diabetes mellitus is a chronic metabolic disorder that is distinguished by hyperglycemia , underutilization of blood glucose , and defects in the metabolism of macronutrients such as carbohydrates , fat , and protein , secondary to the disturbance in insulin action [ 1 , 2 ] .
type 1 diabetes is caused as a result of insulin deficiency due to failure of pancreatic beta - cells .
therefore , diabetic patients need exogenous insulin injection , whereas patients with type 2 , known as insulin independent , do not respond to insulin and consequently can be managed by lifestyle changes .
next to cancer and heart disease , diabetes mellitus is the third most life - threatening disorder which has a high rate of morbidity and mortality worldwide .
prevalence of this disorder is quickly rising in every part of the world . as a result
, it is projected to affect 552 million people in 2030 , rising sharply from 336 million in 2011 .
signs of type 1 and 2 diabetes may include hyperglycemia , abnormal thirst , repeated urination , weight loss and severe hunger , nausea and vomiting , mood changes , and severe weakness and tiredness .
the purpose of this review was to identify anethum graveolens l. ( ag ) as a valuable herbal plant , originating from asian traditional medicine , in the management of diabetes .
conducted studies could allow representing the potential applications for future research . to complete the assumed task ,
traditional sources regarding the usage and the carried out investigation on anethum graveolens l. are collected and explained .
essential assessments of the documented bioactive components particularly in terms of their correlation with recognized traditional use and current pharmacological knowledge are discussed .
phytochemical studies , antidiabetic properties , suggested mechanism , and the main compounds of ag that may be responsible for useful effects of ag are described too .
to prepare this review a pharmacological and phytochemical literature survey was performed using scopus , pubmed , and web of science .
studies have shown that blood lipid peroxidation markedly rises in diabetes due to vascular injury , which is provoked by hyperglycemia and free radicals .
this peroxidation can further aggravate the progress of diabetic complications and is thought to happen as a result of defects in insulin secretion by pancreatic -cells .
diabetes also leads to an impaired lipid profile , including low levels of high - density lipoprotein ( hdl ) cholesterol and hypertriglyceridemia and raised oxidative stress [ 30 , 31 ] .
cvd is the most common complication in diabetes , which is a common reason for premature mortality in diabetic patients . as a result , to reduce the risk of cvd , many studies potentially recommended control of dyslipidemia and hyperglycemia [ 1 , 3234 ] .
in addition to dyslipidemia , hyperglycemia is known as a major risk factor for diabetic complications .
protein glycation is involved in the progress of complications such as retinopathy , neuropathy , nephropathy , dermopathy , and atherosclerotic lesions [ 1 , 33 , 3537 ] . in the chronic state ,
excess glucose binds to free amino groups in tissue or blood proteins and body fluid and disturbs their functions [ 3840 ] .
age formation is known as a key element in diabetes complications [ 4146 ] . in diabetic patients , reactive substances such as hydroxyl radicals ( oh ) , hydrogen peroxide ( h2o2 ) , lipid peroxyl radicals ( loo ) , superoxide anion ( o2 ) , and peroxyl radicals ( roo )
the reaction of these reactive species with polyunsaturated fatty acids ( pufas ) causes lipid peroxidation which is consequently implicated in early diabetes complications , especially premature cardiovascular disease [ 47 , 48 ] .
for instance , superoxide dismutase ( sod ) is known as one of the main endogenous enzymes that removes o2 and produces h2o2 , which is then processed to water by the activity of catalase ( cat ) and glutathione peroxidase ( gpx ) .
hence , sod can work as the chief protector against o2 and it inhibits production of free radicals .
cat is an important enzyme involved in detoxification of hydrogen peroxide to water and oxygen . on the other hand , glutathione s - transferase ( gst ) and glutathione peroxidase ( gpx )
gpx decreases free radical damage by preventing the production of extremely cytotoxic species , for instance , lipid peroxides and other organic hydroperoxides .
gst is therefore believed to preserve the balance of cellular redox conditions [ 47 , 49 ] .
lipid peroxidation naturally occurs on a small level in the body and plays a key role in diabetes and cardiovascular diseases pathogenesis .
