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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins, which are released from the gut into the bloodstream postprandially and enhance glucose-dependent insulin secretion via activation of the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively. Several GLP-1R agonists (GLP-1RA) with improved pharmacokinetic properties have been developed and are currently in clinical use to treat type 2 diabetes and obesity. In addition to improving glucose metabolism, GLP-1RAs potently suppress appetite and body weight. These anorectic and body weight-lowering effects are thought to be mediated by central mechanisms, as indicated also by human studies. However, the neuronal substrates that mediate these effects are still poorly understood.

Alessia Costa, Minrong Ai, Nicolas Nunn, Isabella Culotta, ... Giuseppe D'Agostino

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Current Issue

The activity of glyoxylase 1 is regulated by glucose-responsive phosphorylation on Tyr136

Fabiola Garcia Cortizo, Daniel Pfaff, Angela Wirth, Andrea Schlotterer, ... Aurelio A. Teleman

Objective

Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that glycates proteins. MG has been linked to the development of diabetic complications: MG is the major precursor of advanced glycation end products (AGEs), a risk marker for diabetic complications in humans. Furthermore, flies and fish with elevated MG develop insulin resistance, obesity, and hyperglycemia. MG is detoxified in large part through the glyoxalase system, whose rate-limiting enzyme is glyoxalase I (Glo1). Hence, we aimed to study how Glo1 activity is regulated.

Methods

We studied the regulation and effect of post-translational modifications of Glo1 in tissue culture and in mouse models of diabetes.

Results

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. We find that Glo1 Y136 phosphorylation responds in a bimodal fashion to glucose levels, increasing in cell culture from 0 mM to 5 mM (physiological) glucose, and then decreasing at higher glucose concentrations, both in cell culture and in mouse models of hyperglycemia.

Conclusions

These data, together with published findings that elevated MG leads to hyperglycemia, suggest the existence of a deleterious positive feedback loop whereby hyperglycemia leads to reduced Glo1 activity, contributing to elevated MG levels, which in turn promote hyperglycemia. Hence, perturbations elevating either glucose or MG have the potential to start an auto-amplifying feedback loop contributing to diabetic complications.

The activity of glyoxylase 1 is regulated by glucose-responsive phosphorylation on Tyr136

Fabiola Garcia Cortizo, Daniel Pfaff, Angela Wirth, Andrea Schlotterer, ... Aurelio A. Teleman

Objective

Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that glycates proteins. MG has been linked to the development of diabetic complications: MG is the major precursor of advanced glycation end products (AGEs), a risk marker for diabetic complications in humans. Furthermore, flies and fish with elevated MG develop insulin resistance, obesity, and hyperglycemia. MG is detoxified in large part through the glyoxalase system, whose rate-limiting enzyme is glyoxalase I (Glo1). Hence, we aimed to study how Glo1 activity is regulated.

Methods

We studied the regulation and effect of post-translational modifications of Glo1 in tissue culture and in mouse models of diabetes.

Results

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. We find that Glo1 Y136 phosphorylation responds in a bimodal fashion to glucose levels, increasing in cell culture from 0 mM to 5 mM (physiological) glucose, and then decreasing at higher glucose concentrations, both in cell culture and in mouse models of hyperglycemia.

Conclusions

These data, together with published findings that elevated MG leads to hyperglycemia, suggest the existence of a deleterious positive feedback loop whereby hyperglycemia leads to reduced Glo1 activity, contributing to elevated MG levels, which in turn promote hyperglycemia. Hence, perturbations elevating either glucose or MG have the potential to start an auto-amplifying feedback loop contributing to diabetic complications.

2020 impact factor: 7.4

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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