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Biochemical Profile Indicative of Insulin Resistance in Non- diabetic and Diabetic Cardiovascular Patients.

Byline: NOSHEEN ASLAM, MUNIR AHMAD SHEIKH, KHALIL-UR-REHMAN AND HAQ NAWAZ

ABSTRACT

This study was aimed at assessment of some biochemical profiles associated with cardiovascular complications in non- diabetics and those suffering from diabetes type 2 in order to detect insulin resistance as an underlying cause. A total of 400 blood samples comprising of patients with (n=200) and without type 2 diabetes (n=200) were tested for different biochemical parameters following standard methods. The glycation, advanced glycosylation end products, glucose, insulin, C-peptide and LDL were lower in non-diabetic compared with diabetic subjects having a history of cardiovascular complaints. A positive correlation was found between the level of glycation and AGEs, glucose, HbA1c, C-peptide, cholesterol and LDL in non- diabetic and diabetic groups. There was, however, a negative correlation between the level of glycation and HDL in non- diabetic subjects with cardiovascular disease.

Simultaneous presence of high levels of insulin, glucose and glycation suggested insulin resistance in diabetics as well as non-diabetics at risk of diabetes and associated cardiovascular complications. Therefore, disturbances in the biochemical profile and morbidity among all the groups of the present study were mainly attributed to insulin resistance. Diabetes and associated cardiovascular complications in the context of insulin resistance have been discussed. (c) 2012 Friends Science Publishers

Key Words: Insulin resistance; Biochemical profiles; Diabetes type 2

INTRODUCTION

Insulin helps to transport glucose into the body cells where it is required for the production of energy (Courtney and Olefsky, 2007; Jafri et al., 2011). Liver, fat and muscle cells of insulin resistant individuals; however, do not give response to insulin properly. Consequently, more insulin is produced leading to failure of the pancreas, and excessive glucose accumulates in the blood causing diabetes. Therefore, many people with insulin resistance have high levels of both insulin and glucose circulating in their blood at the same time. Low insulin sensitivity with selective loss of release of insulin identify the individuals who are at increased risk of developing type 2 diabetes (Reaven, 1995; Prato et al., 2005), a risk factor of carotid arteriosclerosis (Fox et al., 2006; Zachary, 2007; Cade, 2008).

Typical findings in insulin resistant patients are low HDL, high triglycerides and normal to slightly increased LDL. This happens, because fat cells are affected by insulin resistance resulting in some enzymes to break fats, releasing fatty acids which then go to the liver (Walcher and Marx,2004). The fatty acids enhanced the production of triglycerides, which then enter the circulation while simultaneously increasing the secretion of carrier protein low density lipoprotein (LDL) (Hodgkinson et al., 2008; Ahmad et al., 2012). When the triglycerides are in blood carried by VLDL, there is transfer of cholesterol ester from HDL to the triglyceride and VLDL leave VLDL and HDL is replaced by the cholesterol ester (Fonseca, 2003). In the same time, newly formed VLDL triglyceride is exchanged for ester of cholesterol in LDL and produces small dense lipoproteins. This bidirectional transfer of triglyceride leads to elevated triglyceride levels.

Thus, HDL is easily broken down and excreted by the kidney (Montagnani et al., 2002). In this way, HDL level is reduced. Such lipid changes can cause deposits of fatty plaque in arteries and results in the CVD (Reaven et al., 2004).

Accumulation of fatty deposits lead to the narrowing of blood vessels (e.g., atherosclerosis) obstructing blood supply to the vital organs like brain, heart, etc. (Kolodgie et al., 2003) and causing stroke, cardiac failure, etc. Nevertheless, glucose plays a crucial role by glycating the proteins in whole body including LDL. Therefore, any disturbance in the normal metabolism of glucose and/or glycation, particularly that resulting from altered insulin functionality has serious consequences. In developing countries like Pakistan, hardly ever regular medical check ups are carried out until and unless the condition gets complicated due to underlying causes such as insulin resistance. The present paper describes some biochemical profiles associated with cardiovascular complications in non-diabetics and those suffering from diabetes type 2.

