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Journal of Stress Physiology & Biochemistry, Vol. 20, No. 3, 2024, pp. 140-145 ISSN 1997-0838 Original Text Copyright © 2024 by Shirur, Dhone, Shah, Sinha and Sachdev
REVIEW
OPEN ACCESS
Role of copper in type 2 Diabetes Mellitus: A mini-review
Varsha Shirur, Swati Kale Dhone, Shreyas Shah, Anamika Sinha and Sanpreet Singh Sachdev*
1 Bharati Vidyapeeth (Deemed to be University) Dental College and Hospital, Sector 7, Belapur CBD, Navi Mumbai - 400614, India
*E-Mail: [email protected]
Received May 1, 2024
Diabetes Mellitus (DM) presents a significant global health challenge, with escalating prevalence rates and associated morbidity and mortality. Despite medical advancements, the mortality rates continue to rise, necessitating a deeper understanding of the pathophysiology and potential therapeutic targets. Copper, a vital trace element, plays an important role in various metabolic processes and homeostatic functions within the human body. Dysregulation of copper metabolism has been implicated in the pathogenesis and progression of DM, contributing to oxidative stress, insulin resistance, altered glycemic control, and metabolic abnormalities. The present review provides an illustrative overview of the role of copper in DM, elucidating its impact on oxidative stress, insulin resistance, glycemic control, and metabolic disturbances.
Key words: Diabetes, Hyperglycemia, Metabolic disorders, Trace elements, Insulin resistance
Diabetes Mellitus is a cause of global concern In the global adult population. India is rightly known as the global hub for diabetes, owing to the high prevalence rate reported across various studies. A significantly high morbidity and mortality rate is associated with the disorder owing to its tendency to cause damage to various organs including arteries, heart, kidneys, brain, nerves, and retina (Fujita et al., 2013).
A recent World Health Organization (WHO) estimate reported that DM accounts for more than 2 million deaths on a global scale and there has been a 3% rise in the mortality rates associated with diabetes despite advancements in medicine (Ong et al., 2023). Numerous bio-molecules and pathways are involved in the pathogenesis process of the disease. To tackle the pathology, however, it is imperative to understand the physiological regulatory processes of blood glucose and insulin. Among the many regulatory parameters, an important association between blood glucose levels, DM, and copper levels in the body (Naka et al., 2103; Samadi et al., 2020).
Pathophysiology of Copper:
Copper is a trace element present in various organs such as the liver, brain, and bones as well as in relatively lesser concentrations in the heart, pancreas, and kidneys (Jomova et al., 2022). The copper element acts as a co-factor in various metabolic reactions and plays a pivotal role in the homeostasis processes of the human body (Figure 1). The intake of copper is generally adequate owing to its abundance in the normal diet (Lelievre et al., 2020). It binds to albumin in the liver after being absorbed and transported from the gastrointestinal system. The circulation of copper in the bloodstream occurs in conjunction with ceruloplasmin (Maung et al., 2021). A copper membrane transporter-1 (CMT-1) protein aids in the transport of the element inside the cells and binds it to metallothioneins (Mandal et al., 2020). Both CMT-1 and metallothioneins are found abundantly in the liver cells, and ultimately the excretion of copper occurs in bile.
Inadequate dietary copper leads to increased production of free radicals, alkaline phosphatase activity,
and cytotoxicity (Davis 2003). Zinc may act as a competitor for the absorption of copper in the small intestine and hence, at times, copper deficiency may be pronounced in individuals with high zinc supplementation (Freeland et al., 2020). Owing to the ability of ceruloplasmin to oxidize iron, a deficiency of copper may lead to the development of symptoms of iron deficiency anemia (Moon et al., 2021).
Ceruloplasmin acts as a chelating agent and absorbs almost 90% of the copper in the blood and the excess of Cu returns to the liver to be excreted into the bile duct through ATP7B, the second human Cu(I)-ATPase (Linder et al., 2020). The toxicity of copper facilitates the formation of reactive oxygen species by acting as a pro-oxidant which may, in turn, cause cell death. This leads to the development of various diseases including Alzheimer's disease, osteoarthritis, and cardiomyopathy (Philbert eta l., 2022; Cui et al., 2022).
Copper and Type 2 Diabetes Mellitus:
Copper dysregulation contributes to oxidative stress, insulin resistance, altered glycemic control, and metabolic abnormalities in DM through various mechanisms (Figure 2).
Oxidative Stress in DM: Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, plays a pivotal role in DM progression (Singh et al., 2022; Jomova et al., 2023). Copper, along with zinc, serves as a cofactor for antioxidant enzymes such as superoxide dismutase (SOD), mitigating ROS-induced damage (Rosa et al., 2021; Chidambaram et al., 2024). Dysregulation of copper-dependent antioxidant systems exacerbates oxidative stress, leading to endothelial dysfunction, p-cell damage, and insulin resistance in DM. Tanaka et al., (2009) demonstrated increased ROS levels in DM patients, implicating copper-mediated oxidative stress in disease pathogenesis. Copper-chelating agents reduce ROS by excreting through the cell in bound forms, highlighting the role of Cu in the pathogenesis of DM (Singh et al., 2022; Jomova et al., 2023).
Copper and Insulin Resistance: Insulin resistance, a hallmark feature of DM, is exacerbated by disruptions
in copper homeostasis. Excess copper accumulation promotes ROS generation and impairs insulin signalling pathways, leading to diminished glucose uptake and utilization by peripheral tissues (Zhang et al., 2021; Badran et al., 2016). Furthermore, copper toxicity potentiates lipid peroxidation and inflammatory cytokine production, further exacerbating insulin resistance (Caturano et al., 2023). The generation of copper-induced oxidative stress in DM highlights its role in insulin resistance and metabolic dysfunction (González-Domínguez et al., 2022).
Copper and Glycemic Control: Disturbances in copper levels have been implicated in altered glycemic control in DM. Elevated copper levels stimulate glycation reactions and ROS-mediated damage to pancreatic p-cells, impairing insulin secretion and exacerbating hyperglycemia (Kant et al., 2021). Conversely, copper deficiency compromises glucose tolerance and
exacerbates diabetic complications. An association between elevated copper levels and impaired glycemic control in DM patients has been found, underscoring the importance of copper homeostasis in metabolic regulation (Hasano et al., 2020).
Copper and Metabolic Abnormalities: Metabolic dysregulation in DM influences trace element metabolism, including copper. Lower copper levels in DM patients have been reported, suggesting a role for copper in metabolic disturbances (Almajdoub et al., 2023; Bj0rklund et al., 2020). Conversely, copper excess contributes to mitochondrial dysfunction and ROS overproduction, perpetuating metabolic abnormalities in DM (Ruiz et al., 2021). Mazi et al. (2020) highlighted the implications of copper dysregulation in lipid and protein metabolism, underscoring its role in DM progression (Zhang et al., 2021).
Figure 1: Role of copper in various homeostatic functions
Figure 2: Dysregulation of copper-zinc-superoxide dismutase system leading to Diabetes mellitus
CONCLUSION
Copper emerges as a key player in the pathogenesis and progression of Type 2 Diabetes Mellitus. Dysregulated copper homeostasis contributes to oxidative stress, insulin resistance, altered glycemic control, and metabolic abnormalities in DM patients. Targeting copper metabolism may offer novel therapeutic avenues for managing DM and mitigating its complications. Further research is warranted to elucidate the precise mechanisms underlying copper-mediated metabolic dysfunction in DM and explore potential interventions targeting copper homeostasis for improved clinical outcomes.
CONFLICTS OF INTEREST
The authors declare that they have no potential conflicts of interest.
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