iron vs type2 diabetes

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from Diabetes

Posted 08/29/2002

José Manuel Fernández-Real, Abel López-Bermejo, and Wifredo Ricart

Abstract and IntroductionAbstract

Emerging scientific evidence has disclosed unsuspected influences between iron

metabolism and type 2 diabetes. The relationship is bi-directional—iron affects

glucose metabolism, and glucose metabolism impinges on several iron metabolic

pathways. Oxidative stress and inflammatory cytokines influence these

relationships, amplifying and potentiating the initiated events. The clinical

impact of these interactions depends on both the genetic predisposition and the

time frame in which this network of closely related signals acts. In recent

years, increased iron stores have been found to predict the development of type

2 diabetes while iron depletion was protective. Iron-induced damage might also

modulate the development of chronic diabetes complications. Iron depletion has

been demonstrated to be beneficial in coronary artery responses, endothelial

dysfunction, insulin secretion, insulin action, and metabolic control in type 2

diabetes. Here, we show that iron modulates insulin action in healthy

individuals and in patients with type 2 diabetes. The extent of this influence

should be tested in large-scale clinical trials, searching for the usefulness

and cost-effectiveness of therapeutic measures that decrease iron toxicity. The

study of individual susceptibility and of the mechanisms that influence tissue

iron deposition and damage are proposed to be valuable in anticipating and

treating diabetes complications.

Introduction

It is increasingly recognized that iron influences glucose metabolism, even in

the absence of significant iron overload. In the generalpopulation, body iron

stores are positively associated with the development of glucose intolerance,

type 2 diabetes,[1-7] and gestational diabetes.[8, 9] Among U.S. adults, men

with newly diagnosed diabetes had an odds ratio (OR) of 4.94 (95%confidence

interval [CI] 3.05-8.01) and women had an OR of 3.61 (2.01-6.48) of having

elevated ferritin concentrations.[6] These figures are especially remarkable

when considering the increased prevalence of elevated iron stores in the

healthy, free-living U.S. elderly population (28% of men and 12.2% of women

showed high iron stores in a recent study).[10]

 

Frequent blood donations, leading to decreased iron stores, have been

demonstrated to reduce postprandial hyperinsulinemia in healthy volunteers,[11]

to improve insulin sensitivity,[12] and to constitute a protective factor for

the development of type 2 diabetes.[13] Phlebotomy was followed by decreases in

serum glucose, cholesterol, triglycerides and a poprotein B,[14] and by

improvement in both -cell secretion and peripheral insulin action in patients

with type 2 diabetes.[15] A significant impact of tissue iron excess on systemic

effects of diabetes is suggested by recent reports in which iron appears to

influence the development of diabetic nephropathy and vascular dysfunction. In

this sense, intravenous administration of deferoxamine resulted in improved

coronary artery responses to cold stress testing in type 2 diabetic subjects[16]

and in amelioration of endothelial dysfunction in subjects with coronary heart

disease.[17]

 

All these observations suggest that iron is more intimately linked to human

pathophysiology than previously thought. In fact, iron metabolism is closely

associated with the clinical presentation of numerous systemic diseases.[18]

Tissue iron excess contributes to produce and amplify the injury caused by free

radicals as well as to modulate various steps involved in the inflammatory

lesion.

 

In this article, we summarize the relationships between iron, insulin

resistance, and type 2 diabetes and discuss the therapeutical and clinical

implications of reducing body iron.

Iron and Insulin Sensitivity

Iron stores, expressed as serum ferritin concentration, have been proposed to be

a component of the insulin-resistance syndrome. Indeed, the concentration of

circulating ferritin was significantly associated with centrally distributed

body fatness as well as with several other measurements of obesity.[19] In the

apparently healthy general population, serum levels of ferritin were also

positively correlated with baseline serum glucose and with the area under the

curve for glucose during the glucose oral tolerance test.[20, 21] In gestational

diabetes, both BMI and serum ferritin levels were found to be independent

predictors of 2-h glucose during an oral glucose tolerance test.[8, 9] Ferritin

levels also correlated with diastolic arterial blood pressure, even after

adjustment for BMI. Of note is the beneficial effect of blood letting, a means

of reducing iron stores, in the treatment of resistant hypertension[22] and in

posttrans plant hypertension associated with erythrocytosis.[23] Serum ferritin

concentration was also directly associated with uric acid (another component of

the insulin resistance syndrome) and inversely related with HDL cholesterol and

the HDL2-to-HDL3 ratio.[21]

 

Insulin resistance itself, assessed by either the euglycemic clamp [24] or the

minimal model,[25, 26] was found to be associated with total body iron stores,

even in the presence of normal glucose tolerance. Dmochowski et al.[25] reported

that serum concentrations of ferritin were negatively correlated with insulin

sensitivity (r = -0.58) in subjects with hemosiderosis. Cavallo-Perinet al.[26]

reported that insulin sensitivity, which correlated closely with iron overload

(r = -0.70), was reduced by 40% in thalassemia patients. Insulin resistance also

appeared to be closely linked to total body iron stores in the general

population.[21] Serum ferritin levels could be a useful marker of insulin

resistance beyond a given threshold.[20, 21] In the study by Toumainen et

al.,[20] the increase in serum insulin concentrations was clearly apparent in

the upper two quintiles of ferritin levels. In a different study, the

correlation between circulating ferritin and insulin resistance was only

observed in the upper two quartiles of ferritin levels.[21] Below this

threshold, the potential tissue effects of siderosis would be negligible.

 

Some comments on the specifity of serum ferritin as an indicatorof iron stores

seem necessary. The relationship between serum ferritin and histochemical

assessment of stainable tissue iron contributes to define threshold values for

serum ferritin, indicating exhausted, small, normal, ample, and increased iron

stores. However, the barrier between " normal " and " small " or " ample " iron

stores is not well defined and remains controversial. Approximately 10% of type

2 diabetic patients with high ferritin levels had transferrin saturations

greater than normal (40%). On the other hand, serum ferritin should be

cautiously evaluated in patients with type 2 diabetes, because it may falsely

indicate " normal iron stores. " It should not be ignored that chronic

inflammation could contribute, to some extent, to increased ferritin

concentration (continued at link at top of message)

 

 

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