Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Design of an islet-on-a-chip device reveals glucose-stimulated respiration is substrate limited by glycolytic flux through PKM2 1.Pancreatic islets respond metabolically to glucose by closing KATP channels resulting in Ca2+-influx and insulin secretion. Previous work showed that the importance of glycolytic flux in triggering insulin secretion. However, it is unclear whether the triggered ( first phase) secretion is further amplified by Ca2+-stimulation of mitochondrial NADH production and/or oxidative phosphorylation (OxPhos). To tease apart the metabolism of first phase glucose-stimulated insulin secretion, we designed an islet-on-a-chip microfluidic device to simultaneously measure O2-consumption rate (OCR) and Ca2+-activity of individual islets with high temporal resolution. We used finite element analysis to optimize the placement of sensor in optically clear microwells on a thin glass coverslip. The microfluidic channels were subsequently fabricated using O2-impermeable plastic to limit outside-in diffusion and push islets in the device against the microsensor. We validated our device using living mouse islets and well-established modulators of respiration. By inhibiting glycolysis and mitochondrial pyruvate transport, we showed islet OxPhos is limited by substrate-NADH rather than ADP in low and high glucose. We subsequently imaged glucose-stimulated OCR and Ca2+-influx simultaneously to reveal a biphasic respiratory response that is determined by glycolytic flux through pyruvate kinase (PKM2) and independent of Ca2+. Ultimately, we validated our device and successfully used it to show islet OxPhos is determined by glycolytic flux and not amplified by Ca2+-activity.

SignificanceLoss of the first phase glucose-stimulated insulin secretion is one of the earliest signs of Type 2 diabetes (T2D). Revealing the mechanisms that trigger and amplify first phase insulin secretion from pancreatic islets could lead to strategies to mitigate the onset of T2D. In this study, we designed an islet-on-a-chip microfluidic device to measure O2-consumption rate and Ca2+ activity of individual islets dynamically through first phase secretion (< 5 min). Our data show first phase islet respiration is limited by glycolytic production of pyruvate independent of Ca2+-influx.
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The categories of this paper are: physiology
10
The categories of this paper are: and
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The categories of this paper are: animal
31
The categories of this paper are: paleontology
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The categories of this paper are: systems
29
The categories of this paper are: education
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The categories of this paper are: pharmacology
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The categories of this paper are: genomics
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The categories of this paper are: epidemiology
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The categories of this paper are: genetics
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The categories of this paper are: biology
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The categories of this paper are: molecular
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The categories of this paper are: zoology
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The categories of this paper are: biophysics
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The categories of this paper are: cognition
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The categories of this paper are: microbiology