Ferritin and Insulin Resistance in Patients with Type 2 Diabetes Mellitus

Transcription

1 Med. J. Cairo Univ., Vol. 77, No. 1, March: 1-6, 9 and Insulin Resistance in with Type 2 Diabetes Mellitus SOAD SULTAN, M.D.*; AMR AL-MELIGI, M.D.*; NAGWA ALTAWEEL, M.D.** and HALA ABD ELAZEM, M.B., B.Ch.*** The Departments of Internal Medicine*, Chemical Pathology**, Faculty of Medicine, Cairo University and Internal Medicine***, Cairo University Student Hospital. Abstract Diabetes mellitus is a syndrome characterized by chronic hyperglycemia and disturbance of carbohydrate, fat and protein metabolism associated with relative or absolute deficiency of insulin secretion and/or insulin action. is the major iron storage protein and plays a key role in iron metabolism. In general population, body iron stores are positively associated with the development of glucose intolerance, type 2 diabetes. The aim of the present study was to measure serum ferritin in patients with type 2 diabetes and to study the relationship between serum ferritin, fasting blood glucose, glycated hemoglobin, insulin level and insulin resistance in patients with type 2 diabetes mellitus. This study involved female patients in child bearing period with type 2 diabetes mellitus selected from diabetes and endocrine clinic in Kasr El-Aini Hospital. Twenty healthy, age matched, females were taken as a control group. All subjects were subjected to: History taking, clinical examination and laboratory Investigation including fasting plasma glucose, glycated hemoglobin (HbA1c), fasting insulin and serum ferritin. We found that serum ferritin was significantly higher in patients with type 2 DM compared with the control group (p<.1) and in patients with type 2 DM ferritin level was positively correlated with fasting blood glucose (p<.1), glycated hemoglobin (p<.1), fasting insulin level (p<.5) and insulin resistance (p<.1). Key Words: Insulin resistance Type 2 diabetes mellitus. Introduction and Aim of the Work DIABETES mellitus consists of a group of disorders involving distinct pathogenic mechanisms with hyperglycemia as the common denominator. Type 2 diabetes mellitus is the end result of insulin resistance starting long before the disease [1]. Iron stores can be reflected by serum ferritin. in the circulation is a secretory form of the protein which is glycosylated and differs in subunit composition from the storage form found in the cells [2]. The serum ferritin level also increases with a number of diseases including, inflammation, cancer and liver diseases [3]. Serum ferritin was reported by some authors to be elevated in diabetic patients, furthermore, it is considered a considerable risk factor in the pathogenesis of some other disorders [4]. Insulin resistance is a major risk factor for type 2 diabetes and cardiovascular diseases [5]. The aim of the present study was to measure serum ferritin in patients with type 2 diabetes and to study the relationship between serum ferritin, insulin resistance and diabetes control in patients with type 2 diabetes mellitus. Subjects and Methods This study involved female patients in child bearing period with type 2 diabetes mellitus selected from diabetes and endocrine clinic in Kasr El-Aini Hospital. Twenty healthy age matched females were taken as a control group. All subjects were subjected to: 1- Full history taking including: Disease duration, menstrual history and hypertension. Exclusion criteria for all studied subjects were: with history of recent iron intake, acute or chronic infection, postmenopausal and chronic liver disease. 2- Clinical examination: Including measurement of blood pressure, BMI and waist circumference. 3- Laboratory investigation: Fasting plasma glucose, glycated hemoglobin (HbA1c), fasting insulin (Radi Immuono Assay) and serum ferritin (ELISA). Calculation of insulin resistance by Homeostasis Model Assessment (HOMA-R) [6]. Fasting Insulin (µlu/ml) x Fasting plasma glucose (mmole)

