Introduction

Diabetes mellitus is perceived to be one among the prevalent threats for public health in the twenty-first century and is mentioned as one of the top ten diseases triggering death (Hu et al. 2018). Diabetes mellitus is a chronic metabolic dysfunction of elevated blood glucose level, which precipitates either due to a deficit in secretion of a hormone termed as insulin or as a result of pancreatic β-cell injury or because of insulin, the tendency to non-utilize owing to insulin resistance (Matzinger et al. 2018). Type I diabetes mellitus and type II diabetes mellitus are two subgroups of diabetes mellitus, and they differ in pathophysiology from each other. Cytotoxic lymphocyte auto-antibodies and the T-helper cells contribute to autoimmune destruction of pancreatic β-cells, which reduces the secretion of insulin and leads to type I diabetes mellitus (Vitak et al. 2017). Whereas due to a cumulative impact of drop in insulin secretion and insulin resistance, type II diabetes mellitus occurs (Acharjee et al. 2013).

The prevalence of type II diabetes mellitus is increasingly growing, and it is estimated that by 2045 approximately 629 million people are expected to have diabetes mellitus. The principal clinical intervention in diabetes mellitus has been known to be glycemic modulation. However, countless risk factors for diabetes, fatal complicacies and the development of vasculopathy prior to diagnosis entail the development of new treatment techniques for successful diabetes management (Dewanjee et al. 2018). Contributing to side effects, the available clinical antidiabetic therapeutics discourage both doctors and patients, gradually turning the emphasis into the innovation of novel antidiabetic treatment strategies, whereas in preclinical studies certain naturally occurring phytochemicals have demonstrated tremendous implications for diabetes and diabetic complications through hitting several targets.

Phytochemicals have been shown to display antidiabetic effects through several pathways, including glucose absorption reduction, β-cell functional mass regeneration, recovery of insulin expression, reversal of insulin resistance, improvement in glucose consumption and modulation in metabolism of lipid and carbohydrate (Bhattacharjee et al. 2016). In addition, the biocompatibility of these phytochemicals makes them an apt choice to be exploited as therapeutic negotiators. The associated poor biopharmaceutical and pharmacokinetic properties largely limit their clinical utility as therapeutic agents (Padhi et al. 2015). To improve their conformity and clinical effectiveness, many pharmaceutical researches have been conducted. In this aspect, the utilization of nanotechnology has been regarded as the best path for enhancing compliance and therapeutic effectiveness through addressing the pharmacokinetic and biopharmaceutical hurdles associated with the conventional therapeutic agents (Padhi et al. 2018). Such nanoformulations provide distinct benefits over conventional delivery system such as stability, high precision, controlled release, high entrapment efficiency, enhanced solubility and bioavailability (Behera and Padhi 2020; Saka and Chella 2020). Herbal drugs are regarded as safe, cheap and popular in comparison with the synthetic drugs. Globally 800 plant species are known to have hypoglycemic properties out of which 450 are the most known to be mostly used for research (Han et al. 2019). Main phytochemicals along with their plant origin are enlisted in Table 1.

Table 1 Phytochemicals for the treatment of diabetes mellitus and their biological sources
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Table 2 Nanophytochemicals for the treatment of complications associated with type 2 diabetes mellitus
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This review article presents an overview of the pharmaceutical advantages conferred by the nanoformulations entrapping various phytochemicals recommended in the treatment of diabetes mellitus and its associated complicacies.

Nanotools for the treatment of type II diabetes mellitus

Nanotechnology has gained enormous attention in both diagnosis and treatment in medical research in the past few years (Verma et al. 2017). It has been showcased that certain unique physical, chemical and biological attributes are gained by nanoscaled materials, making them suitable for numerous biomedical applications (Behera et al. 2020; Khuroo et al. 2014).

It has been ascertained that the engineering of nanocarriers like polymeric nanoparticles, metallic nanoparticles, liposomes, niosomes, micelles, dendrimers, nanostructured lipid carriers and nanofabricated structures has achieved considerable acceptance over contemporary drug delivery systems with respect to potency, durability, bioavailability, bio-distribution and drug release as represented in Fig. 1. In addition, functionalized nanocarriers with suitable ligands end up in targeted drug delivery with improved therapeutic efficacy (Padhi and Behera 2020). The progress and efficacy of nanoenabled formulations of antidiabetic therapeutic agents from plant sources (phytochemicals) are highlighted in the following portion of this article.

