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\def\RunningAuthor{Anggi Muhtar Pratama et al.}
\firstPage{2832}
\articleType{Review Article}
\receivedDate{12 Sep 2020}
\acceptedDate{26 Nov 2020}
\revisedDate{25 Oct 2020}
\journalVolume{2020, 11 (SPL4)}
\journalDoi{ijrps.v11iSPL4.4564}
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\title{\textbf{Nanoparticles of beetroot plant extract (\textit{Beta vulgaris }L\textit{.}) as an alternative therapy for type 1 diabetes mellitus} \textbf{: A review}}
\author{Faizal~Achmad~Hidayat\textsuperscript{1},  
            Herwienda~Fatmayoni\textsuperscript{2},  
            Stefani~Ayuningtyas\textsuperscript{1}, 
            Anggi~Muhtar~Pratama\textsuperscript{*}\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia }~\\{\textsuperscript{2}Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia }~\\{\textsuperscript{3}Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia}}

\begin{abstract}
Type 1 diabetes mellitus is one of the most common degenerative diseases in the world. Out of 463 million diabetes mellitus patients in the world, 10\% of them are type 1 diabetes mellitus patients. One of the complication causes and severity of type 1 diabetes mellitus is oxidative stress. Oxidative stress occurs due to the build-up of excess free radicals obtained from the metabolism of glucose and lipids. Free radicals that cause oxidative stress can be minimized with antioxidants. Beetroot (\textit{Beta vulgaris} L.) is a plant that is rich in antioxidants and can be used as an alternative therapy for type 1 diabetes mellitus. Various flavonoid contents in beetroot extracts include quercetin, rutin, apigenin, kaempferol, and ferulic acid compounds that have antioxidant and antidiabetic activity. With the evolve of nanoparticle technology, it can be used to increase the solubility of drugs in water, to increase the duration of the drug in the systemic circulation, and to make drug release occurs gradually. The properties of this nanoparticle extract are indispensable for the efficacy and efficiency of treatment. The results of this study provide a lot of information and innovation for the development of the use of beetroot and the treatment of type 1 diabetes mellitus.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Beetroot,\newline Antioxidant,\newline Type 1 diabetes mellitus,\newline Nanoparticle
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Anggi~Muhtar~Pratama~\\ Phone:\ +62 856 5577 9801~\\  Email:\ anggi.muhtar.p@mail.ugm.ac.id 
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{ Introduction}
Beetroot plant (\textit{Beta vulgaris } L.) is one of the plants that have various properties because of the compounds contained in it. From the leaves, stems, skin to the flesh of the fruit can be found various compounds that are beneficial for health. Beetroot plant has a variety of health-aiding characteristics such as antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic, and hepatoprotective properties. The characteristics of the beetroot plant are due to the content of bioactive compounds, including betalains, flavonoids, polyphenols, saponins, and inorganic nitrates (NO3) \unskip~\citep{944738:20865474}. Known to one of them, the flavonoid compound quercetin is able to protect beta cells from damage, aid glycogen synthesis, and inhibit the \ensuremath{\alpha }-glucosidase enzyme \unskip~\citep{944738:20865482}. Judging by its efficacy, bioactive compounds in beetroot plant may be potential for anti-diabetic substances.

Currently, 463 million people worldwide have diabetes mellitus. There is the fact that the disease is the highest comorbid for COVID-19 patients during this pandemic. With this knowledge, it is essential to find a cure for diabetes mellitus. Type 1 diabetes mellitus is currently the most difficult to cure. The absence of insulin secretion, commonly referred to as insulin deficiency, causes hyperglycemia in people with type 1 diabetes mellitus. This state of hyperglycemia is based on blood sugar concentrations during fasting above 7\ensuremath{\cdot}0mmol/L (126mg/dL) and sugar-free blood conditions above 11\ensuremath{\cdot}1mmol/L (200mg/dL) \unskip~\citep{944738:20865483,944738:20865476}.

