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Chapter 9Multifaceted effects of HCQ in diabetes mellitus
-508058420Both 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. The ability of HCQ to slow the disease progression in RA and other autoimmune diseases led to its inclusion in the class of disease-modifying antirheumatic 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 CV protective effects.
The observation of reduced insulin requirement by chloroquine (CQ), first described in 1984 in a patient with severe insulin resistance, suggested that treatment with chloroquine or its suitable analogues may be a new approach in the management of diabetes. 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. Hydroxychloroquine showed improved glycemic control in an observational study of 4905 RA patients. There was a reduced risk of developing diabetes in patients with hydroxychloroquine use compared to those who never used hydroxychloroquine. Various actions may be responsible for multifaceted effects of HCQ.
Anti- inflammatory effect of HCQ
Hydroxychloroquine is thought to improve symptoms of systemic diseases by preventing inflammation.

-508057785Inflammatory markers are significantly elevated in diabetes and in patients at risk of diabetes. Interlukin-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). Long term use of HCQ has shown favourable effects in reduction of CRP and other inflammatory markers in SLE and RA patients. The mechanisms by which HCQ helps to control pathogenic inflammation are poorly understood but the anti-inflammatory properties of HCQ are attributed to through the inhibition of TNF-? and other cytokines and inhibition of leukocyte activation.
Various novel mechanism of action how HCQ exerts its therapeutically relevant anti-inflammatory effects 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 type 2 diabetes. 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 IL-1? in macrophages. In vivo, this translates to inhibition of caspase 1-dependent neutrophil recruitment by HCQ. This novel mechanism has implications in both – anti-rheumatic as well as metabolic (anti-diabetic and CV protective) benefits of HCQ.

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Inhibition of endosomal NADPH oxidase (NOX)
NOX enzyme complex is involved in numerous proinflammatory signalling cascades. In particular, signalling 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, signalling 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 signalling pathway common to TNF?, IL-1? and aPL, which depends on activation of endosomal NOX2 and leads to proinflammatory and procoagulant cellular responses. Since signalling endosomes serve as physical platforms for crosstalk between different signalling 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 inhibit lysosomal enzymes that require an acidic pH, and prevent fusion of endosomes and lysosomes. 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.
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 intracellular 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 signalling 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.
In isolated human neutrophils, treatment with HCQ resulted in reduced mobilisation of intracellular calcium, diminished concentration of external oxidants and in decreased phosphorylation of Ca(2+)-dependent protein kinase C isoforms PKC? and PKC?II, which regulate activation of NADPH oxidase on plasma membrane. On the other hand, no reduction was observed in intracellular oxidants or in the phosphorylation of p40(phox) and PKC?, two proteins directing the oxidase assembly to intracellular membranes. Hydroxychloroquine 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.

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, rheumatoid arthritis). 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.
Glucose lowering effect of HCQHydroxychloroquine has shown favorable metabolic effects on glucose control at both peripheral and pancreatic levels. Clinical and experimental evidence show inhibition of insulin degradation, increase of insulin levels and HbA1c reduction in T2DM patients with suboptimal glucose control.
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, Insulin protease (insulinase). Some insulin is, also degraded on the cell membrane in 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)

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 % insulin degradation. It was also observed that insulin-deficient animals 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.
Emami J et al have also shown glucose and insulin homeostasis with HCQ in their experimental study. -2095578740A significant linear relationship between the glucose reduction and HCQ concentration (p<0.001) and HCQ dose (p<0.002) was observed. HCQ appears to sustain higher insulin levels and hence has therapeutic potential in the treatment of patients who have residual ?-cell function.
Improvement in insulin sensitivity – At pancreas level
26670870585Insulin resistance comprises one principal aspect of metabolic syndrome, an amalgamation of risk factors that predict CV events. In a pilot intervention study, Mercer et al demonstrated that six weeks of HCQ treatment improves insulin sensitivity in obese non-diabetic subjects without a known systemic inflammatory condition. Matsuda Insulin Sensitivity Index (ISI), HOMA-IR were assessed at 0, 6 wks and 12 wks (i.e. 6 wks post stopping HCQ). There was a statistically significant increase in Insulin sensitivity index (ISI) after 6 weeks of HCQ 6.5 mg/kg and a decrease in ISI toward baseline after stopping HCQ.
HOMA-IR, a measure of insulin resistance, decreased significantly from 2.1 to 1.8 and crawled back towards baseline after stopping therapy. This degree of improvement in insulin sensitivity may translate into a reduced risk of diabetes.
Further to examine how HCQ affects glucose homeostasis, researchers from the university of Pittsburg (Diabetologia. 2015 Oct;58(10):2336-43) conducted a 13 weeks trial in non-diabetic adults who had risk factors for insulin resistance such as fasting blood glucose (FBG): 100–125 mg/dL, fasting insulin >7 ?U/ml, history of gestational diabetes or a parent with T2DM. The study findings demonstrated that HCQ improves both insulin sensitivity and beta cell function.