Fig. 1
figure 1

Nanotools for the delivery of phytomolecules for amelioration of type II diabetes mellitus. Phyto-constituents entrapped in nano-delivery systems such as liposomes, niosomes, nanostructured lipid carriers, nanomicelles and nanoparticles, ameliorate symptoms of type II diabetes mellitus by increasing the insulin production and secretion, inhibiting gluconeogenesis, reactive oxygen species, oxidative damage, inflammation and controlling cholesterol and triglyceride synthesis. MLV—multilamellar vesicles, SUV—small unilamellar vesicles, LUV—large unilamellar vesicles

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Liposomes

Liposomes are the vesicular structure containing one or more phospholipid bilayers, which are naturally non-toxic phospholipids and cholesterol. They are capable of transporting the active drug molecules to the targeted site within the biological system (McClements 2010). Liposomes fuse with the lipid membrane of the cell and thus discharge the liposomal content into the cytoplasm. Liposomes can entrap both lipophilic and hydrophilic drugs to deliver the target-specific drug with maximum efficacy and safety. Drug delivery through the nano-liposome systems entrapping phyto-bioactive compounds with antidiabetic properties was reported to be significantly improved (Gunasekaran et al. 2014).

In a research study, liposome of quercetin was evaluated in streptozotocin-induced diabetic nephropathy rat model. The in vivo study was conducted by administering quercetin (50 mg/kg), polyethylene glycol 4000 (150 mg/kg) and quercetin liposomes (200 mg/kg) by intragastric route in the group of rats. The study showed high levels of quercetin were present in plasma and kidney tissues in groups treated with quercetin-loaded liposome as compared to free-quercetin-treated group within 60 min. Quercetin liposomes or free quercetin were able to avoid loss of body weight, reduced renal hypertrophy index, decreased blood glycemic levels and decreased secretion of urinary protein for 24 h, but the liposomal quercetin formulation indicated superior therapeutic efficacy as compared to that of quercetin alone (Tang et al. 2020).

Resveratrol is considered to be a potent antioxidant with an insulin-like effect on diabetic cells (Arora and Jaglan 2017). It has proven efficacy in diabetes care, and it majorly acts by decreasing oxidative stress and glucose levels as well as protecting the β-cells accountable for the secretion of insulin. Cytotoxicity study of resveratrol liposomes was carried in β-TC pancreatic cell lines by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and the study indicated that inhibitory concentration (IC50) of resveratrol to be 50.69 µg/ml. Resveratrol liposomes increased the levels of glutathione peroxidase and superoxide dismutase demonstrating the antioxidant activity. Significant differences were observed when compared to insulin levels of resveratrol solution and liposome formulations entrapping resveratrol (p < 0.001). In diabetic cell groups synchronous with increasing insulin levels, the resveratrol liposomes reduced glucose levels and demonstrated sustained antioxidant activity against oxidative stress for a time period of 24 h relative to the resveratrol in solution form (Yücel et al. 2018).

Hyperglycemia, hepatotoxicity, and nephrotoxicity in diabetic mice are more effectively alleviated by thymoquinone-encapsulated nanosized liposomes in comparison with free thymoquinone (Khan et al. 2018). The structural integrity of pancreatic β-cells was seen to be preserved by the liposomal formulation.

Betanin, a bioactive component, has a proven antioxidant activity. In spite of its therapeutic potency and efficacy, stability issues and incomplete oral absorption limit its clinical application. In view of these limitations, betanin nanoliposomes were formulated, which showed a sustained release profile in the simulated intestinal and gastric fluids. The plasma glucose level dropped to 185.11 ± 27.27 mg/dl post-treatment with betanin nanoliposomes, which was lower as compared to pre-treatment plasma glucose levels of diabetic rats (≥ 250 mg/dl). In addition, histopathological research found that damage in the tissues of liver, kidney and pancreas was decreased in betanin-loaded nanoliposome-treated diabetic rats. Hence based on the illustrated results, it can be stated that nanoliposomes are ideal carriers for enhancing the therapeutic efficacy and stability of betanin (Amjadi et al. 2019).

Niosomes

Niosomes are the surfactant-based nanocarriers and categorized as vesicular delivery systems. Uniqueness of vesicular system of niosomes is the presence of nonionic surfactants in aqueous phase, and it is more advantageous than liposomes with respect to drug-loading efficiency, use of less cholesterol and better capability in crossing the biological barriers due to enhanced permeability (Kazi et al. 2010). Niosomes may be classified on the basis of size, number of bilayers as multilamellar vesicles, large unilamellar vesicles, small unilamellar vesicles, proniosomes and bola niosomes (Khoee and Yaghoobian 2017).