the reactive oxygen species such as hydroxyl radical and hydrogen peroxide attacks polyunsaturated fatty acids and causes lipid peroxidation .
iron ion and hydrogen peroxide in a known process , called fenton reaction , lead to formation of hydroxyl radical which is a potent oxidative agent .
oral administration of many herbal plants leads to a marked rise in the activities of sod , cat , gsh , gst , and gpx in diabetes [ 51 , 52 ] .
there are different ways for treatment and control of diabetes , including administration of insulin or hypoglycemic drugs , dietary control , and exercise [ 53 , 54 ] .
furthermore , chemical drugs generally have low efficacy over time , are too expensive , and show severe side effects such that some patients can not tolerate prolonged treatment or taking the high dosages of these drugs .
in contrast , herbal medicines are regarded as potential sources for medication due to their useful effects , negligible side effects in clinical trials , and low cost [ 5359 ] .
people use different medicines such as sulfonylureas ( glimepiride , glipizide , and glyburide ) , biguanides ( metformin ) , thiazolidinediones ( pioglitazone ) , alpha - glucosidase inhibitors ( acarbose ) , meglitinides ( nateglinide ) , and dipeptidyl peptidase 4 inhibitors ( januvia , onglyza ) for control and treatment of hyperglycemia .
more than 10 to 20 percent of diabetic patients are known to eventually stop taking their medications because of the side effects .
some of the diabetes medicines can also cause hypoglycemia which is a harmful and potentially lethal side effect .
additional side effects of several antidiabetic drugs are weight gain , increased risk for fractures especially in women , and gastrointestinal disorders such as abdominal pain , gassiness , vomiting , nausea , diarrhea , and bloating .
edema and increased level of low - density lipoprotein cholesterol ( ldl - c ) were also reported by many patients .
uncommon side effects include congestive heart failure , allergic reactions , and anemia , which can be induced by chemical diabetic medicines [ 30 , 31 ] .
nowadays , many physicians prescribe insulin , thiazolidinediones , sulphonylureas , -glucosidase inhibitors , and so forth , for treatment and control of diabetic complications .
nevertheless , since adverse effects of these medicines are arguable , there is a need for novel agents in diabetes treatment . in this respect
, some herbal medicines due to their lower side effects , low costs , useful properties such as antihyperglycemic , antihyperlipidemic , and antioxidant effects , and especially their natural origin have been proposed for potential management of diabetes [ 76 , 77 ] . however , because of unknown mechanisms , only a small number of plants have been used for the management of diabetic complications .
herbal plants contain many chemical components such as flavonoids ( 30% ) , terpenoids ( 17% ) , saponins ( 9% ) , polyphenols ( 6% ) , alkaloids ( 5% ) , tannins ( 4% ) , polysaccharides ( 3% ) , and miscellaneous compounds ( 17% ) , which are known to have remedial properties .
interestingly , the world health organization ( who ) reported that about 80% of the world 's people presently use herbal plants for treatment of different diseases .
although many plants have been suggested for treatment of diabetes due to their antidiabetic properties , in this review , we will attempt to open a new window toward application of ag and its constituents in the management of type 2 diabetes .
anethon  and the colloquial name of dill is derived from the old norse word 
 ag is the only species of the genus anethum , still classified by several botanists related to peucedanum genus as peucedanum graveolens ( l. ) .
ag is an annual vertical plant with 50150  cm stem belonging to the apiaceae family .
the fruits of ag are brown , flat , tiny , and oval in shape ( figure 1 ) .
ag contains 36% carbohydrates , 15.68% proteins , 14.80% fiber , 9.8% ash , and 8.39% moisture as well as essential oils , fatty oil , minerals , and vitamins .
ag is used in the traditional herbal medicine for the management and prevention of digestive disease , breath problem , motivation of lactation , and also reduction of cholesterol and glucose .
currently , many studies have established these properties ; also , ag is recently known as anticancer , antimicrobial , antigastric irritation , anti - inflammatory , and antioxidant agent . in this respect ,
dill is produced as a hypolipidemic drug ( anethum tablet ) in iran which consists of anethum graveolens ( 68% ) , cichorium intybus ( 5% ) , fumaria parviflora ( 5% ) , and lime ( citrus aurantifolia ) ( 4% ) .
