A SHORT REVIEW ON ANTI-DIABETIC AGENT

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ABOUT AUTHORS:
Deepika Gautam¹*, Deepti Gautam²
¹Department of Chemistry, Lucknow University,
Lucknow, Uttar Pradesh, India
²Department of Nursing, Era’s Lucknow Medical college and Hospital,
Lucknow, Uttar Pradesh, India
*yashdeepika1@gmail.com

ABSTRACT
Different type of natural and synthetic agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reestablished normality. They also reduce chronic diabetic complications, but they do not remove completely them. Thus, for the treatment of type2 diabetes mellitus new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are main cause in the pathogenesis of Type 2 diabetes, in this review we discussed about some natural and synthetic molecule and their targets and some old oral ant diabetic drug and their mode of action.

INTRODUCTION
Diabetes mellitus (DM) is a metabolic disorder characterized by increase glucose level in blood and changes in lipid and protein metabolism^[1]. Because the body cannot release or use insulin normally. insulin is a hormones which is released by pancreas. which maintaining sugar level in blood^[2]. Diabetes mellitus are of two type one is insulin dependent^[3] and another is non-insulin dependent. insulin dependent diabetes called type 1(IDDM), also known as "juvenile diabetes" because it occurs in the young children and adolescents. it is an autoimmune disorder where antibodies are produced against the β cells which release insulin, are destroyed^[3].

Non-insulin dependent called type 2 diabetes mellitus(NIDDM) or "adult-onset diabetes “because occurs in adult. Serious prolong complications include some serious disease like heart disease, stroke, kidney failure, foot ulcers and damage to the eyes^[1] DM can be found worldwide and the population is increasing. According to WHO projections, about 300 million or more people will be affected by diabetes by the year 2025.^[^4]The estimated number of diabetic patients in 2030 will be more than double that in 2005.^[4]according to IDF in 2009 India has the largest number of people — 50.8 million suffering from diabetes in the world, followed by China (43.2 million) and the United States (26.8 million). India continues to be the "diabetes capital" of the world, and by 2030, nearly 9 per cent of the country's population is likely to be affected from the disease, warns the fourth edition of the World Diabetes Atlas launched by the IDF at the 20th World Diabetes Congress in Montreal, Canada. Worldwide, as of 2013, an estimated 382 million people have diabetes, with type 2 diabetes making about 90% of the cases.^[^5,6] This is equal about 8.3% of the adults population,^[^6]equal rates in both women and men.^[^7] Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million deaths per year, making it the 8th leading cause of death.^[^8,9] Diabetes overall at least doubles the risk of death. The number of people with diabetes is estimated up to rise to 592million by 2035.^[^10]The economic costs of diabetes globally was estimated in 2013 at USD 548 billion^[^9] and in the United States in 2012 USD 245 billion.^[^11]

Some Oral anti-diabetic drugs-
Type of anti-diabetic drugs-
· Sulfonylureas/insulin tropics
· Biguanides
· a-Glycosidase inhibitors
· Thiazolidinedione
· DPP-4 inhibitors (Glistens)

Sulfonylureas/insulin tropics-mechanism and targets-
Sulfonylureas reduce the blood glucose level by stimulating the release of insulin from the pancreatic β-cell and sensitivity of peripheral tissue to insulin, number of insulin receptor and suppressing gluconeogenesis in the liver

It bind to receptors on the pancreatic β-cell, and block the k+ on these receptor.it reduce potassium conductance and increased insulin secretion.

Side effects-Hypoglycemia,weight gain

Example and their structure-

Biguanides-mechanism and action is not clear,suppressing hepatic gluconeogenesis

Side effect-Gastrointestinal disturbances, lactic acidosis

α-Glucosidase inhibitors-it reduce the glucose absorption from upper intestines and do not causes hypoglycemia

Eide effect-Gastrointestinal disturbance

Example and their structure-

Thiazolidinediones- they are agonist at the PPARϒ receptor. It increase insulin mediated glucose transport in to muscle and fat tissue and reduce hepatic gluconeogenesis and lower incidence of hypoglycemia

Side effect-cause severe hepatotoxicity and weight and anemia

Example and their structure-

DPP-4 inhibitors (Gliptins)- Reduce glucagon and blood glucose levels by inhibiting DPP-4

Side effect- Nasopharyngitis, Headache, Nausea, Hypersensitivity, Skin reactions

Example and their structure-

Some anti-diabetic agent -

S.N.