Niosomes can entrap hydrophilic and lipophilic drugs and can deliver the drugs in a controlled way at the targeted site. Niosomes are superior than other vesicular systems as they are chemically stable, biodegradable, biocompatible, require low production cost, less toxic and easy to store and handle (Khoee and Yaghoobian 2017). The universality of niosomes can be applicable for designing the drug delivery for oral, pulmonary, nasal, transdermal, ocular and gene delivery (Khan and Irchhaiya 2016).

Lycopene, a potent bioactive of Lycopersicum esculentum, has potential application in diabetes, but its high sensitivity to light, heat and oxidants proves to be a hurdle in its therapeutic applications. In such a scenario, lycopene niosomes were formulated to preserve its activity. The antidiabetic function of the formulation showed a substantial reduction in blood glucose levels. In the treated groups, biochemical markers such as total cholesterol, total glycerides, low-density lipoprotein and very-low-density lipoprotein were substantially reduced relative to the control groups. The overall results indicated that niosomes loaded with lycopene are efficient nanotools against diabetes. For broader applications that can play an important role in drug delivery and formulation science, the niosome formula appeared to be much encouraging (Sharma et al. 2017).

Solid lipid nanoparticles

The solid lipid nanoparticles are considered to be an optimum carrier system for the treatment of type II diabetes mellitus and diabetes-induced oxidative stress in mice through the oral delivery of myricitrin. Myricitrin-encapsulated solid lipid nanoparticles accomplished a continual release from the nanoformulation of myricitrin and demonstrated exceptional therapeutic outcomes in concurrent hyperglycemia, insulin tolerance, myotubal deficiency of glucose absorption and in vitro and in vivo pancreatic apoptosis. Myricitrin solid lipid nanoparticles have been shown to be more efficacious at a much lower dosage than metformin. The stated formulation was also capable of attenuating oxidative stress, fibrosis, inflammation and apoptosis induced by hyperglycemia in high-glucose-exposed in vitro mouse model (Ahangarpour et al. 2018).

Another research study evaluated the efficacy of myricitrin-encapsulated solid lipid nanoparticles on streptozotocin–nicotinamide-induced type II diabetes mellitus of the mouse and hyperglycemic myotube. The in vitro and in vivo studies showed better diabetes conditions and improved hyperglycemia complications. Hence, it can be inferred that the nano-entrapment of myricitrin was able to showcase better antioxidant, antidiabetic and antiapoptotic effects in the mouse and myotube cells (Ahangarpour et al. 2018).

In order to improve the efficacy of resveratrol after oral therapy in diabetic rats, resveratrol-loaded solid lipid nanoparticles were fabricated. The formulation initially showed an initial burst release accompanied by a slow release under standard conditions with an enhanced resveratrol oral bioavailability. The formulation was proved to be substantially advantageous over free resveratrol in overcoming insulin resistance via the stimulation of synaptosomal-associated protein 23 (Snap23), syntaxin-4 (Stx-4), and vesicle-associated membrane protein 2 (Vamp2) mRNAs in tissues of muscle as well as decrease of oxidative stress in type II diabetic rats (Mohseni et al. 2019).

Madureira and co-workers designed physicochemically safe and biologically compatible rosmarinic acid solid lipid nanoparticles using carnauba waxes. Oral delivery of rosmarinic acid could be possible by the nanoformulations as it was found to be stable and biocompatible (Madureira et al. 2015). Additionally, rosmarinic acid solid lipid nanoparticles displayed no signs of in vitro genotoxicity or cytotoxicity as evidenced in the published report (Reis et al. 2016).

Compared to the berberine in native form, berberine-loaded solid lipid nanoparticles were noted to maximize the oral bioavailability, stability as well as antidiabetic potency (Wang et al. 2011). The oral administration of the nanoformulations substantially decreased hyperglycemia, gain of body weight and insulin tolerance in type II diabetes-induced mice (Xue et al. 2013). Furthermore, berberine-entrapped solid lipid nanoparticles had reached maximal liver drug concentration by approximately 20 times more than in plasma and dramatically depleted hepatosteatosis caused by type II diabetes (Xue et al. 2015).

Chitosan-conjugated silybin solid lipid nanoparticles have been identified to be more stable, with notable mucoadhesive properties, continuous release, improved absorption and cellular internalization of silybin after oral absorption (Piazzini et al. 2019). Bixin-loaded solid lipid nanoparticles have been reported to improve their therapeutic potential by improving stability, tissue localization at target sites and controlled release of drug by passive diffusion mechanism and profound cellular internalization of bixin (Rao et al. 2014).

Nanostructured lipid carriers

Nanostructured lipid carrier is a type of lipid-based nanodelivery system having some anchored advantages over solid lipid nanoparticles, like smaller particle size and increased loading capability to accomplish efficient delivery of phytochemicals in type II diabetes mellitus treatment (Ni et al. 2014).

