diabetes (T2DM), diabetic kidney disease (DKD) may present variably, with other kidney disorders and peripheral vascular disease often complicating the diagnosis [53].

Cao 2021 [47] -α Suliman 2021 [48] (VEGF) & ↓ of NFkB, tumor necrosis Yang 2020 [49] . Jia 2021 [50] . Tombulturk 2022 [51] The determining characteristic feature of DN based on histopathological evaluation includes glomerular and tubular epithelial hypertrophy, increased basement membrane thickness and mesangial expansion with the accumulation of extracellular matrix (ECM) proteins [54]. Clinical symptoms include fall in GFR (glomerular filtration rate), glomerular hyperfiltration & increased urinary albumin excretion [55]. In this section we are going to have a comparative analysis between plant based bioflavonoid and metformin to modulate the progression or prevent the occurrence of DN. Hesperidin a potent therapeutic bioflavonoid is present in rich amount on the pigmented external layer of the peel and on the white soft middle portion of citrus fruit especially orange [56], AGEs are believed to play a role in the development of diabetic kidney disease through multiple mechanisms including the creation of oxidative stress and increased production of growth factors and cytokines [57]. According to a study conducted on rats with diabetes, treatment with hesperidin resulted fall in glycated hemoglobin (HbA1C) [58] precursors to AGEs. At the same time, it increased plasma insulin levels and elevated glycogen storage in the hepatic system and skeletal muscles of rats with resistance to insulin caused by diabetes [59, 60]. Another study also demonstrated a prominent fall in plasma glucose levels via influencing enzymes that regulate glucose, as well as restoring normal levels of lipids and adiponectin in rats with artificially induced Insulin dependent diabetes mellitus with STZ [61]. Also normalized the anti-oxidant status in tissue homogenate of diabetic rats. The renoprotective benefits of hesperidin is associated with regulation AGEs/its receptor (RAGE) transduction cascade [62]. Hypolipidemic activity of hesperidin is known to be exerted mainly through inhibition of HMG-CoA reductase and acyl-CoA: cholesterol acyltransferase (ACAT) and enhanced expression of the LDL receptor encoding gene which plays an important role in modulating the disease progression as Lipid nephrotoxicity is thought to be involved in the development of DN, also studies show hypercholesterolemia can exaggerate albuminuria in diabetic rats [63, 64]. The nephron protective effect of metformin on DN in type 2 diabetic rats is mainly brought in by its hypoglycemic, anti-oxidant, hypolipidemic & downregulation of inflammatory cytokines based on reports obtained from animal model of DN [65] very similar to hesperidin but in contrast to standalone treatment with hesperidin metformin is found to be more effective when given in combination than as a monotherapy. Thus, study can also be carried out to investigate the synergistic effect between the two then to be used as a monotherpy for delaying the progression or preventing the occurrence of DN. In conclusion, animal studies provide evidence that flavone glycoside hesperidin in contrast to metformin can be used as therapeutic agents in diabetic nephropathy and consumption of such food's rich in such class of flavonoids can successfully modulate the progression of disease.

