Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet

A decrease in metabolic substrate oxidation appears as a primary defect that, by triggering intracellular accumulation of diacylglycerol and ceramide, hampers insulin signalling and promotes insulin resistance.

“A decrease in metabolic substrate oxidation appears as a primary defect, which, by triggering a cascade of events culminating with the intracellular accumulation of the diacylglycerol and ceramide, hampers insulin signalling and promotes insulin resistance.”

Boosting mitochondrial function may improve insulin sensitivity.

“Compelling evidence suggests that boosting mitochondrial function may represent a valuable therapeutic tool to improve insulin sensitivity.”

• Also stated in: § Mitochondrial Dysfunction and Insulin Resistance · hedged

  “Thus, independently of whether mitochondrial dysfunction is a cause or a consequence of insulin resistance, boosting mitochondrial function remains a promising strategy to improve insulin sensitivity.”

Individuals with T2DM have reduced NADH2-O2 oxidoreductase activity.

“Furthermore, individuals with T2DM have reduced NADH2-O2 oxidoreductase activity (Kelley et al., 2002), which further supports the association between T2DM and mitochondrial dysfunction proposing the latter as an underlying defect in the pathogenesis of insulin resistance.”

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Mitochondrial dysfunction is implicated in the pathogenesis of insulin resistance, the hallmark of type 2 diabetes mellitus.

“Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM).”

• Also stated in: § Introduction · hedged

  “Mitochondrial dysfunction and the subsequent impairment in metabolic fuel oxidation appear to be the metabolic culprit underlying the accumulation of lipotoxic lipid metabolites.”

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• cites Simoneau et al., 1999 sourceNot checked yet

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• cites Kim et al., 2000aNot checked yet

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Skeletal muscle represents an ideal target for the treatment of T2DM.

“Considering the central role of skeletal muscle in the control of glucose homeostasis and the fact that insulin resistance in skeletal muscle is evident decades before β-cell failure and overt hyperglycaemia (Lillioja et al., 1988; Warram et al., 1990), skeletal muscle represents an ideal target for the treatment of T2DM.”

Intramyocellular lipids are a better predictor of muscle insulin resistance compared to adiposity in young, sedentary, lean subjects.

“In support of this notion, intramyocellular lipids represent a better predictor of muscle insulin resistance compared to adiposity in young, sedentary, lean subjects (Krssak et al., 1999).”

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Increased fatty acid availability, sustained by enhanced adipose tissue lipolysis and impaired fatty acid beta-oxidation, bridges to insulin resistance.

“Remarkably, these pathophysiological features of obesity represent the main mechanisms bridging the gap between increased fatty acid availability, sustained by enhanced adipose tissue lipolysis and impaired fatty acid beta-oxidation, and insulin resistance, the hallmark of T2DM.”

Mitochondria are at the interphase between impaired fuel oxidation, particularly fatty acid oxidation, lipotoxicity and insulin resistance.

“Mitochondria, in light of their pivotal role in oxidative metabolism, have been identified as the cellular organelles at the interphase between impaired fuels, and particularly fatty acids oxidation, lipotoxicity and insulin resistance.”

Insulin resistance in skeletal muscle is evident decades before β-cell failure and overt hyperglycaemia.

“Considering the central role of skeletal muscle in the control of glucose homeostasis and the fact that insulin resistance in skeletal muscle is evident decades before β-cell failure and overt hyperglycaemia (Lillioja et al., 1988; Warram et al., 1990), skeletal muscle represents an ideal target for the treatment of T2DM.”

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• cites Warram et al., 1990 sourceNot checked yet

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Accumulation of intramyocellular lipids itself is not sufficient to explain the association between ectopic lipid accumulation and insulin resistance.

“However, the accumulation of intramyocellular lipids itself is not sufficient to explain the association between ectopic lipid accumulation and insulin resistance.”

Genes involved in oxidative metabolism under the control of PGC1α are downregulated in skeletal muscle of individuals with a family history of T2DM and patients with T2DM compared to healthy controls.

“Microarray studies have successively strengthened this association by providing evidence that genes involved in oxidative metabolism and under the control of PGC 1α are downregulated in the skeletal muscle of individuals with a family history of T2DM and patients affected by T2DM compared to healthy controls (Mootha et al., 2003; Patti et al., 2003).”

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Mitochondrial dysfunction and the subsequent impairment in metabolic fuel oxidation underlie the accumulation of lipotoxic lipid metabolites.

“Mitochondrial dysfunction and the subsequent impairment in metabolic fuel oxidation appear to be the metabolic culprit underlying the accumulation of lipotoxic lipid metabolites.”

A decrease in fatty acid oxidation induces the buildup of ceramide and diacylglycerol, which impair the insulin signal transduction pathway.

“In support of this notion, a decrease in fatty acid oxidation induces the buildup of ceramide and diacylglycerol, which have been shown to impair the insulin signal transduction pathway (Samuel et al., 2010).”

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The rate-limiting step in insulin-mediated glucose uptake and intracellular metabolic processing by skeletal muscle is translocation of glucose transporter type 4 (GLUT-4) to the cell surface.

“The rate-limiting step in insulin-mediated glucose uptake and consequent intracellular metabolic processing by the skeletal muscle is the translocation of the glucose transporter type 4 (GLUT-4) at the cell surface.”

Skeletal muscle takes up and metabolises approximately 80% of postprandial circulating glucose.

“Skeletal muscle is pivotal in glucose homeostasis and energy metabolism in light of its capacity to take up and metabolise approximately 80% of postprandial circulating glucose (Shulman et al., 1990).”

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The mechanism by which diacylglycerol induces insulin resistance has been confirmed in humans.

“Importantly, this mechanism has also been confirmed in humans supporting the pathophysiological relevance of diacylglycerol-induced insulin resistance beyond rodent models (Itani et al., 2002).”

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When ROS production overwhelms cellular antioxidant capacity, oxidative stress occurs.

“However, when ROS production overwhelms cellular antioxidant capacity, oxidative stress occurs (Schieber and Chandel, 2014).”

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PGC1α phosphorylation and activation are governed by AMPK.

“PGC 1α phosphorylation and activation are governed by the AMPK (Vaughan et al., 2014), an ancient energy gauge, which in turn is activated to rewire energy metabolisms in response to a drop in ATP:AMP and ATP:ADP ratios (Kahn et al., 2005).”

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Muscle mitochondria oxidative capacity is impaired in patients with overt T2DM.

