C-Reactive Protein and Insulin Resistance in Subjects With Thalassemia Minor and a Family History of Diabetes

Insulin resistance is common in hemoglobinopathy including thalassemias. Excessive iron deposition in the liver is associated with a high prevalence of glucose intolerance in patients with hemoglobinopathy requiring repeated blood transfusion (1). In Hong Kong, up to 8.5% of pregnant women have thalassemia trait (2), which is a minor form of thalassemia and does not require blood transfusion. Furthermore, nearly 50% of patients with type 2 diabetes <35 years of age have a family history of diabetes (3). Both conditions share the common feature of insulin resistance. We postulate that there may be a clustering of these disorders in susceptible individuals. We therefore conducted a case-control study of subjects with normal glucose tolerance to examine the relationship among thalassemias, liver function tests, and index of insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA_IR]).

From a cohort of 835 siblings of young-onset type 2 diabetic patients, 17 normal glucose-tolerant subjects with thalassemia minor and a family history of diabetes were identified. Age-, sex-, and BMI-matched normal glucose-tolerant individuals without thalassemia from the same cohort were selected for comparison. Plasma glucose and serum insulin during the oral glucose tolerance test (OGTT), high sensitive C-reactive protein (hsCRP), plasma lipid concentrations, and indexes of liver function, as well as anthropometric parameters, were measured.

Normal glucose-tolerant individuals with thalassemia minor had higher fasting insulin concentrations (49 [31–65] vs. 29 [20–41] pmol/l, P = 0.003; geometric mean [interquartile range]) and lower HDL cholesterol (1.15 ± 0.31 vs. 1.42 ± 0.39, P = 0.03) than control subjects. Thalassemia minor subjects were more insulin resistant (HOMA_IR: 10.6 [6.3–14.6] vs. 6.1 [4.1–9.1], P = 0.004), had an exaggerated insulin response during the OGTT (insulin area under the curve at 120 min: 52,496 [34,670–91,468] vs. 26,275 [21,377–35,793] pmol · l⁻¹ · min⁻¹, P = 0.007), and higher hsCRP levels (1.06 [0.60–2.25] vs. 0.44 [0.20–0.83] mg/l, P = 0.009) compared with subjects without thalassemia. HOMA_IR correlated with γ-glutamyl transpeptidase (r = 0.595, P < 0.001) and alanine aminotransferase (r = 0.536, P = 0.026) in subjects with thalassemia minor only.

Individuals with thalassemia minor had insulin resistance, increased inflammatory marker, and low HDL cholesterol levels. Normal glucose tolerance was maintained in these individuals by hypersecretion of insulin. The fasting hyperinsulinemia and exaggerated insulin response during the OGTT imply that both the liver and muscle are resistant to insulin action. The strong correlation between hepatic enzymes and HOMA_IR as well as elevated hsCRP in subjects with thalassemia suggests that low-grade hepatic inflammation is closely correlated with insulin resistance. An increased iron turnover from low-grade hemolysis of microcytic erythrocytes may lead to hepatic damage and increased oxidative stress, both of which can contribute to insulin resistance (4). Intriguingly, hepatic iron overload is associated with some features of the metabolic syndrome (5). Our results suggest that the burden of thalassemia minor on glucose homeostasis cannot be fully explained by overweight or a family history of diabetes. We propose that the presence of thalassemia minor may have a direct effect on glucose homeostasis in individuals with a positive family history of diabetes, although the exact mechanism requires further exploration.