AIP Conference Proceedings 2193, 030025 (2019); https://doi.org/10.1063/1.5139362 2193, 030025
© 2019 Author(s).
Treatment of fatty pancreas: Acalypha indica Linn. extract as an alternative to simvastatin
Cite as: AIP Conference Proceedings 2193, 030025 (2019); https://doi.org/10.1063/1.5139362 Published Online: 10 December 2019
Aisyah Aminy Maulidina, and Siti Farida
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Treatment of Fatty Pancreas: Acalypha indica Linn. Extract as an Alternative to Simvastatin
Aisyah Aminy Maulidina
1and Siti Farida
2, 3, a)1Faculty of Medicine, Universitas Indonesia, Jl Salemba Raya No 6, Senen, Central Jakarta 10430 Indonesia
2Department of Medical Pharmacy, Faculty of Medicine, Universitas Indonesia, Jl Salemba Raya No 6, Senen, Central Jakarta 10430 Indonesia
3Drug Development Cluster, Institute of Medical Education and Research Innovation, Universitas Indonesia, Jl Salemba Raya No 6, Senen, Central Jakarta 10430 Indonesia
Corresponding author: a)[email protected]
Abstract. Nowadays, high-fructose/high-cholesterol diet has increased the incidence of dyslipidemia, insulin resistance, and metabolic syndrome, which are the main risk factors of non-alcoholic fatty pancreas disease (NAFPD) and may lead to pancreatic cancer. The pathogenesis and treatment of NAFPD are currently yet to be well-understood. The use of simvastatin in managing the pancreatic disease was shown to reduce cancer risk, but it raised concerns as it was recently found to induce diabetes and worsen hyperglycaemia and A1c levels in pre-existing diabetes. Acalypha indica Linn. (AI) is known to have flavonoids and polyphenols which may decrease LDL and increase HDL level. In contrast to simvastatin, AI may control post-prandial hyperglycemia. A study on rat induced with high-fructose/high-cholesterol diet showed that AI helped reverse fatty formation in the pancreas, which was not significantly different from the rats given simvastatin.
This article reviews the potential use of Acalypha indica Linn. extract as an alternative to modify the risk factors underlying NAFPD.
Keywords: Acalypha indica Linn, cholesterol, fatty pancreas, pancreatic cancer, simvastatin
INTRODUCTION
In this fast-paced era, people tend to eat anything convenient, causing unbalanced daily nutritional intake.
Appetizing food to consume mostly have high cholesterol, while drink tasty beverage mostly contains high value of sweetened corn sugar – a source of high fructose diet. Uncontrolled cholesterol and fructose intake become the risk factors of obesity occurring in people, also causing insulin resistance, diabetes mellitus type 2, and, – which would then usually associated with non-alcoholic fatty liver disease (NAFLD).
NAFLD has been widely known, but there is another fatty accumulation which has just been recognized: non- alcoholic fatty pancreas disease (NAFPD). Despite not being well-understood, the incidence of fatty pancreas needs more focus as researches show that fatty pancreatic infiltration is associated with pancreatic cancer. There has not been any guideline for the treatment of fatty pancreas, but it is believed to be a reversible condition. Efforts for treatment includes modification of its risk factors and the treatment for metabolic syndrome.
The use of statin is a reasonable treatment for fatty pancreas, since statin is shown to reduce the risk of pancreatic cancer. But currently, statin is recognized to have a risk of inducing diabetes. Recently, a study on mice with pancreatic fatty formation showed a reversal of pancreas fatty infiltration with the treatment of simvastatin, and also an extract from Acalypha indica Linn. This article reviews the possibilities of Acalypha indica Linn. extract in comparison with statin for the treatment of fatty pancreas.
Fatty Pancreas, the Silent Old-but-New Disease
Fatty pancreas (here referred to non-alcoholic fatty liver disease/NAFPD) is described as an accumulation of ectopic fat in the pancreas. Unlike fatty liver in which the fatty accumulation occurs intracellularly, fatty components in the pancreas are in the shape of adiposity cell infiltration. The exact pathogenesis of NAFPD is not yet well- understood, but some clinical associations are already known for NAFPD, including fatty liver, diabetes mellitus type 2 (DM T-2) and pre-diabetes, metabolic syndrome, pancreatitis, and pancreas cancer [1, 2].
Studies regarding the association of fatty pancreas and DM T-2 have shown a causal relationship of pancreatic fat infiltration with pancreatic β-cells dysfunction. In human studies conducted by Tushuizen et al [3], pancreatic fatty content of men with DM T-2 is increased compared to men without DM T-2, with statistical significance. Pancreatic infiltration was also found to have a negative correlation with insulin resistance, β-cells glucose sensitivity, and early glucose-stimulated insulin secretion. While regarding pancreas cancer, fatty pancreas - together with obesity - is known to be a risk factor for pancreatic precancerous lesions [4].
The pathophysiology of NAFPD is not clear yet, with two possible mechanisms being an accumulation of intracellular triglyceride in the pancreatic cells, or adipose tissue replacing dead acinar cells of the pancreas; while the fat potentially comes from free fatty acid in the circulation of body, dietary fat, and lipogenesis. Animal studies show a vicious cycle between NAFPD and pancreatic β-cell dysfunction – started by excessive dietary fat intake and hyperglycemia. Hyperglycemic state causes intracellular triglyceride accumulation by decreasing mitochondria β- oxidation through increasing malonyl coenzyme A (malonyl CoA), which causes the inhibition of carnitine-palmitoyl transferase-1 (CPT-1); while free fatty acids in the circulation also directly cause the increase of intracellular triacylglycerol content. The adipocyte-derived cytokines and free fatty acids promote dysfunction β-cells, contributing to decreased insulin production and β-cell death [5].