“Furthermore, assessment of mitochondria function in vivo using non-invasive measurement of the phosphocreatine resynthesis rate after exercise corroborated these remarkable mitochondrial defects at the protein as well as at the transcriptional levels providing further evidence that muscle mitochondria oxidative capacity is impaired in patients with overt T2DM (Schrauwen-Hinderling et al., 2007).”

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PGC1α activity is regulated by both phosphorylation and deacetylation.

“The activity of PGC 1α is regulated by both phosphorylation and deacetylation (Figure 3).”

A compensatory increase in mitochondrial function may offset fatty acid oversupply and prevent deleterious effects on insulin signalling.

“A possible explanation to this conundrum is the compensatory increase in mitochondrial function to offset fatty acid oversupply and prevent their deleterious effects of insulin signalling.”

Mitochondrial dysfunction does not appear to be a prerequisite for the onset of insulin resistance.

“Thus, mitochondrial dysfunction does not appear to be a prerequisite for the onset of insulin resistance.”

Mitochondrial dysfunction appears to be a direct consequence of intrinsic mitochondrial defect at the level of the oxidative phosphorylation system and the electron transport chain rather than a decrease in mitochondrial content assessed by mitochondrial DNA copy number.

“Mitochondrial dysfunction appears to be a direct consequence of intrinsic mitochondrial defect at the level of the oxidative phosphorylation system and the electron transport chain rather than a decrease in mitochondrial content assessed by mitochondria DNA copy number.”

PGC1α promotes fatty acid β-oxidation by functioning as a coactivator for PPARα and δ, which regulate expression of genes involved in mitochondrial fatty acid catabolism.

“Besides its role in mitochondrial biogenesis, PGC 1α plays a pivotal role in promoting fatty acid β-oxidation by functioning as a coactivator for PPARα and δ, which in turn regulates the expression of genes involved in mitochondria fatty acid catabolism (Vega et al., 2000; Wang et al., 2003).”

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ROS can directly induce insulin resistance.

“ROSs, apart from inducing oxidative damage to nuclear DNA, lipids and protein (Cross et al., 1987), are also signalling molecules that can directly induce insulin resistance (Figure 2; Anderson et al., 2009).”

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Mitochondrial function has not been reported to be compromised in obese or type 2 diabetic individuals.

“Particularly, mitochondrial function has not been reported to be compromised in obese or type 2 diabetic individuals (Trenell et al., 2008).”

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In the absence of stimuli that trigger mitochondrial adaptation to match increased energy demand, even slight changes in mitochondrial oxidative capacity, if protracted over time, will result in ectopic lipid accumulation.

“Thus, in the absence of stimuli that trigger mitochondrial adaptation to match increased energy demand, as in response to AMPK activation, even slight changes in mitochondria oxidative capacity, if protracted over time, will result in ectopic lipid accumulation (Figure 2; Montgomery and Turner, 2015).”

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PGC1α-dependent defects in mitochondrial oxidative metabolism are reversible.

“Thus, not only PGC 1α upregulation is paralleled by an improvement in insulin sensitivity, but also PGC 1α-dependent defects in mitochondrial oxidative metabolism are reversible confirming this transcription cofactor as a valuable target to restore insulin sensitivity and the aberrant transcriptional control of mitochondrial biogenesis (Mootha et al., 2003; Patti et al., 2003).”

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PGC1α may be at the interphase among mitochondrial dysfunction, ectopic accumulation of lipotoxic lipid metabolites and insulin resistance.

“Thus, in light of its role in promoting mitochondrial biogenesis and regulating fatty acid β-oxidation, PGC 1α may be at the interphase among mitochondrial dysfunction, ectopic accumulation of lipotoxic lipid metabolites and insulin resistance.”

High-fat diet induced a gradual increase in skeletal muscle mitochondria as indicated by an increase in mitochondrial DNA and proteins with a mechanism dependent on peroxisome proliferator-activated receptor δ (PPARδ) activation and upregulation of PGC1α.

“Instead, the high-fat diet induced a gradual increase in skeletal muscle mitochondria as indicated by an increase in mitochondrial DNA (mtDNA) and proteins with a mechanism dependent on peroxisome proliferator-activated receptor δ (PPARδ) activation and upregulation of PGC 1α (Hancock et al., 2008).”

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PGC1α is a valuable target to restore insulin sensitivity and the aberrant transcriptional control of mitochondrial biogenesis.

“Thus, not only PGC 1α upregulation is paralleled by an improvement in insulin sensitivity, but also PGC 1α-dependent defects in mitochondrial oxidative metabolism are reversible confirming this transcription cofactor as a valuable target to restore insulin sensitivity and the aberrant transcriptional control of mitochondrial biogenesis (Mootha et al., 2003; Patti et al., 2003).”

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TFAM regulates mtDNA transcription by directly interacting with the mitochondrial genome along with mitochondrial transcription specificity factors TFB1M and TFB2M.

“Key in orchestrating this process is the nuclear-encoded mitochondrial transcription factor A (TFAM), which is pivotal in regulating mtDNA transcription by directly interacting with mitochondrial genome along with mitochondrial transcription specificity factors TFB1M and TFB2M (Figure 3; Gleyzer et al., 2005; Ljubicic et al., 2010).”

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Skeletal muscle has enormous spare respiratory capacity allowing a 10-20-fold increase in oxygen consumption above resting, which denies the possibility that a decrease in mitochondrial function of the magnitude observed in type 2 diabetic individuals might lead to accumulation of diacylglycerol and ceramide.

“Indeed, skeletal muscle is characterised by an enormous spare respiratory capacity allowing for a 10–20-fold increase in oxygen consumption above resting, which denies the possibility that a decrease in mitochondrial function of the magnitude observed in type 2 diabetic individuals might lead to the accumulation of diacylglycerol and ceramide (Holloszy, 2008).”

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Glucotoxicity decreases mitochondrial oxygen consumption rate in pancreatic β cells by inducing upregulation of voltage-dependent anion channel-1.

“The detrimental effect of hyperglycaemic glucotoxicity on mitochondria has also been recently described in pancreatic β cells with glucotoxicity decreasing mitochondrial oxygen consumption rate by inducing the upregulation of voltage-dependent anion channel-1 (Zhang et al., 2019).”

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Activation of NRF-1 and 2 and subsequent induction of TFAM are governed by PGC1α.

“The activation of NRF-1 and 2 and the subsequent induction of TFAM are governed by the master regulator of mitochondrial metabolism and biogenesis: PGC 1α (Figure 3).”

Severe hyperglycaemia reversibly decreases mitochondria respiration in human cultured myotubes.