administration of different extractions of ag seed and leaf , as well as its essential oil , in diabetic models significantly reduced triglycerides , total cholesterol , low - density lipoprotein cholesterol ( ldl - c ) , very - low - density lipoprotein cholesterol
( vldl - c ) , and glucose levels , whereas it increased hdl - c level . on the other hand
it has also been shown that the extract from ag flowers had more antioxidant activity than either its seed or leaf extract .
duration of treatment in different experiments was variable ; for example , koppula and choi   used only single dose for one hour , while the treatment period in mansouri et al .
however , almost all of the experiments show that one month is an appropriate time for survey of antidiabetic properties of dill . to survey the effects of ag on dyslipidemia
the rabbit is known as an animal model that has been commonly used for the study of hypercholesterolemia .
only few studies have been done on rabbits , whereas rats are an optional model for diabetes studies .
therefore , as mentioned in table 1 , most of the studies used diabetic rats .
inhibition of intestinal cholesterol absorption , binding to bile acids in the intestine , an increase in fecal excretion , and increasing production of bile acids might be the main mechanisms by which ag exerts its antidiabetic functions .
[ 24 , 82 ] proposed that some components of ag such as carvone , limonene , or -phellandrene are responsible for the hypolipidemic properties of ag , likely through reducing acyl coa carboxylase or 3-hydroxy-3-methylglutaryl - coa ( hmg - coa ) reductase , the key enzymes in fatty acid and cholesterol metabolism .
other studies have suggested that ag components might rise liver ldl receptors , decrease fatty acid synthesis , and impact lipoprotein homeostasis mainly through improvement in lipoprotein metabolism .
furthermore , some studies suggest that ag may improve the lipid profile by its antioxidant properties .
we have also observed that administration of 100 and 200  mg / kg of ag tablet and hydroalcoholic extract of ag in hypercholesterolemic hamsters resulted in significantly reduced hmg - coa reductase activity and mrna levels .
for the first time , we also showed that ag normalized the lipid profile by decreasing hmg - coa reductase in the hypercholesterolemic hamsters and type 2 diabetic rats .
we have also shown that ag increased ldl receptor level in the liver resulting in stimulation of cholesterol clearance from the bloodstream ( unpublished data ) .
the results of abbasi oshaghi et al . 's   study showed that ag significantly increased cholesterol-7-alpha hydroxylase activity , the rate - limiting enzyme in bile acids biosynthesis .
some studies have also reported that rutin and quercetin ( components of dill ) may decrease serum cholesterol and ldl - c levels and decrease liver cholesterol level .
.   showed that treatment of diabetic rats with different extracts of ag normalized lipid deposits in the liver , pancreas , and heart .
hplc analysis showed that ag has high amounts of quercetin which may be responsible for the suppression of hmg - coa reductase activity .
numerous studies that have previously shown the antidiabetic effects of ag are listed in table 1 .
chemical compounds of ag extracts especially flavonoids , terpenoids , alkaloids , tannins , and phytosterols are probably responsible for its hypoglycemic effects .
we found that different extracts of ag reduce ages formation [ 85 , 86 ] .
our study also showed that ag at the dose of 300  mg / kg had potential antioxidant and hypolipidemic effects .
reported significant decline in fasting blood glucose level with 300  mg / kg hydroalcoholic extract of anethum graveolens .
doses of ag up to 2  g / kg in a short period of time did not cause any death in animal models . also , the ag doses up to 1000  mg / kg did not cause any toxic effect in short time experiments .
although different doses of ag were used in animal models , ahmadi mahmoudabadi   reported that the effective dose for metabolic properties is 300  mg / kg in animal models .
different studies showed that both high and low doses of ag have hypoglycemic and hypolipidemic effects .
the doses less than 50  mg / kg could be known without adverse effect in rats and mice . however , piri et al .   demonstrated that 3-week administration of anethum extract at the doses of 50 , 100 , and 200  mg / kg normalized blood lipid , and the change in blood glucose was not significant .
