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Good glucose levels control improve ones overall quality life. Effectiveness of the treatment for diabetes mellitus can be confirmed through monitoring of glucose level regularly to maintain specific levels of glucose to stay healthy. An individual's pattern of life can be revealed by the changes of blood glucose level. Effective glycaemia control can be done at least two or three or more insulin injections daily. A consistent normal level of glycaemic control reflects the normal haemostasis regulation of glucose metabolism. The goal glucose can be achieved with the help of planning of meals, medication is taken at a specific time of the day and useful activities can be done without harming ones health.
Diabetes is a disease that is very common in many countries .About 150 million in the world have diabetes and its is expected to doubled by the year 2025 because of the population growth in developed countries, unhealthy diets such as fast food and obesity ( Jee et al, 2005).
Diabetes mellitus (DM) defined as a metabolic disease caused by the lack of the production of insulin to breakdown glucose results in high blood sugar level. Diabetes is classified into 2 types. Type 1 DM caused by autoimmune disease. The disease causes the destruction of the beta cells of the islets of Langerhans in the pancreas leading to insulin deficiency (Rother, 2007). Type 2 diabetes mellitus caused by insulin secretory defect of the beta cell and insulin resistance in peripheral tissue. Hyperinsulinemia and insulin resistance leads to glucose intolerance. This type of diabetes is more common in women than men especially in women with the history of gestational diabetes (Mayfield, 1998). Gestational diabetes is defined as glucose intolerance in women during pregnancy. (Schmidt et al, 2001)
Table 1 : General characteristics Type 1 and Type 2 diabetes (Reinauer, 2002)
Type 1 Diabetes
Type 2 diabetes
Typical age of onset
Antibodies to cells
Associated to obese
Extremely low to undetectable
Variable: may be low, normal, or elevated depending on the degree of insulin resistance and insulin secretory defect
Main metabolic feature
Metabolic syndrome with insulin insensitivity
High doses required
Prone to developed diabetic complications
There are two categories of ways to monitor diabetic patients. Short term monitoring of diabetes is categorized as testing of the last 24 hours blood glucose levels. Methods such as Fasting Blood Glucose (FBS) and self monitoring method (SMBG) are used. Long term monitoring of diabetes is the testing plasma glucose for the approximately past 90 to 120 days which is the lifespan of a red blood cell. Methods used for monitoring long term are HbA1c and C-peptide. HbA1c is a good marker for testing plasma glucose. However, any mutation in the haemoglobin chain will change and produce false results.
The type of haemoglobin of an individual is inherited by their parents. The normal adult haemoglobin, HbA is the most common type. However, there are over 700 alterations and mutations of the globin gene causes haemoglobin variants that has been been reported so far (Smaldone, 2008). The most common haemoglobinopathy is HbS.
In the blood, the haemoglobin combines with the glucose changing them to HbA1c. The percentage of HbA1c in haemoglobin increases as the red cells are exposed longer to glucose. A1c is the main section of the haemoglobin chain that is bound to glucose. A1c values solidly linked with the blood glucose level when a diabetes patients has normal adult haemoglobin. Therefore, if the patient has haemoglobinopathy, qualitative and quantitative variation of the haemoglobin can affect the accuracy of the test (Tran et al, 2004). The measurement of HbA1c would be incorrect.
Haemoglobinopathies affects the reliabily of HbA1c values by altering the normal metabolism of glycation to A1C instead of the normal haemoglobin HbA. This is because of the obstruction from the structural or chemical variation of haemoglobin chain causing a limitation to methods. (Jain et al, 2009).
2.0 Short term of glucose monitoring
2.1 Fasting Blood Glucose(FBS)
FBS test is used to monitor the effectiveness of different medication of dietary changes on diagnosed diabetic patients from time to time. FBS is a simple fasting measurement for insulin sensitivity in the body. FBS test is often the first test done for the diagnosis of diabetes and used for monitoring as follow up. Venous blood is used to test for FBS. Blood sample is taken after overnight at least 8 hours of fasting (Barret-Connnor, 2002).
