Epinephrine as a Therapeutic Agent for Hyperferritinemia in Diabetes Mellitus and Hypertension

Introduction

Diabetes mellitus (DM) is a chronic disorder that was the first non-communicable disease to be recognized by the United Nations as a 21st century pandemic [1]. It is one of the 4 prioritized non-communicable diseases targeted for action by the World Health Organization, since both its prevalence and number of cases have gradually increased during recent decades [2]. DM is a metabolic disorder characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. T2DM encompasses individuals who have IR or relative insulin deficiency [3]. The pathologic hallmark of DM involves the vasculature, leading to microvascular and macrovascular complications [4]. IR is a defective response to insulin stimulation of target cells in the liver, muscles, and adipose tissues. IR impairs glucose disposal, increasing insulin secretion and causing a hyper-insulinemic state. The metabolic impacts of IR include hyperglycemia, HTN, dyslipidemia, visceral adiposity, chronic inflammatory state, and impaired endothelial layer function [5–7] (Figure 1). Ferritin is the main intracellular iron storage protein and is a biomarker of iron stores and inflammation. High SF level is a common biochemical finding, with a prevalence of 5.9–19.0% in apparently healthy individuals, depending on ethnicity [8]. Increased iron stores have been associated with the development of type T2DM as reported in a meta-analysis of the studies published in 2013 [9]. Ferritin is a shell protein that sequesters iron to prevent iron-mediated oxidative damage by the Fenton reaction [10]. In recent years, the association of SF with several metabolic abnormalities has gained attention. IO reduces not only pancreatic beta-cell function, but also affects glucose and lipid homeostasis by impairing the response to insulin in the liver, muscles, and adipose tissues [11]. SF is closely associated with metabolic syndrome [12], and increased IO is correlated with risk of atherosclerosis and cardiovascular diseases [13]. IO is quite common in HTN [14] and it is detected in 21% of patients with HTN [15].

Epinephrine was reported to normalize elevated SF [16] by its iron chelating effect and it can relieve IO and alleviate IR associated with T2DM and HTN. Thus, epinephrine may be a valuable new therapeutic agent in T2DM and HTN, as well as in many chronic diseases associated with iron overload. We report the case of a patient who had T2DM, HTN, and dyslipidemia associated with hyperferritinemia. He received the conventional treatment for T2DM and HTN for 2 years, but there was poor control of hyperglycaemia and HTN. Since he had elevated SF, he agreed and consented for the use of epinephrine to lower SF. The first clinical effect of epinephrine on SF was reported in 2024, showing that epinephrine resulted in marked decrease of serum ferritin from 2000 to 258 ng/ml, inhibition of ferroptosis, control of cytokine storm, and a recovery of the patient who had severe COVID-19 infection [16]. The present case study explores epinephrine as an iron chelating and antioxidant agent with scavenging and anti-inflammatory properties, as well as its value in treating T2DM and HTN.

