Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Smith, Geoffrey D.; Amos, Tim; Mahler, Robert; Peters, Timothy J.

doi:10.1136/bmj.294.6570.465

Cited by 73 publications

(34 citation statements)

References 10 publications

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“…Clinical manifestations of chloroquine action have also been observed. Thus, in non-insulin-dependent diabetes mellitus, chloroquine improves glucose tolerance (29), increases peripheral glucose disposal, and decreases the metabolic clearance rate of insulin (30). In insulin-dependent diabetes mellitus, chloroquine has been shown to reduce insulin resistance (31).…”

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confidence: 99%

Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes

Bevan

Krook

Tikerpae

et al. 1997

Journal of Biological Chemistry

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Insulin signal transduction, initiated by binding of insulin to its receptor at the plasma membrane, activates the intrinsic receptor tyrosine kinase and leads to internalization of the activated ligand-receptor complex into endosomes. This study addresses the role played by the activated insulin receptor within hepatic endosomes and provides evidence for its central role in insulinstimulated events in vivo. Rats were treated with chloroquine, an acidotrophic agent that has been shown previously to inhibit endosomal insulin degradation, and then with insulin. Livers were removed and fractionated by density gradient centrifugation to obtain endosomal and plasma membrane preparations. Chloroquine treatment increased the amount of receptorbound insulin in endosomes at 2 min after insulin injection by 93% as determined by exclusion from G-50 columns and by 90% as determined by polyethylene glycol precipitation (p < 0.02). Chloroquine treatment also increased the insulin receptor content of endosomes after insulin injection (integrated over 0 -45 min) by 31% when compared with controls (p < 0.05). Similarly, chloroquine increased both insulin receptor phosphotyrosine content and its exogenous tyrosine kinase activity after insulin injection (64%; p < 0.01 and 96% and p < 0.001, respectively). In vivo chloroquine treatment was without any observable effect on insulin binding to plasma membrane insulin receptors, nor did it augment insulin-stimulated receptor autophosphorylation or kinase activity in the plasma membrane. Concomitant with its effects on endosomal insulin receptors, chloroquine treatment augmented insulin-stimulated incorporation of glucose into glycogen in diaphragm (p < 0.001). These observations are consistent with the hypothesis that chloroquine-dependent inhibition of endosomal insulin receptor dissociation and subsequent degradation prolongs the half-life of the active endosomal receptor and potentiates insulin signaling from this compartment.Insulin signal transduction is initiated by binding of insulin to its receptor at the plasma membrane, which in turn leads to the rapid autophosphorylation of multiple tyrosine residues on the intracellular portion of the ␤-subunit and the activation of the receptor tyrosine kinase toward exogenous substrates (1, 2). Following autophosphorylation, the activated ligand-receptor complex is internalized into endosomes in liver (3-6) and low density membranes in adipocytes (7,8) and muscle (9). Endocytosis of activated receptors has the twin effects of concentrating receptors within endosomes and allowing the insulin receptor tyrosine kinase to phosphorylate substrates that are spatio-temporally distinct from the plasma membrane (Ref. 10; reviewed in Ref. 11). Subsequent termination of signal transduction is achieved by endosomal insulin degradation (12-16) following dissociation of insulin from its receptor (14, 17) as the intralumenal environment of the endosome acidifies (18). This loss of the ligand-receptor complex attenuates any further ligand-driven recept...

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confidence: 99%

Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes

Bevan

Krook

Tikerpae

et al. 1997

Journal of Biological Chemistry

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“…The regulation of intraendosomal pH may play a role in modulating insulin sensitivity in vivo (52)(53)(54) since, in type II diabetic patients, the acidotropic agent chloroquine improved glucose metabolism (55)(56)(57)(58)(59)(60)(61). Because chloroquine inhibits intraendosomal insulin degradation it may be inferred that the endosomal accumulation of intact insulin is responsible for the improved insulin sensitivity.…”