FIGURE 1. The vicious cycle of fatty infiltration of the pancreas and β-cell dysfunction.
Although these findings are yet to be consistent in human studies, a study by Lim EM et al[6]demonstrated the reversal of β-cell function in DM T-2 patients through dietary intake restriction, in which is associated with decreased pancreatic and liver triacylglycerol content. These findings propose that reversing fatty pancreas is associated with the reversal of diabetes in patients with DM T-2.
Simvastatin and the concern around its utilization for NAFPD
Currently, there is no consensus for curing fatty pancreas, so the treatment will normally focus on its risk factors, which include dyslipidemia. Statin is a widely-used drug for the treatment of dyslipidemia, through its inhibition of
HMG-CoA reductase in the liver. It is also proposed that statin showed antitumor effects in pancreatic cancer cells in vitro and animal models in vivo, in addition to its effect for metabolic syndrome – which is a risk factor for pancreatic cancer; making the use of statin for fatty pancreas a reasonable choice [7].
But in recent years, several randomized controlled trials have shown the increased risk of hyperglycemia and new- onset diabetes caused by statin therapy. It is reported from The JUPITER trial that there was increasing by 25% in new-onset DM T-2 risk with the use of rosuvastatin 20 mg [8].The METSIM observational study shows an increased risk of 46% in DM T-2 with the use of simvastatin and atorvastatin. The dose-dependent risk is related to the comparison of decreasing insulin secretion and insulin sensitivity between patients with and without statin treatment.
[9].
FIGURE 2. Postulated mechanism of statin-induced β-cell dysfunction.
Sampson UK et al [10] postulated that statin may impair pancreatic β-cell function through several mechanisms, including inhibition of de novo cholesterol production which scarcity will inhibit glucokinase - an enzyme responsible in the cascades of insulin secretion. Inhibition of insulin secretion may also result from inhibition of HMG-CoA reductase by statin. Inhibition of HMG-CoA reductase will suppress the synthesis of ubiquinone (CoQ10) - a factor needed to produce ATP - which is essential for the secretion of insulin. It will also cause upregulation of LDL receptors as well as increase uptake of LDL-cholesterol. This increased uptake will enhance intracellular oxidation of LDL- cholesterol which may cause inflammatory cascades that disturbs the integrity of the pancreatic β-cell. The inflammatory cytokines may also induce overproduction of nitric oxide and it is known to induce cell apoptosis through calpain activation.
Over the findings, the use of statin is still recommended for high cardiovascular risk than the harm from possible of DM T-2 emergence [8].Without high cardiovascular risk, the use of statin should be reviewed strictly.
Acalypha indica Linn. as an alternative for the lipid-lowering agent
The possibility of β-cell dysfunction from the use of statin urges the emergence of another alternatives for dyslipidemia treatment for NAFPD, including herbal-derived alternative. Acalypha indica Linn. (AI), a plant found in tropical and subtropical climate, comes from Euphorbiaceae family. Prior animal studies showed promising effects from the use of AI extract for metabolic syndrome. Several studies show significant effects of AI extract in decreasing free fatty acids and serum glucose level in diabetic rats [11-13].Recent study showed the effect of AI extract for pancreatic fat formation in rats induced with 4-weeks of high-fructose and high-cholesterol diet. The study presented that after the induction, the rats without treatment was found to have 0.699% pancreatic fat percentage, while the rats given AI treatment after the induction had 0.310%. This finding was not significantly different from the rats given
simvastatin after the induction [14]. The mechanism of AI action to reduce hyperlipidemia was still unknown. The polyphenol substance of AI, especially flavonoid and phenol, may have same mechanism with Simvastatin as an HMG-CoA reductase inhibitor. Moreover, another study by Zhang et al. reported that polyphenol substance could rise the AMP-activated protein kinase (AMPK) activity which have role as a main regulator of fatty acid synthesis and oxidation within the body. The administration of AI extract was expected to activate the AMPK and it could lead to prevent fatty accumulation [15].
The reversal effect on fatty pancreas of the rats is attributed to the antidiabetic and antihyperlipidemic effect. These effects of AI extract allegedly result from its polyphenol and flavonoid contents. Some flavonoids are known to stimulate insulin production, decrease post-prandial hyperglycemic state, and lower the circulating lipid levels and oxidation rate. Some flavonoids are known to have these effects, including diosmin, fisetin, morin, eriodictyol, hesperidin, naringenin, apigenin, baicalein, chrysin, luteolin, tangeretin, wogonin, isorhamnetin, kaempferol, rutin, quercetin, isoflavones, genistein, athocyanins, cyanidin, delphinidin, and pelargonidin [16].
CONCLUSION
Fatty pancreas or NAFPD is a newly-recognized condition that is closely related to metabolic syndrome such as dyslipidemia, obesity, and diabetes mellitus type 2. While there has not been any guideline for its treatment, the condition is reversible through its risk modification and related to reversal of diabetes mellitus type 2. The potential use of statin to modify dyslipidemia risk in NAFPD raises concern as statin is known to increase diabetes mellitus type-2 and hyperglycemia risk. Acalypha indica Linn. extract has shown reversible effect on fatty infiltration of rats – an effect believed to derive from its flavonoid content. Further study on the flavonoid content of AI will help researchers understand more about the potential use of AI for its antidiabetic and antihyperlipidemic effects, as well as its potential effect to treat NAFPD.
ACKNOWLEDGMENTS
The publication funding of the article was supported by the PITTA Grand from Directorate of Research and Community Service, Universitas Indonesia with number of contract 2131/UN2.R3.1/HKP.05.00/2018.
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