Serum Ferritin as a Component of the Insulin Resistance Syndrome

E p i d e m i o I o g y / H e a 11 h N A L

Se r v ice s/ Psy eh o so ei a I

R e s e a r c h

A R T I C L E

Serum Ferritin as a Component of the Insulin Resistance Syndrome JOSE-MANUEL FERNANDEZ-REAL, MD WlFREDO RlCART-ENGEL, MD ENRIC ARROYO RAFAEL BALANCA

ROSER CASAMITJANA-ABELLA, MD DOLORES CABRERO, MD MIQUEL FERNANDEZ-CASTANER, MD JOAN SOLER, MD

S

erum ferritin has been proposed as a cardiovascular risk factor. In a study by Salonen et al. (1), serum ferritin concentration had a significant positive correlation with blood glucose, serum triglycerides, and serum apolipoprotein B concentrations, and an inverse correlation with serum HDL2 cholesterol, all components of what has been OBJECTIVE — In epidemiological studies, serum ferritin was the second-strongest determinant of blood glucose (after BMI) in regression models and the third-strongest determinant termed the insulin resistance syndrome (2). of serum insulin (after BMI and age). Its concentration also correlated positively with plasma In a more recent study by this group, involvtriglycerides and apolipoprotein B concentrations, and negatively with HDL2 cholesterol. We ing 1,013 men, serum ferritin was the sechypothesized that serum ferritin could be a marker of insulin resistance. ond-strongest determinant of blood glucose (after BMI) in regression models and the RESEARCH DESIGN A N D METHODS — Oral glucose tolerance and insulin sensi- third strongest determinant of serum insulin tivity (Sh minimal model method) were prospectively evaluated in 36 healthy subjects. The (after BMI and age) (3). In another epidemirelationship between serum ferritin and metabolic control (as measured by HbAlc levels) was ological study, men with the higher intake of also studied in 76 consecutive NIDDM patients. heme iron had increased serum ferritin and RESULTS — In healthy subjects, log-transformed serum ferritin (LOGFER) correlated with an increased risk of coronary heart disease. basal serum glucose (r = 0.44, P = 0.007), but not with BMI, age, systolic or diastolic blood pres- The relative risk of coronary heart disease for sure, total cholesterol, VLDL cholesterol, HDL cholesterol, total triglycerides, VLDL triglyc- the highest versus the lowest quintile of erides, serum insulin, or HbAlc (all P = NS). Identical results were obtained when the two heme iron intake was 7.3 among diabetic lowest quartiles of serum ferritin were evaluated separately. However, in the two highest quar- patients and 1.36 among nondiabetic subtiles, LOGFER correlated with BMI (0.50, P = 0.02), diastolic blood pressure (r = 0.8, P < jects (4). In fact, the changes of stored iron as 0.0001), serum LDL cholesterol (r = 0.57, P = 0.01), VLDL cholesterol (r = 0.48, P = 0.03), total a function of sex and age are quantitatively cholesterol and HDL2 and HDL3 subfractions of HDL cholesterol (r = -0.68, -0.76, -0.55, P quite similar to changes in the incidence of = 0.001, 125 ug/1)

9 7/2

9 9/0

39.6 ± 1.7 29.2 ±1.4 1.01 ±0.02 20.2 ±10 5.1 ±0.18 9.51 ±0.6 5.5 ±0.47 48.4 ±6.4 4.67 ± 0.09 12.8 ±0.84 124.6 ±23.7 27.8 ±7.6 3.1 ±0.3 0.0176 ± 0.003

33.1 ±2.5 26 ±1.8 0.97 ±0.02 25.6 ±15 5.56 ±0.12 11.1 ±2.4 8.98 ±1.23 156.8 ±42 5.17 ±0.14 19.1 ±1.45 221.2 ±33.6 14.4 ± 1.7 1.47 ±0.4 0.0165 ±0.002

P value NS NS NS NS NS NS NS

0.02 0.04 0.01 0.003 0.03 0.13 0.01 NS

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Serum ferritin and the insulin resistance syndrome

Table 4—Clinical characteristics ofNIDDM (group 2) patients

14 r=0.25 p=0.03

13 Characteristic n Age (years) Sex (M/F) BMI (kg/m2) WHR Men Women Diet Hypoglycemic agents Insulin

Value

12

76 56±14 34/42 30.5 ±1.5

11

1.11 ±0.12 0.92 ±0.11 34 (45%) 24 (31%) 28 (37%)