Numerous studies have displayed superior antihyperglycemic effects of baicalin, which acts by inhibition of lipid peroxidation. Baicalin, being a low hydrophilic drug with poor absorption after oral administration, suffers from widespread therapeutic application. In such a pursuit, baicalin-loaded nanostructured lipid carrier was synthesized by using precirol as the solid lipid and miglyol as the liquid lipid and further evaluated for antidiabetic effects. It was noted from the in vivo results that baicalin-loaded nanostructured lipid carriers significantly decreased the fasting blood glucose level, glycosylated hemoglobin, total cholesterol and total glycerides in diabetic group in comparison with the normal control group, implying the fact that the nanoformulation-entrapping baicalin has significant hypoglycemic effect and has a pivotal role in regulating lipid metabolism in type II diabetes mellitus (Xu et al. 2016).

Nanostructured lipid carriers loaded with baicalin have been showcased to be safe for delivery by oral route, providing baicalin by continuous release, and have been shown to improve the hypoglycemic potency of baicalin. At the same dosage, relative to free baicalin and metformin, the regulation of hyperglycemia and hyperlipidemia was found to be more significant in the nanostructured lipid complex of baicalin in diabetic rats (Xu et al. 2016).

Berberine-entrapped selenium-coated nanostructured lipid carriers have been recognized to cause the therapeutic effectiveness of berberine in the treatment of diabetes relative to berberine-entrapped nanostructured lipid carriers and free berberine. Increased absorption in intestine, bioavailability by oral administration and controlled release of berberine were elicited due to selenium modulation of the nanostructured lipid formulation. The selenium-entrapped berberine nanostructured lipid carriers improved the uptake of glucose in diabetic rats by increased diffusion of the phytochemical into enterocytes (Yin et al. 2017).

Oral bioavailability of ferulic acid was found to be increased in ethyl oleate-nanostructured lipid carriers than solid lipid nanoparticles (Zhang et al. 2016). There are reports indicating significant antioxidant and antidiabetic properties of astaxanthin, a natural keto-carotenoid. The ability to boost stabilization and increase the antioxidant function of astaxanthin was demonstrated by astaxanthin-assembled nanostructured lipid carriers (Bhuvaneswari and Anuradha 2012).

Nanomicelles

Micelles are core–shell-type nanostructures containing hydrophobic core and the hydrophilic outer layer to form the shell. They are produced by self-assembling of amphiphilic co-polymers at a critical micellar concentration. The hydrophobic core acts as a suitable carrier for hydrophobic drugs used for antidiabetic treatment (Ahmad et al. 2014).

Silymarin-entrapped nanomicelles were evaluated for its efficacy and mechanism of action in lowering glucose level in streptozotocin-induced diabetic rats. Silymarin-loaded pluronic nanomicelles were fabricated, which were noted to improve antioxidant, antihyperglycemic and antihyperlipidemic activities as compared with free silymarin. The observed effect may be due to sustained release pattern and superior bioavailability conferred by silymarin nanomicelles. Treatment with silymarin nanomicelles showed a high degree of downregulation of fasting blood glucose levels from the initial week following significant suppression of blood glucose levels from the second week of treatment (p < 0.001, p < 0.0001 respectively) as compared to the control group. In particular, silymarin nanomicelles therapy was shown to restore fasting glucose levels to a near-normal range by the end of the second week of therapy and also proved to be better than native silymarin in this aspect (El-Far et al. 2016).

Furthermore, curcumin-loaded pluronic nanomicelles were also evaluated for the treatment of diabetes. The hypoglycemic activity of curcumin nanomicelles was largely attributable to the major upregulation of expression of Pdx-1 and NKx6.1 genes and the optimum redox balance was achieved, contributing to exacerbation of β-cell damage by streptozotocin through up-regulating gene expression for insulin shown by reverse transcriptase polymerase chain reaction studies and the existence of 40% insulin-positive cells through confocal pancreatic microscope pictographs (El-Far et al. 2017).

Morin, a phyto-derived bioflavonoid, has potential benefits that include lowering lipogenesis, gluconeogenesis, inflammation and oxidative stress. Additionally, morin showed insulin-mimetic activity, so believed to be a natural antidiabetic drug (Paoli et al. 2013). Its bioavailability is limited owing to its poor oral solubility, resulting in lower therapeutic benefits. An increased dose, however, can result in toxicity patterns. In such a pursuit, morin was fabricated as mixed micelles with an average particle size of approximately 90 nm. Compared to the native drug, the morin-loaded mixed nanomicelles displayed a 3.6-fold improvement in cellular penetration, with an improved permeability rate of approximately 2.4 times, which enhanced the bioavailability in the systemic circulation (Choi et al. 2015).

