Regulatory Mechanism of Caffeic acid on glucose Metabolism in Diabetes

 

Mohd Yusuf, Mohammad Nasiruddin, Nazneen Sultana, Badruddeen*, Juber Akhtar, Mohammad Irfan Khan, Mohammad Ahmad

Faculty of Pharmacy, Integral University, Lucknow (U.P), India.

 

ABSTRACT:

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, frequent urination, fatigue etc. It became prominent disorder affecting majority of the world population. Phenolic acids i.e. (caffeic acid) are sufficiently present in human dietary products. Hence there is need to evaluate the effect of commonly used phenolic acid compound on human health. Caffeic acid is naturally occurring phenolic compound commonly found in numerous plants, fruits, vegetables. It exhibits different pharmacological activities like anti-diabetic, anti-inflammatory, antioxidant, antimicrobial activities. Caffeic acid acts through different targets regulating the glucose metabolism. It elevates the AMPK level in skeletal muscles, liver, adipocytes and GLUT4 translocation and expression in skeleton muscles thus stimulate the glucose utilization. It also suppress the glucose output from liver. Caffeic acid inhibits the differentiation and adipogenesis. In addition it also helps to increase the exogenous antioxidant i.e. SOD, CAT, TBA, GR_X and thus helps in reducing oxidative stress.

 

 

INTRODUCTION:

Diabetes mellitus is a chronic metabolic disorder affecting a large population of the world. In current scenario it becomes a major public health issue. Current data shows show that approximately 4% of the global population suffers from DM, and this data is expected to reach 5.4% in 2025^[1]. Diabetes mellitus is characterized by various signs and symptoms in which hyperglycemia, frequent urination, polyphagia, blurred vision, fatigue are common. The chronic hyperglycemia are associated with dysfunction and failure of different organs, especially eyes, heart, kidney, blood vessels, nerves. Diabetes mellitus altered several metabolic process like glucose metabolism, fat and protein metabolism resulting from insulin secretion or insulin action or both. Chronic DM or long term DM results in diabetic complications in which, retinopathy (loss of vision), nephropathy (renal failure), foot ulcers, cardiovascular symptoms and sexual dysfunction are common.

 

Hyperglycemia with ketoacidosis or non-ketotic hyper molar syndrome are consequences of acute uncontrolled diabetes mellitus. Elevated blood pressure and altered lipid metabolism are commonly reported in diabetic patient.

 

World Health Organization defines three major types of diabetes mellitus which have different etiology and population distribution: Type1, Type 2 and gestational DM. Type 1 DM caused due to autoimmune defects in which T- lymphocytes attack the β- cells of the pancreas and results in hypo-secretion of insulin (hypoinsulinemia) and therefore results in hyperglycemic condition^[2]. Type 2 DM is caused due to insulin resistance or decrease in insulin sensitivity or inadequate compensatory insulin secretion ^[3]. Insulin resistance is a condition in which cells become unable to respond properly to normal levels of insulin. Insulin resistance primarily in the muscles, liver and adipocytes. Type 2 also known as non-insulin dependent DM and one of the most common in three type DM. Gestational DM is a type of DM diagnosed at the period of pregnancy as a result of glucose intolerance because of reduced β- cell function (Table 1)^[4] .

 

Table 1: Comparison of Diabetes mellitus

Features	Type Ⅰ diabetes mellitus	Type Ⅱ diabetes mellitus
Age of onset	Early childhood or pubertal age20 years	After 40 years
Symptoms	Abrupt and severe due to destruction of β cells of pancreas	Gradual, insidious
Frequency	5-10%	90-95%
Etiology	Autoimmune destruction of β cells of pancreas	Reduced insulin sensitivity
Plasma insulin level	Low	Normal to high
Body weight	Low or normal	Obesity
Blood glucose	Increased	Increased
Insulin sensitivity	Normal	Reduced
Ketosis	Common	Rare
Complications	Ketoacidosis	Hyperosmolar coma
Treatment(Insulin/oral hypoglycemic agents)	Insulin	Oral hypoglycemic agent

