Pierre Maechler

Research

Recent projects and contributions on

Mitochondria and energy metabolism

 

Glutamate dehydrogenase and the ß-cell in health and disease

Using ß-Glud1-/- mice lacking GDH in ß-cells, we demonstrated that the absence of GDH-dependent amplifying preserved a lean phenotype by limiting insulin release to levels preventing excessive fat storage and the accompanying insulin resistance (Vetterli et al. 2016). At the cellular level, in both rodent and human islets, we reported that inhibition of GDH by the polyphenol EGCG reproduced the effects of GDH knockout in the ß-cell (Pournourmohammadi et al. 2017).

Regarding gain of function mutations, we have shown that the GDH-S445L mutation confers hyperactivity to the enzyme due to higher sensitivity to ADP allosteric activation. This renders ß-cells responsive to amino acid stimulation, explaining protein-induced hypoglycemia (Grimaldi et al. 2017).

 

Studies on GDH and the brain – liver axis

Because of the putative importance of GDH in brain and liver tissues, and thanks to our Glud1-floxed mice allowing conditional knockout, we also deleted GDH in CNS and hepatocytes by crossing Glud1-floxed mice with Nestin-Cre and Albumin-Cre animals, respectively. Taking advantage of our Cns-Glud1-/- animals, we characterized mice carrying the Nes-Cre transgene itself (Karaca & Maechler 2014). These investigations paved the way for an extended study showing that, for the brain, glutamate is a necessary GDH-dependent energy substrate (Karaca et al. 2015). Our study shed new light on the major importance of this mandatory fraction of glutamate for central energy homeostasis, directly signaling to the liver. Recently, through a collaborative work, we reported that GDH deficiency is a driver of excess hippocampal excitatory transmission inducing schizophrenia symptoms (Lander et al. 2019).

Regarding GDH in hepatocytes, we generated tamoxifen-inducible liver GDH knockout Hep-Glud1-/- mice (Karaca et al. 2018). This model uncovered the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis, affecting circadian rhythm (Karaca et al. 2018). Moreover, we observed that activating mutation of GDH increases the production of ammonia in isolated hepatocytes (Grimaldi et al. 2017).

 

Mitochondrial dysfunction and metabolic stresses

As a protective approach, we recently reported that resveratrol in the culture medium of INS-1E ß-cells preserves robust glucose-stimulated insulin secretion (Casimir et al. 2019).

Regarding metabolic stresses, we could show that upregulation of UCP2 confers protective effects against glucotoxicity and oxidative stress induced in mouse islets (Li et al. 2017). Extending such stresses to glucolipotoxicity, we delineated the molecular targets shared by different metabolic stressors using transcriptome analyses on insulin-secreting cells (Brun & Maechler 2016). We investigated diabetogenic conditions applied side-by-side on human islets, allowing us to deconstruct global glucolipotoxicity effects and uncover the specific contributions of different stressors (Brun et al. 2015).

We also investigated the effects of chronic exposure to fructose on the ß-cell function. Chronic fructose induced extracellular ATP signaling in the ß-cell, resulting in the potentiation of glucose-stimulated insulin secretion. This effect was mediated by the activation of the purinergic P2Y1 receptors and was associated with the release of cellular ATP through the Panx1 channel (Bartley et al. 2019).