**1.3 Proteins involved in diabetes**

There are following proteins which are genetically linked to diabetes, these proteins with their characteristics and available commercial drugs against these protein markers have been shown in **Table 1**.

**1.4 Significance of** *in silico***, drug designing**

**Protein name Mol. mass**

*DOI: http://dx.doi.org/10.5772/intechopen.82294*

Juxtaposed with another zinc finger

ATP-sensitive inward rectifier potassium channel 11

Potassium voltage-gated channel subfamily KQT member 1

Leucine-rich repeat-containing G-protein coupled receptor 5

Peroxisome proliferator-activated

Thyroid adenoma-associated

receptor gamma

protein

**Table 1.**

protein 1

**(Da)**

*In Silico Proteomics EVOO Therapy for Lipid Lowering in the Patients of Diabetes Mellitus*

Melatonin receptor type 1B 40,188 Da 362 Melatonin

Transcription factor 7-like 2 67,919 Da 619 Sulfonylurea,

**Amino acids**

**Available drugs Structure**

*structure*

*structure*

*structure Tetramer*

*structure*

*Quaternary structure*

*Quaternary structure*

*Quaternary structure*

*structure*

*structure*

*structure*

27,079 Da 243 No drug found *Quaternary*

43,541 Da 390 Sulfonylurea *Quaternary*

74,699 Da 676 Incretin *Quaternary*

99,998 Da 907 No drug found *Quaternary*

57,620 Da 505 Thiazolidinediones,

supplements, DPP4 inhibitors

pioglitazone

linagliptin, incretin

219,607 Da 1953 No drug found *Quaternary*

(Schmidt *et al.*, 2014; Tian *et al.*, 2015).

**1.5 Aims of study**

option of diabetes.

**67**

**1.6 Future prospective**

In silico medical practitioner to select best suitable drug for the treatment of disease. The drug designed by this way prove to be less toxic, fewer or no side effect and more capable than any other drug available. In silico drug designing has application in all the phases of new drug development process. All these in silico analysis are done with the help of different tools and application softwares of bioinformatics

*Proteins involved in diabetes along with their properties, structure and available drugs has been demonstrated.*

Tetraspanin-8 26,044 Da 237 No drug found *Quaternary*

Wolframin 100,292 Da 890 Incretin *Quaternary*

In silico bioinformatics analysis were used to screen and check the therapeutic potential of *Olea europaea* to treat type two diabetes mellitus. For this purpose certain proteins responsible for diabetes were selected and in silico analysis were done to check the reversion effect of *Olea europaea* against these diseases causing proteins expression. The purpose of the study was to screen and isolate potential therapeutic agent present in the *Olea europaea* which could be the best treatment

The *in silico* drug development could be meaningful in the certain aspects:


*In Silico Proteomics EVOO Therapy for Lipid Lowering in the Patients of Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.82294*


#### **Table 1.**

• Clustal Omega

*Biochemical Testing - Clinical Correlation and Diagnosis*

• FATCAT server

• MN convert

• Lipinski's rule

• Patch dock &

• AutoDock Vina

**1.2 Phytochemicals**

**1.3 Proteins involved in diabetes**

Calcium/calmodulin-dependent protein kinase type 1D

Cell division cycle protein 123

Hematopoietically expressed homeobox protein HHEX

Insulin-like growth factor 2 mRNA-binding protein 2

methylthiotransferase

Threonylcarbamoyladenosine tRNA

homolog

**66**

A disintegrin and metalloproteinase with thrombospondin motifs 9

protein markers have been shown in **Table 1**.

**Protein name Mol. mass**

This in silico based approach is used in every stage of drug discovery starting

*Olea europaea* (extra virgin olive oil EVOO) was selected as an anti-diabetic agent as it has many beneficial effects like improvement of hyperglycaemia and lowering of lipid profile of diabetic patients. That is why it was selected and its docking was augmented against certain proteins genetically linked to diabetes.

There are following proteins which are genetically linked to diabetes, these proteins with their characteristics and available commercial drugs against these

Calpain-10 74,952 Da 672 No drug found *Quaternary*

Insulin-degrading enzyme 117,968 Da 1019 6bK inhibitor *Quaternary*

**Amino acids**

**Available drugs Structure**

*structure*

*structure*

*structure*

*structure*

*structure*

*structure*

*structure* Homodimer

*structure*

42,914 Da 385 No drug found *Quaternary*

216,491 Da 1935 No drug found *Quaternary*

39,135 Da 336 No drug found *Quaternary*

65,111 Da 579 No drug found *Quaternary*

30,022 Da 270 No drug found *Quaternary*

66,121 Da 599 No drug found *Quaternary*

**(Da)**

from preclinical phase to terminal phase of drug development process [4].