It has been noted in in vivo experiments that the lack of bioactivity and lower solubility by oral administration contributed to lower bioavailability of genistein. In particular, administration of higher dose was related to emergence of other risks and toxicity patterns. In recent decades, several nanoscale methods have been applied to address toxicity and higher dose effects, enhancing genistein oral distribution (Wu et al. 2016). In such a scenario, genistein-loaded polymeric micelles administered by oral delivery showed an enhanced bioavailability. The observed effect may be attributed to the increase in solubility of the drug with a better permeability (Kwon et al. 2007).

Hyperglycemia, hyperlipidemia, oxidative stress, and hypoinsulinemia have been shown to be attenuated by curcumin-entrapped pluronic nanomicelles administered orally by restricting β-cell injury, fostering β-cell regeneration and activating PDX-1 and NK6 homeobox-1 (NKx6.1) gene activation beyond the results depicted by control group (El-Far et al. 2017).

A nanosystem comprising of apigenin-loaded nano-micelles involving soluplus and pluronic F127 polymers has been reported to achieve sustained release with quadruple bioavailability and reinforce absorption of apigenin gastrointestinal tract as compared to free apigenin in rats. Nano-mixed micelles of apigenin greatly increased the water solubility and cellular uptake of apigenin (Zhang et al. 2017).

As compared to suspension of baicalin in rats, baicalin-encapsulated nanomicelles incorporating pluronic P123 copolymer and sodium taurocholate demonstrated an increase in absorption, circulation time and oral bioavailability by approximately > 1.5 times as compared to native baicalin and can thus contribute as a potential approach to oral delivery of baicalin (Xu et al. 2016).

Self-assembled phospholipidic nanomicelles loaded with mangiferin have been demonstrated to enhance the biopharmaceutical characteristics of mangiferin (Khurana et al. 2017). Following the study, the same research group designed a self-assembled phospholipidic nanomixed micelles system co-loaded with vitamin E-D-alpha-tocopheryl polyethylene glycol 1000 succinate, which also increased the intestinal permeability as well as oral bioavailability of mangiferin (Khurana et al. 2018).

Nanoparticles

Nanoparticles are the most widely used nanomaterial for administration of antidiabetic drugs due to enhanced drug utility and decreased adverse effects. Surface modification can further help in more target-specific delivery of the antidiabetic drugs to control the hyperglycemic conditions (Ponnappan and Chugh 2015).

More recently, the neuroprotective roles of flavonoids are extensively examined in neurodegenerative disorders. Quercetin is a phytoderived bioactive flavone, which has multitude of therapeutic applications. However, it has restricted blood–brain barrier permeability, low oral bioavailability, weak aqueous solubility and fast gastrointestinal digestion, which contribute to high-dose quercetin administration in clinical use. In order to overcome the stated limitations, quercetin was conjugated with super-paramagnetic iron oxide nanoparticles and was further tested in streptozotocin-induced diabetic rats for assessing its benefit as an antidiabetic treatment modality and improving diabetes-related memory impairment. Quercetin–iron oxide nanoparticles and free quercetin induced a substantial decrease in blood glucose level in diabetic rats. Quercetin-loaded super-paramagnetic iron oxide nanoparticles displayed significantly improved efficacy than free quercetin on the upgrading of memory performance (Ebrahimpour et al. 2018).

Carbohydrate biopolymers such as chitosan and alginate were utilized for successful entrapment of a flavanone drug, naringenin. In vivo studies indicated appropriate hypoglycemic effect after oral delivery of the nanoformulations to streptozotocin-induced diabetes in rats. The significant antidiabetic effect is attributed to the stimulatory action of naringenin, which acts by regeneration of β-cell islets, which in turn improves the diabetic condition in rats. The research findings indicated that polymeric formulations entrapping the flavonoids were too effective in the treatment of dyslipidemia; hyperglycemia and hemoglobin iron induced oxidative stress in the type I diabetic paradigm (Maity et al. 2017).

Gallic acid, a phenolic compound, is widely known for its antidiabetic activity. However, because of its deterioration during the absorption process, the use of this compound delivers unsatisfactory outcomes. The approach proposed to solve the problem is to encapsulate it in chitosan nanoparticles that leverage freeze-drying technique to shield the bioactive compound from degradation, improve solubility, and deliver the bioactive compound to the target site. Results of the inhibition test revealed that gallic acid-conjugated chitosan nanoparticles at 50 ppm were able to inhibit alpha-glucosidase activity. It can thus be inferred that gallic acid can be encapsulated in chitosan nanoparticles and has been shown to suppress alpha-glucosidase enzyme (Purbowatiningrum et al. 2017).