The occurrence of insulin deficiency in people with type 1 diabetes mellitus is caused by damage to the pancreatic islet that will cause infiltration of T cells. Subsequent consequences can lead to uncontrolled damage and apoptosis in pancreatic islet cells resulting in insulin production deficiency \unskip~\citep{944738:20865482,944738:20865472}.

Beetroot plants are herbs which are rich in bioactive compounds, one of those compound is flavonoids which have properties as antioxidants. These compounds can inhibit oxidative stress. The oxidative stress in people with type 1 diabetes mellitus also needs to be inhibited so as not to aggravate damage to pancreatic beta cells. Synthetic drugs for type 1 diabetes mellitus therapy which are now circulating on the market can cause side effects such as flatulence, discomfort, and diarrhea that can decrease patient compliance. Therefore herbal medicines are believed to have no side effects or minimal side effects to be alternatives. In addition, nanoparticle-shaped drugs have been studied to enhance the pharmacological effects of various compounds, hence the study of beetroot plant extract nanoparticles as type 1 diabetes mellitus therapy through inhibition of oxidative stress pathways.
    
\section{Materials and Methods}
Articles were obtained from Pubmed website and Google Scholar. Another research obtained from various publishers such as ScienceDirect, SpringerLink, SAGEPub, and Elsevier is also being used. Observational reviews, case-report, and case-series studies are used. Articles obtained were collected using Zotero reference management software. \textbf{\space }
    
\section{Results and Discussion}

\bgroup
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\centering \makeatletter\IfFileExists{images/c4ab026c-5861-4b02-9636-ebdc7968a3ac-upicture1.png}{\includegraphics{images/c4ab026c-5861-4b02-9636-ebdc7968a3ac-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Types of Beetroot Plants. (A) cv Chioggia (B) cv Detroit (C) cv RubyQueen }}
\label{f-95e611b3dcd6}
\end{figure*}
\egroup

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\makeatother 
\caption{\boldmath {Inhibition pathway of type 1diabetes mellitus by beetroot extract nanoparticles}}
\label{f-e334f2540211}
\end{figure*}
\egroup
\textbf{Beetroot plant antidiabetic compounds}

Many herbal plants have anti-diabetic activity, such as acting like insulin, increasing insulin production from pancreatic beta cells, to play a role in healing pancreatic beta cells \unskip~\citep{944738:20865484,944738:20865485}. One of the herbal plants that are often consumed by people is beetroot (\textit{Beta vulgaris } L\textit{.}) which is one of the subtropical plants that can be cultivated well in tropical countries, including Indonesia. In its origin, its tuber is the only part of beetroot plants that are mainly processed into food \unskip~\citep{944738:20865473}. The type of beetroot plant that are often consumed by the public are shown in Figure~\ref{f-95e611b3dcd6}.

In beetroot plants, there is a wide range of antioxidant compounds that serve to stop or prevent oxidation in other organic compounds. In addition, the role of other antioxidants is to capture free radicals that are a by-way result of metabolism, where the metabolic process will be oxidative. The types of antioxidants contained include flavonoid compounds, and previous research has found that flavonoids such as quercetin, vitexin, kaempferol, rutin, and ferulic acid can prevent cell damage, maintain normal cells, and have activity as enzyme inhibitors. These antioxidants can help with the treatment of stress-induced type 1 diabetes mellitus and streptozotocin-nicotinamide \unskip~\citep{944738:20865482,944738:20865480}.


