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Clinical relevance of correlating the degree of retinopathy with the blood glycated hemoglobin concentration in patients with type 2 diabetes mellitus.

Introduction

Diabetic retinopathy, a non-inflammatory degenerative disease of the retina, is a microvascular complication of diabetes mellitus that affects type 1 and 2 diabetic patients when these have a poor compliance with medical treatment, but can also occur as the normal course of the disease after some years in type 1 diabetic patients [1-3].

Diabetic retinopathy is divided into background and proliferative, being the latter the most advanced [4, 5]. Diabetic retinopathy usually leads to vision loss when it is not treated promptly and appropriately. The precipitating cause seems to be the increase in serum glucose concentration [1-5].

Glycated hemoglobin (Hb[A.sub.1c]) forms as a nonenzymatic reaction between glucose and hemoglobin, specifically the amino acid valine of the [beta] chain of A hemoglobin [6]. Hb[A.sub.1c] is an indicator of the long-term average blood glucose concentrations[7], and has been used to estimate the risk of cardiovascular [8] and liver diseases [9], and even death from any cause [10]. Even so, there is a lack of knowledge among patients and a lack of consideration among physicians about the usefulness of Hb[A.sub.1c] as an indicator of damage to susceptible tissues and organs [11].

In this study the plausibility of using the blood Hb[A.sub.1c] concentration as a risk factor for developing diabetic retinopathy was analyzed.

Material and Methods

A cohort of 36 diabetic patients attending the ABC Medical Center in Mexico City participated in a transversal study to analyze the possible correlation between HbA1c and the development and progression of retinopathy. All of them were older than 20 years of age and were diabetic according to the Expert Committee on the diagnosis and classification of diabetes [12]. A clinical history of each patient was taken that included their demographic data as well as the time they had lived with diabetes mellitus.

The ophthalmologic evaluation consisted in analyzing the aspect of the fundus of the eye, with special attention to the retinal blood vessels, and were assigned to several groups according to the following classification: stage 0, without any evidence of retinopathy; stage I or background retinopathy, with microaneurysms, microhemorrhages and hard exudates; stage II or moderate to severe preproliferative retinopathy, with soft exudates and retinal proliferation; stage III or proliferative retinopathy, with retinal blood vessel proliferation.

For the biochemical determinations, blood samples were collected after overnight fasting and serum glucose, urea and creatinine concentrations were assessed in each patient by routine laboratory testing (Abbot Laboratories).

Proteinuria was assessed by dipsticks purchased from AMES laboratories and Hb[A.sub.1c] was measured by ion-exchange high-performance liquid chromatography by using the Merck-Hitachi L-9100 Glycated Hemoglobin Analyzer (Tokyo, Japan). Statistical analysis was performed by the analysis of variance (ANOVA), followed by the post hoc Tukey test. Values were considered statistically significative at p [less than or equal to] 0.05.

Results and discussions

28 of the 36 diabetic patients involved in this study were women and 8 were men with a mean age of 56 years (age range from 22 to 85 years). All of them suffered from type 2 diabetes mellitus. 75% of them were on sulphonylurea and 25% were on daily insulin treatment. The time they had lived with diabetes was 10.3 [+ or -] 5.1 (years [+ or -] SD), being higher in those with diabetic retinopathy (12.5 [+ or -] 5.4 years) than those who did not suffer from diabetic retinopathy (8.8 [+ or -] 4.8; Table 1). This clearly shows a positive correlation between the duration of diabetes and the incidence of retinopathy in diabetic patients.

The degree of retinopathy was more advanced (p < 0.05) in patients with a high blood Hb[A.sub.1c] concentration than in patients with lower levels (Table 2). There was a positive correlate between the time living with diabetes and the blood Hb[A.sub.1c] concentration as well. There was not a positive correlation between the time living with diabetes or the plasma glucose or the blood HbA1c] concentrations with the presence of proteinuria (data not shown).

Discussion:

In this study we show that high blood Hb[A.sub.1c] concentrations positively correlate with the presence of diabetic retinopathy. Data also show that higher blood Hb[A.sub.1c] concentrations are found in patients with more advanced retinopathy. Normal blood Hb[A.sub.1c] concentrations most not exceed 7% [13] and most diabetics present higher than upper limit normal values [14].

Our results are in agreement to those published by Khaw and Wareham (2006), in which an increase of Hb[A.sub.1c] is associated with an increase in the incidence of cardiovascular disease [8]. Hb[A.sub.1c] is also a risk factor for liver diseases [9] and death from any cause [10]. On the other hand, diabetic retinopathy has been correlated with a decrease in kidney function [15], cardiovascular disease [16] and with general microvascular complications [17], which suggest that when a patient has high blood Hb[A.sub.1c] concentrations, quite probably also has other diabetic complications. This makes urgent for patients to be aware that an increased blood Hb[A.sub.1c] concentration indicates a higher probability of suffering from diabetic complications, so that, by keeping a tight control of their blood Hb[A.sub.1c] concentrations, diabetic patient could avoid or at least reduce an important risk factor for serious microvascular complications of diabetes mellitus.