Ferulic acid, a hydroxyl cinnamic acid, has a variety of medicinal properties, which may be due to its strong antioxidant ability, including antidiabetic impact. However, its medicinal uses have remained stagnant owing to its poor bioavailability and clinical efficacy. In the current research, ferulic acid-encapsulated chitosan nanoparticles were produced in order to boost ferulic acid bioavailability. Extended plasma retention time was shown by the encapsulated ferulic acid, and maximum plasma concentration was registered at 60 min. There was a marked drop in blood glucose in the group of rats treated with free ferulic acid and ferulic acid nanoparticles, respectively, though no pronounced decrease was observed in insulin levels.

More interesting findings were reported for rats treated with ferulic acid nanoparticles, where a substantial drop in glucose levels in blood was found over the whole duration of the study relative to all diabetic control groups and glibenclamide-treated rats. Ferulic acid nanoparticles were also evaluated on streptozotocin-induced diabetic Wistar rats and was shown to mitigate the symptoms related to diabetes. Ferulic acid nanoparticles also showed an increase of body weight, a drop in glucose levels in blood and a controlling effect on diabetic rats' blood lipid profile. The positive effect of ferulic acid nanoparticles on the improvement of the hyperglycemic syndrome prevailing in diabetic rats could offer new avenues for diabetes mellitus care and potentially prevent drug-related secondary complications (Panwar et al. 2018).

Glycyrrhizin is an active phytoconstituent of Glycyrrhiza glabra's roots and rhizomes and has proven antidiabetic effects. Glycyrrhizin- and metformin-loaded nanoparticles employing the biocompatible polymers gum arabic and chitosan were evaluated in vivo for their antidiabetic ability in type II diabetes in rats. As compared to the control group, rats treated with glycyrrhizin-loaded nanoparticles at a similar dose of 20 or 40 mg/kg containing 4.2 or 8.4 mg/kg of glycyrrhizin, respectively, demonstrated a substantial dose-dependent drop in blood glucose levels (p < 0.001) as implied by the q values, 22.04 and 23.53, respectively. Similarly, the groups treated with metformin (40 mg/kg) and glycyrrhizin (20 and 40 mg/kg) revealed a substantial drop in blood glucose levels (p < 0.001) relative to rats treated with native metformin. It can be concluded that glycyrrhizin nanoparticles had superior anti-hyperglycemic benefits even though they encompassed only a quarter of the dose compared to the free drug (Rani et al. 2017).

Another research report suggested that curcumin-treated rats displayed slightly higher levels of insulin and insulin receptor gene expression, relative to positive and negative controls. These findings indicated that nano-curcumin could be employed in streptozotocin-induced diabetic rats as antidiabetic treatment, to cause hypoglycemia and to improve gene expression of insulin and insulin receptors. In order to explain the precise mechanism of action of nano-curcumin relating the upregulation of gene expression, further investigations are necessary (Gouda et al. 2019).

Antidiabetic activities have also been demonstrated by berberine, an isoquinoline derivative of alkaloid. Nevertheless, its poor oral bioavailability limits its medicinal use. Nanosuspension of berberine was developed comprising of berberine and D-alpha-tocopheryl polyethylene glycol 1000 succinate. In streptozotocin-induced diabetic C57BL/6 mice, antidiabetic efficacy of berberine nanosuspension was compared to bulk berberine. Superior hypoglycemic and total cholesterol and body weight lowering results were achieved by berberine nanosuspension when administered at a dose of 50 mg/kg by oral route relative to the comparable dosage of bulk berberine and metformin (metformin at a dose of 300 mg/kg). These results suggest that a low dose of berberine nanosuspension in type II diabetic C57BL/6 mice lowered blood glucose and increased lipid metabolism. These observations indicate that delivery of berberine nanosuspension may be a striking approach for the treatment of type II diabetes (Wang et al. 2015).

The connection between diabetes and zinc homeostasis dysfunction enabled nanoparticles of zinc oxide an enticing therapeutic alternative. In diabetes mellitus, the glucose-phosphorylating enzyme glucokinase and the glucose transporter 2 were involved in the regulation of glucose metabolism. Pleiotropic actions on a diverse variety of molecular benchmarks are seen by curcumin, the key polyphenolic phyto-constituent of rhizomes of turmeric. Curcumin exhibits hypoglycemic impact by multiple pathways, including gene expression of glucokinase and glucose transporter 2 in diabetes mellitus. The present research evaluated curcumin nanoparticles, zinc oxide nanoparticles and curcumin–zinc oxide composite nanoparticles on the possible efficacy in streptozotocin-induced diabetic rats. The most potent antidiabetic behavior was shown by curcumin–zinc oxide composite nanoparticles, and the histopathological results confirmed the biochemical and molecular evidence suggesting curcumin–zinc oxide composite nanoparticles as a possible antidiabetic agent (Raslan et al. 2018).

