Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets

PLoS Biol. 2022 Aug 3;20(8):e3001725. doi: 10.1371/journal.pbio.3001725. eCollection 2022 Aug.

Abstract

Recent evidence suggests that circadian clocks ensure temporal orchestration of lipid homeostasis and play a role in pathophysiology of metabolic diseases in humans, including type 2 diabetes (T2D). Nevertheless, circadian regulation of lipid metabolism in human pancreatic islets has not been explored. Employing lipidomic analyses, we conducted temporal profiling in human pancreatic islets derived from 10 nondiabetic (ND) and 6 T2D donors. Among 329 detected lipid species across 8 major lipid classes, 5% exhibited circadian rhythmicity in ND human islets synchronized in vitro. Two-time point-based lipidomic analyses in T2D human islets revealed global and temporal alterations in phospho- and sphingolipids. Key enzymes regulating turnover of sphingolipids were rhythmically expressed in ND islets and exhibited altered levels in ND islets bearing disrupted clocks and in T2D islets. Strikingly, cellular membrane fluidity, measured by a Nile Red derivative NR12S, was reduced in plasma membrane of T2D diabetic human islets, in ND donors' islets with disrupted circadian clockwork, or treated with sphingolipid pathway modulators. Moreover, inhibiting the glycosphingolipid biosynthesis led to strong reduction of insulin secretion triggered by glucose or KCl, whereas inhibiting earlier steps of de novo ceramide synthesis resulted in milder inhibitory effect on insulin secretion by ND islets. Our data suggest that circadian clocks operative in human pancreatic islets are required for temporal orchestration of lipid homeostasis, and that perturbation of temporal regulation of the islet lipid metabolism upon T2D leads to altered insulin secretion and membrane fluidity. These phenotypes were recapitulated in ND islets bearing disrupted clocks.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2* / genetics
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Islets of Langerhans* / metabolism
  • Lipid Metabolism
  • Lipids
  • Membrane Fluidity
  • Sphingolipids / metabolism

Substances

  • Insulin
  • Lipids
  • Sphingolipids

Grants and funding

This work was funded by Swiss National Science Foundation grant 310030_184708/1 (CD); the Vontobel Foundation (CD); the Novartis Consumer Health Foundation (CD); European Foundation for the Study of Diabetes EFSD/Novo Nordisk A/S Programme for Diabetes Research in Europe 2020 (CD); the Swiss Life Foundation (CD); the Olga Mayenfisch Foundation (CD); Leenaards Foundation (CD); the Swiss Cancer Research foundation (CD); Fondation pour l'innovation sur le cancer et la biologie (CD); Ligue pulmonaire genevoise (LPGE, CD); Bo and Kerstin Hjelt Foundation for diabetes type 2 (U L-M. and VP); Young Independent Investigator Grant SGED/SSED (VP and FS). SC was supported by funds from the Research Council of Norway (NFR 251041) and Novo Nordic Foundation (NNF15OC0015054 and NNF21OC0067325). HR was supported by the Swiss National Science Foundation grant 310030_184949 and the NCCR Chemical Biology (51NF40-185898). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.