• VMD

• JALVIEW

*Proteins involved in diabetes along with their properties, structure and available drugs has been demonstrated.*

#### **1.4 Significance of** *in silico***, drug designing**

In silico medical practitioner to select best suitable drug for the treatment of disease. The drug designed by this way prove to be less toxic, fewer or no side effect and more capable than any other drug available. In silico drug designing has application in all the phases of new drug development process. All these in silico analysis are done with the help of different tools and application softwares of bioinformatics (Schmidt *et al.*, 2014; Tian *et al.*, 2015).

#### **1.5 Aims of study**

In silico bioinformatics analysis were used to screen and check the therapeutic potential of *Olea europaea* to treat type two diabetes mellitus. For this purpose certain proteins responsible for diabetes were selected and in silico analysis were done to check the reversion effect of *Olea europaea* against these diseases causing proteins expression. The purpose of the study was to screen and isolate potential therapeutic agent present in the *Olea europaea* which could be the best treatment option of diabetes.

#### **1.6 Future prospective**

The *in silico* drug development could be meaningful in the certain aspects:


resources. It is therefore necessary that cheap and quick methods are made available which can be used to screen population so that the diseases can be detected at a very early stage. Research and development work based on the samples from our population groups is essential because findings have been reported to be dependent on race variations, and socio-economic and other factors. Thus the studies reported on the basis of population groups in other parts of the world may not be valid at least in

*In Silico Proteomics EVOO Therapy for Lipid Lowering in the Patients of Diabetes Mellitus*

This study reports identification of some of the cheapest way to lower the cholesterol profile in the diabetes mellitus in the local population by using advance technologies. In this work, the prime focus was to the use of olive oil as therapy for cholesterol lowering agent to improve and reducing the chance of blood pressure, lipids and hence diabetes and cardiovascular disease will be discussed. The findings from present research work would prove better treatment options for diabetic patients by introduction and characterization of

DM is one out of many lethal melodies. It is ranked fourth deadliest malady, and

Results generated from this research will help devise for the novel diagnostic procedures for early and control of diabetes complications in our population. These findings will provide a base in planning better treatment strategies for diabetic patients by suggested dose of olive oil nutritional supplement. The research work proposed to be undertaken under this project shall elucidate the roles of olive oil in diabetes mellitus in our population. Therapy for the diabetes to be investigated should lead to not only saving lot of precious lives but also ensure saving of huge numbers of man-hours and colossal amount financial resources spent on treatment and patient maintenance. The other financial gains accruing from this project is the application of the project results in developing therapy methods locally for routine

Diabetes has been grouped into two types since 600 BC but the clear classifica-

tion into two types was done in nineteenth century. Diabetes of young before ketoacidosis and diabetes of obese people, later these two types were named as MODY by WHO. By the discovery of human leukocyte antigen (HLA) and antibodies in 1970, it was become clear that all the patients on insulin treatment were suffering with autoimmune disorder [6]. WHO revised the classification into two types of diabetes in 1980 and 1985 based on the clinical findings, which were insulin-dependent diabetes mellitus (IDDM) and the noninsulin-dependent diabetes mellitus (NIDDM). Classification of 1999 was accepted and revised with small changes and diabetes was grouped into (T1DM), (T2DM), gestational diabetes

For the diagnosis of diabetes, the diagnostic criterion has been adopted and revised over and again by world health organization (WHO). The current criteria states that diabetes is diagnosed by the elevated level of glucose in the bloodstream

T1DM is an autoimmune ailment caused when the body's immune system attack on the Beta-cells in the islets of pancreas gland. As a conclusion body produce very

the rate of prevalence is increasing sharply. Olive oil a liquid fat captured from olives tree crop cultivating in the Mediterranean Basin. Complete olives are pressed

some cases.

new therapy methods.

*DOI: http://dx.doi.org/10.5772/intechopen.82294*

use in our clinical laboratories.

mellitus, and some other types [7].

of diabetic patients (**Table 2**).

**2.2 Type 1 diabetes mellitus**

**69**

**2.1 Classification**

to gain olive oil.


#### **2. Diabetes mellitus**

Diabetes is a persistent ailment which happens because of the raised blood glucose due to the lack of the body' ability to produce insulin secretion or sufficient insulin secretions. Insulin secretion is obtained from the pancreas gland in the body and is prerequisite for the transport of glucose from bloodstream to the living cells where it is utilized to obtain energy for the body. Deficit of insulin or impotence of cells to response to insulin results in high level of blood glycaemia or hyperglycaemia which is distinctive feature of diabetes. Hyperglycaemia, if remained uncontrolled over long period, can cause severe damage to different body parts leading to development of disabling or many life-threatening health issues like cardiovascular disorders, neuropathy, nephropathy and eye diseases leading to retinopathy and blindness. Proper management of diabetes helps prevent or delay those complications (Atlas 2017 intro 1).