2 2 & Insulin Resistance in with Type 2 Diabetes Mellitus Results The results shown Tables (1-5) & Figs. (1-6). Table (1): Comparative study of Mean ± SD for age and anthropometric measures in patients group and control group. Age (yrs.) Weight (Kg) BMI (Kg/m 2 ) Waist (Cm) 41.3± ± ± ± (n=) 42.3± ± ± ± 1.77 NS: Non-significant. NS <.5 <.1 <.1 Table (2): Comparative study of Mean ± SD of the laboratory data between controls group and patients group. (n=) FPG (mmol/l) 4.98± ±5.53 <.1 HbA1c (%) 3.65± ± 1.65 <.1 (ng/ml) 31.24± ±27.35 <.1 Fasting Insulin 64.57± ± <.1 (µlu/ml) Insulin resistance 14.37± ±24.24 <.1 Mean value Fig. (1): Mean values of ferritin (ng/ml) in the patients group and controls. *p<.1. Mean value Fig. (2): Mean values of insulin resistance in the patients group and controls. *p<.1. Table (3): Correlation between ferritin and each of fasting insulin, FBG, HbA1c and insulin resistance in patients group. Correlation coefficient (r) Vs fasting insulin.342 <.5 Vs FBG.661 <.1 Vs HbA1c.497 <.1 Vs insulin resistance.657 <.1 Fasting insulin Fig. (3): Correlation between fasting insulin and ferritin in patients group (r=.342; p<.5*). Fasting plasma glucose Fig. (4): Correlation between fasting plasma glucose and ferritin in patients group (r=.661; p<.1*). Insulin resistance Fig. (5): Correlation between insulin resistance and ferritin in patients group (r=.657; p<.1 *).

3 Soad Sultan, et al. 3 HBA1c Fig. (6): Correlation between ferritin and HBA1c in patients group. (r=.497; p<.1 *). Table (4): Correlation between insulin resistance and different parameters in patients group. Variable correlated Insulin resistance Vs. waist.374 <.5 Insulin resistance Vs. age NS Insulin resistance Vs. blood NS pressure Insulin resistance Vs. BMI.429 <.1 NS = Not significant. Correlation coefficient (r) Table (5): Comparison in laboratory data between control, diabetic normotensive and diabetic hypertensive groups. Diabetic normotensive Diabetic hypertensive FPG (mmol/l) 4.98± ±5.16a 12.98±5.94b HbA1c (%) 3.65± ± 1.93 a 6.± 1.34b (ng/ml) 31.24± ±26.22a 63.96±27.59b Fasting insulin (µlu/ml) 64.57± ± 13.8a 78.86± b Insulin resistance 14.37± ±23.33 a 46.±25.54b ap<.1 bp<.1 cp=.354 NS ap<.1 b p<.1 cp=.432 NS ap<.5 bp<.1 cp=.11 NS ap<.1 b p<.1 cp=.98 NS ap<.1 b p<.1 cp=.515 NS Data were expressed as mean ± SD. p<.5 = significant. a = Comparison between diabetic normotensive group and control group. b = Comparison between diabetic hypertensive group and control group. c = Comparison between diabetic normotensive group and diabetic hypertensive. Discussion Type 2 diabetes, is a global health problem of continually increasing magnitude [7]. Diabetes mellitus is a syndrome characterized by chronic hyperglycemia and disturbance of carbohydrate, fat and protein metabolism associated with relative or absolute deficiency of insulin secretion and/or insulin action. Insulin resistance is defined as a subnormal biological response to insulin exposure and may be observed at cellular level, intact tissues or at the whole body level. Most often this term used to signify resistance to actions of insulin on glucose metabolism and it is a major risk factor for type 2 diabetes [5]. is the major iron storage protein and plays a key role in iron metabolism. Serum ferritin concentration is directly related to body iron stores in healthy individuals, and is also an acute phase reactant which increases during inflammation [8]. In general population, body iron stores are positively associated with the development of glucose intolerance, type 2 diabetes. The purpose of this study was to identify the relationship between ferritin and insulin resistance in patients with type 2 diabetes mellitus and if there is a relationship between ferritin level and diabetic control. Our study involved patients with type 2 diabetes mellitus and subjects as control. Our study showed significantly higher body weight, body mass index and waist circumference in type