MATERIALS AND METHODS

A total of 400 male patients with (n=200) and without type 2 diabetes (n=200) between the age of 40-60 were enrolled in this study and placed in five groups (Table I). Collection of samples: Fifty blood samples of each of the above categories were collected from D.H.Q. Hospital Faisalabad, National Hospital Faisalabad, Chiniot Dialysis Centre Faisalabad and Allied Hospital Faisalabad, Pakistan. Blood sample from each patient was collected by using sterilize disposable syringe by venipuncture. The blood was transferred into EDTA (anticoagulant) containing tubes. The samples were mixed gently by tapping and were then centrifuged at 3000 rpm. Plasma fractions were collected and stored at -20oC. Normal plasma was pooled from blood samples of healthy male.

Dialysis of plasma samples: For glucose determination, plasma samples were first dialysed as free glucose is the major hindrance in estimation of glycation level (Trinder, 1969). So, it was removed by using dialyzing membrane. Plasma samples were dialyzed against dist. H2O for 24 h at constant stirring at room temperature. After dialysis, samples were again placed in 5 mL capped glass tubes at -20oC. Glycated albumin was also dialysed against dist. H2O at 4oC and samples were stored (For ELISA standard) at -20oC. Parameters: The samples from all the subjects in above groups were assessed for glycation (Thiobarbituric Acid Method; Fluckiger and Winterhalter, 1976; Furth, 1988),advanced glycation endproducts (ELISA; Zhang et al.,2005), glucose (standard kit method), HbA1c (Bisse and Abraham, 1985), insulin (ELISA; Clark and Hales, 1994), serum C-peptide (ELISA; Horwitz et al., 1975) and lipid profile (Friedewald et al., 1972; Lopes-Virella et al., 1977).

Statistical analysis: The ranges, means+-SD, correlation values and significance of differences in means were calculated by ANOVA following Steel et al. (1997).

RESULTS AND DISCUSSION

The glycation, advanced glycosylation end products (AGEs), glucose, insulin, C-peptide and LDL were lower in non-diabetic compared with diabetic subjects in all the groups (Table II). A positive correlation was found between the level of glycation and AGEs (r=0.011236: r=0.00543), glucose (r=0.0013214: r=0.01121354), HbA1c (r=0.0011365: r=0.036987), C-peptide (r=0.0006398: r=0.011214), cholesterol (r=0.002156: r=0.002369) and LDL (r=0.003396: r=0.01145) in non-diabetic and diabetic groups, respectively. There was however, a negative correlation between the level of glycation and HDL in non- diabetic (r=-0.001214) and diabetic (r=-0.011785) subjects with cardiovascular disease.

The higher (p=0.9679) levels of insulin in diabetics may be attributed to insulin resistance (Mack et al., 2004; Samaras et al., 2006), which adds to the cardiovasular complications (Fernandez and Ricart, 2003; Jeppesen et al.,2007) due to endothelial dysfunction, a precursor for adverse cardiovascular events. Interestingly, a positive correlation between glycation level and insulin level in non- diabetic (r=0.001245) and diabetic cardiovascular diseased subjects (r=0.002565) was recorded. Simultaneous presence of high levels of insulin, glucose and glycation suggested insulin resistance in diabetics as well as non-diabetics at risk of diabetes and associated cardiovascular complications. Therefore, disturbances in the biochemical profile and morbidity among all the groups of the present study are mainly attributed to insulin resistance. Diabetes and associated cardiovascular complications in the context of insulin resistance have been discussed as under.

Non enzymatic glycation has been well reported in diabetics (Austin et al., 1990; Halton et al., 1993; Stoynev et al., 2004) due to post translational modification of proteins by the sugars and their de-gradational products (Argirov et al., 2003). This may also be attributed to the Maillard reaction between sugar and proteins contributing to the increased chemical modification and cross-linking of long lived tissue proteins in diabetes (Fu et al., 1994).

Higher levels of AGEs in diabetic patients may lead to vascular complications (Goh and Cooper, 2008; Peppa and Raptis, 2008). AGEs affect extracellular proteins and activate cytokine production and transcription factors by binding to AGE receptors; and thus, accumulation of AGEs has been predicted to closely correlate with the development of cardiovascular complications (Zieman and Kass, 2004; Meerwaldt et al., 2008). Likewise, chronic hyperglycemia has a central role in complications in diabetics through production of AGEs from glucose (Lee et al., 1998; Thorpe and Baynes, 2003; George and Sivakami, 2004) and/or glycation of human serum albumin (Kobayashi et al., 1991).