The results of this study can be integrated to preexisting data by suggesting that by independently analyzing the duration of diabetes, the plasma glucose concentration and the blood HbA1c concentration, physicians could have an important tool to predict diabetic retinopathy or other complications of diabetes mellitus in their patients, which would mean that appropriately measuring and interpreting blood Hb[A.sub.1c] concentrations, could be of paramount importance for the appropriate counseling and treatment of diabetic patients.

Results from this and other studies showing a positive correlation between high blood Hb[A.sub.1c] and organ damage in diabetic patients lead us to conclude that what has been the state of the glucose control during the last three months for diabetic patients, as shown by their blood Hb[A.sub.1c] levels, should be considered their lifestyle, unless proven otherwise, even though it is known that the blood Hb[A.sub.1c] concentration reflects better the plasma glucose concentration average closest to the moment of the assessment than the complete lifestyle of the erythrocyte [18].

Even though the duration of diabetes mellitus has a positive relation with the development of retinopathy [19], it has a stronger correlation with the HbA1c concentration [20]. Our results show a stronger correlation between high Hb[A.sub.1c] concentrations and retinopathy in women and that the degree of damage also depends on the increase in HbA1c. This is important because strongly emphasizes the need of keeping Hb[A.sub.1c] concentrations low, modifying lifestyles if necessary in order to reach this goal.

Because Hb[A.sub.1c] is evaluated in erythrocytes, it must be considered that its measure could give useful results only in the absence of any erythrocyte dysfunction [18]. For those patients with erythrocyte anomalies in number or hemoglobin concentration, fructosamine [21] or glycated albumin [22] could be more appropriate or maybe even the peptide pigment epithelial derived factor, a novel substance found increased in the serum of type 1 [23] and type 2 diabetics [24] with retinopathy.

References

[1.] Morello, C.M., 2007. Etiology and natural history of diabetic retinopathy: an overview. Am J Health Syst Pharm, 64(17 Suppl 12): S3-7.

[2.] Simo, R., E. Carrasco, M. Garcia-Ramirez, C. Hernandez, 200.6 Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev., 2: 71-98.

[3.] Wilkinson-Berka, J.L., C. Wraight, G. Werther, 2006. The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. Curr Med Chem., 13: 3307-17.

[4.] Bloomgarden, Z.T., 2007. Screening for and managing diabetic retinopathy: current approaches. Am J Health Syst Pharm, 64(17 Suppl 12): S8-14.

[5.] Cunha-Vaz, J., 2007. Characterization and relevance of different diabetic retinopathy phenotypes. Dev Ophthalmol, 39: 13-30.

[6.] Peterson, K.P., J.G. Pavlovich, D. Goldstein, R. Little, J. England, C.M. Peterson, 1998. What is hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry. Clin Chem., 44: 1951-8.

[7.] Rahbar, S., 2005. The discovery of glycated hemoglobin: a major event in the study of nonenzymatic chemistry in biological systems. Ann N Y Acad Sci., 1043: 9-19.

[8.] Khaw, K.T., N. Wareham, 2006. Glycated hemoglobin as a marker of cardiovascular risk. Curr Opin Lipidol., 17: 637-43.

[9.] Schnedl, W.J., S.J. Wallner, C. Piswanger, R. Krause, R.W. Lipp, 2005. Glycated hemoglobin and liver disease in diabetes mellitus. Wien Med Wochenschr, 155: 411-5.

[10.] Gao, L., F.E. Matthews, L.A. Sargeant, C. Brayne, 2008. MRC CFAS. An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health, 8: 54.

[11.] Wang, S., G. Tikellis, N. Wong, T.Y. Wong, J.J. Wang, 2008. Lack of knowledge of glycosylated hemoglobin in patients with diabetic retinopathy. Diabetes Res Clin Pract., 81: e15-7.

[12.] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care, 26: 3160-3167.

[13.] Goulle, J.P., C. Lacroix, D. Bouige, 2002. Glycated hemoglobin: a useful post-mortem reference marker in determining diabetes. Forensic Sci Int., 128: 44-9.

[14.] Bajkowska-Fiedziukiewicz, A., K. Cypryk, T. Kozdraj, A. Mikolajczyk-Swatko, M. Kosinski, M. Jozefowska, 2008. Self-monitoring of blood glucose and treatment outcomes in type 2 diabetic patients. Pol Arch Med Wewn, 118: 267-72.

[15.] Matsuyama, K., N. Ogata, M. Matsuoka, C. Shima, M. Wada, N. Jo, M. Matsumura, 2008. Relationship between pigment epithelium-derived factor (PEDF) and renal function in patients with diabetic retinopathy. Mol Vis., 14: 992-6.

[16.] Hiller, R., R.D. Sperduto, M.J. Podgor, F.L. Ferris, P.W. Wilson, 1988. Diabetic retinopathy and cardiovascular disease in type II diabetics. The Framingham Heart Study and the Framingham Eye Study. Am J Epidemiol., 128: 402-9.