the safe and effective dose in human studies is reported as 650  mg / kg . in an in vitro study ,
abbasi oshaghi et al .   found that different extracts of ag at the concentrations of 0.032 , 0.065 , 0.125 , 0.25 , 0.5 , and 1  mg / ml reduced ages formation ; fructosamine level and carbonyl groups , also , raised thiol groups in type 2 diabetic animals .
oxidation of carbonyl and thiol groups on blood proteins significantly reduces by anethum in a dose dependent manner . according to the study conducted by adisakwattana et al . , polyphenolic compounds in plant extract may play a major role in the inhibition of ages formation .
ages are recognized to contribute to the production of oxidative stress and inflammation , which are related to the diabetes complications .
it has been reported that administration of age - rich diets in an animal model is associated with rising of blood and tissue ages and the conditions like atherosclerosis .
.   showed that administration of ag powder in type 2 diabetic patients reduced fasting blood glucose and normalized insulin resistance and lipid profiles .
as mentioned above , ag is rich in antioxidant compounds ; therefore , antioxidant and flavonoid components of ag probably are able to repair damaged -cells and insulin secretion .
it has been shown that ag significantly increases total antioxidants in the pancreas and also regenerates histopathological changes .
takahashi et al .   have shown that ag extract normalized lipid profile in diabetic obese mice by activating peroxisome proliferator - activated receptor- ( ppar- ) and increasing fatty acid oxidation - related genes expression .
our colorimetric and hplc analysis also showed that dill had a high amount of quercetin , phenol , flavonoid , tannin , saponin , and alkaloid .
therefore , we can conclude that components of dill are responsible for its metabolic effects .
mishra   reported that aqueous extract of ag has a high amount of carvone , which is accountable for its antidiabetic activity .
the ethanolic extract of ag which is prepared in india showed very low antidiabetic properties . on the other hand , mudassir et al .   reported that the prepared ethanolic extract of ag in pakistan significantly reduced blood glucose ( 34% reduction ) .
they declared that hypoglycemic effects of ag might be due to the inhibition of intestinal glucose absorption . in our laboratory , we have previously shown that ag has potential antioxidant activity .
our results are in agreement with the results of a previous study by bahramikia and yazdanparast , indicating dpph radical scavenging activity of ag . in our study , 1  mg / ml of ag water extract showed 96.04% scavenging of h2o2 , whereas only 27.26% radical scavenging activity was reported for ag ethanolic extract .
ag also showed fe ion chelation which is known as a defense mechanism against oxidative damage by declining free radical production via fenton reaction . in this reaction , iron(ii ) is oxidized by h2o2 to create potential free radicals such as hydroxyl radical .
the results of a study by bahramikia and yazdanparast   showed that crude extract of ag exhibited a moderate no scavenging activity . in line with this observation
, we showed a nitric oxide scavenging activity of ag similar to the known radical scavengers , ascorbic acid and butylated hydroxytoluene ( bht ) .
interestingly , we showed that no scavenging activity of ag is comparable with the activity of ascorbic acid and/or bht .
we showed that a 1  mg / ml solution of dill water extract has 90.41% no scavenging activity which was much greater than that observed ( 78.49% ) for ethanolic extract of ag by orhan et al . .
we have also detected a greater antioxidant activity for ag water extract compared with methanolic extracts .
interestingly , the antiradical and antioxidant properties of ag in all tests were similar to ascorbic acid and bht .
the results of many studies established the notion that the particular parts of dill are often discriminated by significant diversity in their constituents ' chemical compounds .
it has been reported that ethanolic extract of ag has very low antidiabetic properties when compared with the aqueous extract
concordant with the hypoglycemic function of ag ethanolic extract , other studies have reported that this extract significantly reduces blood lipids [ 24 , 82 ] .
interestingly , we showed that different extracts of ag significantly reduced glucose level , but the reduction by water or hydroalcoholic extract was more as compared with the methanolic extract .
furthermore , with review of the literature , we can find that different preparations such as hexane , ethanolic , water , and hydroalcoholic extracts of seed and leaf have been used in different studies ( table 1 ) .