“Severe hyperglycaemia has been shown to reversibly decrease mitochondria respiration in human cultured myotubes (Rabøl et al., 2009), which supports the possibility that mitochondrial dysfunction may arise in response to sustained hyperglycaemia and energetic substrates oversupply to skeletal muscle.”

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The insulin sensitising effect of exercise is paralleled by a concomitant exercise-induced upregulation of PGC1α.

“In support of this notion, the insulin sensitising effect of exercise (Meex et al., 2010) is paralleled by a concomitant exercise-induced upregulation of PGC 1α (Uguccioni et al., 2010).”

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AMPK is activated in response to a drop in ATP:AMP and ATP:ADP ratios.

“an ancient energy gauge, which in turn is activated to rewire energy metabolisms in response to a drop in ATP:AMP and ATP:ADP ratios (Kahn et al., 2005).”

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Upregulating PGC1β or activating heat shock protein 72 to increase mitochondrial function above the physiological adaptive response triggered by lipid oversupply mitigates lipid-induced insulin resistance.

“In agreement with this, upregulating PGC 1β or activating heat shock protein 72 to increase mitochondrial function above the physiological adaptive response triggered by lipid oversupply mitigate lipid-induced insulin resistance (Wright et al., 2011; Henstridge et al., 2014).”

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• cites Henstridge et al., 2014 sourceNot checked yet

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A high-fat diet induces insulin resistance in rodent models.

“A high-fat diet has been widely described to induce insulin resistance in rodent models (Williams et al., 2014), and it has also been used to elucidate the relationship between the metabolic insult elicited by increased fatty acids supply, insulin resistance and mitochondrial function.”

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A 35% decrease in ADP-stimulated mitochondrial respiration was reported in patients with T2DM after normalisation for mitochondrial content.

“In support of this, a 35% decrease in ADP-stimulated mitochondrial respiration was reported in patients with T2DM after normalisation for mitochondrial content (Phielix et al., 2008).”

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Diet-induced insulin resistance in rats and mice was not associated with a decrease in skeletal muscle mitochondrial proteins.

“Similar to humans, diet-induced insulin resistance in rats and mice was not associated with a decrease in skeletal muscle mitochondrial proteins.”

Absolute or relative energy deficits, underlain by a drop in ATP levels or an increase in ATP demand, trigger mitochondrial fusion.

“Particularly, absolute or relative energy deficits, underlain by a drop in ATP levels or an increase in ATP demand, trigger mitochondrial fusion (Liesa and Shirihai, 2013; Hesselink et al., 2016)”

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• cites Hesselink et al., 2016 sourceNot checked yet

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A single nucleotide polymorphism in the SIRT3 gene is associated with increased susceptibility to develop the metabolic syndrome in humans.

“The importance of SIRT3 in metabolic health has been also demonstrated in humans where a single nucleotide polymorphism in the SIRT3 gene has been associated with increased susceptibility to develop the metabolic syndrome (Hirschey et al., 2011).”

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Mitofusin-2 transcript levels increase upon weight loss.

“Nonetheless, mitofusin-2 transcript levels increased upon weight loss (Bach et al., 2005)”

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SIRT3 regulates energy metabolism and fatty acid β-oxidation by regulating AMPK phosphorylation and PGC1α expression, as shown by decreased phosphorylated AMPK:total AMPK ratio and downregulation of PGC1α in skeletal muscle of SIRT3 KO mice.

“SIRT3 appears to regulate energy metabolism and, particularly, fatty acid β-oxidation, by regulating AMPK phosphorylation and PGC 1α expression as demonstrated by the decrease in phosphorylated AMPK:total AMPK ratio and the downregulation of PGC 1α in the skeletal muscle of SIRT3 KO mice (Palacios et al., 2009).”

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Mitochondrial protein hyperacetylation is a putative mechanism underpinning ectopic lipid accumulation and insulin resistance.

“suggesting mitochondrial protein hyperacetylation as a putative mechanism underpinning ectopic lipid accumulation and insulin resistance.”

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Dysregulation of mitochondrial dynamics with a shift towards fission promotes metabolic dysfunction, as shown by the onset of obesity and insulin resistance following ablation of fusion protein in mice.

“In support of this paradigm, dysregulation of mitochondria dynamic with a shift towards fission promotes metabolic dysfunction as demonstrated by the onset of obesity and insulin resistance following the ablation of fusion protein in mice (Quiros et al., 2012; Sebastian et al., 2012).”

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• cites Sebastian et al., 2012 sourceNot checked yet

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Mitochondrial protein acetylation is susceptible to changes in energy or nutrient availability independently of whether such metabolic perturbation arises from nutrient deficiency or excess.

“Thus, mitochondrial protein acetylation is susceptible to changes in energy or nutrient availability independently on whether such metabolic perturbation arises from nutrient deficiency or excess.”

Mitochondrial fusion allows the exchange of damaged mtDNA with intact mtDNA through intimate interaction between isolated mitochondria.

“Indeed, mitochondria fusion allows the exchange of damaged mtDNA with intact mtDNA resulting from the intimate interaction between isolated mitochondria.”

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Mitochondrial fission promotes the removal of dysfunctional mitochondria via an autophagic process termed mitophagy.

“On the contrary, mitochondria fission promotes the removal of dysfunctional mitochondria via an autophagic process termed mitophagy (Westermann, 2010).”

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Acetylation of mitochondrial proteins is a pivotal post-transcriptional modification governing mitochondrial metabolism.

“Acetylation of mitochondrial proteins has been described as a pivotal post-transcriptional modification in governing mitochondrial metabolism as shown by the acetylation of the intermediate metabolic enzymes involved in the tricarboxylic acid cycle and fatty acid β-oxidation (Zhao et al., 2010).”

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AMPK promotes SIRT1-dependent PGC1α deacetylation by increasing intracellular NAD+ levels.

“Particularly, AMPK has been shown to promote SIRT1-dependent PGC 1α deacetylation by increasing intracellular NAD+ levels and leading to the subsequent activation of SIRT1 with this mechanism being proposed as key in allowing the cell to switch between different metabolic substrates (Cantó et al., 2010).”

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Disruption of mitochondrial dynamics compromises mitochondrial quality and cellular bioenergetics.

“Thus, considering the importance of mitochondrial dynamics in maintaining and promoting mitochondria health and allowing the cells to adapt and respond to metabolic challenges, it appears evident that disruption of mitochondrial dynamics compromises mitochondrial quality and cellular bioenergetics.”