[17.] Cheung, N., T.Y. Wong, 2008. Diabetic retinopathy and systemic vascular complications. Prog Retin Eye Res., 27: 161-76.

[18.] Saudek, C.D., R.L. Derr, R.R. Kalyani, 2006. Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c. JAMA., 295: 1688-97.

[19.] Klein, R., M.D. Knudtson, K.E. Lee, R. Gangnon, B.E. Klein, 2008. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology, 115: 1859-68.

[20.] Klein, R., B.E. Klein, S.E. Moss, M.D. Davis, D.L. DeMets, 1988. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA., 18: 260:2864-71.

[21.] Macdonald, D.R., A.M. Hanson, M.R. Holland, B.M. Singh, 2008. Clinical impact of variability in HbA1c as assessed by simultaneously measuring fructosamine and use of error grid nalysis. Ann Clin Biochem., 45(Pt 4): 421-5.

[22.] Inaba, M., S. Okuno, Y. Kumeda, S. Yamada, Y. Imanishi, T. Tabata, M. Okamura, S. Okada, T. Yamakawa, E. Ishimura, Y. Nishizawa, 2007. Osaka CKD Expert Research Group. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol., 18: 896-903.

[23.] Ogata, N., M. Matsuoka, K. Matsuyama, C. Shima , A. Tajika, T. Nishiyama, M. Wada, N. Jo, A. Higuchi, K. Minamino, H. Matsunaga, T. Takeda, M. Matsumura, 2007. Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab., 92: 1176-9.

[24.] Katakami, N., H. Kaneto, Y. Yamasaki, M. Matsuhisa, 2008. Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy. Diabetes Res Clin Pract., 81: e4-7.

(1) Guillermo Gutierrez-Espindola, (2) Roberto De Haro, (3) Segundo Moran, (3) Alexander Krouham, (3) Ricardo Washington and (4) Jose D. Mendez

(1) Department of Hematology, Specialties Hospital, National Medical Center, Mexican Institute of Social Security, Mexico City, 06703 D.F., Mexico

(2) Medicine Section, Iztacala Faculty, National Autonomous University of Mexico, Los Reyes Iztacala, Tlalnepantla, State of Mexico, 54090, Mexico.

(3) Department of Internal Medicine, ABC Medical Center, Mexico City, Mexico

(4) Medical Research Unit in Metabolic Diseases, National Medical Center, Mexican Institute of Social Security, P.O. Box A-047, Mexico City, 06703 D.F., Mexico

Guillermo Gutierrez-Espindola, Roberto De Haro, Segundo Moran, Alexander Krouham, Ricardo Washington and Jose D. Mendez; Clinical Relevance of Correlating the Degree of Retinopathy with the Blood Glycated Hemoglobin Concentration in Patients with Type 2 Diabetes Mellitus, Adv. Environ. Biol., 3(2): 171-174, 2009

Corresponding Author

Dr. Jose D. Mendez, Medical Research Unit in Metabolic Diseases National Medical Center Mexican Institute of Social Security P.O. Box A-047 Mexico City, 06703, D.F Mexico E-mail: mendezf@servidor.unam.mx
Table 1: Clinical characteristics and associated factors [+ or -]

Clinical characteristic/Factor   Men (n = 8)         Women (n = 28)

Age (years [+ or -] SD)          59.2 [+ or -] 12.9  54.4 [+ or -] 12.5
Time with diabetes
  (years [+ or -] SD)            9.3 [+ or -] 5.2    10.5 [+ or -] 5.8
Obesity (BMI > 30)               0                   2
Hypertension                     2                   7
Retinopathy                      3                   12
Neuropathy                       1                   0
High [HbA.sub.1c] (> 7%)         5                   15
Proteinuria                      5                   6
Ischemic cardiomyopathy          2                   3
Brain vascular disease           1                   0
Amputated limbs                  2                   1

BMI = body mass index
SD = Standard deviation
Hb[A.sub.1c] = Glycated hemoglobin

Table 2: Plasma glucose and blood Hb[A.sub.1c] concentrations
according to the degree of retinopathy

Degree of
retinopathy   n    Glucose(mg/dl [+ or -] SD)   HbA1c (% [+ or -] SD)

0             21   147 [+ or -] 36              8.5 [+ or -] 3.1
I             10   156 [+ or -] 31              9.29 [+ or -] 3.7
II            2    183 [+ or -] 44              9.95 [+ or -] 2.3
III           3    194 [+ or -] 68              10.2 [+ or -] 2.8

0 = without retinopathy
I = fundus retinopathy
II = preproliferative retinopathy
III = proliferative retinopathy
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Title Annotation:Original Article
Author:Gutierrez-Espindola, Guillermo; de Haro, Roberto; Moran, Segundo; Krouham, Alexander; Washington, Ri
Publication:Advances in Environmental Biology
Article Type:Report
Geographic Code:1MEX
Date:May 1, 2009
Words:2320
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