Fenofibrate, Troglitazone, and 15-Deoxy-Δ12,14-prostaglandin J2Close KATPChannels and Induce Insulin Secretion

Shimomura, Kenju; Shimizu, Hiroyuki; Ikeda, Mizuho; Okada, Shuichi; Kakei, Masafumi; Matsumoto, Shigeji; Mori, Masataka

doi:10.1124/jpet.104.067249

Cited by 25 publications

(14 citation statements)

References 46 publications

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“…Whereas the reduction in K ATP current and concomitant depolarization of V m is only moderate with 1-10 mM pioglitazone or with 1 mM troglitazone, K ATP channels were completely blocked by 10 mM troglitazone. An inhibition of K ATP current of b-cells or insulin-secreting cell lines by glitazones is in agreement with findings of several other groups (Lee et al, 1996;Sunaga et al, 1999;Shimomura et al, 2004;Chang et al, 2009). However, this direct interaction of troglitazone with K ATP channels obviously does not result in stimulation of insulin secretion.…”

Section: Discussionsupporting

confidence: 80%

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

et al. 2012

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Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin secretion of b-cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on stimulus-secretion coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin secretion (radioimmunoassay), cell membrane potential, various ion currents (patchclamp), mitochondrial membrane potential (DC), and cytosolic Ca 21 concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin secretion depending on the drug and glucose concentration. It depolarized the DC, thus lowering ATP production, which resulted in opening of ATP-dependent K 1 channels (K ATP channels) and reduced insulin secretion. However, it also exerted direct inhibitory effects on K ATP channels that can explain enhanced insulin secretion. Troglitazone also inhibited the currents through voltage-dependent Ca 21 and K 1 channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on b-cell SSC that have to be considered as undesired side effects because the influence of these compounds on b-cells is not controllable. The final effect on insulin secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on b-cells are negligible under in vivo conditions.

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Section: Discussionsupporting

confidence: 80%

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

et al. 2012

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“…However, our data showing that gemfibrozil increases a chloride conductance in glucose-inhibited neurons within several minutes is more consistent with a direct action on an ion channel rather than effects mediated via PPAR␣. Direct effects of gemfibrozil on ion channels have been reported previously (25,39). Nevertheless, further in vitro and in vivo studies need to be performed to confirm the involvement of a CFTR channel in ARC glucose-inhibited neurons and in brain glucose sensing.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

et al. 2007

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Four types of responses to glucose changes have been described in the arcuate nucleus (ARC): excitation or inhibition by low glucose concentrations <5 mmol/l (glucose-excited and -inhibited neurons) and by high glucose concentrations >5 mmol/l (high glucose-excited and -inhibited neurons). However, the ability of the same ARC neuron to detect low and high glucose concentrations has never been investigated. Moreover, the mechanism involved in mediating glucose sensitivity in glucose-inhibited neurons and the neurotransmitter identity (neuropeptide Y [

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“…SUR1 also serves as a target for the sulphonylurea drugs which stimulate insulin secretion by closing K ATP channels [8,9]. …”

Section: Structure and Functionmentioning

confidence: 99%

“…These drugs bypass β-cell metabolism and directly bind to K ATP channels in the β-cell membrane. This induces channel closure which leads to insulin secretion and thus normalises the blood glucose levels of diabetic patients [8,9].…”

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confidence: 99%

The KATP Channel and Neonatal Diabetes

Shimomura

2009

Endocr J

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Abstract. ATP-sensitive potassium (K ATP ) channels play a key role in glucose-dependent insulin secretion in pancreatic β-cells. Recently, activating mutations in β-cell K ATP channels were found to be an important cause of neonatal diabetes. In some patients, these mutations may also affect K ATP channel function in muscles, nerves and brain which can result in a severe disease termed DEND syndrome (Developmental delay, Epilepsy and Neonatal Diabetes). This review focuses on mutations in the pore-forming K ATP channel subunit (Kir6.2) that cause neonatal diabetes and discusses recent advances in our understanding of clinical features of neonatal diabetes, its underlying molecular mechanisms and their impact on treatment.

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Fenofibrate, Troglitazone, and 15-Deoxy-Δ^12,14-prostaglandin J₂Close K_ATPChannels and Induce Insulin Secretion

Cited by 25 publications

References 46 publications

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

The KATP Channel and Neonatal Diabetes

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