Mitochondria fission is regulated by dynamin-1-like protein and its cognate outer membrane receptor mitochondrial fission 1 protein.

“Mitochondria fission is regulated by dynamin-1-like protein and its cognate outer membrane receptor: mitochondrial fission 1 protein (Wai and Langer, 2016).”

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A high-fat diet also increases mitochondrial protein acetylation.

“Counterintuitively, a high-fat diet also increases mitochondrial protein acetylation (Hirschey et al., 2011).”

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Mitochondrial function is regulated by acute changes in mitochondrial architecture (mitochondria dynamics), which encompasses fusion and fission cycles and is crucial for cells to respond to short-term metabolic perturbations.

“Mitochondrial function is further regulated by acute changes in mitochondrial architecture, termed mitochondria dynamics, which encompasses cycles of fusion and fission and is crucial to allow the cells to respond to short-term metabolic perturbations (Wai and Langer, 2016).”

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Maintenance of a healthy cellular mitochondrial network depends on the balance between fusion and fission cycles.

“The maintenance of a healthy cellular mitochondrial network is dependent on the balance between fusion and fission cycles (Westermann, 2010)”

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Mitochondrial hyperacetylation and the downstream decrease in mitochondrial function negatively impact fatty acid β-oxidation.

“Mitochondrial hyperacetylation, and the downstream decrease in mitochondrial function, also negatively impacts on fatty acid β-oxidation (Anderson and Hirschey, 2012)”

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AMPK increases PGC1α expression.

“Furthermore, besides its role in promoting PGC 1α phosphorylation AMPK also increases its expression (Garcia-Roves et al., 2008; Vaughan et al., 2014).”

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• cites Vaughan et al., 2014 sourceNot checked yet

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SIRT3 deletion in mice exacerbates the deleterious effect of a high-fat diet on metabolic health, resulting in accelerated obesity, insulin resistance, hyperlipidaemia and steatohepatitis compared to wild-type littermates.

“SIRT3 plays a central role in the regulation of mitochondrial and energy metabolism with its deletion in mice exacerbating the deleterious effect of a high-fat diet on metabolic health resulting in accelerated obesity, insulin resistance, hyperlipidaemia and steatohepatitis compared to their wild-type littermates (Hirschey et al., 2011).”

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MAM reduction may represent a link between mitochondrial dysfunction and insulin resistance in skeletal muscle.

“indicating that the MAM reduction may represent a link between mitochondrial dysfunction and insulin resistance in skeletal muscle.”

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Interaction between mitochondria and ER has been demonstrated in mouse and human primary hepatocytes and in mice.

“The interaction between mitochondria and ER has been demonstrated in mouse and human primary hepatocytes and in mice (Tubbs et al., 2014; Theurey et al., 2016).”

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An imbalance in mitochondrial dynamics with a shift towards fission negatively impacts fatty acid β-oxidation.

“An imbalance in mitochondrial dynamics with a shift towards fission also negatively impacts on fatty acid β-oxidation”

Interaction between mitochondria and the sarcoplasmic reticulum has been confirmed in skeletal muscle.

“Remarkably, the interaction between mitochondria and the sarcoplasmic reticulum (SR) has been confirmed in skeletal muscle (Tubbs et al., 2018; Thoudam et al., 2019).”

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• cites Thoudam et al., 2019 sourceNot checked yet

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Mitochondrial electron transport chain complexes can assemble into multimeric supercomplexes.

“The electron transport chain complexes despite existing in single free moving proteins, due to their high plasticity, are able to assemble into multimeric super assembled structures termed supercomplexes (Lapuente-Brun et al., 2013; Kühlbrandt, 2015).”

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Lipid overconsumption appears to be detrimental to mitochondrial health.

“As discussed in the previous sections, lipid overconsumption appears to be detrimental to mitochondrial health.”

Defective mitochondrial supercomplex assembly represents a putative mechanism linking impaired mitochondrial oxidative metabolism, insulin resistance and lipotoxicity.

“Thus, defective mitochondrial supercomplex assembly represents another putative mechanism linking impaired mitochondrial oxidative metabolism, insulin resistance and lipotoxicity”

A decrease in mitochondrial respiration supported by complex I and complex II substrates or octanoyl carnitine significantly correlates with glycated haemoglobin.

“Most importantly, a decrease in mitochondrial respiration supported by complex I and complex II substrates or octanoyl carnitine significantly correlated with glycated haemoglobin (Antoun et al., 2015).”

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Dysregulation of interactions between mitochondria and the ER is implicated in the pathogenesis of insulin resistance.

“Particularly, the dysregulation of the interactions between mitochondria and the ER has been reported to be implicated in the pathogenesis of insulin resistance (Flamment et al., 2012; Sebastian et al., 2012; Tubbs et al., 2018).”

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• cites Tubbs et al., 2018 sourceNot checked yet

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Overconsumption of fat (50% of total energy intake) for 3 days is sufficient to affect the expression of genes involved in mitochondria electron transport chain and mitochondrial biogenesis in skeletal muscle, including members of mitochondrial complex I and II as well as PGC1α and β.

“In support of this, the overconsumption of fat (50% of total energy intake) for 3 days was sufficient to affect the expression of genes involved in mitochondria electron transport chain and mitochondrial biogenesis in skeletal muscle including members of mitochondrial complex I and II as well as PGC 1α and β (Sparks et al., 2005).”

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Mitochondria-SR interactions are reduced in the skeletal muscle of high-fat or genetically induced obese and diabetic mice and in human primary myotubes treated with palmitic acid.

“Mitochondria-SR interactions have been reported to be reduced in the skeletal muscle of high-fat or genetically induced obese and diabetic mice as well as in human primary myotubes treated with palmitic acid (Tubbs et al., 2018)”

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Defective fatty acid β-oxidation is a pivotal metabolic defect in obesity and insulin resistance.

“which in turn has been described as a pivotal metabolic defect in obesity and insulin resistance (Kelley et al., 1999; Simoneau et al., 1999)”

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The deleterious effect of augmented mitochondria-SR interactions relies on mitochondrial Ca2+ accumulation, underpinned by activation of PDK4 and subsequent stabilisation of key proteins involved in mitochondria-SR interactions.

“This relies on mitochondrial Ca2+ accumulation, which is underpinned by the activation of pyruvate dehydrogenase kinase 4 (PDK4) and the subsequent stabilisation of key proteins involved in mitochondria-SR interactions”

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Increased lipid supply to skeletal muscle represents a key driver of mitochondrial dysfunction.