During fasting, insulin in the body will be used up for glycolysis converting glucose to glycogen. When the glucose level becomes too low, haemostasis starts taking place by releasing glucagon. Glucagon is a physiological hormone that converts stored glycogen into glucose into the blood stream. The conversion raises the blood glucose level and preventing hypoglycaemia (Nuack et al, 1993). If glucose level is normal during the test, it shows that insulin and haemostasis process is working properly and the patient is not diabetic. The insulin is sensitive enough to detect the glucose level in the blood stream
Table 2 : Reference Range for Fasting Blood glucose
Prediabetes or Impaired Glucose Tolerance
101 - 126 mg/dL
5.6 to 7 mmol/L
Diagnosis of diabetes
F/N :Recently the normal range of fasting plame glucose has been revised. Abnormal level of plasma has been change from <110mg/dL to <99 mg/dL. Patinets with plasma glucose between the range are at increased range of getting Type 2 diabetes. (Tirosh, 2005)
2.2 Self-Monitoring Blood Glucose (SMBG)
SMBG is widely accepted as treatment for Type 1 diabetes but SMBG for Type2 is still open for discussion. Detailed information of blood glucose levels are collected time to time. These enable more precise insulin dosing for more consistent glucose level. By self monitoring, patients can manage their disease independently.
A self monitoring technique usually uses a blood glucose meter. The skin, usually the finger is pricked for blood. Then the blood is applied on the test strip which is chemically active. Lastly the glucose is determined by electrical characteristic measurement. The test is quick and accurate. Most meters have memory enable to store test results. These results can be connected to the computer or to be consulted by the health care provider. Hyperglycemia and hypoglycemia can be detected instantly. Health care provider may suggests an adjustment of diets, exercise and dosage of insulin
Figure : variation of blood glucose meter device. The meter(right), has the ability to record results in the device. http://labspace.open.ac.uk/mod/resource/view.php?id=211607 [ 27/2]
Figure : The graph shows a graph of self monitoring shows the level of glucose is normal. The normal range used is 80-180 mg/dl is used in the example graph http://www.freestylenavigator.com/ab_nav/url/content/en_US/10.20:20/general_content/General_Content_0000010.htm [27/2]
Figure : graph shows monitoring of glucose daily in the period of 90 days. The graph shows hyperglycemia in the afternnon an evening. Actions of regimen adjustment include more day time insulin of modification or dietary intake could be taken instantly to avoid complications in long term. Saudek C.D, Derr R.L, Klyani R.R,(2006), "Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c", JAMA,Vol.295, No.14, pp.1688-1697 [27/2]
DCCT recommends SMBG is performed at least 1 time per day to improve their glycemic control. However only 40% of people follow the recommendation whereas only 26% patients with diabetes Type 1 and Type 2 follow the recommendation (Sacks et al, 2002). Women with gestational diabetes are recommended to self- monitor twice a day.
SMBG is usually recommended to non-insulin treated Type 2 diabetes as a possibility to improved glycemic control. But, the existing evidence of effectiveness is questionable. A meta-analysis by Coster et al (2000), shows that self-monitoring does not show any benefit for type 2 diabetes. Another study done by Farmer (2007) shows no significant improvement in self-monitored Type 2 patients when compared to non-self monitoring patients after 12 months. However, a study done by Guerci et al, (2003) shows that 680 out of 988 Type 2 diabetic patients managed to lower their HbA1c by monitoring their blood glucose themselves.
3.0 Long term of glucose monitoring
Good metabolic control for long term influences the severity of diabetes mellitus. Maintaining blood glucose concentration as normal as possible needs the determination of long term glucose control. Glycated haemoglobin (HBA1c) measurement is an example of a marker for testing patients' plasma glucose for long term monitoring
HbA1c plays a big role in the management of diabetes as the majority of studies on diabetes and complication are based on the results of HbA1c. Blood glucose level of the past three to four months could be monitored by the determination of the ratio of glycated to nonglycated by the HbA1C chromatography fraction.
. According to Lenzi (1987), correlation with 24 hour urine mean plasma glucose, and other indexes of metabolic control is about sixty to ninety days. Haemoglobins pick up an amount of glucose depends on how much glucose is in the bloodstreams as red cells move around. If there is an average of high glucose in the bloodstream for 90 to 120 days, the HbA1c will be high.
HbA1c is a stable minor haemoglobin variant with glucose at the N-terminal amino group of the Î²-chain of the normal adults' haemoglobin A. The molecular structure of the HbA1c is -N-(1-deoxy) - fructosyl-haemoglobin (Morris, 2009). Glucose attach to haemoglobin in vivo by postransional enzymatic attachment on the N-terminal valine residues of the Î²-chain of the haemoglobin (Peterson et al, 1998). The result of the modification causes the haemoglobin to be unstable and undergoes irreversible Amadori rearrangement called glycation to form stable ketoamine. Certain lysine residues on the haemoglobin chains also go through glycation. These katoamine are measured by total glycohaemoglobin or total glycated haemoglobin. Glycated haemoglobin can be differentiated from unglycated haemoglobin based on their charge or their structural characteristic.( Saudek et al, 2006).
