Relationship between beta-globin gene carrier state and insulin resistance
© Bahar et al.; licensee BioMed Central Ltd. 2012
Received: 13 July 2012
Accepted: 10 November 2012
Published: 19 November 2012
To assess the relationship between being beta globin gene carrier and developing insulin resistance.
This study was conducted on 164 subjects including 82 healthy ones and 82 patients with beta thalassemia minor (microcytosis (MCV <80 fl) and hypochromia (MCH <25 pg) and HbA2 ≥ 3.5% using HPLC). Fasting blood glucose (FBS) values of 100–125 mg/dl were considered as impaired fasting glucose, and above 125 mg/dl as diabetes mellitus. Two hours After 75 gram glucose load(GTT), blood sugar level of 140–199 mg/dl was considered as impaired glucose tolerance and above 199 mg/dl as diabetes mellitus. Insulin resistance was diagnosed based on homeostasis model assessment method (HOMA).
According to FBS and BS2hPG values, the percentages of diabetes mellitus, pre diabetes, and normal glucose tolerance in case group was 8.5%, 9.8% and 81.7%, respectively. There was no case of diabetes mellitus in control group and 6.1% of this group were pre diabetic and 93.9% of them had normal glucose tolerance test (P = 0.02). Relative risk for diabetes mellitus and insulin resistance in the cases with minor thalassemia was 2 (95% CI: 1.8-2.5) and 2.02 (95% CI: 1.7-2.4), respectively.
The risk of developing diabetes and insulin resistance in patients with thalassemia minor is two times greater than the general population. Considering the high serum levels of CRP in these cases, the inflammation noted in liver cells could be considered as the underlying cause of insulin resistance, impaired glucose tolerance and diabetes in these patients.
KeywordsThalassemia minor Insulin resistance Impaired glucose tolerance Diabetes mellitus HOMA
Insulin resistance is a common problem in patients with different types of hemoglobinopathies including beta thalassemia major. Excessive iron deposition in the pancreas and liver of patients suffering from thalassemia major as well as insulin resistance has been described . It is believed that the increase in iron overload may damage the pancreatic β cells . Increased iron turnover, similarly, may damage liver, contributing to oxidative stress and insulin resistance . The reported prevalence of impaired glucose tolerance and diabetes mellitus in thalassemia major is up to 24% and 26% respectively and it is believed that insulin resistance can be occurred in these patients before the onset of glucose intolerance or diabetes mellitus . Insulin resistance in beta thalassemia minor (carrier state) has been demonstrated as well .
Considering high number of complications associated with insulin resistance and impaired glucose metabolism, the present study was designed to evaluate the prevalence of these metabolic disorders in patients with beta thalassemia minor.
Materials and methods
After being approved by the Ethical Board of Mazandaran University of Medical Sciences, Sari, Iran this study was conducted on 82 individuals with beta thalassemia minor and 82 healthy subjects as control group[according to P1=6% (prevalence of IGT in normal population), P2=14% (prevalence of IGT in beta thalassemia minor), d2=10% , Z1-β ,Z1- α/2=1.96]. The diagnosis of beta thalassemia minor was based on the detection of hemoglobin (Hgb) A2 > 3.5% by column chromatography (Spain bio system Co.) and hemoglobin electrophoresis using HPLC (High-performance liquid chromatography) and cellulose acetate gel.
Subjects in the two groups were matched in terms of body mass index (BMI) and family history of diabetes mellitus. Age range was from 20 to 60 years of age. Blood pressure values were normal (having diastolic blood pressure < 80 mmHg and systolic blood pressure < 120 mmHg) .
Exclusion criteria consisted of history of kidney, liver and heart disease, history of diabetes, receiving medications which affect carbohydrate metabolism (such as corticostroids,cyclosporin,closapin) and waist circumference (WC) more than 102 cm in men and more than 88 cm in women .
Anthropometric measurements including weight and height were obtained with light clothing and without shoes by trained technicians following international guidelines. The height (to the nearest 0.1 cm) and weight (to the nearest 0.1 kg) were measured using a stediometer and a digital scale (Micro life ws80, Switzerland), respectively. The BMI was calculated as the body weight divided by the height squared (Kg/m2). WC was measured using a non-elastic flexible anthropometric tape (to the nearest 0.1 cm) in the standing position. The tape was applied horizontally midway between the lowest rib margin and the iliac crest.