Vicenin-2 gold nanoparticles were also evaluated their effect on the glucose utilization efficiency in 3T3-L1 adipocytes. When incubated with vicenin-2 gold nanoparticles, a concentration-dependent increase in glucose uptake was noted in 3T3-L1 adipocytes. A close interaction of vicenin-2 with the protein-tyrosine phosphatase 1B and 5’ adenosine monophosphate-activated protein kinase binding pockets was unveiled in the docking results. This indicated that the developed vicenin-2 gold nanoparticles could facilitate the use of cellular glucose regulated by intracellular vicenin-2 accessibility, which may serve as a novel nano-drug for diabetes treatment (Chockalingam et al. 2015).

Stevia rebaudiana has become a lead candidate for diabetes treatment owing to its hypoglycemic and antihyperlipidemic properties. The result demonstrated for the first time that the titanium dioxide–Stevia rebaudiana nanoformulation at a dose of 20 and 30 μM was able to reverse the alloxan-induced hyperglycemic effect. In addition, the insulin, glycosylated hemoglobin, cholesterol and triglyceride concentrations demonstrated a substantial recovery from baseline values. Hence, it can be inferred that titanium dioxide could also be used as an appropriate vehicle for the sustained release of active compounds for the treatment of diabetes mellitus (Langle et al. 2015).

In improving the therapeutic efficacy and bioavailability of different drugs, biodegradable polymers have been used for innovative drug delivery systems, which gained considerable attention (Parhi, 2020). 14-Deoxy 11, 12-didehydro andrographolide-entrapped polycaprolactone nanoparticles were synthesized and the confocal microscopy experiments with rhodamine 123-loaded polycaprolactone nanoparticles showed a time-dependent internalization of the nanoparticles in L6 myoblasts. For 14-deoxy 11, 12-didehydro andrographolide-entrapped polycaprolactone nanoparticles, a maximum uptake of 108.54 + 1.42% at 100 nM on L6 myotubes, a dose-dependent rise in glucose uptake was observed, confirming its antidiabetic efficacy (Kamaraj et al. 2017).

Nanophytochemicals for the treatment of complications associated with type II diabetes mellitus

In patients with type I and II diabetes mellitus, the associated complications are typical and are also accountable for remarkable morbidity and mortality. The complications are notably divided into microvascular and macrovascular where the former includes neuropathy, nephropathy and retinopathy and the later includes cardiovascular disease, stroke and peripheral artery diseases (Papatheodorou et al. 2018). The other related complications include dental disease, reduced resistance to complications and birth complications that are not included under the above-mentioned categories rather included under gestational diabetes (Papatheodorou et al. 2018; Deshpande et al. 2008). Diabetes-induced cataract also proved to be a major cause of blindness in a number of subjects. The risks of cataract were noted to be higher in type II diabetes mellitus patients as compared to the non-diabetic ones (Li et al. 2014). Some other complications include diabetic wounds, severe hypoglycemia and higher risk of cardiovascular disease (Papatheodorou et al. 2018).

A typical associated complication is diabetic peripheral neuropathy, which precipitates with risk of age, smoking, disease period, hypertension, elevated triglyceride levels, alcohol intake, higher body mass index and taller height. Polyneuropathy, a form of diabetic peripheral neuropathy, leads to weakness of muscles, sensory loss and pain including burning sensation and lack of sensation in feet. Patients with diabetic peripheral neuropathy are often noted with a risk of foot ulceration (Li et al. 2014).

Diabetic nephropathy or persistent proteinuria with patients without urinary tract infections or other diseases may be noticed in individuals with type II diabetes mellitus. People with type II diabetes mellitus and diabetic nephropathy are more likely to develop stroke and coronary heart disease than the people with only diabetes (Deshpande et al. 2008).

Retinopathy is associated with prolonged hyperglycemia. The impairment of vision in patients with diabetes increases with age, and women are more prone to the disability than men (Deshpande et al. 2008).

Ischemic heart disease and stroke enlist for higher proportion of morbidity in diabetes mellitus (Deshpande et al. 2008). Cardiovascular disease is the most prevalent case of morbidity and mortality in diabetes mellitus. In diabetic patients, the risk associated with cardiovascular diseases like obesity, dyslipidemia and hypertension is common (Leon 2015).

