Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus

Powrie, Jake; Smith, Geoffrey D.; Shojaee‐Moradie, Fariba; Sönksen, Peter H.; Jones, R. H.

doi:10.1152/ajpendo.1991.260.6.e897

Cited by 48 publications

(50 citation statements)

References 25 publications

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“…This would suggest that inhibition of autophagy or other lysosomal functions may turn out to be beneficial, probably due to inhibition of hepatic insulin degradation [101] or, as more recently proposed, by inhibiting lysosome-dependent lipolysis in adipose tissue macrophages [11].…”

Section: Autophagy In Beta Cell Physiology and Diabetesmentioning

confidence: 87%

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

et al. 2014

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Autophagy is a lysosomal degradation pathway recycling intracellular long-lived proteins and damaged organelles, thereby maintaining cellular homeostasis. In addition to inflammatory processes, autophagy has been implicated in the regulation of adipose tissue and beta cell functions. In obesity and type 2 diabetes autophagic activity is modulated in a tissue-dependent manner. In this review we discuss the regulation of autophagy in adipose tissue and beta cells, exemplifying tissue-specific dysregulation of autophagy and its implications for the pathophysiology of obesity and type 2 diabetes. We will highlight common themes and outstanding gaps in our understanding, which need to be addressed before autophagy could be envisioned as a therapeutic target for the treatment of obesity and diabetes.

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Section: Autophagy In Beta Cell Physiology and Diabetesmentioning

confidence: 87%

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

et al. 2014

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“…A few small randomized controlled trials showed that HCQ lowers HbA 1c and LDL cholesterol levels in patients with type 2 diabetes (106-110). The mechanisms of hypoglycemia with HCQ are inferred from studies of the parent drug, chloroquine, which has been shown to increase insulin levels in man by both increasing insulin secretion and inhibiting its degradation (111 It also remains a challenge to adequately assess inflammation in man, since crude surrogate markers are being used, and it is currently difficult to appreciate tissuespecific variations in the level and type of inflammation. Preclinical studies in animal models are most helpful in this regard; however, it may be difficult to extrapolate from findings in animal models to the clinical setting.…”

Section: Salsalatementioning

confidence: 99%

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

et al. 2016

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The association between hyperglycemia and inflammation and vascular complications in diabetes is now well established. Antidiabetes drugs may alleviate inflammation by reducing hyperglycemia; however, the anti-inflammatory effects of these medications are inconsistent and it is unknown whether their beneficial metabolic effects are mediated via modulation of chronic inflammation. Recent data suggest that immunomodulatory treatments may have beneficial effects on glycemia, b-cell function, and insulin resistance. However, the mechanisms underlying their beneficial metabolic effects are not always clear, and there are concerns regarding the specificity, safety, and efficacy of immune-based therapies. Herein, we review the anti-inflammatory and metabolic effects of current antidiabetes drugs and of anti-inflammatory therapies that were studied in patients with type 2 diabetes. We discuss the potential benefit of using anti-inflammatory treatments in diabetes and important issues that should be addressed prior to implementation of such therapeutic approaches.The prevalence of diabetes is on the rise, with 415 million people affected worldwide according to recent data from the International Diabetes Federation (1). This number is predicted to increase further, with 642 million people expected to develop diabetes by 2040. While many factors are known to contribute to the development of diabetes and its complications, the involvement of the immune system in the pathogenesis of metabolic diseases has been gaining interest. It has long been appreciated that inflammation is central to the pathology of the pancreatic islet in type 1 diabetes. However, growing evidence suggests that inflammation also plays an important role in the pathogenesis of type 2 diabetes, including obesity-related insulin resistance, impaired insulin secretion, and diabetes-related vascular complications. Pioneering studies suggest that immunomodulatory treatments may improve glycemia, b-cell function, and/or insulin resistance in patients with type 2 diabetes (2,3). These studies constitute a proof of concept that chronic inflammation is implicated in the pathophysiology of type 2 diabetes, and therefore targeting inflammation may ameliorate diabetes, preventing its progression and vascular complications. However, the effects of immunomodulatory treatments are not limited to tissues involved in disease pathophysiology and thus might have unwarranted side effects. Moreover, current antidiabetes drugs may alleviate systemic and tissue-specific inflammation (4-12), and therefore the added value of using specific immunomodulatory treatments needs to be confirmed. Herein, we review the anti-inflammatory and metabolic effects of standard antidiabetes medications and of novel anti-inflammatory treatments. We further discuss issues that should be addressed prior to implementation of immune-based therapy in the treatment of diabetes.

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“…We employed immunoblotting to assess the extent of phosphorylation at Ser 21 and Ser 9 of GSK-3␣ and GSK-3␤, respectively, as a measure of insulin-induced GSK-3 inactivation. In parallel with our observations on PI 3-kinase and Akt, bafilomycin did not affect GSK-3 serine phosphorylation at 2 min after insulin but inhibited it by 20% (p Ͻ 0.05 versus insulin alone) at 15 after insulin (Fig.…”

Section: Figmentioning

confidence: 99%

Effect of Inhibiting Vacuolar Acidification on Insulin Signaling in Hepatocytes

Balbis

Baquiran

Dumas

et al. 2004

Journal of Biological Chemistry

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Previous studies have shown that the endosomal apparatus plays an important role in insulin signaling. Inhibition of endosomal acidification leads to a decrease in insulin-insulin receptor kinase (IRK) dissociation and insulin degradation. Thus, vacuolar pH could function as a modulator of insulin signaling in endosomes. In the present study we show that in primary hepatocytes pretreated with bafilomycin, there is an inhibition of vacuolar acidification. Incubation of these cells with insulin was followed by an augmentation of IRK activity but an inhibition of phosphatidylinositol 3-kinase/Akt activity and a decrease in insulin-induced DNA and glycogen synthesis. Bafilomycin treatment inhibited IRK recycling to the plasma membrane without affecting IRK internalization. Impaired IRK recycling correlated with a decrease in insulin signaling. We suggest that inhibiting vacuolar acidification sequesters activated IRKs in an intracellular compartment(s) where signaling is inhibited. This implies that endosomal receptor trafficking plays a role in regulating signal transduction.

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Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus

Cited by 48 publications

References 25 publications

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

Effect of Inhibiting Vacuolar Acidification on Insulin Signaling in Hepatocytes

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