Name and source

Activity & Mechanism

Genistein12 branches of Tetracera scandens (Dilleniaceae

Glucose-uptake activity in basal and insulin-stimulated L6 myotubes (0–25 mM), acting by AMPK activation and GLUT4 and GLUT1

(IC50 range = 20–37 µM)

3’,5’-diprenylgenistein branches of Tetracera scandens (Dilleniaceae)

Glucose-uptake activity in basal and insulin-stimulated L6 myotubes (0–25 mM), acting by AMPK activation and GLUT4 and GLUT1

(IC50 range = 20–37 µM)

Alpinumisoflavone

branches of Tetracera scandens (Dilleniaceae)

Glucose-uptake activity in basal and insulin-stimulated L6 myotubes (0–25 mM), acting by AMPK activation and GLUT4 and GLUT1

(IC50 range = 20–37 µM)

Derrone

branches of Tetracera scandens (Dilleniaceae

Glucose-uptake activity in basal and insulin-stimulated L6 myotubes (0–25 mM), acting by AMPK activation and GLUT4 and

(IC50 range = 20–37 µM)

6,8-diprenylgenistein

branches of Tetracera scandens (Dilleniaceae

Glucose-uptake activity in basal and insulin stimulated L6 myotubes (0–25 mM), acting by AMPK activation and GLUT4 and GLUT1 over-expressio

(IC50 range = 20–37 µM)

Vanilic acid & sulphate

Derivatives13

Green algae

Cladophora socialis

Inhibition of protein tyrosine phosphatase 1B (PTP1B),an important enzyme in regulating the insulin receptor, with IC50

values of 3.7µM

Cinamaldehyde

Cinanamonum zeylanicum Biume

Inhibition of protein tyrosine phosphatase 1B (PTP1B),an important enzyme in regulating the insulin receptor, with IC50

values of 1.7 µM

Cinchonain Ib

Eriobotrya japonica14 LINDL (Rosaceae)

leaves

Enhanced insulin secretion from INS-1 cells (rat insulinoma cell), as well as reduced plasma insulin level in rats after 108 mg /kg oral administration

Steppogenin-4’-O-β-D-glucoside15

root

bark of Morus alba L. (Moraceae)

Showed a hypoglycemic effect

at 50 mg kg_1 (p.o.) in alloxan-induced diabetic mice

Two bis(catechol glycoside) esters16

leaves of Dodecadenia grandiflora (Lauraceaes

Compounds (100 mg kg_1 bw, p.o.) showed significantantihyperglycemic

activity in STZ-induced diabetic rats

kraussianone-1

kraussianone-217

Roots of Eriosema kraussianum N.

E. Br. (Fabaceae)

Compounds 1and 12 (20–80 mg/ kg p. o.) resulted in dose-dependent hypoglycaemia in rats, with

glibenclamide (10 mg/ kg bw, p. o.) as the positive control

Davidigenin18

Artemisia dracunculus L. (Asteraceae),

This extract inhibited aldose

reductase (ALR2) activity by 58% to 77% at 3.75 mg/ mL

6,demethoxycapillarisn

Artemisia dracunculus L. (Asteraceae),

Inhibited phosphoenol pyruvate carboxykinase (PEPCK) mRNA levels related to the gluconeogenesis pathway, with IC50 values of 43µM,it also activated

the PI3K pathway, similarly to insulin,

4-hydroxyderricin19

ethanol extract of Angelica keiskei

Koidzumi (Apiaceae/Umbelliferae)

Prevented progression of diabetes in genetically impaired KK-Ay mice,

which develop diabetes and show hyperglycemia with aging because of insulin resistance (positive control: 0.05% diet of pioglitazone).30showed acute blood glucose lowering effects (50 mg kg_1 bw) in

ALX-induced diabetic rats and promoted glucose-induced

insulin secretion after oral treatment in hyperglycemic rats.

Xanthoangelol19

ethanol extract of Angelica keiskei

Koidzumi (Apiaceae/Umbelliferae)

. Prevented progression of diabetes in genetically impaired KK-Ay mice,

which develop diabetes and show hyperglycemia with aging because of insulin resistance (positive control: 0.05% diet of pioglitazone).30showed acute blood glucose lowering effects (50 mg kg_1 bw) in

ALX-induced diabetic rats and promoted glucose-induced

insulin secretion after oral treatment in hyperglycemic rats.

Apigenin-5-O-[α-L-rhamnopyranosyl-(1-4)-6-O-β-Dacetylglucopyranoside]20

leaves of Cephalotaxus sinensis

Anti-hyperglycemic

Apigenin-

5-O-[a-L-rhamnopyranosyl-(1-4)-6-O-β-D-glucopyranoside20

leaves of Cephalotaxus sinensis

Anti-hyperglycemic

Apigenin21

leaves of Cephalotaxus sinensis

Increased level of glucose transporterGLUT-4 was also seen from mice adipocytes treated with 14 (0.1mg, 2

mg/ml.

Apigenin-O-{20-O-α-L-rhamnopyranosyl)-β-L-fucopyranoside21

Averrhoa carambola L.

