The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here:

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

David Nicholls

Visiting research fellow

Default user image.

Chronic high glucose and pyruvate levels differentially affect mitochondrial bioenergetics and fuel-stimulated insulin secretion from clonal INS-1 832/13 cells.


  • Isabel Göhring
  • Vladimir Sharoyko
  • Siri Malmgren
  • Lotta Andersson
  • Peter Spégel
  • David Nicholls
  • Hindrik Mulder

Summary, in English

Glucotoxicity in pancreatic β-cells is a well-established pathogenetic process in Type 2 Diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machi-nery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mM glucose (low-G), 16.7 mM glucose (high-G) or 2.8 mM glucose plus 13.7 mM pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization and insulin secretion, when stimulated acutely with 16.7 mM glucose or 10 mM pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24 h culture in low-G medium. After 2 h at 2.8 mM glucose, high-G cells did not retain increased levels of glycolytic or TCA-cycle intermediates, but nevertheless displayed increased glycolysis, increased respiration and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concen-trations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulus-secretion coupling by extra-mitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.


  • Diabetes - Molecular Metabolism
  • Medicine, Lund
  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year







Journal of Biological Chemistry





Document type

Journal article


American Society for Biochemistry and Molecular Biology


  • Endocrinology and Diabetes



Research group

  • Diabetes - Molecular Metabolism
  • Genomics, Diabetes and Endocrinology


  • ISSN: 1083-351X