Interacting Pathways Linking Glucose and Iron Metabolism
Insulin is an anabolic hormone that stimulates the cellular uptake of many nutrients, including hexoses, amino acids, cations and anions. Intestinal absorption of nonheme iron is tightly regulated in keeping with the body requirements, and absorption of iron is minimal when body iron stores are normal. Absorption of heme iron (largely provided by red meat in western countries) does not appear to be dependent on body iron content. In the steady state, circulating iron is bound to transferrin and is taken up from the blood by a high-affinity specific transferrin receptor. The transferrin-receptor complex is internalized by endocytosis and released into a nonacidic cellular compartment, where it can be used in the synthesis of essential cellular components. Insulin is known to cause a rapid and marked stimulation of iron uptake by fat cells, redistributing transferrin receptors from an intracellular membrane compartment to the cell surface. Insulin is also responsible for the increased ferritin synthesis in cultured rat glioma cells. Importantly, transferrin receptors have been shown to colocalize with insulin-responsive glucose transporters and insulin-like growth factor II receptors in the microsomal membranes of cultured adypocytes, suggesting that regulation of iron uptake by insulin occurs in parallel with its effects on glucose transport.
Reciprocally, iron influences insulin action. Iron interferes with insulin inhibition of glucose production by the liver. Hepatic extraction and metabolism of insulin is reduced with increasing iron stores, leading to peripheral hyperinsulinemia. In fact, the initial and most common abnormality seen in iron overload conditions is liver insulin resistance.There is some evidence that iron overload also affects skeletal muscle, the main effector of insulin action.
Oxidative stress induces both insulin resistance [by decreasing internalization of insulin] and increased ferritin synthesis.
Iron is intimately linked to oxidative stress. Iron participates, through the Fenton reaction, in the formation of highly toxic free radicals, such as hydroxide and the superoxide anion, which are capable of inducing lipid peroxidation. For iron to act as a prooxidant agent, it must be in its free form. Iron can be released from ferritin by the action of reducing agents that convert Fe3+ into Fe2+. Glycation of transferrin decreases its ability to bind ferrous iron and, by increasing the pool of free iron, stimulates ferritin synthesis. Glycated holotransferrin is additionally known to facilitate the production of free oxygen radicals, such as hydroxide, that further amplify the oxidative effects of iron.
The fraction of nonused and highly toxic iron is stored as ferritin molecules in order to be neutralized. Apoferritin, the protein fraction of ferritin, is spatially folded to create a central groove that holds oxidized iron molecules [Fe3+]. apoferritin is a high-molecular weight (450 kDa) multimeric protein (24subunits of heavy and light chains) that exhibits exquisite high capacity for iron storage (4, 500 mol iron per mole of ferritin). Synthesis of apoferritin is induced at both the transcriptional and posttranscriptional levels by the presence of free iron. The increase in Fe2+ down regulates the affinity of iron-regulatory element (IRE) binding protein (BP) for its IRE binding site in the 5' region of ferritin mRNA, leading to increased ferritin translation.
The heavy chain in the apoferritin molecule exerts ferroxidase activity, catalyzing the oxidation of Fe2+ into Fe3+, which prevents iron-induced cyclic red-ox reactions that would spread and amplify the oxidative damage. This activity occurs underaerobic conditions, allowing the storage of intracellular iron. When concentrations of antioxidants are low, the reducing potential and anaerobiosis progressively increase, facilitating a rapid release of iron from ferritin. Additionally, the ferroxidase activity in the heavy chain is down regulated in this setting, decreasing the incorporation of iron into ferritin. The overall result of oxidative reactions is an increase in the availability of free iron from the ferritin molecule as well as from other molecules undergoing degradation, such as the heme group. These events, in turn, can enhance and amplify the process of generation of free radicals, causing cellular and tissue damage. The oxidative stress also down regulates the affinity of IRE for IRE-BP. Thus, ferritin can act both as a source or iron, which induces oxidative stress, and as a mechanism that protects against iron toxicity.
Hyperferritininemia is present in 6.6% of unselected patients with type 2 diabetes. Serum concentrations of ferritin are usually increased in poorly controlled type 1 and type 2diabetic subjects, and ferritin has been shown to predict HbA1c independently of glucose, probably reflecting increase doxidative stress. Short-term improvement in glycemic control is followed by variable decreases in serum ferritin concentration.
In summary, a scenario can be envisioned in which the physiological action of insulin leads to increased uptake of different nutrients and iron. Any factor causing hyperinsulinemia (weight gain, aging, repeated usual-life infections, or periodontitis) amplifies this process, determining increased deposition of iron, which in the long-term worsens insulin resistance.
Diabetes. 2002;51(8) © 2002 American Diabetes Association, Inc.
Cite this: Cross-Talk Between Iron Metabolism and Diabetes - Medscape - Aug 01, 2002.