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bioRxiv · 10.1101/2024.08.15.608033

Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion

Murao, N.·Morikawa, R.·Seino, Y.·Shimomura, K.·Maejima, Y.·Ohno, T.·Yokoi, N.·Yamada, Y.·Suzuki, A.
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Abstract

2Glucose triggers insulin secretion from pancreatic {beta}-cells through intracellular glucose metabolism, ATP production, and closure of ATP-sensitive K+ channels (KATP channels). Fructose also stimulates insulin secretion, but the underlying mechanisms remain unclear. This study investigated the contribution of phospholipase C (PLC) signaling and fructose metabolism to fructose-stimulated insulin secretion (FSIS) using MIN6-K8 clonal {beta}-cells and mouse islets. Fructose-induced PLC activation, assessed by inositol 1-phosphate accumulation, was reduced in fructose-unresponsive {beta}-cell models, such as diabetic mouse islets and KATP channel-deficient {beta}-cells, suggesting that {beta}-cell fructose responsiveness is primarily determined by PLC signaling. Although FSIS was dependent on KATP channels and Ca2+ influx, the ATP/ADP ratio was unexpectedly lowered by fructose, and suppression of intracellular fructose metabolism hardly affected FSIS. Metabolic flux analysis revealed that the accumulation of fructose 1-phosphate (F1P) suppressed pyruvate kinase (PK) activity, contributing to ATP depletion. Strikingly, a small-molecule PK activator, TEPP-46, antagonized F1P-mediated PK suppression, prevented the drop in the ATP/ADP ratio, and restored FSIS in MIN6-K8 cells, normal mouse islets, and fructose-unresponsive diabetic mouse islets. These findings revealed the metabolic effects of fructose in {beta}-cells and identified PK as a key regulator linking {beta}-cell fructose metabolism and FSIS, thereby providing new insights into the mechanisms of insulin secretion and potential therapeutic targets for fructose-associated metabolic diseases. 1 GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/608033v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@11ce1e9org.highwire.dtl.DTLVardef@1339f22org.highwire.dtl.DTLVardef@1493a5org.highwire.dtl.DTLVardef@e97026_HPS_FORMAT_FIGEXP M_FIG C_FIG Left: Fructose-stimulated insulin secretion (FSIS) is driven by sweet taste receptor (STR)-mediated PLC signaling in pancreatic {beta}-cells. Meanwhile, fructose metabolism does not promote FSIS because fructose causes accumulation of fructose 1-phosphate (F1P), which suppresses pyruvate kinase M2 (PKM2), lowering the ATP/ADP ratio. Right: A small-molecule PK activator counteracted F1P-mediated PKM2 inhibition, prevented ATP decrease, and substantially enhanced FSIS in normal and diabetic mouse {beta}-cells. Thus, PK has been identified as a key regulator linking {beta}-cell fructose metabolism and FSIS.

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Murao, N., Morikawa, R., Seino, Y., Shimomura, K., Maejima, Y., Ohno, T., Yokoi, N., Yamada, Y., Suzuki, A.. 2024-08-15. Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion. https://doi.org/10.1101/2024.08.15.608033

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