The Journal of International Medical Research 2002; 30: 433 437 The Effects of High Haematocrit Levels on Glucose Metabolism Disorders I ÇAPOĞLU 1, N ÜNÜVAR 1, Y BEKTAş 2, Ö YILMAZ 3 AND MD KAYA 4 1 Division of Endocrinology and Metabolism; 2 Division of Pulmonary Disease; and 3 Division of Internal Medicine, Atatürk University Medical Faculty, Erzurum, Turkey; 4 Division of Computer Programming, Atatürk University Vocational High School, Erzurum, Turkey There has been only limited research investigating the possible association between raised haematocrit levels, glucose intolerance and type 2 diabetes. In the present study, we explored the association between high haematocrit levels and impaired glucose tolerance by performing oral glucose tolerance tests in 46 patients with chronic obstructive pulmonary disease and no previous history of diabetes mellitus or glucose intolerance. A glucose metabolism disorder was observed in 12 (26%) patients (type 2 diabetes in six patients and impaired glucose tolerance in a further six). There was a significant association between high haematocrit levels and the presence of a glucose metabolism disorder, which was independent of other risk factors. High haematocrit levels may be an independent risk factor for type 2 diabetes and impaired glucose tolerance. KEY WORDS: TYPE 2 DIABETES; IMPAIRED GLUCOSE TOLERANCE; GLUCOSE METABOLISM DISORDER; HAEMATOCRIT; CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) Introduction Diabetes mellitus is a chronic disease caused by inherited or acquired deficiency in insulin production, or by an insufficient response to insulin that is produced. Impaired glucose tolerance (IGT) is characterized by blood glucose levels above the normal range, but below that diagnostic for diabetes. Type 2 diabetes (formerly non-insulin dependent diabetes mellitus) accounts for approximately 90% of diabetes cases worldwide. People with this condition often have no early symptoms and are not diagnosed until complications are already present. Awareness of the risk factors for type 2 diabetes will promote screening, early detection and treatment in high-risk populations, with the goal of decreasing both micro- and macrovascular complications. Patients with type 2 diabetes nearly always exhibit insulin resistance and pancreatic β-cell dysfunction. 1 Chronic obstructive pulmonary disease (COPD) and diabetes have frequently been observed as comorbid diseases. Antonelli Incalzi et al. 2 found the frequency of diabetes in 270 patients with COPD to be 14%. 2 Patients with COPD are known to have a raised haematocrit level, which has been suggested to be an independent risk factor for ischaemic heart disease and stroke, 3,4 and may also be an independent risk factor for type 2 diabetes. 5,6 In this study, we investigated whether or not glucose intolerance or diabetes was present in 433
patients with COPD, but no previous history of diabetes or IGT, by performing oral glucose tolerance tests (OGTTs). If either condition was present, we determined whether or not the glucose metabolism disorder was related to high haematocrit levels. Patients and methods PATIENTS Forty-six patients (29 men and 17 women; mean age, 59.7 years) were included in the study. Patients were diagnosed with COPD if they had emphysema, chronic bronchitis, chronic asthma, or a combination of these diseases, based on the American Thoracic Society definition. 7 Patients receiving corticosteroids, oral contraceptive drugs, phenytoin, thiazide group diuretics and those with hypertension were excluded from the study. The study was approved by the ethics committee of Atatürk University, and informed consent was obtained from all participants. METHODS Patients fasted from 19.00 on the day before the study. OGTTs were performed on each patient between 07.00 and 09.30 in the morning in accordance with the World Health Organization (WHO) criteria. After collection of the fasting blood sample, each patient was given a glucose load (75 g anhydrous glucose in 250 ml of water) and, after 2 h, a second blood sample was collected. Serum glucose was measured using the glucose oxidase method (Hitachi 717, Automatic Analyser, Boehringer Mannheim, Tokyo, Japan). Results were classified according to the WHO criteria: (i) Diabetes mellitus: fasting plasma glucose > 7.0 mmol/l and/or plasma glucose > 11.1 mmol/l 2 h after 75 g oral glucose loading; (ii) IGT: fasting plasma glucose < 7.0 mmol/l and plasma glucose 7.8 mmol/l, but < 11.1 mmol/l 2 h after oral glucose loading. 