Diabetic neuropathy

Diabetic neuropathy predominantly affects lengthier nerve fibers more severely than those that are shorter due to a proportional decrease in nerve conduction speed with increasing nerve length [66]. Hyperglycemia, along with metrics like fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and disease duration, are the main risk factors for developing prediabetic neuropathy and diabetic peripheral neuropathy (DPN) in prediabetic and diabetic patients [67]. As a result, anomalous experiences of tremors, pain, pressure, and temperature perception are typically experienced in the lower limbs [68]. The predominant emphasis in examining morphological modifications in Diabetic neuropathy has been on the nerves in the extremities, specifically on phenomena such as axonal degeneration, demyelination, and Schwann cell ailments [69]. This section addresses the possible value of early treatment of peripheral neuropathy utilizing phytochemical methods or metformin in slowing the advancement of diabetic complication. Lim et al. studied ways hesperidin shields nerve cells against damage owing to elevated blood sugar levels. SH-SY5Y nerve cells subjected to excessive glucose promoted oxidative stress mediated dysfuntion. It substantially lowered reactive oxygen species generated by hyperglycemia & suppressed intracellular reactive oxygen species growth in dose-dependent manner. Hesperidin showed protection towards glucose-mediated DNA damage, decreased Endoplasmic Reticulum (ER) stress and demonstrated anti-apoptotic abilities hesperidin's powerful antioxidant capabilities shielded nerve cells against excessive glucose-mediated oxidative damage, ER stress, and cell death [70]. Research conducted by Bayir and colleagues on neuropathic rats induced with STZ revealed the ability of hesperidin to greatly reduce STZ-mediated pain stimulus and high blood sugar levels [71]. Moreover, histological study of sciatic nerve demonstrated decreased impairment with hesperidin therapy. Another investigation examined the curative abilities of hesperidin for its usage in reducing oxidative stress in STZ-induced DM in rats, therapy with hesperidin substantially alleviated these abnormalities, showing its extraordinary antioxidant action [72]. Research on metformin for diabetic neuropathy showed that metformin could reverse the low end threshold to pain stimuli and nociception in rats treated with fructose, suggesting that fructose's impact on pain is due to insulin resistance rather than high blood sugar [73]. One of the processes behind diabetic neuropathy is inflammation of the peripheral nerves. Metformin lowers inflammation [74] by activating AMPK to target inflammatory markers such as C- RP, IL-6, TNF-α [75]. For neuropathy caused by diabetes in STZ-induced diabetic mice, metformin raised motor nerve conduction velocity [76]. Part of the development of diabetic issue is merely linked to oxidative stress, AMPK can reduce oxidative stress and shield nerve cells from damage caused by oxidative stress by means of its activation [77]. However, absorption of Vit B12 resulting in neurological issues (such as peripheral and autonomic neuropathy, painful neuropathy) [78] accelerating the development of diabetic neuropathy thus providing a more favourable relevance for alternate use of metformin with hesperidin. In the end, we have underlined in- vivo studies demonstrating the efficacy of hesperidin in comparison to metformin for having the possibility to be employed as alternative therapeutic or augmenting agent in diabetic neuropathy.

Diabetic retinopathy

Primary cause for blindness among diabetic patients is diabetic retinopathy (DR) mainly caused due to progressive damage in the cellular and vascular elements of the retina [79]. It is anticipated that worldwide incidence of Retinopathy caused by diabetes will experience a substantial increase in the coming decades, with an estimation of 130 million in 2030, and 161 million by the year 2045 [80]. It is seen that among the diverse type of diabetes, patients with Type 1 DM are very much susceptible to DR [81]. Diabetic retinopathy is strongly associated with longer diabetes duration, high blood sugar, and hypertension, with elevated HbA1c levels contributing to its progression [82]. The retinal lesions seen in diabetic retinopathy, including microaneurysms, hemorrhages, and hard exudates, mainly stem from damage to the retinal microvasculature [83]. Defects in the retinal layer was described by Singer et al. [84]. Shehata et al. made a study using Streptozotocin mediated DM in rats that indicated therapy with hesperidin lowered the thickness of different retinal layers based on morphometric analysis report [85]. Oxidative Imbalance is thought to a major reason behind development of DR [86]. The retina is additionally vulnerable to oxidative species because of its greater O2 demand, the substantial quantities of PUFA (poly unsaturated fatty acid) present in the structure, and continuous stimulation to light makes it more evident causing mitochondrial dysfunction and Endoplasmic Reticulum stress [87] which is ameliorated by the potential anti-oxidant capacity of hesperidin in preventing DR [88]. Roy et al. [89] have elucidated that malfunctioning mitochondria and stress within the endoplasmic reticulum are present in DR which was found to be alleviated by hesperidin therapy [90]. Kowluru et al. reported the association of retinal neuron apoptosis with mitochondrial dysfunction [91]. Metformin is postulated as safeguarding retinal cells from undergoing apoptosis triggered by Reactive Oxygen Species mainly by modulating MnSOD scavengers of oxidative species and down regulation of NOX which is triggered by elevated blood glucose level and increases oxidative stress [92]. Autophagy is frequently suggested as a dual-edged weapon in DR: Autophagy can assist cells in overcoming stressful circumstances during mild distress; yet, too much autophagy results in massive cell mortality and DR exacerbation [93]. Excessive autophagy has been associated with turn releases large amount of vascular endothelial growth factor (VEGF) [94] a pro-angiogenic factor that tends to cause damage in the Blood Retina Barrier (BRB) [95] and MC (Müller cells) death which are involved in maintaining the normal retinal physiology in an animal model [96]. Thought to reduce VEGFR2's phosphorylation, metformin also induces VEGF-A mRNA splicing to VEGF120, hence lowering activity between VEGFR2 and VEGF-A. This stops angiogenesis thereby reversing the development of DR [97]. In a nutshell, evidence from in-vivo and molecular studies provide sufficient evidence for a beneficial effect of hesperidin in diabetic retinopathy in contrast to metformin which has profound positive effect on DR.