The term diabetes was initiated from Greek word "syphon" or "mellitus" means Honeyed proposed by Rollo in late eighteenth century [5]. Matthew Dobson for the first time reported the hyperglycemic nature of diabetes in his article during 1776; he observed elevated glucose level in urine and plasma of patients. Holt et al. [6] reported the raised level of ketone bodies in diabetes.

Million people die of diabetes each year, mostly from cardiovascular disease exacerbated by lipid disorders and other complications. Identification of new treatment strategies using olive oil for lipid lowering in diabetes through proteomic analysis was needed. With the increase in the world population the proportion of diabetes is also increasing with great speed so, the more health care budget is needed to cope with this problem. As without proper primary strategies and care it will take the face of epidemic which will kill millions of lives in the world. With this speed it is possible that diabetes would become the number one killer of the world within next coming 25 years. Abrupt actions are required to root out the diabetes from the world.

Olive oil supplementation with daily food intake might play a protective role to reduce lipid profile in diabetes due to the beneficial effect of olive oil exerted by its antioxidant constituents.

In most of the cases when the disease is detected it is already too late to be cured. The percentage of fatalities in patients is therefore very high. Not only there is a vast number of precious lives are lost but the treatment and maintenance of such patients is a heavy financial burden on the individual families and the national

#### *In Silico Proteomics EVOO Therapy for Lipid Lowering in the Patients of Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.82294*

resources. It is therefore necessary that cheap and quick methods are made available which can be used to screen population so that the diseases can be detected at a very early stage. Research and development work based on the samples from our population groups is essential because findings have been reported to be dependent on race variations, and socio-economic and other factors. Thus the studies reported on the basis of population groups in other parts of the world may not be valid at least in some cases.

This study reports identification of some of the cheapest way to lower the cholesterol profile in the diabetes mellitus in the local population by using advance technologies. In this work, the prime focus was to the use of olive oil as therapy for cholesterol lowering agent to improve and reducing the chance of blood pressure, lipids and hence diabetes and cardiovascular disease will be discussed. The findings from present research work would prove better treatment options for diabetic patients by introduction and characterization of new therapy methods.

DM is one out of many lethal melodies. It is ranked fourth deadliest malady, and the rate of prevalence is increasing sharply. Olive oil a liquid fat captured from olives tree crop cultivating in the Mediterranean Basin. Complete olives are pressed to gain olive oil.

Results generated from this research will help devise for the novel diagnostic procedures for early and control of diabetes complications in our population. These findings will provide a base in planning better treatment strategies for diabetic patients by suggested dose of olive oil nutritional supplement. The research work proposed to be undertaken under this project shall elucidate the roles of olive oil in diabetes mellitus in our population. Therapy for the diabetes to be investigated should lead to not only saving lot of precious lives but also ensure saving of huge numbers of man-hours and colossal amount financial resources spent on treatment and patient maintenance. The other financial gains accruing from this project is the application of the project results in developing therapy methods locally for routine use in our clinical laboratories.

#### **2.1 Classification**

• Reduction of drug invention time and cost

*Biochemical Testing - Clinical Correlation and Diagnosis*

• To improvement in result analysis

those complications (Atlas 2017 intro 1).

reported the raised level of ketone bodies in diabetes.

• Lead identification

• Lead optimization

• Target validation

**2. Diabetes mellitus**

from the world.

**68**

antioxidant constituents.

• Target identification

• Harmless, effective and target specific drug development

• Develop efficient bioinformatics ways and algorithms for

Diabetes is a persistent ailment which happens because of the raised blood glucose due to the lack of the body' ability to produce insulin secretion or sufficient insulin secretions. Insulin secretion is obtained from the pancreas gland in the body and is prerequisite for the transport of glucose from bloodstream to the living cells where it is utilized to obtain energy for the body. Deficit of insulin or impotence of

remained uncontrolled over long period, can cause severe damage to different body parts leading to development of disabling or many life-threatening health issues like cardiovascular disorders, neuropathy, nephropathy and eye diseases leading to retinopathy and blindness. Proper management of diabetes helps prevent or delay

The term diabetes was initiated from Greek word "syphon" or "mellitus" means Honeyed proposed by Rollo in late eighteenth century [5]. Matthew Dobson for the first time reported the hyperglycemic nature of diabetes in his article during 1776; he observed elevated glucose level in urine and plasma of patients. Holt et al. [6]