“Thus, it appears that increased lipid supply to skeletal muscle represents a key driver of mitochondrial dysfunction (Schrauwen et al., 2010).”

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The role of mitochondria-SR interactions in promoting insulin signalling in skeletal muscle is a matter of contention.

“Nonetheless, the role of mitochondria-SR interactions in promoting insulin signalling in skeletal muscle is emerging as a matter of contention”

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Dysregulation of MAMs may contribute to skeletal muscle insulin resistance in mice and humans.

“Not surprisingly, also in consideration of the pivotal role of skeletal muscle in the regulation of glucose homeostasis, the dysregulation of MAMs may contribute to skeletal muscle insulin resistance in mice and humans (Tubbs et al., 2018; Thoudam et al., 2019).”

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• cites Thoudam et al., 2019 sourceNot checked yet

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Acute elevation of circulating fatty acid levels decreases the expression of PGC1α and β alongside other genes involved in mitochondrial metabolism.

“The negative impact of fat oversupply to skeletal muscle has been confirmed by acute elevation of circulating fatty acid levels, which also decreased the expression of PGC 1α and β alongside other genes involved in mitochondrial metabolism (Richardson et al., 2005; Hoeks et al., 2006)”

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Lipotoxicity and ROS have been proposed as mediators of fatty acid oversupply-induced mitochondrial dysfunction.

“Particularly, lipotoxicity and ROS have been proposed as the mediators of fatty acid oversupply-induced mitochondrial dysfunction (Schrauwen et al., 2010).”

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The downstream event responsible for the deleterious metabolic effect of augmented mitochondria-SR interactions is accumulation of Ca2+ in mitochondria.

“The downstream event being held responsible for the deleterious metabolic effect of augmented mitochondria-SR interactions is the accumulation of Ca2+ in the mitochondria (Thoudam et al., 2019).”

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MAM formation appears to act as an important regulator of mitochondrial function and insulin sensitivity.

“Nonetheless, independently on this contention, MAM formation appears to act as an important regulator of mitochondrial function and insulin sensitivity”

Defective fatty acid β-oxidation contributes to the accumulation of lipotoxic lipid species and insulin resistance.

“and contributes to the accumulation of lipotoxic lipid species and insulin resistance.”

The palmitic acid-induced increase in mitochondrial fission is associated with increased oxidative stress and loss of ATP synthesis.

“Not surprisingly, this process was associated with increased oxidative stress and loss of ATP synthesis (Jheng et al., 2012)”

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In the C2C12 muscle cell line, both palmitic and stearic acid challenge induce mitochondrial dysfunction characterised by mitochondria membrane hyperpolarisation and defective ATP generation.

“The effect of long-chain saturated fatty acids was confirmed in C2C12 muscle cell line in which both palmitic and stearic acid challenge induced mitochondrial dysfunction characterised by mitochondria membrane hyperpolarisation and defective ATP generation (Hirabara et al., 2010).”

• cites Hirabara et al., 2010 sourceNot checked yet

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Accumulation of non-metabolisable fatty acids in mitochondria has been associated with insulin resistance.

“a phenomenon which has been associated with insulin resistance (Koves et al., 2008).”

• cites Koves et al., 2008 sourceNot checked yet

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Replacement of lard with fish oil (40% fat J/J) in chronic (6 weeks) high-fat feeding positively affects mitochondrial dynamic behaviour in association with improvement of insulin resistance in both skeletal muscle and liver in Wistar rats.

“Remarkably, the replacement of lard with fish oil (40% fat J/J) in chronic (6 weeks) high-fat feeding positively affected mitochondrial dynamic behaviour in association with the improvement of insulin resistance in both skeletal muscle and liver in Wistar rats (Lionetti et al., 2013, 2014).”

• cites Lionetti et al., 2013Not checked yet

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• cites Lionetti et al., 2014Not checked yet

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Mitochondrial uncoupling may represent a further mechanism by which omega-3 PUFAs exert beneficial effects on insulin sensitivity.

“Mitochondrial uncoupling results in a decrease in mitochondrial energy production efficiency leading to an increase in fatty acid catabolism and lower ectopic lipid accumulation, which may represent a further mechanism by which omega-3 PUFAs exert their beneficial effects on insulin sensitivity.”

Long-chain saturated fatty acids play a key role in promoting insulin resistance by impairing mitochondrial bioenergetics and dynamic behaviour.

“As described earlier, long-chain saturated fatty acids play a key role in promoting insulin resistance by impairing mitochondrial bioenergetics and dynamic behaviour.”

Increased fatty acid utilisation is likely to contribute to a decrease in ectopic lipid accumulation, playing an important role in counteracting lipotoxicity and insulin resistance onset.

“The increased fatty acid utilisation is likely to contribute to a decrease in ectopic lipid accumulation playing an important role in counteracting lipotoxicity and insulin resistance onset.”

Omega-3 PUFAs improve skeletal muscle insulin sensitivity by modulating mitochondrial function.

“On the contrary, omega-3 PUFAs have been reported to improve skeletal muscle insulin sensitivity by modulating mitochondrial function.”

• cites Xu, 2015Not checked yet

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• cites Lalia and Lanza, 2016 sourceNot checked yet

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Diverse dietary fat sources may differently affect mitochondrial function and insulin resistance development in skeletal muscle via different mechanisms.

“Diverse dietary fat sources may differently affect mitochondrial function and insulin resistance development in skeletal muscle via different mechanisms (Putti et al., 2015a,b).”

• cites Putti et al., 2015a,bNot checked yet

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An increase in mitochondrial CPT-1 activity has been shown in skeletal muscle of rats fed a high-fat diet containing menhaden oil.

“An increase in mitochondrial carnitine palmitoyl transferase 1 (CPT-1, the rate limiting enzyme in fatty acid β-oxidation) activity has been shown in skeletal muscle of rats fed a high-fat diet (200 g fat/kg) containing menhaden (fish) oil (Power and Newsholme, 1997).”

• cites Power and Newsholme, 1997Not checked yet

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Ceramide may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.

“indicating that this lipotoxic metabolite may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.”

• cites Smith et al., 2013 sourceNot checked yet

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• cites Jheng et al., 2012 sourceNot checked yet

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A link between mitochondrial dynamics and inflammation exists, as shown by downregulation of Mfn2 gene expression induced by TNF-α in cells in culture.

“In support of this, a link between mitochondrial dynamics and inflammation exists as shown by the downregulation of Mfn2 gene expression induced by TNF-α in cells in culture (Bach et al., 2005).”