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2 9
125 pg/1 in our study). In the recent report by Tuomainen et al. (3), both blood glucose and serum insulin were elevated at mildly increased (150 ug/1) serum ferritin concentrations, a level very similar to that obtained in our study. Below this threshold of serum ferritin, the interaction between serum ferritin and insulin resistance is possibly diluted, and the influence of other factors (for example, obesity) predominates. The relationship between serum ferritin and histochemical assessment of stainable tissue iron contributes to defining threshold values for serum ferritin that indicate exhausted, small, normal, ample, and increased iron stores (30). However, the barrier between "normal" and "small" or

"ample" iron stores is not well defined and remains controversial. Only 20% of men and 8% of women heterozygous for hemochromatosis had serum ferritin concentrations that exceeded the 95th percentile value for the age-matched male control subjects (31). Recently, it has been claimed that normal iron stores are null iron stores (32). Elevated iron stores could enhance oxidation of lipids, especially of free fatty acids, through accelerated production of free radicals, as ferrous iron is a potent catalyst. The degree of iron overload necessary to induce insulin resistance is unknown. It appears that the initial and most common defect in patients with an earlier stage of damage induced by iron overload is one of livermediated insulin resistance (33-35). A reduced hepatic insulin extraction, resulting in hyperinsulinemia, correlates with the degree of iron overload (36). Iron deposition in the liver may also cause insulin resistance by interfering with the ability of insulin to suppress hepatic glucose production. Furthermore, increased iron content has also been found in the peripheral muscle tissue (37), the principal site of overall glucose disposal (38). In patients with hemochromatosis and hemosiderosis, insulin resistance—evaluated by the euglycemic glucose clamp (39) or minimal model method (40,41)—correlated with iron overload, even in the presence of normal glucose tolerance (40,41). Dmochowski et al. (40) found that serum ferritin level inversely correlated with S\ (r = —0.58). However, no data about the relation of S] with serum fer-

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ritin was investigated in control subjects. Cavallo-Perin et al. (41) found that S\ was reduced by 40% in thalassemic subjects, and again it was inversely correlated with iron overload (r = —0.70). Although control subjects were also evaluated, the relationship between iron stores and Si was not examined in this group. The tissue responsible for insulin resistance in situations of high-normal iron stores can not be inferred from these studies, although model-derived Si is dominated by extrahepatic insulin effects (19). If serum ferritin is important in the development of insulin resistance, the higher the ferritin levels, the higher the incidence of NIDDM. We are unaware of studies aimed to test this hypothesis directly, but given the usually strong relationships between iron stores and the hematocrit level, the report by Wannamethee et al. (42) is interesting. In this study, an independent linear association between hematocrit level and the risk of NIDDM was found in a general population sample of middle-aged men after 12 years of follow-up (42). In another recent study, the glucose clearance rate, as calculated by the hyperinsulinemic isoglycemic clamp, was inversely related to the hematocrit level. This relationship was independent of sex, BMI, and age (43). This association did not result from acute hemodynamic changes on insulin sensitivity, and "may therefore reflect the presence of a common determinant" (43). High hemoglobin levels had also predicted subsequent glucose intolerance (44) and diabetes (45). Serum ferritin concentrations are significantly increased in patients with poorly controlled diabetes (46,47), and short-term improvement in glucose control is associated with a marked decrease in serum ferritin concentration (46). A derangement in other serum parameters of iron metabolism is frequently found in patients with poorly controlled diabetes (46-48). In NIDDM, about 10% of patients with high ferritin levels had transferrin saturations greater than 40% (46). A correlation between serum ferritin and HbAlc has already been reported (46-48), but to our knowledge, serum ferritin had not been described to be an independent predictor of HbAlc levels. However, although serum ferritin may be involved in the development of insulin resistance in diabetic patients, it is also possible that the presence of insulin resistance could affect serum ferritin levels. Only a prospective study design

could address these issues. More research is needed to evaluate whether high serum ferritin levels reflects increased body iron stores in NIDDM—through liver magnetic resonance studies—and whether modifications of iron stores (iron chelators or phlebotomy) in these subjects affects glucose metabolism. Finally, serum ferritin should be cautiously evaluated in NIDDM patients, because it may indicate falsely normal iron stores. In summary, the correlations between serum ferritin and diastolic blood pressure, HDL cholesterol, glucose AUC, and Si suggest that the former may be a simple marker of the insulin resistance syndrome. Serum ferritin may also be a marker of poor metabolic control in the diabetic patient.

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