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Chapter 9?Multifaceted effects of HCQ in diabetes mellitus
Both chloroquine (CQ) and hydroxychloroquine (HCQ) have 4-aminoquinoline nucleus. Presence of a hydroxy group at the end of the side chain in HCQ makes it less toxic and more effective than chloroquine (Figure 1). (reference needed) The ability of HCQ to slow the disease progression in rheumatic arthritis (RA) and other autoimmune diseases led to its inclusion in the class of disease-modifying anti-rheumatic drugs (DMARDs). A renewed interest has been generated in HCQ in the last decade due to research focused on its glucose lowering, lipid lowering, antiplatelet, antithrombotic and cardiovascular (CV) protective effects.2-6

Figure 1: Chemical structures of CQ and HCQ

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The observation of reduced insulin requirement by CQ, first described in 1984 in a patient with severe insulin resistance, suggested that treatment with CQ or its suitable analogues may be a new approach in the management of diabetes.7 Later on, Smith and colleagues reported that the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes.8 HCQ showed improved glycemic control in an observational study of 4,905 RA patients. There was a reduced risk of developing diabetes in patients with HCQ use compared to those who never used HCQ.9 (reference needed) Various actions may be responsible for the multifaceted effects of HCQ.
Anti-inflammatory effect of HCQ
Hydroxychloroquine is thought to improve symptoms of systemic diseases by preventing inflammation. Inflammatory markers are significantly elevated in diabetes and in patients at risk of diabetes.10 Interleukin-6 and C-reactive protein (CRP) are two sensitive physiological markers of sub-clinical inflammation, associated with hyperglycemia, insulin resistance, and overt type 2 diabetes mellitus (T2DM).11 Long term use of HCQ has shown favourable effects in reduction of CRP and other inflammatory markers in systemic lupus erythematosus (SLE) and RA patients.12,13 The mechanisms by which HCQ helps to control pathogenic inflammation are poorly understood but the anti-inflammatory properties of HCQ are attributed to the inhibition of tumor necrosis factor-alpha (TNF-?) and other cytokines and inhibition of leukocyte activation. Figure 2 displays different types of inflammatory markers.14,15
Figure 2: Inflammatory markers that play a role in type 2 diabetes

Various novel mechanisms of action underlying therapeutically relevant anti-inflammatory effects of HCQ are:
Inhibition of the ion channels (Ca++ activated K+ channels)
Ion channels are considered key determinants in the leukocyte biology. Among others, the Ca++ activated K+ channels are believed to promote pathogenic inflammation. Furthermore, NLRP3 inflammasome has been shown to play a key role in promoting atherosclerosis as well as T2DM. The inhibition of Ca++ activated K+ channels by HCQ may lead to impaired inflammasome activation. Also, in vitro studies show that HCQ inhibits ATP-induced caspase 1 activation and secretion of the mature form of interleukin-1 beta (IL-1?) in macrophages. In vivo, this translates to inhibition of caspase 1-dependent neutrophil recruitment by HCQ.16 This novel mechanism has implications in both anti-rheumatic as well as metabolic (anti-diabetic and CV protective) benefits of HCQ.
Inhibition of endosomal NADPH oxidase (NOX)
NOX enzyme complex is involved in numerous proinflammatory signaling cascades. In particular, signaling of TNF? via TNF-receptor 1 (TNFR1) and IL-1? via IL-1R are mediated in part by uptake of the ligand-receptor complexes into the endosome, activation of endosomal NOX and generation of superoxide and subsequently other reactive oxygen species (ROS). Inhibition of endosomal NOX massively reduces downstream activation of NF?B via these pathways. But, signaling still proceeds with reduced intensity indicating that the endosomal route accounts for part of the cytokine effects.
HCQ has high affinity to acidic compartments, i.e., lysosomes and endosomes. HCQ blocks a signaling pathway common to TNF?, IL-1? and antiphospholipid antibody (aPL), which depends on activation of endosomal NOX2 and leads to proinflammatory and procoagulant cellular responses. Since signaling endosomes serve as physical platforms for crosstalk between different signaling pathways, this might explain the apparently heterogeneous therapeutic profile of HCQ. As a lysosomotropic weak base, HCQ is rapidly protonated, thereby increasing the pH of endolysosomal vesicles. This may block lysosomal enzymes that need an acidic pH. As a consequence, fusion of endosomes and lysosomes is prevented. Inhibition of endosomal NOX2 can explain reduction of cytokine production and plasma concentrations or inhibition of different immune effector cells by HCQ. This effect of HCQ provides an explanation for its beneficial role in the prevention of thromboembolic events.17
Selective inhibition of extracellular oxidants liberated from human neutrophils
Reactive oxygen species produced by neutrophils can exert pro- or anti-inflammatory effects, with respect to their extra- or intra-cellular location. External oxidants may increase the risk of tissue damage, block resolution and lead to permanent inflammation. On the other hand, oxidants inside neutrophils would not be affected, as they are involved in intracellular signaling and can suppress inflammation. The optimal antioxidant should thus preferentially decrease external oxidants. The anti-inflammatory drug, HCQ causes selective inhibition of extracellular oxidants in neutrophils.18