• cites Bach et al., 2005 sourceNot checked yet

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Exposure to long-chain saturated fatty acids has consequences on mitochondrial health, as demonstrated in the L6 rat cell line in which palmitic acid induced mitochondrial dysfunction associated with increased mtDNA damage, induction of JNK, apoptosis, and insulin resistance, all underlain by increased mitochondrial ROS generation.

“Indeed, the exposure to long-chain saturated fatty acids is not without consequences on mitochondrial health as demonstrated in the L6 rat cell line in which palmitic acid, the main long-chain saturated fatty acid in the Western diet, induced mitochondrial dysfunction associated with increased mtDNA damage, induction of c-Jun N-terminal kinases (JNK), apoptosis, and insulin resistance all under”

• cites Yuzefovych et al., 2010 sourceNot checked yet

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Palmitic acid affects mitochondrial biogenesis by decreasing PGC1α protein levels and expression of TFAM in L6 skeletal muscle cells.

“Furthermore, palmitic acid also affected mitochondrial biogenesis by decreasing PGC 1α protein levels and the expression of TFAM in L6 skeletal muscle cells (Yuzefovych et al., 2010).”

• cites Yuzefovych et al., 2010 sourceNot checked yet

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The positive effect of omega-3 PUFAs on inflammation and insulin resistance is associated with improved mitochondrial function and a shift towards fusion processes in rat liver.

“In agreement with the pro-fusion effect of omega-3 PUFAs on skeletal muscle mitochondria, the positive effect of omega-3 PUFAs on inflammation and insulin resistance was also associated with improved mitochondrial function and a shift towards fusion processes in rat liver (Lionetti et al., 2014)”

• cites Lionetti et al., 2014Not checked yet

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Despite obese insulin resistant subjects presenting similar amounts of intracellular triglycerides as endurance athletes, the degree of lipid peroxidation is 4.2-fold higher in obese insulin resistant individuals than endurance athletes.

“despite obese insulin resistant subject presenting similar amount of intracellular triglycerides as endurance athletes, the degree of lipid peroxidation was 4.2-fold higher in obese insulin resistant individuals than endurance athletes (Russell et al., 2003)”

• cites Russell et al., 2003 sourceNot checked yet

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The tendency to mitochondrial fusion induced by dietary omega-3 PUFAs, compared to dietary long-chain saturated fatty acids, may be related to the anti-inflammatory effect of omega-3 PUFAs as opposed to the pro-inflammatory effect of long-chain saturated fatty acids.

“Noteworthy, the tendency to mitochondrial fusion induced by dietary omega-3 PUFAs, compared to dietary long-chain saturated fatty acids, may also be related to the well-known anti-inflammatory effect of omega-3 PUFAs as opposed to long-chain saturated fatty acid, which, instead, has been reported to be pro-inflammatory (Sergi et al., 2018b).”

• cites Sergi et al., 2018bNot checked yet

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The detrimental effect of ceramide on mitochondrial bioenergetics and dynamics as well as insulin signalling is prevented by inhibiting mitochondrial fission.

“Remarkably, the detrimental effect of ceramide on mitochondrial bioenergetics and dynamics as well as insulin signalling were prevented by inhibiting mitochondrial fission (Smith et al., 2013).”

• cites Smith et al., 2013 sourceNot checked yet

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Omega-3 PUFAs increase mitochondrial content in skeletal muscle as demonstrated by upregulation of transcription factors governing mitochondrial biogenesis, including PGC1α and NRF1, in skeletal muscle of mice fed a high-fat diet supplemented with fish oil for 10 weeks.

“Omega-3 PUFAs have been shown to increase mitochondrial content in skeletal muscle as demonstrated by the upregulation of transcription factors, which govern mitochondrial biogenesis, including PGC 1α and NRF1, in the skeletal muscle of mice fed a high-fat diet (60% energy from fat) supplemented with fish oil (3.4% kcal from n-3 PUFAs) for 10 weeks (Lanza et al., 2013).”

• cites Lanza et al., 2013 sourceNot checked yet

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The protective effect of omega-3 PUFAs against insulin resistance relies on overlapping mechanisms in diverse peripheral tissues.

“suggesting the protective effect of omega-3 PUFAs against insulin resistance relying on overlapping mechanisms in diverse peripheral tissues.”

• cites Lionetti et al., 2014Not checked yet

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The impact of fatty acids on metabolic health is dictated by their chemical characteristics, with unsaturated, medium- and short-chain fatty acids being beneficial compared to long-chain saturated fatty acids.

“especially considering that the impact of fatty acids on metabolic health is dictated by their chemical characteristics with unsaturated fatty acids, medium- and short-chain fatty acids being proven as beneficial to metabolic health, compared to long-chain saturated fatty acids (Roche, 2005; Holland et al., 2007; van Dijk et al., 2009;”

• cites Roche, 2005 sourceNot checked yet

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• cites Holland et al., 2007 sourceNot checked yet

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• cites van Dijk et al., 2009 sourceNot checked yet

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A high-fat diet downregulates the protein levels of SIRT3.

“Finally, a high-fat diet has also been reported to downregulate the protein levels of SIRT3 (Palacios et al., 2009)”

• cites Palacios et al., 2009 sourceNot checked yet

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Treatment of muscle cells with cell permeable ceramide C2 induces mitochondrial fission underpinned by upregulation of dynamin-related protein 1.

“Particularly, treatment of muscle cell with the cell permeable ceramide C2 induced mitochondrial fission underpinned by the upregulation of dynamin-related protein 1.”

• cites Smith et al., 2013 sourceNot checked yet

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Exposure of C2C12 muscle cells to palmitic acid results in increased mitochondria fission as demonstrated by increased mitochondrial fragmentation orchestrated by upregulation of dynamin-related protein 1 and mitochondrial fission 1 protein.

“In support of this notion, exposure of C2C12 muscle cells to palmitic acid resulted in increased mitochondria fission as demonstrated by increased mitochondrial fragmentation orchestrated by the upregulation of dynamin-related protein 1 and mitochondrial fission 1 protein (Jheng et al., 2012).”

• cites Jheng et al., 2012 sourceNot checked yet

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SIRT3 is a key regulator of mitochondrial energy metabolism.

“which represents a key regulator of mitochondrial energy metabolism (Palacios et al., 2009; Hirschey et al., 2010, 2011; Anderson and Hirschey, 2012).”

• cites Palacios et al., 2009 sourceNot checked yet

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• cites Hirschey et al., 2010 sourceNot checked yet

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• cites Hirschey et al., 2011 sourceNot checked yet

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The effects of caloric restriction on mitochondrial function are not consistent across studies or across tissues.