Case Report

A 63-year-old man of Mediterranean ethnicity, who was a smoker and did not drink alcohol, presented with a 2-year history of T2DM, HTN, and dyslipidemia. He had a family history of ischemic heart disease, but no history of HH, previous blood transfusion, hemolytic anemia, or oral or parenteral iron therapy. The condition started 2 years ago, manifested by increased thirst, frequent urination, increased hunger, frequent tooth infections, multiple headaches, and anxiety. His laboratory results and clinical examination led to diagnoses of T2DM and HTN. He was receiving oral hypoglycemic agents; glimepiride 2 mg/day and metformin 500 mg twice daily, bisoprolol 5 mg/day, amlodipine 5 mg/day, and atorvastatin 20 mg/day. He was also overweight; his hight was 175 cm, his weight was 86 kg, and his body mass index (BMI) was 28.08 Kg/m2. His vital signs were normal except for high blood pressure (BP), which was 145–160 (systolic BP)/100–105 mmHg (diastolic BP) on 3 occasions. A physical examination revealed normal breath sounds and heart sounds, no symptoms or signs of chronic inflammation, and no organomegaly. His complete blood count, hepatic and renal function tests, lipid profile, serum iron, and transferrin saturation were normal. While his initial and weekly follow-up SF values, fasting plasma glucose (FPG), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and glycated haemoglobin (HbA1c), as well as his BP and the time-line of his illness, are shown in Table 1. Chest X-ray and electrocardiography (ECG) results were normal. Abdominal and pelvic ultrasonography were done, showing fatty liver and senile enlarged prostate. Non-contrast multi-slice computed tomography (CT) revealed atheromatous calcification of the abdominal aorta, its bifurcation, and left renal vessels. Due to his high SF level (1370 ng/L), hematological and oncological consultations were done to exclude other causes of hyperferritinemia such as hereditary hemochromatosis (HH), chronic liver diseases, and diseases associated with hemolytic anemia such as β-thalassemia, which can lead to abnormal iron overload. However, there were no symptoms of fatigue, right upper-quadrant abdominal pain, arthralgias, impotence, decreased libido, or symptoms of heart failure. Similarly, there were no physical findings of an enlarged spleen or liver, no manifestations of chronic liver disease, testicular atrophy, congestive heart failure, skin pigmentation, or arthritis, and no splenomegaly that would raise the suspicion of hemochromatosis. Measuring transferrin saturation (TSAT) is another simple investigation in screening for HH, and TSAT above 45% in women or above 50% in men should prompt further genetic testing. Rheumatic/inflammatory disease and hematological malignancy, as well as solid-organ tumors, were also excluded based on clinical examination, laboratory investigations, and CT.

It was recommended to start iron chelating medications. We informed the patient that previous use of epinephrine resulted in normalizing his SF level and we obtained written informed consent for repurposing use of epinephrine. FPG and BP were measured before and after each injection, then epinephrine 0.6 mcg/kg was injected subcutaneously (S/C) twice daily (4 hours in between the 1st and 2nd injection) in the anterior upper thigh for 6 weeks (5 times/week) under hemodynamic monitoring (ECG and BP). The patient was discharged 1 hour after every 2nd injection, and after 4 weeks of epinephrine use he had hypoglycemia and hypotension, which were managed by holding OHA and antihypertension medications, dietary modifications, and frequent daily monitoring of blood sugar and BP, especially at bed time and before meals. The results were normalization of SF, complete resolution of hyperglycemia, and relieved HTN. HbA1c became normal after 4 months. He is now doing well and is still under strict medical supervision, with no adverse effects of epinephrine use detected.

Discussion

This is the first clinical use of epinephrine as an iron chelating agent in a patient with T2DM and HTN. It resulted in normalization of elevated SF, hyperglycemia, and HTN. Our results agree with Cutler, who proposed that a high SF concentration can cause diabetes, and he treated 9 patients with diabetes who had high SF concentrations with intravenously administered deferoxamine as an iron chelating agent, and in 8 of those patients their diabetic medication was discontinued after their SF concentration was normalized [17]. Epinephrine 0.6 mcg/kg was prescribed to a 64-year-old man with a medical history of ischemic heart disease, previous coronary artery bypass grafting surgery, generalized skin rash accompanied by severe itching, and swelling of lips and tongue due to COVID-19 infection [16]. This dose was successfully normalized the SF without adverse effects, which is why we used this same dose and injection route. Our patient was under close clinical observation with repeated laboratory investigations for more than 10 months, with no adverse effects and a stable metabolic state.