Low glycation at low glucose levels has also been reported previously (Eble et al., 1983; Winocour et al., 1992). Regarding HbA1c, results are in support of the earlier workers (Singer et al., 1992; Viktrorova et al., 1993; Arun et al., 2002).

As far as C-peptide, it was also reported higher (Stadler et al., 2005; Chailurkit et al., 2007) in diabetics due to higher levels of insulin and glucose intolerance. The insulin resistance causes abnormal metabolism of glucose ultimately leading to increased glycation of proteins. The cholesterol levels were lower (p less than 0.0001) in normal compared with both diabetic and non-diabetic subjects with cardiovascular disease. Large variation in the cholesterol levels within groups indicates different stages of cardiovascular disease. Higher cholesterol has also been reported earlier in insulin resistant subjects (Jakus et al.,1999; Taylor, 2002; Garvey et al., 2003; Surekha et al.,2007). Glycation of plasma protein may contribute to excess risk of developing atherosclerosis diabetic patients causing an increase in the level of cholesterol (Calvo et al., 1993).

The values of HDL were lower in all groups of cardiovascular patients compared with the normal subjects. The reduction of HDL values was however, more

Table I: Details of patients sampled for investigation in the present study

Groups1###Non-diabetics###Diabetics

1###Hyperlipidemia having no cardiovascular symptoms###Hyperlipidemia having no cardiovascular symptoms

2###Hyperlipidemia and hypertension###Hyperlipidemia and hypertension

3###Hyperlipidemia, hypertension and myocardial ischemia without infarction###Hyperlipidemia, hypertension and myocardial ischemia without infarction

4###Hyperlipidemia, hypertension and previous attack of myocardial###Hyperlipidemia, hypertension and previous attack of myocardial infarction

###infarction

5###Non diabetic with no history of cardiovascular diseases as control

Each group had 50 subjects

Table II: Biochemical profiles of diabetic and diabetic type 2 subjects with cardiovascular complaints in 0comparison with the healthy ones

Subjects###ND###NDHNCYD###NDHH###NDHHMIS###NDHHMI###DHNCVD###DHH###DHHMIS###DHHMI###"P"

###value

Glycation###0.47+0.17###0.58+0.14###0.57+0.13###0.60+0.13###0.57+0.13###1.65+0.24###1.70+0.29###1.70+0.30###1.71+ 0.27###less than 0.0001

level###(0.2-0.8)###(0.34-0.81)###(0.35-0.81)###(0.31-0.84)###(0.31-0.84)###(0.99-1.99)###(0.96-2.03)###(0.98-2.1)###(1.12-2.1)

(mole/mole

of protein)

AGEs (per###59.71+-6.38###67.09+-10.56###66.08+- 9.65###68.09+-9.66###68.61+- 9.90###87.71+- 2.76###88.33+- 3.42###88.00+-3.40###88.83+-2.63###less than 0.0001

ug of###(46.73-71.45)###(47.23-85.46) (44.66-85.63) (49.62-86.16) (45.82-86.99) (79.84-93.56) (78.47-94.32) (77.42-94.21) (83.56-93.98)

plasma

protein)

Glucose###96.32+-12.82###108.62+-15.45###107.32+-13.26 108.24+-14.00###107.48+-14.56 164.14+-17.76###161.42+-20.79 161.64+-21.07###167.28+-22.17###less than 0.0001

(mg/dl)###(75-124)###(80-131)###(80-131)###(82-132)###(80-136)###(130-199)###(122-200)###(133-210)###(133-211)

HbAlc(%)###5.36+-0.79###6.38+-0.67###6.01+-0.62###5.90+-0.72###5.94+-0.70###7.71+-0.93###7.61+-0.78###7.64+-0.78###7.82+-0.80###less than 0.0001

###(4.2-6.2)###(5.2-7.6)###(4.8-7.4)###(4.2-7.1)###(4.3-7.0)###(7.0-9.8)###(6.6-9.3)###(7.0-9.5)###(6.6-9.5)

Insulin###17.11+2.97###18.26+4.12###17.06+3.75###18.28+4.11###17.9 +3.94###15.32+4.71###17.24+6.61###17.13+5.81###15.45+6.52###0.9679