4 4 & Insulin Resistance in with Type 2 Diabetes Mellitus 2 diabetes mellitus patients compared to controls. Also fasting plasma glucose, fasting insulin, HbA1c, insulin resistance are significantly higher in type 2 diabetes mellitus compared to controls. In agreement with our results, Kim et al., (), found significantly higher BMI, fasting plasma glucose, fasting insulin and insulin resistance in type 2 diabetes mellitus compared to controls [9]. Hu et al., (1), reported that insulin resistance and risk of type 2 diabetes mellitus increased with increase in body fat [1]. Our study showed a statistically significant higher serum ferritin in type 2 diabetes mellitus patients compared with controls (p<.1). In agreement with our results, Kaye et al., (1993), reported that type 2 diabetes mellitus is frequently associated with elevated level of serum ferritin [4]. Jiang et al., (4), found that the concentration of serum ferritin was significantly higher in patients with type 2 diabetes mellitus compared with control subjects after correction for other risk factor of diabetes including markers of obesity and inflammation [11]. Also, Campenhout et al., (6), found that, serum ferritin level was higher in diabetic patients with the absence of a relation between ferritin and CRP (C Reactive Protein) which attributed the elevated serum ferritin to increased iron stores rather than to a pro-inflammatory state [12]. Also Gorokhova, et al., (7), found significantly higher serum ferritin in patients with DM than nondiabetics [13]. In contrast to our results, Kim et al., (), found no statistically significant elevation in serum ferritin in patient with type 2 diabetes mellitus compared to controls [9]. Also Dinnen et al., (1994), reported that type 2 diabetes was not associated with a substantial level of iron overload [14]. Although many previous studies have demonstrated the relation of increased serum ferritin levels with a variety of conditions that contribute to the metabolic syndrome and type 2 diabetes mellitus, these studies have considered high ferritin as a reflection of iron overload [15]. Other authors considered ferritin as acute phase reactant as Hernandez et al., (5) who found increased serum ferritin concentration in diabetic group compared with control group. They suggested that the cause of elevation serum ferritin is inflammatory mechanism rather than iron store [16]. Hepatic iron overload syndrome, unrelated to hereditary hemochromatosis has been described and is characterized by hyperferritinemia, normal transferrin saturation and increased prevalence of glucose tolerance and diabetes [17]. Mendler et al., (1999), reported that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and a constant association of insulin resistance irrespective of liver damage [18]. The metabolic syndrome is closely linked to insulin resistance and numerous studies indicate a link to hepatic iron overload. Increased serum ferritin, reflecting hepatic iron overload is often associated with insulin resistance [19]. Bozzini et al., (5), reported increased prevalence of body iron excess in patients with the metabolic syndrome []. Our study, showed a significant positive correlation in a diabetic group between ferritin and each of FPG ( p<.1), HbA1c (p<.1) and fasting insulin (p<.5). In contrast with our results, Kim et al., (), reported ferritin level did not correlate with FPG in type 2 diabetes (9). Oba et al., (1997), reported that in diabetic patients, ferritin was not significantly related to Hb1Ac and fasting plasma glucose [21]. Jehn et al., (4), found no constant association between fasting insulin and ferritin in premenopausal women; they found consistent association between fasting insulin and ferritin in postmenopausal women and men [22]. In agreement with our results, Ford and Cogswell, (1999), reported that a significant positive correlation was found between serum ferritin concentration and concentrations of fasting insulin, plasma glucose and glycosylated hemoglobin [23]. Tuomainen et al., (1997), reported that fasting concentrations of serum insulin, plasma glucose were raised with statistically significant elevation in men with high serum concentrations of ferritin [3]. There is increasing evidence that moderately elevated body iron stores, below levels found in genetic hemochromatosis, may be associated with adverse health outcomes. Elevated serum ferritin levels independently predicted incident type 2 diabetes in prospective studies in apparently healthy men and women [11]. In cross sectional studies, elevated ferritin levels have been associated with hypertension [24], dysplipidemia [25], elevated fasting insulin, blood glucose [3] and central adiposity [26]. Jehn et al., (4), reported a positive association between elevated iron store and prevalence of metabolic syndrome [22]. In our study, there is a statistical positive correlation in diabetic between serum ferritin and insulin resistance (r=.657, p<. 1). In agreement with our results, Eshed et al., (1), found a positive correlation between plasma ferritin and insulin resistance and with risk of type 2 diabetes [27]. They also reported that substantial iron overload is not a feature of diabetes mellitus. Sheu et al., (3), reported that serum ferritin positively associated with insulin resistance in women not men [28]. In contrast to our results, Kim et al. () did not found a relationship between ferritin and insulin resistance [9]. Jehn et al., (4), also reported no consistent association between serum ferritin and insulin