Million people die of diabetes each year, mostly from cardiovascular disease exacerbated by lipid disorders and other complications. Identification of new treatment strategies using olive oil for lipid lowering in diabetes through proteomic analysis was needed. With the increase in the world population the proportion of diabetes is also increasing with great speed so, the more health care budget is needed to cope with this problem. As without proper primary strategies and care it will take the face of epidemic which will kill millions of lives in the world. With this speed it is possible that diabetes would become the number one killer of the world within next coming 25 years. Abrupt actions are required to root out the diabetes

Olive oil supplementation with daily food intake might play a protective role to reduce lipid profile in diabetes due to the beneficial effect of olive oil exerted by its

In most of the cases when the disease is detected it is already too late to be cured. The percentage of fatalities in patients is therefore very high. Not only there is a vast number of precious lives are lost but the treatment and maintenance of such patients is a heavy financial burden on the individual families and the national

cells to response to insulin results in high level of blood glycaemia or hyperglycaemia which is distinctive feature of diabetes. Hyperglycaemia, if

> Diabetes has been grouped into two types since 600 BC but the clear classification into two types was done in nineteenth century. Diabetes of young before ketoacidosis and diabetes of obese people, later these two types were named as MODY by WHO. By the discovery of human leukocyte antigen (HLA) and antibodies in 1970, it was become clear that all the patients on insulin treatment were suffering with autoimmune disorder [6]. WHO revised the classification into two types of diabetes in 1980 and 1985 based on the clinical findings, which were insulin-dependent diabetes mellitus (IDDM) and the noninsulin-dependent diabetes mellitus (NIDDM). Classification of 1999 was accepted and revised with small changes and diabetes was grouped into (T1DM), (T2DM), gestational diabetes mellitus, and some other types [7].

> For the diagnosis of diabetes, the diagnostic criterion has been adopted and revised over and again by world health organization (WHO). The current criteria states that diabetes is diagnosed by the elevated level of glucose in the bloodstream of diabetic patients (**Table 2**).

#### **2.2 Type 1 diabetes mellitus**

T1DM is an autoimmune ailment caused when the body's immune system attack on the Beta-cells in the islets of pancreas gland. As a conclusion body produce very


glucose but as the time passes productive ability of insulin producing cell is lost ultimately a state of inadequate insulin production is developed. Usually type 2 diabetes occurs in older adults but it is increasingly seen in children, adolescent and young adults due to physical inactivity, poor diet increasing level of obesity (13–15). Type 2 diabetes alarming incidence in Pakistan is associated with poor diet etc. [9]. The estimated prevalence of Pakistan ranges from 7.6 to 11% in 2011 [10]. The

*In Silico Proteomics EVOO Therapy for Lipid Lowering in the Patients of Diabetes Mellitus*

GDM is a non-pathophysiological condition and one out of seven new born has gestational diabetes according to [11]. GDM caused by glucose intolerance which was first diagnosed in pregnancy period and may remain after pregnancy (Gavin III *et al.*, 1997). The development of undiagnosed asymptomatic T2DM and T1DM during pregnancy is referred as GDM [12]. The occurrence of GDM is reported during the last 6 months of the pregnancy while the development of diabetes in

Latent Autoimmune Diabetes in Adults (LADA) non-officially called as Type 1.5 diabetes. The term 1.5 indicates that disease is a type 1 diabetes mellitus but it shares

symptoms of T2DM are like T1DM (**Figures 3** and **4**).

women during first trimester is termed as T2DM [13].

**2.4 Gestational diabetes mellitus (GDM)**

*DOI: http://dx.doi.org/10.5772/intechopen.82294*

**2.5 Type 1.5 diabetes**

**Figure 3.**

**Figure 4.**

**71**

*Different risk factors of typ. 2 diabetes mellitus (T2DM).*

*The symptoms of typ. 2 diabetes.*

little or none insulin with a relative or absolute deficiency of insulin in the body. The reason of this deadliest process are not completely understood but it is thought that genetic susceptibility and environmental factors like viral infection, toxins and some dietary factors could be the cause of the problem (Chapt1 type1 10). Type 1 diabetes occurs mostly in children and adolescents. It is managed with proper daily injections of insulin otherwise the survival of the patient would be impossible. Type 1 is diagnosed by raised level of glucose and with the specific symptoms (**Figure 2**). Type 1 diabetes incidence rate in Karachi, the largest city of Pakistan is 1.02/100,000 in comparison to type 2 diabetes mellitus [8].