\begin{table*}[!htbp]
\caption{\boldmath {Effective dosage of nanoparticles of antidiabetic compounds of beetroot plant extract} }
\label{tw-80443415d1d5}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20360000000000003\linewidth-2\tabcolsep}p{\dimexpr.11540000000000003\linewidth-2\tabcolsep}p{\dimexpr.09569999999999999\linewidth-2\tabcolsep}p{\dimexpr.18549999999999997\linewidth-2\tabcolsep}p{\dimexpr.39980000000000004\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compound & Animal Target & Method & Dosage & Source\\
\tblmidrule 
Quercetin &
  Mice &
  In vivo &
  25 mg/Kg BW &
  \unskip~\cite{944738:20865488}\\
Kaempferol &
  Mice &
  In vivo &
  100 mg/Kg BW &
  \unskip~\cite{944738:20865491}\\
Rutin &
  Mice &
  In vivo &
  20 mg/Kg BW &
  \unskip~\cite{944738:20865478}\\
Apigenin (vitexin) &
  Mice &
  In vivo &
  1 mg/Kg BW &
  \unskip~\cite{944738:20865494}\\
Ferulic Acid &
  Mice &
  In vivo &
  10 mg/Kg BW &
  \unskip~\cite{944738:20865471}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Antioxidant compounds and their effects on glucose regulation} }
\label{tw-f8c2aed4eb05}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2007\linewidth-2\tabcolsep}p{\dimexpr.2049\linewidth-2\tabcolsep}p{\dimexpr.3556\linewidth-2\tabcolsep}p{\dimexpr.23880000000000003\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Compound & Part of plant*) & Activities **) & Mechanism ***)\\
\tblmidrule 
Quercetin &
  Tubers and stems &
  1. Reduces hyperglycemia \mbox{}\protect\newline 2. Reduces pancreatic islets \mbox{}\protect\newline 3. Helps regenerate pancreatic islets &
  1. Inhibits \ensuremath{\alpha }-glucosidase so that insulin sensitivity increases\\
Kaempferol &
  Tubers and stems &
  1. Antidiabetic \mbox{}\protect\newline 2. Anti-apoptotic &
  1. Fixes AMP \mbox{}\protect\newline 2. Suppress caspase-3 activity\\
Rutin &
  Stems &
  1. Anti-diabetic \mbox{}\protect\newline 2. Anti-apoptotic &
  1. Decreases ROS formation \mbox{}\protect\newline 2. Increases Bcl-2 activity \mbox{}\protect\newline 3. Decreases caspase-3 activity\\
Apigenin (Vitexin) &
  Leaves &
  1. Reducing hyperglycemia \mbox{}\protect\newline 2. Anti-apoptotic \mbox{}\protect\newline 3. Repair oxidative damage to B cells &
  1. Improve translocation of GLUT4 \mbox{}\protect\newline 2. Inhibits NF-Kb activation \mbox{}\protect\newline 3. Reducing the production of ROS\\
Ferulic acid &
  Tubers and stems &
  1.Hypoglycemic activity &
  1. Stimulating insulin secretions\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*) \unskip~\cite{944738:20865479}  **) \unskip~\cite{944738:20865481,944738:20865475,944738:20865493}  ***) \unskip~\cite{944738:20865481,944738:20865475,944738:20865493}}
\end{tablenotes}
\end{threeparttable}

\end{table*}
\textbf{Formulation of beetroot plant extract nanoparticles as type 1 diabetes mellitus therapy}

There are various problems in terms of herbal medicine testing, such as bioavailability, solubility, active substance absorption, and low stability. They are overcoming those problems requiring a good formulation of the drug. Thus, beetroot plant extracts are made in nanoparticle size, which is then formulated in tablet-ready form. Nanoparticle-sized drugs have advantages such as increasing the solubility of the drug in water, increasing the duration of the drug in the systemic circulation, and can be formulated in order to have a gradual release of the drug so that the frequency of administration of the drug can be reduced. Nanoparticles have also been studied to improve the efficacy and bioavailability of flavonoid compounds \unskip~\citep{944738:20865487,944738:20865478,944738:20865477}. 