5 Soad Sultan, et al. 5 resistance in premenopausal women and observe trend of increasing insulin resistance with increase serum ferritin in postmenopausal women and men [22]. Iron is a transition metal that can be easily become oxidized and thus acts as an oxidant. The general effect of catalytic iron is to convert poorly reactive free radicals such as hydrogen peroxide into highly reactive radicals such as the hydroxyl radical. Increased accumulation of iron affects insulin synthesis and secretion in the pancreas [29], and interferes with the insulin extracting capacity of the liver [] and Iron deposition in muscle decreases glucose uptake because of muscle damage [31]. Conversely, insulin stimulates cellular iron uptake through increased transferrin receptor externalization [32]. Iron deposition in the liver may also cause insulin resistance by interfering with the ability of insulin to suppress hepatic glucose production [9]. The causes and consequences of the Insulin Resistance-Hepatic Iron Overload (IR- HIO) are unknown. Treatment of IR-HIO is focused on metabolic syndrome and phlebotomies are questionable because the overload is moderate and intestinal absorption of iron seems to be low [33]. Fifty percent of transfusion-treated thalassemia patients have an abnormal glucose tolerance [34] and up to 65% of hereditary hemochromatosis patients develop diabetes mellitus [35] and the relationship between high iron intake and highly body stores outside the setting of genetic iron overload and type 2 diabetes is well recognized [23]. Loma Lind University's Adventist Health Study was the first to report the association between meat intake and type 2 diabetes risk [36]. Numerous studies have confirmed that this association is related to the high heme content of meat and increased dietary heme intake [37]. High body iron stores have been linked to insulin resistance [28] and metabolic syndrome []. Therapy with an ironchelating agent led to an improvement in the control of diabetes in a group of patients with poorly controlled type 2 diabetes mellitus [38]. Increased iron stores predicted the development of diabetes in epidemiological studies [23]. It is interesting that a lower prevalence of diabetes was recorded among frequent blood donors [39]. Reactive oxygen species interfere with insulin signaling at various levels, impairing insulin uptake through a direct effect on insulin receptor function [] and inhibiting the translocation of GLUT4 in the plasma membrane [41]. Conclusion: In this study we found that serum ferritin was significantly higher in patients with type 2 DM compared with the control group and in patients with type 2 DM ferritin level was positively correlated with fasting blood glucose, glycated hemoglobin, fasting insulin level and insulin resistance. Limitations of the study: This study can be done on a larger number of patients with correlation between ferritin level and diabetic complications. Markers of acute phase reactants such as CRP, ESR and IL6 can be done to exclude that the elevated ferritin level was one of them. Recommendations: Screening diabetic patients for serum ferritin level can be done and if high with no explanation (as acute phase reactant)? Iron chelators can be used. with type 2 diabetes mellitus can be advised not to take iron supplements with no known indications. References 1- SHERWIN R.S.: Diabetes mellitus. In: Bennet J.C. and Plum F (editors). Cecil Textbook of Medicine, WB Saunders Company, p. 1258, GIBSON R.S. and MACDONALD A.C.: Serum ferritin and dietary iron in a sample of preschool children. J. Can. Diet. Asc., 49: 22-31, TUOMAINEN T.P., NYYSSONEN K., SALONEN R., et al.: Body iron stores are associated with serum iron and blood glucose concentration. A population study in eastern Finnish men. Diabetes Care., (3): , KAYE T.B., GUAY A.T., SIMSON D.C., et al.: Noninsulin dependent diabetes mellitus and elevated serum ferritin level. J. Diab. Complic., 7 (4): 246-9, GINSBERG H.N.: Insulin resistance and cardiovascular disease. J. Clin. Invest., 16 (4): Comment J. Clin. Invest., 16 (5): ,. 6- MATTHEWS D.R., HOSKER J.P., RUDENSKI A.S., et al.: Homeostasis Model Assessment insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man. Diabetologica., 28 (7): 41-9, ZIMMET P., ALBERTI K.G. and SHAW J.: Global and societal implications of the diabetes epidemic. Nature, 414: , FUMERON F., PEAN F., DRISS F., et al.: and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years. Diabetes Care., 29: 9-94, KIM N.H., JUNG HEON OH, KYUNG MOOK CHOI, et al.: Serum ferritin in healthy subjects and type 2 diabetic patients. Yonsei Medical Journal, Vol. 41, No. 3, pp ,.

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