Section: Figmentioning

confidence: 99%

ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase

Contrerès

Faure

Baquiran

et al. 1998

Journal of Biological Chemistry

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Incubating endosomes with ATP decreased binding of 125 I-insulin but not 125 I-labeled human growth hormone. Increasing ATP concentrations from 0.1 to 1 mM increased ␤-subunit tyrosine phosphorylation and insulin receptor kinase (IRK) activity assayed after partial purification. At higher (5 mM) ATP concentrations ␤-subunit tyrosine phosphorylation and IRK activity were markedly decreased. This was not observed with nonhydrolyzable analogs of ATP, nor with plasma membrane IRK, nor with endosomal epidermal growth factor receptor kinase autophosphorylation. The inhibition of endosomal IRK tyrosine phosphorylation and activity was completely reversed by bafilomycin A 1 , indicating a role for endosomal proton pump(s). The inhibition of IRK was not due to serine/threonine phosphorylation nor was it influenced by the inhibition of phosphotyrosyl phosphatase using bisperoxo(1,10-phenanthroline)oxovanadate anion. Prior phosphorylation of the ␤-subunit with 1 mM ATP did not prevent the inhibition of IRK activity on incubating with 5 mM ATP. To evaluate conformational change we incubated endosomes with dithiothreitol (DTT) followed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions. Without DTT the predominant species of IRK observed was ␣ 2 ␤ 2. With DTT the ␣␤ dimer predominated but on co-incubation with 5 mM ATP the ␣ 2 ␤ 2 form predominated. Thus, ATP-dependent endosomal acidification contributes to the termination of transmembrane signaling by, among other processes, effecting a deactivating conformational change of the IRK. Following insulin binding to its receptor in intact cells the insulin receptor kinase (IRK)1 undergoes tyrosine autophosphorylation and kinase activation (1, 2). Equally rapidly there is internalization of activated insulin-IRK complexes into ENs (3, 4). IRK signaling appears largely to involve tyrosine phosphorylation of adaptor proteins, including insulin receptor substrate-1 (5), insulin receptor substrate-2 (6, 7), and SHC (8), which function as docking entities to entrain the insulin signaling sequence. The observation that the activated IRK is internalized to ENs is consistent with the occurrence of transmembrane signaling intracellularly (9, 10). Indeed studies in liver parenchyma have shown that the accumulation of activated IRKs exclusively in ENs is sufficient to promote insulin receptor substrate-1 tyrosine phosphorylation (11). In adipocytes it has also been shown that internal membranes are the principal sites where insulin receptor substrate-1 phosphorylation and phophatidylinositol 3-kinase activation occur (12). Given the above, understanding the mechanisms controlling receptor function in ENs is important for understanding the regulation of insulin signaling. Studies have shown that the level of IRK tyrosine phosphorylation and hence activity is altered and ultimately reduced by an IRK-associated phosphotyrosine phosphatase in ENs (4, 13). Discovery of the endosomal acidic insulinase (14) has demonstrated a mechanism by which intraendosomal insulin concentrat...

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“…These observations suggested that treatment with CQ or suitable analogues may be a new approach to the management of diabetes [20]. A case report suggests that HCQ reduces insulin dose with good glycaemic control in patients with rheumatoid arthritis [21,22].…”

Section: Antidiabeticsmentioning

confidence: 99%

“…Type 1 diabetic patients receiving insulin, HCQ has shown a dramatic return of sensitivity to insulin and a series of severe hypoglycaemic attacks heralds after 2 months of concurrent use, and it is necessary to drastically reduce the daily dose of insulin [8,20]. The patients with type 2 diabetes mellitus show a significant improvement in their glucose tolerance.…”

Section: Antidiabeticsmentioning

confidence: 99%

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

Al‐Bari¹,

Islam²

2015

J. Sci. Res.

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The popularity of chloroquine (CQ) analogues, for malaria treatment in many countries emanates from it being cheap, widely available, relatively well tolerated, and having a rapid onset of action. Thus, CQ analogues are commonly sold as over-the-counter (OTC) medications. CQ analogues like hydroxychloroquine (HCQ) alone and/or other drugs in combination have been used as anti-inflammatory and immunomodulatory drugs in the treatment of various rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, dermatomyositis, Sjögren's syndrome, chronic juvenile arthritis, psoriatic arthritis, and have shown clinical benefits with an acceptable safety profile. As anti-inflammatory mechanism, CQ inhibits pro-inflammatory cytokine release, antigen processing and blocking the actions of histamine and phospholipase A 2 . CQ analogue has also been studied for its potential as an enhancing agent in cancer therapies in various clinical trials. In many cases, the lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity to inhibit inflammatory disorders. Moreover, it is indicated that the efficacy of conventional therapies can be dramatically enhanced if CQ analogues are given in combination. Although majority of CQ analogue in combination therapies improves overall the outcome, such treatments are often associated with serious toxicities leading to fatal.

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Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Cited by 73 publications

References 10 publications

Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes

Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes

ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

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