8 RESPIRATORY FUNCTION TEST Forced expiratory volume in 1 s ( ) was measured using a Vitalograph Spirometer (V-max 22, Sensor Meds, Lenexa, KA, USA). Spirometry testing was performed in patients during their stable period. The degree of respiratory failure was categorized according to the European Respiratory Society classification: (i) Mild respiratory failure: 70%; (ii) Moderate respiratory failure: 50 69%; (iii) Advanced respiratory failure: < 50%. 9 HAEMATOCRIT LEVELS Non-fasting venous blood samples (2 ml) were collected into vacuum tubes. Haematocrit was measured using a Coulter S electronic particle counter (Beckman Coulter, Model STKS, Florida, USA). Patients were divided into three groups based on haematocrit levels: group 1, < 42%; group 2, 42 48%; group 3, > 48%. STATISTICAL ANALYSIS Data were analysed using the statistical package SPSS version 9.0 (SPSS, Chicago, IL, USA) and expressed as mean ± SE. Stepwise multiple regression analyses were used to obtain correlation values and assess the independent effects of risk factors on blood glucose. P < 0.05 was considered statistically significant. Results The mean duration of COPD in the patients was 13.3 ± 3.5 years. Other mean values were, 62.2 ± 11.9%; BMI, 27.2 ± 3.6 kg/m 2 ; and haematocrit, 45.2 ± 4.7%. The interpretation of the OGTT results is shown in Table 1. Of the 46 patients in 434
TABLE 1: Results of oral glucose tolerance tests in 46 patients with chronic obstructive pulmonary disease and no previous history of diabetes or impaired glucose tolerance (IGT) Normal (n) IGT (n) Type 2 diabetes (n) (%) Mild ( 70) 14 3 2 Moderate (50 69) 15 2 2 Advanced (< 50) 5 1 2 Body mass index (kg/m 2 ) < 25 10 1 25 30 20 2 2 > 30 4 3 4 Haematocrit (%) < 42 9 1 42 48 21 4 2 > 48 4 1 4, forced expiratory volume in 1 s. whom OGTTs were performed, diabetes was identified in six and IGT in a further six. When we analysed the data using stepwise multiple regression with duration of COPD,, BMI, haematocrit and diabetic tendency as variables, haematocrit and BMI were independently and significantly correlated with diabetic tendency (P = 0.03 and P = 0.02, respectively), whereas duration of COPD and did not reach statistical significance (P = 0.48 and P = 0.83, respectively). Discussion The present study shows a comparatively strong and independent relationship between haematocrit levels and diabetic tendency in patients with COPD. It is known that COPD and diabetes are comorbid diseases, 2 but the mechanism for this association is not clear. For this reason, we investigated the duration of COPD,, BMI and haematocrit in patients with no previous history of IGT or diabetes. While haematocrit and BMI were found to have a close correlation with IGT and diabetes, the other parameters were not correlated with the glucose metabolism disorders. Obesity is a frequent cause of insulin resistance and poses a major risk for the onset of type 2 diabetes. Insulin resistance is also directly related to BMI, 10 and in our study, the relationship between BMI and diabetes was significant. In addition, we found that haematocrit was an independent predictor of type 2 diabetes. The mechanisms that underline the association between haematocrit and diabetes risk are unclear; 6 in fact, evidence for the relationship is sometimes conflicting. The first of two studies by Wannamethee et al. 6 found that diabetic patients showed significantly lower levels of haematocrit than non-diabetics, while the second study, involving the same population of 7735 middle-aged men and published 2 years later, revealed a strong positive association between haematocrit and diabetes risk. 11 Umeki et al. 12 also confirmed that of patients with COPD, a high percentage exhibited IGT. One explanation for the association between insulin and haematocrit may be the 435