A fasting blood sample (FBS) was taken from all the participants. Serum FBS was analyzed by enzymatic calorimetric method using glucose kit of Parsazmoon Co, Iran. AST (Aspartate aminotransferase) and ALT (Alanine aminotransferase) were measured by calorimetric method using Biosystem kit, Spain and Hitachi917, Germany. High sensitive C-reactive protein (hs-CRP) was measured by imminotorbidometry assay by Pars Azmoon kit, England, using Hitachi917 machine Germany. ELISA test with Hitachi auto analizer using Monobind kit, USA was used to assess serum insulin levels. A standard oral glucose tolerance test (OGTT) was performed in all subjects.
Individuals with abnormal FBS (FBS ≥100) and/or abnormal OGTT (blood sugar 2 hours post-prandial (BS 2hpp) ≥140) were re-tested. FBS values below 100 mg/dl were considered as normal, 100–125 mg/dl as impaired fasting glucose, and above 125 as diabetes. BS 2hpp below 140 mg/dl was considered as normal, 140–199 mg/dl as impaired glucose tolerance and above 199 as diabetes .
(Insulin Sensitive) HOMA-IR < 2.24
(Intermediate) 2.24 ≤ HOMA-IR ≤ 3.59
(Insulin Resistance) HOMA-IR > 3.59
The student t-test and chi-squared test were used to compare demographic data between the two groups. Relative Risk was measured to test the risk of diabetes and insulin resistance in two groups. P value less than 0.05 was considered statistically significant.
Demographic findings of the subjects with beta thalassemia minor regarding demographic data, Sari, Iran, 2010
(N = 82)
Mean ± SD
Mean ± SD
Systolic blood pressure(mmHg)
Diastolic blood pressure(mmHg)
According to FBS and BS2hPG values, the percentages of cases with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance were 7.3%, 11% and 81.7%, respectively. There was no case of diabetes mellitus in control group and 7.3% of subjects had impaired fasting glucose or impaired glucose tolerance. (P = 0.02).
Laboratory values of liver enzymes, CRP, fasting insulin, HOMA-IR in each group
(N = 82)
Mean ± SD
Mean ± SD
20.9 ± 7.3
23.6 ± 8.1
15.5 ± 7.5
18.3 ± 12.8
2.97 ± 1
3.9 ± 3.2
Fasting serum insulin (μIU/ml)
5.9 ± 2
6.5 ± 5.3
1.1 ± 0.4
1.2 ± 0.4
Relative risk of developing diabetes mellitus (based on FBS and BS2hPG values) and insulin resistance(based on HOMA-IR) in patients with beta thalassemia minor were 2 (CI 95%: 1.8-2.5) and 2.025 (CI 95%: 1.7-2.4) respectively.
In line with previous studies, our findings revealed that the relative risk of developing diabetes mellitus and insulin resistance in patients with beta thalassemia minor is two times higher than the general population. Tang et al. reported that thalassemia minor patients with normal glucose tolerance have higher fasting insulin levels and insulin resistance (HOMA-IR) than the healthy controls matched for age, gender and BMI . In another study Alhezmy et al. reported that 6 percent of thalassemia major patients and only 2 percent of the kids with thalassemia minor or no hemoglobinopathy were diagnosed with diabetes mellitus. The prevalence of impaired glucose tolerance was, similarly, higher in patients with thalassemia major compared to those suffering from thalassemia minor and healthy subjects. In this study, subjects were not matched in terms of BMI and family history of diabetes; both of which play an important role in the development of diabetes and insulin resistance .
Corroborating previous studies, our research reported significantly higher CRP levels in thalassemia minor patients . This finding can explain the higher prevalence of insulin resistance in these patients . Mean AST and ALT levels were also higher in this group of patients . The correlation between ALT levels and insulin resistance has been reported in other studies [12–15]. Berget et al. while studying a group of adolescents, pointed out that any increase in ALT levels, even when it is within the normal range, lowers the sensitivity of the cells to insulin, contributing to impaired glucose tolerance and increased levels of free fatty acids and triglycerides . In another study in Native American adults (Pima Indians), ALT was reported as a predictor of type II diabetes . Considering the higher serum levels of liver enzymes and hs-CRP in thalassemia minor patients, the inflammation of liver cells could be accounted for the underlying cause of insulin resistance and impaired glucose tolerance in these patients . In other words, liver inflammation and increased oxidative stress secondary to microcytic erythrocytes hemolysis is the main reason contributing to higher prevalence of diabetes in thalassemia minor patients. According to this concept Noetzli et al. in their study showed that Pancreatic iron overload and diabetes mellitus (DM) are common in thalassemia major patients and iron deposition in pancreas is the strongest predictor of beta cell toxicity and total body iron burden, age, and body habitus also influence glucose regulation too .