The formation rate of glycohaemoglobin is directly proportional to the glucose concentration. This is because 120-day life span of erythrocytes is glycating continuously everyday. One precaution is that HbA1c reflects the recent changes in glycemic control but not the levels of glucose over the previous 120 days (Saudek et al, 2006).
Although variation between individuals HbA1c are small, there is big variability in HbA1c between individuals that are unconnected to glycaemic status suggesting low and high glycators However, after minimizing the variation, by multiple observations per patient, results in non-diabetic individuals are narrow ( Rohlfinge et al, 2002) other factors causing this consistent discrepancies should be investigated.
Improvement of glycaemic control measured by HbA1c was shown by United Kingdom Prospective Diabetes Study and DCCT. The study shows that it is an effective way to reduce complications of microvascular in individuals with Type 1 and Type 2 diabetes (Hempe et al, 2002). In the year 1998 and 1993 respectively, and followed by the American Diabetes Association both established the relationship of HbA1c levels and risks for diabetic patients. The relationship between daily-monitored blood glucose determinations and HbA1c must be clearly defined. Therefore, appropriate daily plasma glucose level goals could be set for the patients by their health-care providers to archive HBA1c levels with low risk for adverse outcomes (Rohlfinge et al, 2002).
Table 3: Recommended ranges for blood glucose level and HbA1c
Average blood glucose
4.0 - 6.5 %
Normal for non - diabetic
- 8.0 mmol/l
6.5 - 7.5%
Target range forr diabetic
8.0 - 10.0 mmol/l
8.0 - 9.5%
11.0 - 14.0 mmol/l
Figure : HbA1c graph shows normal linear regression at the end of 3 months. http://media.photobucket.com/image/normal%20%252523HbA1c%20graph/stratplan/Averageglucosegraph.jpg
3.2. Monitoring glucose level using C-peptide values.
Type1 diabetes is T-cell mediated autoimmune disease that caused by the loss of beta cells that secret insulin. T-cell antibodies are produced to autoimmune attack against the normal insulin-secreting pancreatic beta cell. C-peptide is used to monitor insulin secretion in patients with insulin antibodies. C-peptide would not be cleared by the liver before appearing in the systemic circulation. Human C- peptide concentration in urine and blood plasma can show evidence of early phase of insulin secretory failure in the preclinical stages of diabetes (Keymeulen et al, 2005). C-peptide secreted from beta cells are in equimolar with insulin thereby has proved to be useful for the study and monitoring of Type1 diabetes. This discovery provides firm scientific basis for the use of C-peptide concentration as a marker of beta cells secretory activity (Poloncky and Rubentein, 1984).
Immunoassays such as RIA and ELISA for plasma and urinary C-peptide are well established. However their specificity is questionable as the lack of similarities between the assays which may contribute by the differences in antibody specifics or matrix effect. Another assay used for measuring C-peptide is isotope-dilution assays (IDA). IDA is an alternative detection of C-peptide because of their increased specificity. Peptide quantification by liquid chromatography-mass spectrometry (LC/MS) in urine and plasma had low sensitivity, required sample preparation and large sample volume. A modified 2 dimensional (2D)LC/MS IDA method were invented to overcome these limitation (Rogatscky et al, 2006).
C-peptide levels are used to maintain good glucose control after autologous non-myeloablative haematopoietic stem cell plantation. High C-peptide levels can help by reducing intake of daily doses insulin and the possibility of insulin independence. This effect can last up to 24 months and maintained up to at least 36 months According to recent study done by Couri et al(2009), 20 of 23 patients become insulin free as long as 4 years with good glucose control. The C-peptide data confirmed the increased endogenous insulin production as the predominate mechanism of glycaemic control in Type1 diabetes.
4.0 Complication of measurement of HbA1c with the presence of haemoglobinoathies
HbA1c measurement is used in diabetic person for evaluating long term control of diabetes. DCCT confirmed that the development and progression of long term complications in Type 1 diabetes depends on the degrees of glycemic control, which is determined by glycohaemoglobin present (Peterson et al, 1998). However, some haemoglobinopathies can cause false results in HbA1c determination.