effect of insulin-like growth factor-1 (IGF-1) on red blood cell development. IGF-1, which is associated with insulin resistance, may stimulate erythropoiesis, thus increasing haematocrit levels. This has been demonstrated in rats. 13 Patients with COPD tend to develop secondary polycythemia, characterized by an increase in red blood cell count, as a physiological response to chronic hypoxia. Like patients with COPD, people living at high altitudes also have high haematocrit levels compared with those living at lower altitudes, and short-term ascents to high altitude have been demonstrated to increase insulin resistance. 14 Raised haematocrit levels may also cause increased blood viscosity, which has been shown to have a negative association with the rate of glucose disposal. 15 If this condition persists, we can hypothesize that it may lead to insulin resistance, thus a possible explanation for the relationship between haematocrit and insulin resistance may be haemodynamic. An association between haematocrit and glucose metabolism disorders is supported by Barbieri et al., 16 who found that in patients with a higher red blood cell count, plasma haemoglobin level, haematocrit level and plasma iron concentration were associated with higher insulin resistance. We conclude that insulin resistance and high haematocrit levels may trigger each other via the physiopathological mechanisms mentioned above. These views strongly support the hypothesis that high haematocrit levels may be an independent risk factor for type 2 diabetes. Further studies on this topic, involving greater numbers of cases, should be performed to obtain a conclusive answer. Received for publication 20 February 2002 Accepted 4 March 2002 2002 Cambridge Medical Publications References 1 Bailey CJ, Turner RC: Metformin. N Engl J Med 1996; 334: 574 579. 2 Antonelli Incalzi R, Fuso L, De Rosa M, Forastiere F, Rapiti E, Nardecchia B, et al: Comorbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J 1997; 10: 2794 2800. 3 Wannamethee G, Shaper AG, Whincup PH: Ischaemic heart disease: association with haematocrit in the British Regional Heart Study. J Epidemiol Community Health 1994; 48: 112 118. 4 Wannamethee G, Perry IJ, Shaper AG: Haematocrit, hypertension and risk of stroke. J Intern Med 1994; 235: 163 168. 5 Smith S, Julius S, Jamerson K, Amerena J, Schork N: Hematocrit levels and physiologic factors in relationship to cardiovascular risk in Tecumseh, Michigan. J Hypertens 1994; 12: 455 462. 6 Wannamethee SG, Perry IJ, Shaper AG: Hematocrit and risk of NIDDM. Diabetes 1996; 45: 576 579. 7 Committee on Diagnostic Standards for Non- Tuberculous Respiratory Disease: Clinical bronchitis, asthma or pulmonary emphysema. Am Rev Respir Dis 1987; 85: 762 766. 8 The Expert Committee on the Diagnosis and Classifications of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classifications of Diabetes Mellitus. Diabetes Care 1997; 20: 1183 1197. 9 ERS Consensus Statement: Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur Respir J 1995; 8: 1398 1420. 10 Perry IJ, Wannamethee SG, Walker MK, Thomson AG, Whincup PH, Shaper AG: Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men. BMJ 1995; 310: 560 564. 11 Wannamethee G, Shaper AG: Haematocrit: relationships with blood lipids, blood pressure and other cardiovascular risk factors. Thromb Haemost 1994; 72: 58 64. 12 Umeki S, Hisamoto N, Hara Y: Study on background factors associated with impaired glucose tolerance and/or diabetes mellitus. Acta Endocrinol (Copenh) 1989; 120: 729 734. 13 Kurtz A, Zapf J, Eckardt KU, Clemons G, Froesch ER, Bauer C: Insulin-like growth factor I stimulates erythropoiesis in hypophysectomized rats. Proc Natl Acad Sci U S A 1988; 85: 7825 7829. 14 Sawhney RC, Malhotra AS, Singh T: 436
Glucoregulatory hormones in man at high altitude. Eur J Appl Physiol Occup Physiol 1991; 62: 286 291. 15 Moan A, Nordby G, Os I, Birkeland KI, Kjeldsen SE: Relationship between hemorrheologic factors and insulin sensitivity in healthy young men. Metabolism 1994; 43: 423 427. 16 Barbieri M, Ragno E, Benvenuti E, Zito GA, Corsi A, Ferrucci L, et al: New aspects of the insulin resistance syndrome: impact on haematological parameters. Diabetologia 2001; 44: 1232 1237. Address for correspondence Professor N Ünüvar Atatürk University PTT, PO Box 56, 25171 Erzurum, Turkey. E-mail: unuvarnecdet@hotmail.com 437