In isolated human neutrophils, treatment with HCQ decreased the mobilisation of intracellular calcium, reduced the levels of external oxidants and diminished the phosphorylation of Ca++-dependent protein kinase C isoforms PKC? and PKC?II, which regulate activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase on plasma membrane. On the other hand, no reduction was seen in intracellular oxidants or in the phosphorylation of p40(phox) and PKC?, the two proteins that direct the oxidase assembly to intracellular membranes. HCQ reduced neutrophil-derived oxidants potentially involved in tissue damage and protected those capable to suppress inflammation. The observed effects may represent a new mechanism involved in the anti-inflammatory activity of this drug.19
Inhibition of inducible NO synthase (iNOS)
Macrophages produce nitric oxide (NO) via inducible NO synthase (iNOS). Although iNOS was originally isolated from activated macrophages, its expression is induced in many cell types. The NO production by iNOS is responsible for bacterial killing in macrophages. On the other hand, it has also been implicated in many inflammatory diseases with autoimmune background (e.g. vasculitis, lupus, RA). Inhibition of NO production in macrophages may contribute to resolution of inflammation. Perecko et al studied the effect of HCQ on NO production in different macrophage cell types. The results of the study showed that HCQ inhibited NO production in macrophages indicating its anti-inflammatory action in diseases with autoimmune background.20
Glucose lowering effect of HCQ
Hydroxychloroquine has shown favorable metabolic effects on glucose control at both peripheral and pancreatic levels. Clinical and experimental evidences show inhibition of insulin degradation, increase in insulin levels and HbA1c reduction in T2DM patients with suboptimal glucose control.21-23
Inhibition of insulin degradation – At peripheral level
Insulin degradation is a complex process which is not completely elucidated. Insulin is known to have a short plasma half-life of 4–6 minutes due to its rapid uptake and degradation in all insulin sensitive tissues of the body. More than 50% of insulin is cleared in a single pass through the liver.

The initial step in insulin degradation is binding of insulin to the cell membrane mediated by specific insulin receptors. After binding to the receptor, internalization of insulin into endosomes takes place. Once the insulin-receptor complex has been internalized, insulin undergoes rapid degradation through insulin degrading enzymes (IDEs): glutathione insulin transhydrogenase, lysosomal protease, and insulin protease (insulinase). Some insulin is also degraded on the cell membrane in the absence of internalization, and is metabolized by membrane bound insulin protease. It accounts for more than 95% of all insulin degrading activity in human muscle and fibroblast cells (Figure 3).
Figure 3: Inhibitory action of HCQ on insulin degradation

HCQ, is an acidotrophic drug. It selectively concentrates in endosomes causing an increase in pH. Increase in pH inhibits the action of IDEs, and thus insulin degradation. This unique action of HCQ increases blood insulin levels leading to favorable metabolic effects.

This mechanism of HCQ has been elucidated in an experimental study where HCQ significantly reduced percentage insulin degradation. It was also observed that insulin-deficient experimental models had decreased insulin degrading activity which may be due to a reduction in enzyme synthesis. This may be interpreted as a protective mechanism, such that in the presence of low levels of insulin, less is degraded. HCQ also increased insulin binding to its receptor and altered hepatic insulin metabolism, thereby potentiating insulin action.24
Emami J et al25 have also shown glucose and insulin homeostasis with HCQ in their experimental study. A significant linear relationship between the glucose reduction and HCQ concentration (p

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