Haemoglobinopathies are categorized into 3 main types. The first type is the mutation of the haemoglobin structure, for example haemoglobin S. HbS is a haemoglobin variant associated with sickling disorder. Mutated Î²-globin gene that produces HbS will cause precipitation and polymerization of the red cells causing them to sickle. HbC is also a haemoglobinophathy resulting from a single base pair mutation in the Î²-globin gene.. Double heterozygosity of Î²-C and Î²-S leads to a severe sickling disorder (Hendrik, Huisman, 1997). Hb O Arab and Hb D Punjab similarly have major clinical impact with the co-inheritance with HbS (Clarke et al, 2000). If HbS is inherited with either both, severe sickling disorder could happen.
The next category is when haemoglobin fails to synthesis one or more of the normal globin chain at a normal rate, for example thalessemia. Thalassemias are defined as deletion or the mutation of genes the normal globin gene that affects the transcription or stability of mRNA products. Thalassemia manifests from mild anaemia with microcytosis in thalassemia trait to anaemia severe enough to cause death such as Hb Barts hydrops fetalis or Î²-thalassemia major (Olivieri, 1999 ; Clarke et al, 2000). HbE has a certain structural variant that have manifestations of thalassemia. Co-inheritance of HbE trait and thalassemia syndromes which occur in the same group produces one primary clinical importance which is thalssemia major (Hendrik and Huisman, 1997).
Another type of haemoglobinopathy happens when the normal neonatal fails to switch HbF to HbA completely. Example of this haemoglobinopathy is the hereditary persistence of foetal haemoglobin (HPFH). The Î³-gene is Hb F fails to change to Î²-gene that a health normal adult HbA have. Gamma chains are synthesized either with glysine or alanine at the 136th position on the Î³-gene (Friedman and Schwarts, 1976).
Any alteration of the globin chain such as haemoglobinopathies or thalassemia can cause any inaccurate results. HbA1c values in patients with no haemoglobin variants are highly sensitive in showing elevations of blood glucose. A difference of 1% in HbA1c results can change 1.4- 1.9 mmol/l in an average blood glucose concentration (Schnedl et al, 2000). NH2 terminal valine excess of the globin chain can be glycated. Mutation at the NH2- terminal of the haemoglobin chain causes low HbA1c values in the non-diabetic reference range for immunoagglutination test
The mutation of the globin chain causes an abnormal peak on chromatography making the reading of A1C values unreliable. Haemoglobin variants such as HbS make red cells more prone to haemolysis and leads to a shortened red-cell survival thereby decreased exposure time of haemoglobin to glucose. This will make the glycosylation process slower and the level of HbA1c lower will be than expected (Smaldone, 2008). An individual with a trait gene for haemoglobinoopathies will also interfere with the A1C values. False results of decreased in HbA1c values happens when HPLC methods separates the non-glycated Hb-variants instead of the glycated counterparts.(Prins et al, 2005) .
Values vary depending on the types of disorders and the assays such as the separation of haemaglobin variant and HbA1c. The irregularities come from the distinct solvent mixture, column including temperature pressure in each system. The same haemoglobin variant can cause different results for different methods. An algorithms is use to calculate HbA1c. Any unrecognisable peaks presence can affect the calculations and lead to inaccurate results (Bry et al, 2001).
HbA1c values can determined with various methods including boromite affinity essay, High-performance liquid chromatography (HPLC) and immunoagglutination but will give false results.
Table 4: HbA1c results in patients with haemoglobin variants.
Nondiabetic reference range
Hb Graz 1
Hb Graz 2
Hb Graz 3
Hb Sherwood Forest
Hb O 1
Hb O 2
Hb S 1
Hb S 2
Hb S 3
N.R: No results, A.S: Abnormal Seperation [HbGraz 1:Type2 diabetes with Hb Graz, Hb Graz 2and Hb Graz 3: non-diabetic with Hb Graz, Hb Sheerwood Forest: Non-diabetic with Hb Sheerwoob Forest, Hb O1: diabetic with HbO, HbO2: Non-diabetic with HbO, HbD: Type2 diabetes with HbD, HbS1:Non-diabetic with HbS, HbS2 :Diabetic with HbS, HbS3: Non-diabetic with HbS trait ].(Schnedl et al,2000).