“However, this is not consistent across studies or across tissues (Hancock et al., 2011; Lanza et al., 2012; Walsh et al., 2014).”

• cites Hancock et al., 2011 sourceNot checked yet

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• cites Lanza et al., 2012 sourceNot checked yet

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• cites Walsh et al., 2014 sourceNot checked yet

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Significant reduction in ROS production with caloric restriction is more likely if the duration of the caloric restriction exceeds 20 months.

“Of note, significant reduction in ROS production was more likely if the duration of the caloric restriction exceeded 20 months.”

• cites Walsh et al., 2014 sourceNot checked yet

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In the Civitarese et al. (2007) study, there was no change in key enzymes involved in mitochondrial activity.

“However, there was no change in key enzymes involved in mitochondrial activity.”

• cites Civitarese et al. (2007)Not checked yet

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A high-protein diet increases postprandial fat oxidation following a high-protein meal.

“and to increase postprandial fat oxidation following a high-protein meal (Labayen et al., 2004)”

• cites Labayen et al., 2004 sourceNot checked yet

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In rats that underwent every other day feeding for 4 weeks, no change was observed in markers of mitochondrial biogenesis or oxidative capacity in isolated mitochondria from brain or heart.

“Chausse et al. (2015) observed no change in markers of mitochondrial biogenesis, or in the oxidative capacity in isolated mitochondria from brain, or heart in rats who underwent every other day feeding for 4 weeks.”

• cites Chausse et al. (2015)Not checked yet

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In female mouse strains with increased, no change, or reduced lifespan in response to 40% CR, 10 months of CR did not alter the nDNA:MtDNA ratio or protein levels of markers of mitochondrial biogenesis in liver or skeletal muscle.

“CR for 10 months did not alter the nDNA:MtDNA ratio, protein levels of markers of mitochondrial biogenesis in liver or skeletal muscle, in any of the mouse strains that were investigated.”

• cites Mulvey et al. (2017) sourceNot checked yet

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In 12 overweight men and women, 6 months of 25% CR stimulated markers of mitochondrial biogenesis and mtDNA content.

“Civitarese et al. (2007) reported that markers of mitochondrial biogenesis and mtDNA content were stimulated in response to 6 months of 25% CR in 12 men and women who were overweight.”

• cites Civitarese et al. (2007)Not checked yet

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Caloric restriction reduces mitochondrial production of ROS.

“and reduces mitochondrial production of ROS (Bevilacqua et al., 2005).”

• cites Bevilacqua et al., 2005 sourceNot checked yet

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In animals whose lifespans are shortened by CR, reduced oxygen consumption rates were observed in isolated mitochondria from hepatocytes.

“Reduced oxygen consumption rates in isolated mitochondria from hepatocytes were observed in animals whose lifespans are shortened by CR.”

• cites Mulvey et al. (2017) sourceNot checked yet

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Caloric restriction increases mitochondrial biogenesis.

“A number of studies have shown that CR increases mitochondrial biogenesis (Nisoli et al., 2005; Lopez-Lluch et al., 2006)”

• cites Nisoli et al., 2005 sourceNot checked yet

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• cites Lopez-Lluch et al., 2006 sourceNot checked yet

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Long-term caloric restriction prevents age-related loss of mitochondrial oxidative capacity and efficiency in isolated mitochondria and in muscle fibres.

“although CR prevented age-related loss of mitochondrial oxidative capacity and efficiency in isolated mitochondria and in muscle fibres”

• cites Hancock et al., 2011 sourceNot checked yet

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In the Chausse et al. (2015) study, no difference in mitochondrial bioenergetics or redox homeostasis was observed in skeletal muscle.

“No difference in mitochondrial bioenergetics or redox homeostasis was observed in skeletal muscle.”

• cites Chausse et al. (2015)Not checked yet

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A high-protein diet promotes a higher rate of fatty acid oxidation than a high-carbohydrate counterpart.

“a high-protein diet has been shown to promote a higher rate of fatty acid oxidation than a high-carbohydrate counterpart (Raben et al., 2003)”

• cites Raben et al., 2003 sourceNot checked yet

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Long-term caloric restriction does not alter markers of mitochondrial biogenesis.

“Similarly, long-term CR did not alter any markers of mitochondrial biogenesis”

• cites Hancock et al., 2011 sourceNot checked yet

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Protein and most likely branched chain amino acids may boost oxidative metabolism.

“suggesting that protein and most likely branched chain amino acids may boost oxidative metabolism.”

Essential and/or branched chain amino acids support cardiac and skeletal muscle through increased mitochondrial biogenesis and function in both mice and humans.

“More recently, essential and/or branched chain amino acids have been shown to support cardiac and skeletal muscle through increased mitochondrial biogenesis and function in both mice and humans (D’Antona et al., 2010; Tatpati et al., 2010; Valerio et al., 2011).”

• cites D’Antona et al., 2010 sourceNot checked yet

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• cites Tatpati et al., 2010 sourceNot checked yet

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• cites Valerio et al., 2011 sourceNot checked yet

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• AssumptionRests on an assumption: Impaired mitochondrial function in skeletal muscle is one of the major predisposing factors to metabolic diseases such as insulin resistance, T2DM, and cardiovascular diseases.

Hancock et al. could not detect changes in mRNA or protein levels of markers of mitochondrial biogenesis, or citrate synthase activity, in muscle from rats that underwent 30% caloric restriction for 14 weeks.

“Hancock et al. could not detect any changes in mRNA or protein levels of markers of mitochondrial biogenesis, or citrate synthase activity in muscle from rats that underwent 30% CR for 14 weeks (Hancock et al., 2011).”

• cites Hancock et al., 2011 sourceNot checked yet

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Individuals who had a more coupled phenotype at baseline were able to better improve mitochondrial function in response to CR.

“Contrary to expectations, individuals who had a more coupled phenotype at baseline were able to better improve mitochondrial function in response to CR.”

• cites Sparks et al. (2016) sourceNot checked yet

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Caloric restriction increases mitochondrial efficiency.

“and mitochondrial efficiency (Nisoli et al., 2005)”

• cites Nisoli et al., 2005 sourceNot checked yet

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Short-term, late-onset IF protects against oxidative damage in the brain.

“By contrast, Singh et al. (2012) have reported protection against oxidative damage in the brain by short term, late onset, IF.”