Diabetic cardiovascular disease (CVD)

It is widely recognized that DM increases the risks and mortality rates associated with heart diseases [98]. Individuals who have diabetes are more likely to develop cardiovascular disease, specifically heart failure, following a heart attack [99] than those without diabetes even prior to attaining enough blood sugar levels for a suspicion of diabetes, this risk rises gradually with elevated fasting blood sugar levels[100, 101]. A complex link between T2DM and CVD is thought to be associated common T2DM phenotypes include being overweight, lipid disorders, and high blood pressure all raise the likelihood of CVD in concert [102]. Cardiac dysfunction in diabetes mellitus is often asymptomatic and may not be detected until advanced stages of the disease [103]. A key feature of diabetic cardiomyopathy is left ventricular (LV) diastolic dysfunction, which often appears before clinically significant LV systolic dysfunction [104, 105]. In diabetes, excess fatty acid oxidation and hyperglycemia increase flux into the hexosamine biosynthetic pathway, leading to the production of UDP-GlcNAc. This promotes O- GlcNAcylation of proteins, which interferes with key cardiac functions like eNOS activity and SERCA2a expression. These disruptions impair calcium handling and cardiac relaxation. Oxidative stress further amplifies this pathway, contributing to cardiomyocyte dysfunction and apoptosis. Ultimately, this mechanism links hyperglycemia to diabetic heart complications [106]. This part of the article aims to underline the most recent findings on the relationship and comparative evaluation between Hesperidin and Metformin in diabetic heart ailments. Kosmas et al., claims that dyslipidemia plays a key role in heart diseases, with LDL-C (low-density lipoprotein cholesterol) being the primary contributing factor. Additionally, elevated plasma triglyceride levels and reduced high-density lipoprotein cholesterol level also links metabolic syndrome (MetS) with cardiovascular ailments [107]. Based on study made by Rekha et al., on diabetic myocardial infraction (DMI) rat model it showed that hesperidin successfully reduced LDL and increased HDL levels and also decreased cholesterol and TG (Triglyceride) ACAT (acyl-CoA: cholesterol acyltransferase) [108]. Metformin replicates certain advantages of cutting back calories such as enhancing responsiveness to insulin, and decreased levels of LDL and cholesterol, all without the need for calorie restriction. A recent meta-analysis report shows that in T2DM patients treatment with metformin prominently dropped the risk for CVD [109] through suppression of gluconeogenesis [110], activates 5' adenosine monophosphate-activated protein kinase (AMPK), which in turn enhances the functioning of endothelial nitric oxide synthase (eNOS) which has a direct impact on protecting the endothelium in individuals with T2DM [111], reduces plasma triglyceride, overall cholesterol, and LDL cholesterol levels, whereas serum HDL-C levels either increase or remain unchanged [98] which in turn are all the major factors for aggravating CVD. Hyperglycemia and CVD have both been investigated in numerous animal studies [112, 113]. The excessive production of Endothelin-1 (ET-1), a powerful constrictor of blood vessels made by heart cells which impacts heart contraction, is present in people with diseases associated with oxidative stress like obesity and T2DM, changes in the levels of ET-1 and its interaction proteins are seen as cardiovascular conditions progress [114]. Hesperdin’s effect on a animal model of diabetic cardiomyopathy where the heart undergoes change at structural, functional, and regulatory levels showed suppression in endothelin (ET)-1 secretion mainly due to its anti-oxidant potential [115]. Metformin is though proven to inhibit the expression of endothelin 1 (ET-1) partially in cancer research made by Liu et al. thus can be hypothesised for its cardioprotective effect against diabetic cardiomyopathy [116]. Acute myocardial infarction (AMI) is a consequence of a fatal breakdown of heart tissue in the heart due to a blockage in the coronary arteries, leading to reduced blood flow though not much of studies have been carried out but hesperidin is known to carry out its protective effect mainly through SIRT1/Nrf2/HO-1 signaling pathway [117]. On the other hand, a study on the damage caused by Myocardial ischemia-reperfusion in rats sheds light on how metformin activates the AMPK/PGC1α pathway to protect against mitochondrial dysfunction. The activation of AMPK promotes PGC1α activity, leading to increased gene transcription of mitochondrial DNA and proteins, which reduces mitochondrial fission, decreases apoptosis in the ischemic myocardium, and lowers infract size, ultimately providing cardioprotective benefits [118]. In conclusion, several therapeutic strategies have been proposed, especially in vivo studies where hesperidin seems to have a potential to exceed the cardio-protective impact of metformin on treating cardiovascular disease in diabetes mellitus.