Using of plants in the synthesis of nanoparticles is quite novel foremost to truly green chemistry, which provides advancement over chemical and physical method as it is cost-effective and environment friendly easily scaled up for large scale synthesis and in this method, there is no need to use high pressure, energy, temperature and toxic chemicals \unskip~\citep{944738:20865486}. Quercetin, kaempferol, rutin, apigenin, and ferulic acid compounds have been studied and proven to be anti-diabetic substances in the form of nanoparticles. The test animals used in the in vivo test were diabetic mice induced with streptozotocin 40-60 mg/KgBB intravenously with each dose of antioxidants presented in Table~\ref{tw-80443415d1d5}.

\textbf{Pathophysiology of type 1 diabetes mellitus}

Type 1 diabetes mellitus is widely regarded as damage to insulin-producing beta cells, which are genetically related or caused by the immune system. Type 1 diabetes mellitus can be found at all ages, but the most common incidences are in children. The highest appearance occurs at the age of 5-7 years and or approaches during puberty. Type 1 diabetes mellitus is also commonly found in adult men and boys. Globally, the prevalence of type 1 diabetes mellitus varies substantially. In many countries, the incidence of type 1 diabetes fluctuates \unskip~\citep{944738:20865492}.

Diagnosis of type 1 diabetes mellitus historically includes blood sugar levels when fasting more than 7mmol/L (126mg/dL), overall blood sugar from 11-1 mmol/L (200mg/dL) or higher with symptoms of hyperglycemia, or abnormality 2 oral glucose tolerance test \unskip~\citep{944738:20865492}. In type 1 diabetes mellitus, oxidative stress mechanisms are found that can aggravate tissue injuries. Processes that play a role in oxidative stress in diabetes mellitus include glycolysis pathways (glucose metabolism) and fat metabolic pathways. The mechanism of the body's resistance to oxidative stress is through endogenous antioxidants \unskip~\citep{944738:20865470}.

Mice induced with streptozotocin may experience damage to pancreatic beta cells in the presence of nitrite oxide donated by streptozotocin through increased activity of guanyl cyclase and the formation of cGMP and can activate ROS. Nitrite oxide and ROS (Reactive Oxygen Species) are the main causes of damage to pancreatic beta cells. ROS species can also be produced from glucose oxidation that will always produce waste in the form of oxidative ions. ROS ions include O, OH-, H2O2, and CO- ions. These ions will cause oxidative stress as they will damage the structure of other compounds such as proteins and lipids \unskip~\citep{944738:20865482}. In the case of type 1 diabetes mellitus, ROS will aggravate tissue wounds and will slow tissue healing, so that beta tissue cells will slow grow and minimize the insulin production necessary to convert glucose that enters the body to become glycogen \unskip~\citep{944738:20865479,944738:20865493}. In addition, in the absence of oxidative compounds, it will induce the infiltration of apoptotic T cells so as to trigger tissue death and worsen the state of pancreatic tissue \unskip~\citep{944738:20865490}. If this happens, then cell repair will not occur and there will continue to be a reduction in the amount of insulin production which results in an excess metabolism of glucose and produces more ROS \unskip~\citep{944738:20865482}.

Advanced Glycation End Products (AGEs) is a series of glycation end result products. In the process of glycation, there will be a lot of ROS so that in the course of type 1 diabetes mellitus, it is necessary to cut the path of the metabolism of AGEs, namely with the administration of antioxidants \unskip~\citep{944738:20865482,944738:20865470}. Antioxidant compounds can bind to and disable free radicals and inhibit the formation of AGEs by inhibiting G3Pase which converts G3P into pyruvate, prevents it from further oxidation, and also inhibits 1.6-bisphosphatase of similar function \unskip~\citep{944738:20865482}.

\textbf{Antidiabetic Activity of Nanoparticles Extract Beetroot Plants}

Reduced amounts of insulin produced, increased ROS production, and excess pancreatic beta-cell apoptosis is hallmarks of type 1 diabetes mellitus. Bioactive compounds in beetroot plants such as quercetin, kaempferol, rutin, apigenin, and ferulic acid can help overcome the condition by increasing insulin sensitivity, lowering ROS production, suppressing caspase-3 activity which is a factor of apoptosis, and stimulating insulin secretions described in detail in Table~\ref{tw-f8c2aed4eb05}.