-209551243330A potential mechanism by which HCQ might affect insulin sensitivity could be modulation of adipose tissue inflammation and adiponectin production. It is known that altered adipokine profile contributes to the development of impaired glucose homeostasis, low-grade inflammation and obesity-related comorbidities. Significant increase in plasma adiponectin level after HCQ (400 mg/day) treatment (18.7%) but not after placebo (0.7%) in this study suggests the possibility of anti-inflammatory effects of HCQ in adipose tissue. By increasing adiponectin levels HCQ may enhance the positive metabolic effects not only at the peripheral sites but also at the pancreas.
? cell preservation – At pancreas level
?-cell apoptosis and ?-cell proliferation are key players in the dysfunctional remodeling of the islets of Langerhans (IOL) and consequent hyperglycemia in T2DM. Early changes in T2DM include IOL hypertrophy/hyperplasia followed by degenerative changes, their atrophy and infiltration by inflammatory cells particularly macrophages. Histological and immunohistological results of the study showed preservation of beta cells with HCQ. (Figure)
31146752952115Immunohistological results
a- Control group, b – Diabetes group, c – Diabetes + HCQ group
00Immunohistological results
a- Control group, b – Diabetes group, c – Diabetes + HCQ group
3543302952115Histological results
a- Typical view of IOL, b – Disrupted IOL in diabetes group, c – Preservation in IOL in HCQ group
00Histological results
a- Typical view of IOL, b – Disrupted IOL in diabetes group, c – Preservation in IOL in HCQ group

In immunohistological results, most of the cells of IOL of the control group showed an intense widely distributed insulin immunoexpression all over the islets. On the other hand, the IOL of the DM group exhibited fewer less intense insulin expressing cells. Minimal affection of the IOL was denoted in the HCQ + DM group with preservation of most of their insulin expressing cells which appeared numerous and had intense reaction compared with the DM one. Thus, HCQ shows a favorable effect on the structure of endocrine pancreas in a type 2 diabetic model.

CV protective effects of HCQCardiovascular disease (CVD) due to atherosclerosis is the leading cause of death in chronic inflammatory disorders. This may be due to the adverse effects of chronic inflammation on the vasculature. In an inception cohort of RA patients, treatment with HCQ was independently associated with a 72% reduction in all incident CVD events and a 70% reduction in the risk of incident composite coronary artery disease CAD, stroke, transient ischemic attack TIA. The biological plausibility of this protective association is supported by the favorable associations of HCQ with beneficial changes in lipid profiles, reduced risk of thrombotic events and platelet inhibitory effect.

Lipid lowering effect of HCQ
Lipid lowering effect of 4-Aminoquinolines is known for long when in 1986, Beynen ll showed that low-dose chloroquine decreased cholesterol Synthesis. The induction of inflammation provides a link between hyperlipidemia and atherogenesis. HCQ is known to improve inflammatory markers. Several studies have demonstrated the lipid lowering activity of HCQ.
The latest in this series of studies was a study conducted by Pareek A et al. The authors assessed efficacy and safety of atorvastatin + HCQ combination in comparison with atorvastatin monotherapy in the treatment of dyslipidemia. Eligible patients were randomized to receive either atorvastatin 10 mg or atorvastatin 10 mg + hydroxychloroquine 200 mg for 24 weeks. Patients were divided into two cohorts: Cohort 1 – patients with normoglycemia (HbA1c: 5.7% and taking no anti-diabetic medicine) and Cohort 2 – patients with pre-diabetes (HbA1c: 5.7% to 6.4% and no anti-diabetic medicine), patients with type 2 diabetes (HbA1c 6.5% or patients taking anti-diabetic medicine). There was a significantly greater percentage reduction in LDL-C, non-HDL-C and TC in patients treated with combination therapy than atorvastatin alone. (Table).
Lipid profile Mean % change at week 24
ATV ATV + HCQ P value
TC (mmol/L) -24.41 -29.30 0.013
LDL-C (mmol/L) -32.52 -39.54 0.008
HDL-C (mmol/L) +2.20 +7.55 0.129
Non-HDL-C (mmol/L) -30.37 -36.76 0.009
TG (mmol/L) -10.52 -12.72 0.668
ATV: atorvastatin, (+): increase in levels, (-): decrease in levels.

The addition of HCQ resulted in a 5.16% incremental fall at Week 12 and 7.02% incremental fall at Week 24 in LDL-C along with significant decrease in HbA1c and FBG levels. Significantly more patients achieved LDL-C and TC goals and lesser patients developed diabetes with combination therapy.
Anti thrombotic effect of HCQ
An apparent effect of HCQ to reduce thromboembolic events has been recognized for more than two decades. Carter et al in 1971, found that HCQ, though not anticoagulant, is an effective agent in reducing deep venous thrombosis (DVT) in the leg after major surgery. The incidence of DVT was reduced to 5% compared with an incidence of 16% in a similar untreated group of patients. Further, HCQ was used as a prophylactic prevented thrombotic events in the postoperative period following total hip arthroplasty. Subsequent analyses of clinical data supports the use of HCQ to prevent emboli in thousands of patients following orthopedic procedures. Several studies—both prospective and retrospective in SLE have found reduction in thrombosis risk with HCQ usage.

Several mechanisms have been proposed for the anti-thrombotic effects of HCQ. Many years ago, HCQ was shown to reduce platelet aggregation in vitro, but this effect was not measured in patients treated with HCQ. Platelet aggregation also may be reduced by HCQ through inhibition of the alpha- granule release reaction, but this also was limited to in vitro measurements.

Anti platelet effect of HCQ
Hydroxychloroquines Efficacy as an Antiplatelet Agent (HEAT trial) evaluated its antiplatelet effect and compared it head-on with the commonly prescribed antiplatelet therapies in humans. Study showed 11% reduction in platelet aggregation with HCQ and 31.2% reduction on combining it with aspirin. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values.

Antiplatelet action may be downstream to the production of thromboxane A2 in the arachidonic acid pathway. HCQ’s accumulation in dense granule in platelets may inhibit aggregation by decreasing the secretion of aggregation amplifying substances from platelet granules.
With possible additional beneficial effects over the traditional risk factors of CVD like hyperglycemia and hyperlipidemia, as shown in other studies, future studies might focus upon the potential of HCQ as an antiplatelet and anti-inflammatory agent for the treatment of CVD.

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