SF was first reported to be linked to IR in 1998 [18], and its severity is closely related to the level of SF [19]. Increased iron stores predispose to IR, while iron removal restores the response to insulin and delays diabetic complications [20,21]. IO impacts glucose metabolism through modulating insulin availability and insulin receptor sensitivity [22,23]. Excessive iron deposition causes ferroptosis of insulin-secreting pancreatic β cells, thus decreasing insulin synthesis and secretion [24]. Increased iron content in muscle tissue [25] can interfere with glucose disposal, uptake, and utilization [26], since muscle is the principal site for glucose disposal [27]. Thus, IO can contribute to both IR and decreased insulin secretion [28]. Insulin stimulates ferritin synthesis and facilitates iron uptake [29], and, conversely, iron influences insulin signalling [30] and reduces the hepatic extraction and the metabolism of insulin, leading to peripheral hyperinsulinemia [31], and can increase cellular oxidative stress, inhibiting the internalization and the actions of insulin [32]. The effect of iron depletion on glucose metabolism by phlebotomy was reported to improve IR in patients with T2DM associated with hyperferritinemia [33,34]. Flavonoids possess a highly iron chelation ability and reliable antioxidants. Thus, flavonoids can regulate iron metabolism and be used to treat iron overload [35]. Flavonoids, as natural products, have been shown to effectively and safely ameliorate T2DM and its complications by regulating insulin resistance [36]. Although IO remains under-appreciated [37], it induces ferroptosis, which is an iron-dependent form of nonapoptotic cell death characterized by IO and accumulation of lipid hydroperoxides [38]. Ferroptosis plays an important role in the development and progression of T2DM and its complications [24] and leads to IR [39], abnormal metabolism in the liver, and neurological and vascular diseases [40] (Figure 2).

Hyperinsulinemia and IR are associated with HTN [41–44]. IR induced by IO can be a causative factor in vascular endothelial dysfunction [45], sympathetic overactivity [46], and atherosclerosis by iron itself. Atherosclerosis can develop due to iron promoting direct endothelial toxicity and oxidizing low-density lipids [47–49]. Ferritin levels are also correlated with elevated diastolic BP [29] and this was obvious in our patient. Increased SF causes vascular oxidative stress and impairs vasoreactivity, which leads to inflammation, endothelial damage, and atherosclerosis, leading to HTN [50], which was manifested as atheromatous calcification of the abdominal aorta and its bifurcation in the CT of our patient.

Hyperinsulinemia can affect the renovascular system, which promotes renal sodium and water retention by increasing tubular reabsorption of sodium [51–53], which can lead to HTN. Thus, insulin can interfere with the systemic rennin-angiotensin system and leads to the development of HTN [54–56]. Consequently, IR and mediated effects of IO on the vascular endothelial and autonomic nervous system can contribute to the development of HTN. Ferrous ions (Fe2+) can form highly reactive oxygen species (ROS) through the Fenton reaction, thereby contributing to oxidative stress (OS), cellular damage, and many pathogenic processes [57].

