Insulinotropic Action of Methyl Pyruvate: Secretory, Cationic, and Biosynthetic Aspects

Malaisse, Willy; Jijakli, Hassan; Ulusoy, Sadık; Cook, Lynda; Best, Leonard; Viñambres, Concepción; Villanueva-Peñacarrillo, María Luisa; Valverde, Isabel; Sener, Abdullah

doi:10.1006/abbi.1996.0504

Cited by 22 publications

(10 citation statements)

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“…This notion is supported by data reported by Malaisse et al. [51], who showed that methyl pyruvate causes less lactate production than sodium pyruvate in pancreatic islets, a finding that is consistent with decreased cytoplasmic metabolism and increased mitochondrial metabolism by the ester. Furthermore, Rocheleau et al.…”

Section: Introductionsupporting

confidence: 84%

Ethyl pyruvate: a novel anti‐inflammatory agent

Fink

2007

Journal of Internal Medicine

150

115

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Abstract. Fink MP (University of Pittsburgh Medical School, Pittsburgh, PA, USA). Ethyl pyruvate: a novel anti-inflammatory agent (Review). J Intern Med 2007; 261: 349-362.Ethyl pyruvate (EP) is a simple derivative of the endogenous metabolite, pyruvic acid. Treatment with EP has been shown to improve survival and/or ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, such as severe sepsis, acute respiratory distress syndrome, acute pancreatitis and stroke. EP was originally regarded as simply a way to administer pyruvate anion, whilst avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including EP, have pharmacological effects, such as suppression of inflammation, that are quite distinct from those exerted by pyruvate anion. EP has been tested in human volunteers and shown to be safe at clinically relevant doses. It remains to be determined whether EP can be used successfully to treat human diseases.

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Section: Introductionsupporting

confidence: 84%

Ethyl pyruvate: a novel anti‐inflammatory agent

Fink

2007

Journal of Internal Medicine

150

115

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“…However, methyl pyruvate has been reported to stimulate insulin secretion directly through ATPsensitive K ϩ channels and not cause a significant rise in NAD(P)H intensity (34). This metabolite also causes less lactate production, which is consistent with decreased cytoplasmic metabolism and increased mitochondrial metabolism (35). The addition of methyl pyruvate caused larger and sustained NAD(P)H (f) and LipDH (q) responses (Fig.…”

Section: Fig 7 Nad(p)h and Mitochondrial Nadh Responses To Glucosesupporting

confidence: 52%

“…In contrast to exogenous pyruvate, fast methyl pyruvate transport likely increases the availability of pyruvate to PDH. Also, methyl pyruvate has been shown to cause less lactate production than pyruvate (35), consistent with its being less metabolized in the cytoplasm than exogenous pyruvate.…”

Section: Fig 7 Nad(p)h and Mitochondrial Nadh Responses To Glucosementioning

confidence: 89%

Quantitative NAD(P)H/Flavoprotein Autofluorescence Imaging Reveals Metabolic Mechanisms of Pancreatic Islet Pyruvate Response

Rocheleau

Head

Piston

2004

Journal of Biological Chemistry

182

158

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Glucose-stimulated insulin secretion is a multistep process dependent on ␤-cell metabolic flux. Our previous studies on intact pancreatic islets used two-photon NAD(P)H imaging as a quantitative measure of the combined redox signal from NADH and NADPH (referred to as NAD(P)H). These studies showed that pyruvate, a non-secretagogue, enters ␤-cells and causes a transient rise in NAD(P)H. To further characterize the metabolic fate of pyruvate, we have now developed one-photon flavoprotein microscopy as a simultaneous assay of lipoamide dehydrogenase (LipDH) autofluorescence. This flavoprotein is in direct equilibrium with mitochondrial NADH. Hence, a comparison of LipDH and NAD(P)H autofluorescence provides a method to distinguish the production of NADH, NADPH, or both. Using this method, the glucose dose response is consistent with an increase in both NADH and NADPH. In contrast, the transient rise in NAD(P)H observed with pyruvate stimulation is not accompanied by a significant change in LipDH, which indicates that pyruvate raises cellular NADPH without raising NADH. In comparison, methyl pyruvate stimulated a robust NADH and NADPH response. These data provide new evidence that exogenous pyruvate does not induce a significant rise in mitochondrial NADH. This inability likely results in its failure to produce the ATP necessary for stimulated secretion of insulin. Overall, these data are consistent with either a restricted pyruvate dehydrogenasedependent metabolism or a buffering of the NADH response by other metabolic mechanisms.

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“…In other reports, KIC induced slow Ca 2ϩ oscillations (31) and secretion in the absence of substimulatory glucose (14,40), which agrees with our data. In some of these studies, the nonglycogenic substrate (MeP) was applied in a concentration (20 mM) (5) that has been shown to block secretion (30), making it difficult to interpret such data. Some secretagogues, such as glyceraldehyde, have been shown to be toxic and not metabolized via the glycolytic pathway to an extent proposed earlier (27), and fuels such as pyruvate or succinate are not membrane permeable and, as such, would not stimulate metabolism in contrast to their methylated analogs (24).…”

Section: Discussionmentioning

confidence: 99%