Peripheral vascular diseases may lead to injuries that do not heal which proceeds to gangrene and then amputation. This is caused due to narrowing of blood vessels carrying blood to different parts and organs of the body. In case of diabetic patients, peripheral vascular disease increases with age, duration of diabetes and presence of neuropathy (Deshpande et al. 2008).

Different mechanisms involved in amelioration of diabetic microvascular and macrovascular complications by nanophytochemicals are represented in Figs. 2 and 3.

Fig. 2
figure 2

Mechanisms involved in treatment of diabetic microvascular complications by nano-phytochemicals. Microvascular complications associated with type II diabetes mellitus including neuropathy, nephropathy, retinopathy and cataract are regulated by different intracellular markers. Cataract can be treated by nano-phytomolecules by decreasing protein insolubilization, regulation of polyol pathway and protein glycation. Retinopathy can be treated by downregulation of angiogenesis proteins; decrease in free radical, mRNA expression of vascular endothelial growth factor-1, tumor necrosis factor-α, monocyte chemotactic proteins-1, intracellular adhesion molecules-1, interleukin-6, interleukin-1β; increased biosynthesis of reduced glutathione, decrease in phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated protein kinase 1/2. Nephropathy can be ameliorated by regulation of expression of intracellular adhesion molecules-1, reduction of transforming growth factor-1β and upregulation of Smad 2/3. Neuropathy can be treated by nano-phytomolecules by upregulation of interleukin-1β, decrease of phosphorylated protein kinase B levels, decrease in upregulated calcitonin gene-related peptide expression, interleukin-6, tumor necrosis factor-α phosphorylation and activation of extracellular signal-regulated protein kinase 1/2. VEGF—vascular endothelial growth factor; TNF—tumor necrosis factor; MCP-1—monocyte chemotactic proteins-1; ICAM—intracellular adhesion molecules; IL—interleukins; TGF—transforming growth factor; ERK—extracellular signal-regulated protein kinase, AKT—protein kinase B; CGRP—calcitonin gene-related peptide]

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Fig. 3
figure 3

Mechanisms involved in treatment of diabetic macrovascular complications by nano-phytochemicals [Macrovascular complications of type II diabetes mellitus include cardiomyopathy, diabetic complications, diabetic foot ulcer and diabetic wound healing. Nano-phytoconstituents can ameliorate the cardiomyopathy by downregulation of receptor for advanced glycation end products. Diabetic foot ulcer can be treated by nano-phytoconstituents by increase in interferon gamma, tumor necrosis factor-α, interleukin-1α, interleukin 6 and matrix metallopeptidase 9 and decreased expression of vascular endothelial growth factor-α and interleukin-1β. Diabetic wound healing can be enhanced by inhibition of expression of nuclear factor kappa-light-chain-enhancer of activated B cell, tumor necrosis factor-α, interleukin-6 and increase in expression of vascular endothelial growth factor, cluster of differentiation-31, responding to matrix metallopeptidase 9; increase in re-epithelization and reorganization of dermis; increase in expression of aquaporin 3, increase in wound closure efficiency, increased superoxide dismutase activity, decrease in gene expression of collagen I and collagen III leading to wound healing. Other diabetic complications can be treated by decreasing C reactive protein, interleukin-6 and tumor necrosis factor-α. RAGE—receptor for advanced glycation end products; INF-ϒ—interferon gamma; TNF—tumor necrosis factor; IL—interleukins; MMP9—matrix metallopeptidase 9; VEGF—vascular endothelial growth factor; NF-κB—nuclear factor kappa-light-chain enhancer of activated B cells; CD-31—cluster of differentiation 31; AQP3—aquaporin 3 gene; SOD—superoxide dismutase; Col I and Col III—collagen I and collagen III; CRP—C reactive protein]

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Conclusion

Diabetes mellitus is a complicated metabolic disorder, and owing to its complex pathophysiology, its treatment is often troublesome. Despite the evidence provided over recent decades about the impact on the quality of life and human health by phytochemicals, their efficient delivery stands as a conundrum. Nano-based drug delivery systems have been developed in recent years as one of the key methods for remedying these challenges in order to enhance the effectiveness of herbal extracts in the treatment of diabetes mellitus and its related complications. As demonstrated, nanoformulations of phytomedicines such as nanostructured lipid carriers, solid lipid nanoparticles, colloidal nanoemulsion systems and other formulations have shown a substantial improvement in antidiabetic effects of the phytochemicals as compared to the conventional ones. The results of the discussed studies explicitly illustrate that by different nano-delivery methods, most phytochemicals can be efficiently developed and thus successfully administered to elicit the requisite therapeutic outcome. In addition, the targeted distribution of nano-formulated phytochemicals will pave the pathway to integrate conventional medicine with modern pharmaceutical methodologies.