A study was done by Schnedl (2000) shows various haemoglobinopathies causes different false results in different methods. Hb Graz shows extremely high HbA1C values in HPLC 1 and causes low values in all DCA, Intregra and Tina which is the immunological methods. Non-diabetic patients with HbGraz, Hb Graz 1 and 2 has lower value than the reference range. The mutated haemoglobin raised the values of the true value. Haemoglobin variant Hb Sherwood Forest, the results in HPLC1 is very high and very low in HPLC3 compared to the non-diabetic reference range. This depends on the additional peak in HbA1c peak calculation. Hb O Padova shows a difference in the results for a diabetic person and non-diabetic. For IMx, the mean difference was 2.7% and a mean difference of 3.6% for the immunoagglutination methods. Hb D HbA1c values are low in HPLC 1. HPLC 3 chromatogram could not recognize the haemoglobin variant and shows HbA1C results below the non-diabetic range even though the subject has diabetes. Hb S causes the low value of HbA1C percentage for HPLC 1. DCA shows subject HbS1 has Hb S but not diabetic has HbA1c values out of the non-diabetic reference range, meanwhile subjects HbS2 and HbS3 which is diabetic with HbS in the reference range. Mutation of haemoglobin chains can cause false results of HbA1c values (Schnedl et al, 2000).
Scientific study done by Little et al (2008),HbE showed some interference from the 23 HPLC methods. All 22 HPLC methods show an obstruction from the mutant haemoglobin except 1 which produces false results. Reporting of false results can cause under treatment hyperglycemia and higher risks of complications.
The results of this assignment show that there is more to controlling diabetes than just lowering HbA1C levels and normal glucose levels. Datas collected by Harris,(2001) suggested that each diabetes therapy category is related to the frequency of testing and HbA1c values.
SMBG is the best way to monitor diabetes mellitus. There is evidence showing decreased in HbA1c values for Type 1 diabetic patients with higher frequency of self- monitoring who self-adjust their insulin level (Davidson et al, 2005).Success of self regulation requires practice of strict plans that fits into their daily lives. However there is no indications of involving SMBG in the daily life of Type 2 diabetes patients (McAndrews et al, 2007). Type1 DM patients have been taught skills and strategies to adjust insulin to response to glucose level and diet.
Newly recognized method of self-monitoring, Continuous Glucose Monitoring System (CGMS) has been introduced recently. CGMS provides information of blood glucose profile even the most active SMBG would not provide (Ludvigsson and Hanas, 2003) such as the direction, the frequency, magnitude and the causes of unstable blood glucose. (Klonoff, 2005) Unlike SMBG, no blood was needed for the testing. Glucose level is tested through the skin using body fluid. A study done by Bode et al (1999), support the suggestion that CGMS helps to improve the glycemic control of diabetic patients. According to his study, HbA1c levels of nine subjects with type decrease from 9.9 to 8.8% using CGMS shows that CGMS has the potential to provides valuable information to help improve glycemic control and reduce the risk of long term complications.
Figure : the graph shows hyperglycemia during the month of March. Hyperglycemia can be detected instantly and shows adjusement in diet or medication is needed. Saudek C.D, Derr R.L, Klyani R.R,(2006), "Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c", JAMA,Vol.295, No.14, pp.1688-1697 [27/2]
If haemoglobinopathy is present in a diabetic patient, HbA1c cannot be used to monitor blood glucose on the patient as haemoglobin variant can cause false results. An alternate method that is not affected by the haemoglobin variant can be used to produce accurate results of glucose level such as fructosamine. Fructosamine is the measurement of glucose concentration for the past 2 -3 weeks instead of 90 days of HbA1c. Because fructosamine relies on serum protein glycation, results are not affected by any alterations of the globin gene (Smaldone, 2008).
Advance and modern technologies have enabled monitoring glucose level in a diabetes person and to live a better quality life. Glucose concentration can be measured noninvasively without obtaining a drop of blood. Painless sensing devices could monitor the plasma glucose concentration or in the body fluid. Other bodily fluid that could contain glucose besides blood such as saliva, urine, sweat or tears (Eduardo et al, 2008) is proportional to the plasma glucose concentration (Alexeev et al, 2004) This device allows fast determination and immediate feedback blood glucose determination providing big improvement for glycaemic control. (Eduardo et al, 2008). Example of these painless devices are near-infrared light spectroscopy, far-infrared radiation spectroscopy , radio wave impedance, optical rotation of polarized light which focuses on their aqueous humor of the eye, reverse iontophoresis which detects glucose concentration by fluid extracting from skin and interstitial fluid harvesting( Klonoff ,1997; Eduardo et al, 2008).