(miu/ml) C-###(10.0-20.5)###(10.0-25.0)###(9.0-24.0)###(11.0-25.0)###(9.0-25.0)###(13.0-23.4)###(5.6-29.1)###(4.5-28.9)###(3.4-32.9)

C-peptide###2.22+-0.84###2.47+-0.79###2.36+-0.60###2.47+-0.78###2.47+-0.70###3.96+-0.65###4.15+-0.69###3.93+-1.16###3.38+-1.0###less than 0.0001

(ng/ml)###(0.4-3.5)###(1.2-3.8)###(0.7-3.1)###(1.2-3.8)###(0.7-3.8)###(1.9-5.2)###(2.1-5.6)###(1.9-5.7)###(1.3-5.7)

Cholesterol###175.58+-15.68###262.98+-17.64###262.54+-13.70 261.64+-14.75###264+-15.31 253.66+-19.66###252.32+-16.11 246.48+-18.18###251.62+-19.67 less than 0.0001

(mg/dl)###(140-200)###(201-296)###(240-288)###(222-288)###(241-307)###(223-289)###(220-290)###(209-278)###(216-288)

HDL###38.84+7.45###38.96+4.84###37.96+ 3.25###38.70+4.89###39.14+5.07###34.88+6.04###34.5+6.05###34.04+7.01###33.92+8.32 less than 0.0108

(mg/dl)###(30-65)###(30-50)###(31-43)###(28-49)###(29-48)###(25-50)###(21-43)###(22-22)###(20-30)

LDL###106.74+-16.46###174.38+-15.09###170.14+-18.30 176.42+-12.70###171.44+-16.96 173.26+-14.49###174.42+-19.30 175.12+-17.88###176.06+-15.57 less than 0.0001

(mg/dl)###(60-130)###(140-199)###(141-197)###(151-199)###(140-200)###(143-198)###(140-203)###(139-203)###(136-204)

ND= Normal non-diabetic; NDHNCVD= Non-diabetic, hyperlipidemic having no cardiovascular symptoms; NDHH= Non-diabetic, hyperlipidemic and hypertensive; NDHHMIS= Non-diabetic, hyperlipidemic, hypertensive and myocardial ischemia without infarction; NDHHMI= Non-diabetic, hyperlipidemic, hypertensive and previous attack of myocardial infarction; DHNCVD= Diabetic, hyperlipidemic having no cardiovascular symptoms; DHH= Diabetic, hyperlipidemic and hypertensive; DHHMIS= Diabetic, hyperlipidemic, hypertensive and myocardial ischemia without infarction; DHHMI= Diabetic, hyperlipidemic, hypertensive and previous attack of myocardial infarction pronounced in diabetics compared with non-diabetics with cardiovascular disease. Defect in insulin action and/or the associated hyperinsulinemia may lead to an increase in plasma triglyceride and a decrease in HDL and high blood pressure (Reaven, 1993; Hirayama et al., 2009).

Alteration in function of HDL caused by exposure to hyperglycemia could contribute to the accelerated atherosclerosis observed in type 2 diabetes (Hedrick et al., 2000). The LDL values were lower in normal subjects and higher in cardiovascular diseased patients with or without insulin resistance. There was however, a large variation in the level of LDL in all the four groups of cardiovascular patients indicating the projected risk of further complications. Findings of the present study endorse the previous reports (Buse et al.,2004; Chan et al., 2005; Pasupathi et al., 2009). AGE-LDL activates TLR4-mediated signaling pathway and induces proinflammatory cytokine production (Hodgkinson et al.,2008), which partly explains the increased risk of atherosclerosis observed in diabetics.

Similarly, alteration (glycation) in function of LDL cholesterol caused by exposure to hyperglycemia could contribute to accelerated diabetic complications like cardiovascular diseases (Hedrick et al., 2000). According to Hodgkinson et al. (2008) there is substantial evidence indicating that glycated LDL promotes atherosclerosis.

CONCLUSION

Insulin resistance is the major underlying factor leading to diabetes and cardiovascular diseases in the local human population. Therefore, efforts may be made to devise the strategies aimed at improving insulin sensitivity of the available chemicals/biologicals.

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Author:Aslam, Nosheen; Sheikh, Munir Ahmad; Khalil-ur-Rehman; Nawaz, Haq
Publication:International Journal of Agriculture and Biology
Article Type:Report
Geographic Code:9PAKI
Date:Feb 28, 2012
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