 

Mechanism of chemical induced Diabetes:

Streptozotocin (STZ): is an antibiotic obtained from Streptomycetes acromogenes widely used for inducing both insulin dependent and non- insulin dependent types of diabetes in experimental animals. To induce insulin dependent DM in rats a single I.V. dose of 40 to 60 mg/kg body wt. is required ^[5]. STZ is also administered through intraperitoneal route (IP) for inducing diabetes ^[6]. After two hours administration of STZ increase in blood glucose level (hyperglycemia) associated with reduced blood insulin level is observed, STZ affects glucose oxidation and also reduces insulin biosynthesis and their release from β-cells ^[7]. STZ is transported through GLUT2 receptor inside the pancreatic β-cells ^[8] where it gets accumulated intracellularly and alters the DNA of the pancreatic β-cells and results in fragmentation. STZ also induces alkylation in pancreatic β-cells and thus results in cell death. Nitrosourea moiety of STZ is responsible for alkylation of DNA. Nitrosourea moiety donates Nitric oxide (NO) which acts as a free radical (ROS) and produces DNA damage (Figure 1)^[9].

 

Figure 1: The action of STZ on β-cells.

 

Alloxan:

It is also used for inducing diabetes like STZ. Alloxan can be given parentrally for induction of diabetes i.e. I.V, I.P, S.C. The dose of Alloxan necessary for inducing diabetes varies based on the type of animal species. Commonly used dose of alloxan for inducing diabetes is 65mg/kg body weight. Alloxan causes production ROS due to reduction to dialuric acid ^[10]. The dialuric acid undergoes autoxidation and generates superoxide radicals, hydrogen peroxide radicals and other ROS and ultimately causes necrosis of β-cells (Figure 2) ^[11,12].

 

Figure. 2: Showing the action of Alloxan on β-cells.

 

Role of Oxidative stress in DM:

Diabetes mellitus sometimes also known as oxidative stress metabolic disorder. Oxidative stress is a condition occurs when there is imbalance between free radical generation and body endogenous antioxidant defense mechanism. Increased in blood glucose level results in increased   free radicals accumulation inside body^[13,14]. Generation of free radicals due to uncontrolled hyperglycemia occurs via different pathways i.e. a) increased glycolysis^[15], b) activation of intracellular sorbitol pathway, c) autoxidation of glucose ^[16], d) non enzymatic protein glycation. Body endogenous antioxidant play an important role in preventing generation of free radicals by scavenging the free radicals generated during various metabolic process. But when endogenous antioxidant defense system falls then the condition called oxidative stress takes place. Which further leads to generation of ROS which further leads to oxidation of cellular component like lipid, proteins, and nucleic acid and this leads to development and progression of diabetes. From in vivo studies it was concluded that prolonged hyperglycemia results in induction of mitochondrial ROS which reduces the first phase insulin secretion. Endogenous antioxidant like Superoxide dismutases (SOD), catalases, glutathione peroxidase, glutathione reductase prevent the oxidative stress by scavenging the free radicals or by binding to metal that stimulate the formation of free radicals (Figure 3).

 

Figure 3: The association between OS and DM.

 

Caffeic acid:

Description:

·      Caffeic acid (3,4-dihydroxycinnamic acid) is an important phenolic acid widely found in fruits, grains and other dieatry food.

·      Caffeic acid is found in different variety of fruits, vegetables in free and conjugate form. It is also found in sweet potato, green coffee beans, apple etc (Table 2).

 

Chemical and Physical Properties:

a)       Colour: Caffeic acid occurs as yellow prism or plates from water.

b)       Melting point: The melting point of caffeic acid is 225º C.

c)       Solubility: Highly soluble in hot water and cold ethanol while sprangly soluble in cold water.

d)       Stability: It is found in both cis and trans forms but trans form is found more predominant. Solution of caffeic acid and its derivatives (chlorogenic acid and isochlogenic acid) are found to be unstable in sunlight and UV light.