there is some diversity in the dill composition in different countries ; for example , american dill oil has a high amount of alpha - phellandrene , while carvone and limonene are the main constituents of asian and european dill .
in addition to essential oils especially carvone , limonene , and alpha - phellandrene , dill also contains fatty oil , proteins , carbohydrates , moisture , fiber , ash , vitamins ( a and niacin ) , and mineral elements ( calcium , potassium , magnesium , phosphorus , and sodium ) .
this plant is known as a rich source of flavonoids , phenolic compounds , saponins , cardiac glycosides , and terpenes .
jana and shekhawat   reported that there are several volatile components of ag seeds and herb .
for instance , carvone is the main odorant of ag seed and limonene , -phellandrene , myristicin , and dill ether are the most vital odorants of ag herb .
larijani et al .   also reported that seeds and leaves of ag have different components and consequently have different therapeutic effects .
different parameters such as cultivating area , genotype , and environmental factors have huge effects on the composition of ag extracts .
furthermore , reichert et al .   reported that the different parts of ag have different compounds and these compounds may change depending on the stage of plant growth . for example , sefidkon   reported that -phellandrene and limonene are the major constituents of dill oil , while singh   showed that carvone , dill apiole , limonene , trans- and cis - dihydrocarvone , and linalool are the main constituents .
consequently , the different components which are reported by the different studies also depend on the different plant growth stage , cultivating area , and the particular part of the plant that is used .
different compounds of ag have been described in the different published reports which are listed in table 2 .
however , it has been shown that ag administration is safe , and it may rarely lead to allergic reactions , vomiting , diarrhea , oral pruritus , urticaria tongue , and throat swelling ; furthermore , it is not suggested in pregnancy .
mirhosseini et al .   reported that ag did not have any side effects , as compared with gemfibrozil , in treated patients .
other clinical trial studies did not report the side effect of ag [ 11 , 13 , 26 , 27 ] .
herbal medicines have multiple key components such as flavonoids , terpenoids , saponins , polyphenols , tannins , alkaloids , and polysaccharides that have their individual remedial properties .
herbal medicines especially ag have a lot of useful properties including antihyperlipidemic , antihypercholesterolemic , antidiabetic , anticancer , antioxidant , antistress , antisecretory , cardioprotective , antispasmodic , and diuretic effects .
moreover , epidemiologic experiments reported a converse relationship between ag consumption and risk of diabetes and cvd progression .
recent literature strongly supports the suggestion that consumption of ag has a significant antidiabetic effect in both humans and animals . according to the reported antidiabetic effects of dill , it can be suggested for the management of diabetic patients . however , the diverse preparations , dose of ag , period of ag consumption , and interaction with other drugs must be normalized .
more studies are required to recognize the specific constituents of ag that are accountable for most of its valuable properties .
although all components of ag have antioxidant , hypoglycemic , and hypolipidemic effects , these components are at low levels in dill and possibly have synergic effects .
moreover , the findings suggest that activation of ldl - r , ppar - alpha , and other fa oxidation - related genes and also inhibition of hmg - coa reductase contribute to the hypolipidemic effects of ag .
 
 aim . there is evidence that anethum graveolens ( ag ) has been used for centuries in asian traditional medicine , and its constituents have useful effects on the control and management of diabetes and cardiovascular disorders . 
 ag has many useful effects , including hypolipidemic and hypoglycemic effects , and it has been reported to reduce the incidence of diabetic complications . 
 it acts mainly by affecting antioxidant capacity and change in some genes in glucose and lipid pathways . 
 the aim of the present paper was to summarize pharmacological effects of ag in the management of diabetes . 
 methods . to prepare this review , 
 a pharmacological and phytochemical literature survey was performed using scopus , pubmed , and web of science . also , some historical and ethnopharmacological literature sources were used . 
 results . this review plans to provide readers with an assessment of the pharmacological effects of ag , especially in diabetes . 
 conclusion . 
 the paper highlights the therapeutic effects of ag which would aid in supporting their safe use in the management of diabetes and cardiovascular diseases . 