Acute blood glucose lowering effects (50 mg/ kg bw) in ALX-induced diabetic rats and promoted glucose-induced insulin secretion after oral treatment in hyperglycemic rats

Apigenin-6-C-β-L-fucopyranoside 21

Averrhoa carambola L

(50 mg/kgbw, p.o.) Lowered blood glucose in hyperglycemic rats, promoted glucose-induced insulin secretion, and stimulated glycogen synthesis

Pongamol22

fruit of Pongamia

pinnata (L.) Pierre (Fabaceae)

Exhibited anti-hyperglycemic activity. In streptozotocin (STZ)-induced diabetic rats, the blood glucose lowering effects of pongamol were 22% ,

Karanjin22

fruit of Pongamia pinnata (L.) Pierre (Fabaceae)

exhibited anti hyperglycemic activity. In streptozotocin (STZ)-induced diabetic rats, the blood glucose lowering effects of karanjin 20%

Kaempferol23

Euonymus

alatus (Celastraceae)

compound 1 (5–50 mM) significantly improved insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes, and they also served as weak partial agonists in a PPAR-g reporter gene assay without inducing differentiation of 3T3-L1 preadipocytes, an effect shown by traditional PPAR-g agonists

Quercetin23

Euonymus

alatus (Celastraceae

(5–50 mM) Significantly improved insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes, and they also served as weak partial agonists in a PPAR-g reporter gene assay without inducing differentiation of 3T3-L1 preadipocytes, an effect shown by traditional PPAR-g agonists

Aspalathin24

(FabaceaeAspalathus linearis),

Increase glucose uptake by L6 myotubes at 1–100 mM concentrations in a dose-dependent manner, and to increase insulin secretion from cultured RIN-5F cells at 100 mM

Coagulin C25 aqueous extract of Withania coagulans Dunal (Solanaceae)

Inhibited post-diet glucose rise

Karaviloside26XI bitter melon (Momordica charantia)

Stimulated glucose transporter 4 (GLUT4) translocation to the cell membrane, which was associated with increased activity of AMPK

Stigmasterol27 bark of Butea monosperma

(Lam.) Kuntze (Fabaceae)

Reduced serum triiodothyronine(T3),thyroxin (T4) and glucose concentrations were found as well as decreased activity of hepatic G-6-Pase and increased insulinlevels, indicating that it exhibits both thyroid-inhibiting and hypoglycemic properties

Costunolide28

Roots of Costus Speciosus

Decreased glycosylated hemoglobin (HbA1c), serum total cholesterol, LDL cholesterol,and triglyceride levels were seen as well as increased plasma insulin, tissue glycogen, HDL cholesterol, and serum protein

Spicatanol29

Hedychium spicatum Ham. Ex Smith (Zingiberaceae)

Intestinal a-glucosidase inhibitory activities IC50 of 34.1 µM.

Palbinone30

Paeonia suffruticosa

Andrew (Paeoniaceae)

Exhibited the most potent activity by increasing the levels of phospho-AMPK, phospho-ACC, and phospho-GSK-3b in a dose-dependent manner, and triggering glucose uptake and glycogen synthesis in insulin-resistant human HepG2 cells

Swietenine31

seeds of Swietenia macrophylla King. (Meliaceae)

Exhibited significant hypoglycemic activity comparable to that of human insulin in an in vitro glucose utilization assay

Scopoletin (7-hydroxy-6-methoxycoumarin)32

leaves of Aegle marmelos Linn. Corr (Rutaceae).

Inlevo-thyroxine-treated animals, decreased levels of serum thyroid hormones, glucose, and hepatic G-6-Pase were seen in the scopoletin-administrated group

Moracin M33

root bark of Morus alba L. (Moraceae),

Moracin M(100 mg /kg, p.o.) decreased the fasting blood glucose level

Mullberroside A33 root bark of Morus alba L. (Moraceae),

Hypoglycemic effects in alloxan-induced diabetic mice

Epicatechin34 (Green tea)

Preventing T1D BY modulating immune function and thereby preserving islet mass

1,5 anhydro-D-glucitol35

(nearly all food )

Potent and selective renal sodium-glucose co transporter 2 (SGLT2) inhibitor with anti-hyperglycemic activity

Caftaric acid 36

(Corni Fructus)

Hypoglycemic and Beta-Cell Protective

Dapagliflozin 37

Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

GPR-14238

EC50-1.5µM

F=3.9% in cynomolgus monkey

4-(5-(4-(piperidin-1-yl)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine39

Histamine H3 receptor antagonist

(2R)-2-(3-{3 [(4Methoxyphenyl)carbonyl]-2-methyl-6(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid40

Peroxisome Proliferator-Activated Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume

Canagliflozin41

Highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice

Tofogliflozin42

Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

IC50(hSGLT2):2.9 nM

IC50(hSGLT1): 8,444 nM

Selectivity : (hSGLT1)/ (hSGLT2)=2,912 fold

F(%)(mice)=75%

(monkey) 85%

(2S,3R,4R,5S,6R)-2-(4-(4-ethoxybenzyl)-2-methoxy-3-methylphenyl)-tetrahydro-6-(hydroxymethyl)-2H-thiopyran-3,4,5-triol43

Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type2 Diabetes Treatment

IC50:2.26Nm (hSGLT2)

IC50:3990Nm(hSGLT1)

CONCLUSION
In this review we discussed about some recent discoveries of pure anti-diabetes compound and their structure and biological activities.in this review we discussed some natural and synthetic compound which differ from anti-diabetes drug in structure and mechanism of action. Which may be helpful in designing and synthesis of new drugs.

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