 

 

 

Table 2: Different Sources of caffeic acid

S. No	Sources	Part of Plant	Concentration (mg /Kg)
1	Brocoli	Florets	8
2	Cauliflower	Leaves	9-29
3	Fennel	Tuber	100
4	Garlic	Dry bulb skin	<20
5	Parsley	Whole plant leaves	6
7	Onion	Green leaves	< 0.5-15
8	Blue berry	Fruit	83-588
9	Strawberry	Fruit	< 0.5-14
10	Apple	Fruit	0-10

 

Caffeic acid is found to have both antioxidant and anti-dabetic activity. Caffeic acid significantly lowers the fasting glucose level as compared to control db/db mice. Caffeic acid helps in lowering the glycosylated hemoglobin level a well reliable marker of chronic diabetes. The rise in hepatic GK results in higher utilization of blood glucose for energy production or accumulation of glycogen in liver^[17]. Study result claimed that experimental animal treated with caffeic acid have higher hepatic glycogen content^[18]. Decrease in hepatic GK activity results in release of glucose into circulation due to increased gluconeogenesis. G6Pase and PEPCK are the enzyme which plays an important role in regulating the gluconeogenesis and glucose output from liver. A study showed that caffeic acid significantly decreases the hepatic PEPCK and G6Pase activity and their mRNA expression in db/db mice showing a reduced hepatic glucose production. Caffeic acid also lowers the hepatic GLUT2 protein expression and thus lowers the hepatic glucose output. Thus this shows that caffeic acid reduces the hepatic glucose output by stimulating the hepatic glucose utilization^[19].

 

Another action of caffeic acid by which it helps in regulating glucose metabolism is that caffeic acid stimulates the transport of blood glucose into adipose tissues. Normally the transport of glucose in liver and adipocytes are controlled by various mechanisms. Humans and rodents with type 2 DM generally have over GLUT2 expression however, over expression of GLUT4 in adipose tissue reduce the insulin resistance and pancreatic defects in db/db mice^[20]. Caffeic acid increases the GLUT4 protein expression in adipocytes thus helps in regulating the hyperglycemia or glucose metabolism. Caffeic acids plays dual role in regulating the glucose level i.e. increases the insulin release from pancreatic β-cells and also reduces insulin resistance in adipose tissue and liver^[21]. It is found that hyperglycemia for longer duration results in production of reactive oxygen species (ROS) that leads to cell damage.

 

Increased ROS content inside body leads to generation of oxidative stress which further leads to damage of erythrocyte and liver injury in diabetes thus causes altered hepatic glucose regulating enzymes^[22]. In normal condition liver and erythrocytes contains sufficient level of antioxidant like SOD, CAT and GSH-P_X which protect the body from ROS damage^[23]. But prolonged exposure of hyperglycemia leads to suppression of antioxidant (SOD, CAT) enzymatic activity. Recent studies suggest that TBK1 (tank binding kinase-1) and IKKe (I-Kappa- B Kinase epsilon) mRNA and protein expression is elevated in obese mice which results in development of inflammatory or metabolic disorders like type 2 diabetes. Some phytochemicals like phenolic acids results in inhibition of IKKe and TBK-1. Therefore administration of IKKe and TBK-1 inhibitors to experimental animal treated with high fat diet (HFD), results in reversible weight loss, increased insulin sensitivity, suppression of inflammatory response. Polyphenolic acids obtained from green tea are capable to breed thermogenesis and energy expenditure, thereby alleviate fat accumulation thus reducing the insulin resistance^[24].