The certain limitation of our study was that serum level of ferritin a marker of liver inflammation was not measured though we measured the CRP another marker of inflammation.
The present study revealed that similar to thalassemia major sufferers, the prevalence of insulin resistance and diabetes is higher in patients with thalassemia minor than the general population. Considering the high prevalence of thalassemia minor in our country and the fact that impaired glucose metabolism is associated with multiple complications, it is recommended to screen thalassemia minor patients for glucose tolerance at a younger age. Further studies are also required to detect other mechanisms contributing to insulin resistance in these patients.
This study was Dr Mehrnoosh Sohrab postgraduate thesis and was supported by a grant from Mazandaran University of Medical Sciences.
Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
- Suvarna J, Ingle H, Deshmukh CT: Insulin resistance and beta cell function in chronically transfused patients of thalassemia major. Indian Pediatr 2006, 43:393–400.PubMed
- Khalifa AS, Salem M, Mounir E, El-Tawil MM, EL-Sawy M, MM AAL-a, Abnormal glucose tolerance in Egyptian beta-thalassemia patients: possible association with genotyping: Pediatr Diabetes. 2004, 5:126–132.PubMedView Article
- Maddux BA, See W, Laurence JC, Goldfine AL, Goldfine ID, Evans JL: Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells micromolar concentrations of alpha-lipoic acid. Diabetes 2001, 50:404–410.PubMedView Article
- Tong Peter CY, Ng Maggie CY, Ho Vhung S, So Wing Y, Li June KY, Lam Chris WK, Cockram Clive S, Chan Juliana CN: C-reactive protein and Insulin resistance in subject with thalassemia minor and a family history of diabetes. Diabetes Care 2002, 25:1480–1481.PubMedView Article
- Chobanian AV, Bakris GL, Black HR, et al.: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003, 289:2560.PubMedView Article
- Grundy SM, Cleeman JI, Daniels SR, et al.: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005, 112:2735.PubMedView Article
- Genuth S, Alberti KG, Bennett P, et al.: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003, 26:3160.PubMedView Article
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985,28(7):412–9.PubMedView Article
- El-Hazmi MAF, Al-Swailem A, Al-Fawaz I, Warsey AS, Abdulmohsen A-S: Diabetes mellitus in children suffering from β-thalassaemia. J of Tropical Pediatr 1994, 40:261–266.View Article
- Gelaye B, Revilla L, Lopez T, Suarez L, Sanchez SE, Hevner K, et al.: Association between insulin resistance and C - reactive protein among Peruvian adults. Diabetol Metab Syndr 2010,2(1):30.PubMedView Article
- Burget TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al.: Alanine aminotransferase and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrine Metab 2006,91(11):4287–94.View Article
- Sattar N, Scherbakova O, Ford I, O'Reilly DS, Stanley A, Forrest E, et al.: Elevated Alanine aminotransferase predicts new onset type 2 Diabetes independently of classical risk factors, metabolic syndrome and C-reactive protein in the West of Scotland coronary prevention study. Diabetes 2004,53(11):2855–60.PubMedView Article
- Kawasaki T, Hashimoto N, Kikuchi T, Takahashi H, Uchiyama M: The relationship between fatty liver and hyperinsulinemia in obese Japanese children. J Pediatr Gastroentrol Nutr 1997,24(3):317–321.View Article
- Chan DF, Li AM, Chu WC, Chan MH, Wong EM, Liu EK, et al.: Hepatic steatosis in obese Chinese children. Int Obes Relat Metab Disord 2004,28(10):1257–63.View Article
- Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE: Obesity, Insulin resistance and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 2003,143(4):500–505.PubMedView Article
- Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC: Pancreatic iron and glucose dysregulation in thalassemia major. Am J Hematol 2011. Epub ahead of print
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