Fe2+ ions are the most powerful pro-oxidant among the various species of metal ions and can facilitate the production of ROS within animal and human systems, and the ability of substances to chelate iron can be a valuable antioxidant [58]. Thus, Fe2+ chelation can present an important anti-oxidative effect by retarding metal-catalysed oxidation [59]. Epinephrine interacts with Fe2+ and/or ferric (Fe3+) ions from plasma labile iron pool (LIP), with coordinate binding and redox reactions. Epinephrine and Fe2+ build a colorless complex that is stable under anaerobic conditions. The kinetics of formation of epinephrine/Fe3+ complex and epinephrine/Fe2+ systems were compared, showing that epinephrine can still bind Fe2+ more rapidly because it is vastly more soluble at physiological pH than Fe3+. Fe2+ and Fe3+ may not share a common site of coordinate bonds formation [61]. Coordinate binding of Fe2+ to epinephrine could involve N in the amine group, which is a softer base than hydroxyl groups. Epinephrine combines through its oxygen atoms on catechol rings as sites of coordinate binding with Fe3+. A study on the impact of iron binding on biological performance of epinephrine concluded that binding of epinephrine to adrenergic receptors and their activation is impeded by formation of a complex of epinephrine with iron [61], which explains the absence of tachycardia and hypertension in our patient. Antioxidants can protect the human body from free radicals and ROS effects. They retard the progression of many chronic diseases as well as lipid peroxidation. The ability of catecholamines to reduce free radicals can be predicted based on their O-H bond strength and oxidation-reduction potentials. The catechol moiety is crucial for the ability of catecholamines to trap free radicals. The ability of catecholamines, including adrenaline, to scavenge free radicals in an aqueous solution and in a phospholipid bilayer is fast and effective in vitro [62,63]. Thus, adrenaline and nor-adrenaline may play a protective role against oxidative stress by scavenging free radicals and sequestering metal ions that promote ROS production via the Fenton reaction [64]. The main action of epinephrine(l-adrenaline) as a lipid peroxidation inhibitor may be related to its iron binding capacity [60]. Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL1β are widely acknowledged as important pathophysiological factors involved in IR [65]. However, short-term preexposure of healthy humans to a constant infusion of epinephrine before injection of low-dose endotoxin attenuates the production of the pro-inflammatory cytokine TNF and simultaneously potentiates production of the anti-inflammatory cytokine IL-10 [66]. Epinephrine inhibits the pro-inflammatory activities and oxidant production by neutrophils, which is stimulated with formyl peptides in vitro [67–70] and the anti-inflammatory interactions of epinephrine were attenuated by propranolol [67]. Figure 3 shows the explored actions of epinephrine. The interaction between ferritin and epinephrine was first reported in 1956, and an experimental study concluded that circulating ferritin can inhibit the vasoconstrictor response to epinephrine [71]. More recently, in 2020, it was found that epinephrine interacts with Fe3+ or Fe2+ ions from plasma (LIP) in vitro [61]. The first clinical effect of epinephrine on normalizing elevated SF was reported in 2024 in a case of severe COVID-19 [16]. Currently, IO is treated by phlebotomy, but this had known limitations and adverse effects [72], or by iron chelating agents, which has neurotoxic, hepatic, and renal adverse effects [73], and are more expensive than epinephrine. Thus, epinephrine may have value in treating medical disorders accompanied by IO, such as HH [74], neurodegenerative diseases like AD [75], PD [76], and MS [77]. Extensive studies are recommended for possible application of epinephrine as a new iron chelating and therapeutic agent in IO disorders. Further research is needed, with inclusion of additional cases, to confirm this hypothesis linking epinephrine’s iron chelating and antioxidant effects in resolution of IR and HTN, and to enhance the robustness of our findings. Further validations are needed through biochemical assays to monitor the levels of ROS, lipid peroxidation, and ferroptosis markers. Future studies may find more convenient application routes, doses of epinephrine, and dose-response relationships to the decrease of ferritin in different populations and various chronic diseases. This was a report of just 1 case, and further studies are needed to validate this hypothesis.

Conclusions

Epinephrine may decrease SF level by its iron chelating effect, and thus may eliminate IO associated with T2DM and HTN. Epinephrine may be an effective antioxidant agent and has ROS scavenging properties in addition to its anti-inflammatory effects. Epinephrine may have therapeutic potential in alleviating IR due to IO and thus may lead to recovery of T2DM and HTN associated with hyperferritinemia. Epinephrine may present potential therapeutic value to medical disorders accompanied by IO such as HH, and neurodegenerative diseases like AD, PD, and MS. Epinephrine may also be used to prevent the complications of T1DM. As a new clinical indication, extensive future studies are required for further assessment of potential therapeutic uses, long-term safety, and inclusion of additional cases to confirm this hypothesis linking epinephrine’s iron chelating and antioxidant properties to resolution of IR and HTN, and to enhance the robustness of our findings. Further validations are needed through biochemical as-says to monitor the levels of ROS, lipid peroxidation, and ferroptosis markers.