• cites Singh et al. (2012) sourceNot checked yet

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The Mulvey et al. (2017) study could not demonstrate a beneficial effect of CR on mitochondrial dysfunction in the long-lived strain.

“This study could not demonstrate a beneficial effect of CR on mitochondrial dysfunction in the long-lived strain.”

• cites Mulvey et al. (2017) sourceNot checked yet

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In the Menshikova et al. (2017) study, citrate synthase, a marker of mitochondrial content, was increased.

“However, citrate synthase, a marker of mitochondrial content was increased (Menshikova et al., 2017).”

• cites Menshikova et al., 2017 sourceNot checked yet

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Long-term caloric restriction reduces oxidative damage.

“and reduced oxidative damage (Hancock et al., 2011).”

• cites Hancock et al., 2011 sourceNot checked yet

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In contrast to CR, body weight is not changed, or modestly reduced, in chow-fed IF vs AL animals.

“In contrast to CR, body weight is not changed, or modestly reduced, in chow fed IF vs. AL animals (Goodrick et al., 1990).”

• cites Goodrick et al., 1990 sourceNot checked yet

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Resveratrol countered high-fat diet-induced metabolic deterioration via mechanisms partly relying on its beneficial effects on mitochondrial health and function.

“resveratrol countered high-fat diet-induced metabolic deterioration with a mechanisms which relayed albeit in part, on its beneficial effects on mitochondrial health and function (Haohao et al., 2015).”

• cites Haohao et al., 2015 sourceNot checked yet

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A small increase in mitochondrial function may not be sufficient to enhance insulin sensitivity if not supported by higher levels of physical activity.

“suggesting that a small increase in mitochondrial function may not be sufficient to enhance insulin sensitivity if not supported by higher levels of physical activity (de Ligt et al., 2018).”

• cites de Ligt et al., 2018 sourceNot checked yet

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In rats, resveratrol counteracts the deleterious effect of a high-fat diet on metabolic and mitochondrial health.

“Furthermore, resveratrol has been shown to counteract the deleterious effect of a high-fat diet on metabolic and mitochondria health in rats.”

• cites Haohao et al., 2015 sourceNot checked yet

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Branched chain amino acid supplementation is associated with increased skeletal muscle fatty acid catabolism in vitro.

“which was also associated with an increase in skeletal muscle fatty acid catabolism in vitro (Liang et al., 2014).”

• cites Liang et al., 2014Not checked yet

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In first-degree relatives of type 2 diabetic individuals, resveratrol increases mitochondrial respiration on octanoyl-carnitine.

“Remarkably, the effect of resveratrol was confirmed in the first-degree relatives of type 2 diabetic individuals with resveratrol increasing mitochondrial respiration on octanoyl-carnitine (de Ligt et al., 2018).”

• cites de Ligt et al., 2018 sourceNot checked yet

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In type 2 diabetic individuals, epicatechin-rich cocoa increases mitochondrial biogenesis in skeletal muscle, shown by increased SIRT1-PGC1α activation and increased abundance of mitochondrial complex I and V.

“The administration of a epicatechin-rich cocoa in type 2 diabetic individuals resulted in an increase in mitochondria biogenesis in skeletal muscle as demonstrated by an increased activation of the SIRT1-PGC 1α axis and an increase in the abundance of mitochondrial complex I and V (Taub et al., 2012).”

• cites Taub et al., 2012 sourceNot checked yet

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Resveratrol has beneficial effects on metabolic health due to its ability to modulate mitochondrial function, biogenesis, and oxidative metabolism.

“resveratrol has emerged in the recent years for its beneficial effects on metabolic health due to its ability to modulate mitochondria function and biogenesis and oxidative metabolism (Christenson et al., 2016).”

• cites Christenson et al., 2016 sourceNot checked yet

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In vivo, quercetin supplementation does not affect fatty acid β-oxidation or respiratory exchange ratio.

“Nonetheless, these effects on lipid metabolism were not confirmed in vivo as demonstrated by quercetin supplementation failing to affect fatty acid β-oxidation or respiratory exchange ratio (Dumke et al., 2009).”

• cites Dumke et al., 2009 sourceNot checked yet

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In vitro, quercetin increases fatty acid β-oxidation in C2C12 myotubes, hepatocytes, and HeLa cells.

“Quercetin has been reported to modulate fatty acid metabolism in vitro with an increase in fatty acid β-oxidation being reported in C2C12 myotubes, hepatocytes and Hela cells (Suchankova et al., 2009; Eid et al., 2010).”

• cites Suchankova et al., 2009 sourceNot checked yet

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• cites Eid et al., 2010 sourceNot checked yet

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Quercetin has a favourable effect on skeletal muscle and mitochondrial biogenesis and function via activation of the SIRT1-AMPK-PGC1α axis.

“Quercetin has widely been reported for its favourable effect on skeletal muscle and mitochondria biogenesis as well as function via the activation of the SIRT1-AMPK-PGC 1α axis (Davis et al., 2009).”

• cites Davis et al., 2009 sourceNot checked yet

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Interventions aimed at increasing mitochondrial function (e.g., exercise) represent a valuable therapeutic tool to improve skeletal muscle insulin sensitivity.

“confirming that interventions aimed at increasing mitochondrial function (i.e., exercise) represent a valuable therapeutic tool to improve skeletal muscle insulin sensitivity.”

• AssumptionRests on an assumption: Athletes have higher mitochondrial oxidative capacity relative to sedentary individuals and appear protected, albeit in part, from lipid-induced insulin resistance.

Increasing mitochondrial function represents a promising approach to enhance insulin sensitivity.

“Nonetheless, independently on whether mitochondrial dysfunction represents a primary defect in the pathogenesis of insulin resistance, increasing mitochondrial function represents a promising approach to enhance insulin sensitivity.”

• AssumptionRests on an assumption: Mitochondrial dysfunction is a metabolic defect associated with insulin resistance and T2DM.

Resveratrol did not induce an increase in insulin sensitivity in first-degree relatives of type 2 diabetic individuals.

“resveratrol did not induce an increase in insulin sensitivity in these individuals”

• cites de Ligt et al., 2018 sourceNot checked yet

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Quercetin can stimulate mitochondrial oxidative metabolism by directly decreasing ATP:AMP ratio, which activates AMPK and its downstream catabolic pathways.

“Furthermore, quercetin can stimulate mitochondria oxidative metabolism by directly decreasing ATP:AMP ratio, which in turn results in the activation of AMPK and its downstream catabolic pathways (Dorta et al., 2005).”

• cites Dorta et al., 2005 sourceNot checked yet

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