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Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP
N Lembert1, H C Joos, L A Idahl
1Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany. nicolas.lembert@uni-tuebingen.de
Abstract:
The role of mitochondria in stimulus-secretion coupling of pancreatic beta-cells was examined using methyl pyruvate (MP). MP stimulated insulin secretion in the absence of glucose, with maximal effect at 5 mM. K+ (30 mM) alone, or in combination with diazoxide (100 microM), failed to enhance MP-induced secretion. Diazoxide (100 microM) inhibited MP-induced insulin secretion. MP depolarized the beta-cell in a concentration-dependent manner (5-20 mM). The sustained depolarization induced by 20 mM MP was not influenced by 100 microM diazoxide, but the continuous spiking activity was suppressed by 500 microM diazoxide. Pyruvate failed to initiate insulin release (5-20 mM) or to depolarize the membrane potential. ATP production in isolated beta-cell mitochondria was detected as accumulation of ATP in the medium during incubation in the presence of malate or glutamate in combination with pyruvate or MP. There was no difference in ATP production induced by pyruvate/malate or MP/malate in isolated beta-cell mitochondria. ATP production by MP/glutamate was higher than that induced by pyruvate/glutamate, but it was much lower than that induced by alpha-ketoisocaproate/glutamate. Pyruvate (5 mM) or MP (5 mM) had no effect on the ATP/ADP ratio in whole islets, whereas glucose (20 mM) significantly increased the whole islet ATP/ADP ratio. It is concluded that MP-induced beta-cell membrane depolarization or insulin release does not relate directly to mitochondrial ATP production. Instead MP may exert a direct extramitochondrial effect, or it may stimulate beta-cell mitochondria to produce coupling factors different from ATP to initiate insulin release.
Insights
Methyl pyruvate (MP) stimulates insulin secretion and beta-cell depolarization independently of mitochondrial ATP production. This suggests MP acts extramitochondrially or via non-ATP factors in pancreatic beta-cells.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolism
Background:
- Mitochondria play a crucial role in stimulus-secretion coupling in pancreatic beta-cells.
- Understanding the precise mechanisms of insulin secretion is vital for diabetes research.
Purpose of the Study:
- To investigate the role of mitochondria in methyl pyruvate (MP)-induced insulin secretion and beta-cell depolarization.
- To determine if mitochondrial ATP production is the primary mediator of MP's effects.
Main Methods:
- Experiments utilized methyl pyruvate (MP) and pyruvate on pancreatic beta-cells.
- Insulin secretion, membrane potential, and mitochondrial ATP production were measured.
- Effects of diazoxide, an ATP-sensitive potassium channel opener, were assessed.
Main Results:
- MP stimulated insulin secretion and beta-cell depolarization without glucose.
- MP-induced effects were not directly correlated with mitochondrial ATP production.
- Pyruvate did not elicit insulin release or membrane depolarization.
Conclusions:
- MP-induced insulin secretion and beta-cell depolarization are not directly linked to mitochondrial ATP production.
- MP may act via extramitochondrial pathways or stimulate mitochondria to produce non-ATP coupling factors.
- These findings offer new insights into the regulation of insulin secretion.