 

Some study shows that experimental animals treated with caffeic acid results increase in antioxidant enzymatic activities like SOD, CAT, TBA in both erythrocytes and in liver when compared to normal control group^[25]. In diabetic condition auto-oxidation of glucose and protein glycation results in lipid peroxidation which further leads to generation of free radicals formation. The important free radicals that occur in diabetes are superoxide (O₂), Hydroxyl (OH), peroxyl (LOO^-) radicals^[26]. Lipid peroxidation results in oxidation of cholesterol, oxidation of unsaturated poly acyl groups of phospholipids which may alter the structure and function of membrane. The lipid peroxidation results in decrease the life span of erythrocytes, membrane fluidity, viscoelasticity and deformability which may results in Type 2 diabetes complications^[27].

 

Certain enzyme like SOD, CAT, GP_X, GR plays a major role against oxidative stress. These enzymes cause conversion of free radical species to non-radicals species ^[28]. It was found that in diabetic rats the enzymatic antioxidant activities of SOD, CAT, GP_X, GR reduces while the MDA activity increases^[29]. But administration of diabetic rats with caffeic acid causes increase in enzymatic antioxidant activities of SOD, CAT, GP_X, GR as compared with diabetic control rats. The antioxidant action of caffeic acid is based on free radicals scavenging activity which is based on their hydrogen or electron donating capacity (Figure 4).

 

Caffeic acid is an important antioxidant having anti-diabetic properties by increasing the insulin release and also decreases hepatic glucose output along with increased glucose disposal inside the adipose tissue in type 2 diabetes. Additionally caffeic acid is an effective in preventing oxidative stress as well as also helpful in preventing/suppressing the Type 2 diabetes complications.

 

Figure.4: Caffeic acid regulating glucose metabolism

 

Pharmacological activity and uses of caffeic acid

Different no. of studies have been performed to develop new drug based on Caffeic acid for use in treatment of asthma, and other allergy associated disease ^[30]. Caffeic acid also has antimicrobial and antibacterial action. Bactericidal activity of Caffeic acid will be shown only after oxidation of Caffeic acid under alkaline condition. Caffeic acid also found use in anti-wrinkle tropical formulation. Some studies shows that w/o based emulsion containing aquous extract of Polygonum minus seed improve facial skin elasticity and also decreases the wrinkle ^[31]. This effect of Polygonum minus seed extract is due to the presence of Caffeic acid (Table 3).

 

Table 3: Reported Pharmacological activities of Caffeic acid

S. No	Activity	Mechanism	References
1	Hypoglycemic Activity	Caffeic acid stimulate insulin release & transport of blood glucose into adipose tissues.	[32]
2	Antioxidatnt activity	Polyphenolics (Caffeic acid) inhibit the formation hydroxyl radicals. It also acts by scavenging the generation of free radicals.	[33], [36]
3	Anti-inflammatory	Caffeic acid suppress the inflamatory cytokines e.g TNF-α, IL-1β & NO. It also lowers the Cardiac MCP-1 protein production.	[34]
4	Anti-microbial activity	Caffeic acid results changes in cell surface hydrophobicity and it also causes the K+ leakage.	[35]

 

 

CONCLUSION:

Caffeic acid is an important phenolic compound having antioxidant/anti-inflamatory activity. It exhibits anti-hyperglycemic action by stimulating the transport of blood glucose into adipose tissues and it also increases the insulin secretion from β-cells. It also lowers the hepatic GLUT2 protein expression thus lowers hepatic the hepatic glucose output, while it also increases the GLUT4 protein expression in adipocytes thus helps in regulating the glucose metabolism. Moreover animal treated with caffeic acid causes increase in exogenous antioxidant enzymatic activities i.e. SOD, CAT, Thiobarbituric acid in liver and erythrocytes. The caffeic acid also possess other pharmacological activities like anti-coagulatory, anti-aging or anti-wrinkle activities.

 

ACKNOWLEDGEMENT:

Authors are thankful to the Faculty of Pharmacy Integral University Lucknow for providing suitable facilities & support for the successful completion of this study (IU/R&D/2019-MCN0000000).

 

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Received on 17.04.2019           Modified on 25.05.2019

Accepted on 29.06.2019         © RJPT All right reserved