The initial target of therapy is to reduce glucose metabolism and glycation by administering the types of flavonoids quercetin and vitexin which have a function as an \ensuremath{\alpha }-glucosidase inhibitor, so that glucose absorption in the intestinal wall will be inhibited and have an effect on reducing the amount of glucose that should be metabolized. This state results in difficulty of converting glucose into glycogen so that it can reduce the number of free radicals, which are by product metabolites \unskip~\citep{944738:20865479,944738:20865493}.

After inhibiting the amount of glucose in the body, the next step is to prevent the glucose from being metabolized. Rutin and vitexin can be used because they have the effect of inhibiting the formation of the G3Pase and 1,6-bisphosphatase enzymes so that they prevent glyceraldehyde-3-phosphate from being metabolized further. Through this step, the formation of AGEs can be prevented. By inhibiting the formation of AGEs, it will reduce the amount of free radical production resulting from the formation of AGEs \unskip~\citep{944738:20865490,944738:20865489}.

The next step of this therapy is to reduce free radicals. Flavonoids that play a role in this process include vitexin and rutin. The activity of these compounds can suppress the number of free radicals that are present and generated from glucose metabolism. This reduction in free radicals will have the effect of reducing the damage to other compounds in cells and preventing apoptotic T cell infiltration so that it can prevent pancreatic beta-cell apoptosis and accelerate recovery and maintain insulin production \unskip~\citep{944738:20865490,944738:20865494}.

The final step in antioxidant therapy is the recovery of pancreatic beta cells and prevention of cell apoptosis. The flavonoids that play a role are quercetin, vitexin, kaempferol, and ferulic acid. These compounds have activities to increase cell proliferation, improve tissue structure, and anti-apoptotic activity so that they can be used to repair tissue and beta cells of the pancreas and promote normal cell proliferation and increase insulin production\unskip~\citep{944738:20865490,944738:20865482}.

The steps above can ultimately increase insulin production so that the increase in the insulin hormone will increase the synthesis of glucose into glucagon. Even though it still produces radical waste in the process, the free radicals that are formed will decrease compared with initial one, especially when the process of forming AGEs which will cause many free radicals which trigger oxidative stress, which result in damage to pancreatic beta cells (Figure~\ref{f-e334f2540211}). Type 1 diabetes therapy using antioxidants in the form of nanoparticles can also increase the bioavailability of antioxidants in the body so that the dose required is smaller than the form of ordinary particles.
    
\section{Conclusions}
Nanoparticles extract of beetroot (\textit{Beta vulgaris} L.) containing antioxidant compounds can reduce oxidative stress, so that they help the recovery of type 1 diabetes mellitus. Existing antioxidant compounds will inhibit glucose absorption into the body, inhibit the glucose degradation process, bind and inactivate radical compounds that will reduce damage to pancreatic beta cells, the proliferation of beta cells and prevent cell apoptosis, thereby increasing insulin production and normalizing the body's glucose homeostasis. Because of this activity, beetroot extract has the potency to be an anti-diabetic agent and can be formulated into nanoparticle drugs which mainly increase the bioavailability and efficacy of beetroot plant extracts in the body.
\section*{Acknowledgement}The author would like to thank the Indonesian Ministry of Education and Culture (Student Creativity Program)  and Universitas Gadjah Mada for providing facility to this research. 

\textbf{Funding Support}

This study was funded by the Indonesian Ministry of Education and Culture (Student Creativity Program) by grant number 1686/E2/TU/2020.

\textbf{Conflict }\textbf{o} \textbf{f Interest}

The authors declare that they have no conflict of interest. 
    

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