The combination of loss of glyoxalase1 and obesity results in hyperglycemia

Lodd, Elisabeth; Wiggenhauser, Lucas Moritz; Morgenstern, Jakob; Fleming, Thomas; Poschet, Gernot; Büttner, Michael; Tabler, Christoph T.; Wohlfart, David Philipp; Nawroth, Peter P.; Krøll, Jens

doi:10.1172/jci.insight.126154

Cited by 47 publications

(65 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GLO-1 knock-out in Drosophila was recently shown to resemble features of type 2 diabetes development, namely insulin resistance and glucose intolerance [51]. Similarly, Lodd et al (2019) have shown increased susceptibility to diet-induced insulin resistance in GLO-1 knockout zebrafish [52]. On the other hand, GLO-1 knockout mice have shown a lower susceptibility to MG, due to a compensatory increase of other enzymatic systems, namely Aldo-keto reductases [53].…”

Section: Development Of Animal Modelsmentioning

confidence: 98%

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

Matafome

2020

Diabetology

View full text Add to dashboard Cite

The term glycotoxins includes the group of advanced glycation end-products (AGEs) and their precursors, most of them highly reactive intermediary compounds, such as methylglyoxal (MG). Glycotoxins were initially thought to participate in the development of diabetic complications because of their increased formation from glucose. However, they also form and accumulate in tissues since the early stages of disease, such as metabolically unhealthy obesity and prediabetes. Such accumulation has been suggested to result from dysregulated activity of detoxification systems, such as the glyoxalase system, as well as increased dietary consumption, namely from high-glucose and high-fructose foods processed at high temperatures. Although some studies may have used supraphysiological doses, in vitro systems and animal models have shown glycotoxin-induced insulin resistance. Moreover, dietary glycotoxin restriction was shown to improve insulin resistance in humans and glyoxalase (GLO)-1 upregulation improved insulin sensitivity and metabolic function. This review summarizes the current knowledge about glycotoxin involvement in the development of insulin resistance, the mechanisms involved and the usefulness of GLO-1 modulation, and a possible therapeutic strategy to improve insulin sensitivity.

show abstract

Section: Development Of Animal Modelsmentioning

confidence: 98%

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

Matafome

2020

Diabetology

View full text Add to dashboard Cite

show abstract

“…Recent advancements regarding genetic engineering of model organisms and isolated cells via CRISPR Cas9 technique unlocked the possibilities to generate gene KOs in a fast, convenient, and efficient way [ 69 ]. Using this CRISPR Cas9 technique, independent work groups were able to establish Glo1 KOs in zebrafish, drosophila fly, and mammalian in vitro and in vivo models [ 70 , 71 , 72 ]. Surprisingly, the effect of the complete global Glo1 KO was rather mild, at least in fish and mammals.…”

Section: Glo1 Is Not Indispensable For Crude and Complex Organismsmentioning

confidence: 99%

“…This led to the authors’ hypothesis, that MG is not the cause of late diabetic complications due to increased formation of AGEs and DNA modifications, but rather more the reason for insulin resistance due to hyperglycemia similar to what is observed in type 2 diabetic patients [ 71 ]. In the model organism zebrafish, a partial knock-down of Glo1 resulted in the elevation of MG levels and in alterations of the intersomitic blood vessels, but the complete loss of Glo1 in zebrafish showed a completely different picture [ 57 , 70 ]. The Glo1 KO fish survived until adulthood without any obvious growth deficits and showed only mildly increased MG levels in the tissue.…”

Section: Glo1 Is Not Indispensable For Crude and Complex Organismsmentioning

confidence: 99%

“…Once the Glo1 KO zebrafish were challenged by high nutrient intake, fasting blood glucose levels were increased and retinal blood vessel alterations occurred. In this study, it has been revealed that the relatively mild increase in MG levels may be explained by the increased expression and activity of several subtypes of the ALDH family (3a1, 3a2a, 9a1a2 and 9a1b), potentially responsible for the alternative detoxification of MG [ 70 ]. Looking into the mammalian model systems, a Glo1 KO in HEK293 cells showed elevated MG-H1 following exogenous MG stimulation as compared to wild-type cells [ 64 ].…”

Section: Glo1 Is Not Indispensable For Crude and Complex Organismsmentioning

confidence: 99%

“…This is also shown by the hypersensitivity towards exogenous MG in Glo1 KO in vitro models [ 64 , 72 ]. However, the capacity of AKR and ALDH is enough to prevent any major damage in a Glo1 KO mice and zebrafish model, even under hyperglycemic conditions [ 70 , 74 ]. This, therefore, brings up the question of whether the whole story of the glyoxalase system is already known?…”

Section: Modifications Of Glo1 and Other Possible Intracellular Immentioning

confidence: 99%

See 2 more Smart Citations

The Glyoxalase System—New Insights into an Ancient Metabolism

et al. 2020

Self Cite

View full text Add to dashboard Cite

The glyoxalase system was discovered over a hundred years ago and since then it has been claimed to provide the role of an indispensable enzyme system in order to protect cells from a toxic byproduct of glycolysis. This review gives a broad overview of what has been postulated in the last 30 years of glyoxalase research, but within this context it also challenges the concept that the glyoxalase system is an exclusive tool of detoxification and that its substrate, methylglyoxal, is solely a detrimental burden for every living cell due to its toxicity. An overview of consequences of a complete loss of the glyoxalase system in various model organisms is presented with an emphasis on the role of alternative detoxification pathways of methylglyoxal. Furthermore, this review focuses on the overlooked posttranslational modification of Glyoxalase 1 and its possible implications for cellular maintenance under various (patho-)physiological conditions. As a final note, an intriguing point of view for the substrate methylglyoxal is offered, the concept of methylglyoxal (MG)-mediated hormesis.

show abstract

Emerging Targets in Type 2 Diabetes and Diabetic Complications

et al. 2021

Self Cite

View full text Add to dashboard Cite

Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment-or even the prevention-of type 2 diabetes along with its complications.

show abstract

The combination of loss of glyoxalase1 and obesity results in hyperglycemia

Cited by 47 publications

References 69 publications

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

The Glyoxalase System—New Insights into an Ancient Metabolism

Emerging Targets in Type 2 Diabetes and Diabetic Complications

Contact Info

Product

Resources

About