Glucose Control in Severely Burned Patients Using Metformin

Jeschke, Marc G.; Abdullahi, Abdikarim; Burnett, Marjorie; Rehou, Sarah; Stanojcic, Mile

doi:10.1097/sla.0000000000001845

Cited by 50 publications

(25 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, aggressive insulin therapy has been associated with episodes of hypoglycemia which can worsen patient outcomes 15 . To that effect, we have recently demonstrated in a controlled trial that metformin treatment is equal to insulin in its ability to reduce glucose levels following a severe burn, with the additional benefits of decreased lipolysis, improved insulin resistance and a lower incidence of hypoglycemic episodes 16 .…”

Section: Introductionmentioning

confidence: 99%

Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction

Auger

Sivayoganathan

Abdullahi

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Thermal injury induces a complex immunometabolic response, characterized by hyperglycemia, extensive inflammation and persistent hypermetabolism. It has been suggested that attenuation of the hypermetabolic response is beneficial for patient wellbeing. To that effect, metformin represents an attractive therapeutic agent, as its effects on glycemia, inflammation and bioenergetics can improve outcomes in burn patients. Therefore, we studied metformin and its effects on mitochondrial bioenergetics in a murine model of thermal injury. We set out to determine the impact of this agent on mitochondrial hypermetabolism (adult mice) and mitochondrial dysfunction (aged mice). Seahorse respirometry complimented by in-gel activity assays were used to elucidate metformin’s cellular mechanism. We found that metformin exerts distinctly different effects, attenuating the hypermetabolic mitochondria of adult mice while significantly improving mitochondrial bioenergetics in the aged mice. Furthermore, we observed that these changes occur both with and without adenosine monophosphate kinase (AMPK) activation, respectively, and analyzed damage markers to provide further context for metformin’s beneficial actions. We suggest that metformin has a dual role following trauma, acting via both AMPK-dependent and independent pathways depending on bioenergetic status. These findings help further our understanding of metformin’s biomolecular effects and support the continued use of this drug in patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction

Auger

Sivayoganathan

Abdullahi

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…The detrimental effect trauma has on mitochondrial bioenergetics is multifactorial. Following severe burn injury, increased lipolysis leads to an augmentation in circulating free fatty acids which exert their lipotoxic effects on the electron transport chain [8]. For instance, linoleic acid inhibits mitochondrial complexes I and V, subsequently dropping ATP levels and causing necrosis [9].…”

Section: Introductionmentioning

confidence: 99%

Hepatic mitochondrial bioenergetics in aged C57BL/6 mice exhibit delayed recovery from severe burn injury

Auger

Sivayoganathan

Abdullahi

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

Severe burn injuries initiate a cascade of downstream events, culminating in multiple organ dysfunction, sepsis, and even death. The elderly are in particular vulnerable to such outcomes, due primarily to a scarcity of knowledge on trauma progression at the biomolecular level in this population. Mitochondria, the cellular powerhouses, have been increasingly scrutinized recently for their contribution to trauma outcomes. We hypothesized that elderly have a worse outcome compared to adult patients due to failed recovery of hepatic mitochondria. Using a murine model of burn injury, Seahorse respirometry and functional proteomic assays, we demonstrate the impact of thermal trauma on hepatic mitochondrial respiration in adult and aged mice. While the mitochondria in adults rebound from the initial insult within 7 days of the injury, the older animals display delayed recovery of mitochondrial bioenergetics accompanied by uncoupling and an oxidative environment. This is associated with a state of increased protein oxidation and nitrosylation, along with increases in circulating mtDNA, a known damage-associated molecular pattern. These findings suggest that hepatic mitochondria fail to normalize after trauma in aged mice and we suggest that this cellular failure is associated with organ damage and subsequently increased morbidity and mortality in elderly burn patients.

show abstract

“…By inhibiting complex I of the electron transport chain, metformin may also lower the mitochondrial hyperactivity seen following a severe burn [180]. Recently we have demonstrated that metformin decreases glucose in burn patients equally as effectively as insulin with the additional benefit of a reduction in hypoglycemic episodes [181]. Furthermore, metformin significantly decreased the circulation of saturated fatty acids and down-regulated the concentrations of serum IL-1β and monocyte chemoattractant protein-1, thus making it likely that this agent has anti-inflammatory effects [181].…”

Section: Treatment Options To Alleviate the Hypermetabolic Responsementioning

confidence: 99%

“…Recently we have demonstrated that metformin decreases glucose in burn patients equally as effectively as insulin with the additional benefit of a reduction in hypoglycemic episodes [181]. Furthermore, metformin significantly decreased the circulation of saturated fatty acids and down-regulated the concentrations of serum IL-1β and monocyte chemoattractant protein-1, thus making it likely that this agent has anti-inflammatory effects [181]. Interestingly, other studies have shown that metformin does not improve the rate of protein breakdown, and that the anti-catabolic benefits of this intervention are mainly attributable to increased protein synthesis, thus improving net muscle protein balance and preventing tissue wasting [182].…”

Section: Treatment Options To Alleviate the Hypermetabolic Responsementioning

confidence: 99%

“…The use of metformin has been associated with a rare condition known as lactic acidosis, particularly in patients with some degree of renal dysfunction, and caution should be taken. However, the ease of oral administration and economic benefits of metformin makes it an attractive therapeutic option for the long-term control of insulin resistance and tissue catabolism [181]. …”

Section: Treatment Options To Alleviate the Hypermetabolic Responsementioning

confidence: 99%

See 1 more Smart Citation

The biochemical alterations underlying post-burn hypermetabolism

Auger¹,

Samadi²,

Jeschke³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

A severe burn can trigger a hypermetabolic state which lasts for years following the injury, to the detriment of the patient. The drastic increase in metabolic demands during this phase renders it difficult to meet the body’s nutritional requirements, thus increasing muscle, bone and adipose catabolism and predisposing the patient to a host of disorders such as multi-organ dysfunction and sepsis, or even death. Despite advances in burn care over the last 50 years, due to the multifactorial nature of the hypermetabolic phenomenon it is difficult if not impossible to precisely identify and pharmacologically modulate the biological mediators contributing to this substantial metabolic derangement. Here, we discuss biomarkers and molecules which play a role in the induction and mediation of the hypercatabolic condition post-thermal injury. Furthermore, this thorough review covers the development of the factors released after burns, how they induce cellular and metabolic dysfunction, and how these factors can be targeted for therapeutic interventions to restore a more physiological metabolic phenotype after severe thermal injuries.

show abstract

Glucose Control in Severely Burned Patients Using Metformin

Cited by 50 publications

References 51 publications

Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction

Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction

Hepatic mitochondrial bioenergetics in aged C57BL/6 mice exhibit delayed recovery from severe burn injury

The biochemical alterations underlying post-burn hypermetabolism

Contact Info

Product

Resources

About