Emerging diabetic complication

In the present scenario diabetic population still carry a great weight from the well-known classic problems. Development knowledge and has shown clear relationships between DM and an array of comorbidities, including dementia, mood disorders, obstructive breathing during sleep and hepatic impairment [119]. Learning & memory impairment establishes an alarming complication of DM, but the underlying molecular mechanisms are still not clear, prolonged hyperglycemia are thought to alter the synaptic plasticity and neurotransmitter level such as DA (dopamine) & Serotonin (5HT) in the brain involved in cognitive function driven by glucotoxicity Pignalosa et al. [120]. One of the most promising treatment options for cognitive impairment and memory loss is flavonoids [121]. Hesperidin is one such flavonoid and many studies [122, 123] have been carried for ameliorating the cognitive decline mediated by DM with novel approaches. In a study DM was found to affect the hippocampus region of the brain involved in learning and memory by promoting inflammatory cytokines like IL-6, TNF-α, MDA, and ROS and decreasing IL-4, IL-10, SOD, and CAT. These reflect as impairment of cognitive functions which was found to be reversed by hesperidin [124]. A different research study replicated dementia in humans by conducting experiments on diabetic mice to investigate the impact of metformin. The study found that diabetes mellitus (DM) has a significant role in activating DRP1 through mitochondrial fission, which is linked to various neurodegenerative diseases. Metformin effectively prevented the activation of mitochondrial fission by modulating the AMPK signal pathway, thereby safeguarding the mitochondria and synaptic plasticity in the hippocampus of diabetic mice. [125]. Depression is another such complication that can be mediated by DM (Figure 6) with a very high occurrence rate in people with T1DM [126] Both the forced swimming and tail suspension tests, utilized for evaluating depression, have demonstrated the antidepressant properties of hesperidin. Hesperidin exhibited benefits for depression by enhancing mRNA levels of Glo-1 and its activity in the amygdala and hippocampal region of diabetic rats, thus reducing the production of AGEs and oxidative stress-related damage [127, 128]. The effectiveness of antidepressant drugs in treating depressive disorders in individuals with type 2 diabetes mellitus (T2DM) has been largely unsuccessful due to non-compliance with the therapy. However, the use of the anti-diabetic drug metformin has provided valuable insights into the treatment of depressive disorders associated with T2DM by promoting growth of neurons (neurogenesis), spatial memory function, and protecting brain cells against oxidative imbalance [129]. The presumed antidepressant effect of metformin indicates that depressive disorders may be influenced by both oxidative stress and inflammation through different signaling proteins and channels, such as Nrf2, pro-inflammatory cytokines, and the AMPK/BDNF and NFκB pathways [130]. Metformin has been demonstrated to activate AMPK, which in turn enhances the synthesis of BDNF [131] as inadequate amounts of BDNF

(Source data: Hamal et al. 2022 & Yang et al. 2020) [117,118].

Conclusion

Cellular and preclinical research have demonstrated that the plant-based flavonoid hesperidin and oral hypoglycemic medication metformin has the ability to combat diabetic complications. Research also indicates that both medicinal products to some extent share a similar molecular approach in effectively controlling the course of the disease. This information thus provides a strong rationale for implementing a novel formulation & combination strategy in a well-designed trial for patients with diabetic complications. These strategies thus may also help reduce the dosage and use of alternative oral hypoglycemic agents (OHA) that can cause significant hypoglycemia when used over a long period of time at standard therapeutic doses.

Acknowledgement

The authors report no acknowledgements.

Competing interests

The authors report no conflict of interest.

Funding statement

The author has no relevant financial or non-financial interest to disclose.

Ethics approval and consent to participate

This study does not involve experiments on animals or human subjects.

Data availability

All data generated or analyzed during this study are included in this published article.

References

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