Chronic Reduction of Plasma Free Fatty Acid Improves Mitochondrial Function and Whole-Body Insulin Sensitivity in Obese and Type 2 Diabetic Individuals

Daniele, Giuseppe; Eldor, Roy; Merovci, Aurora; Clarke, Geoffrey D.; Xiong, Jie; Tripathy, Devjit; Taranova, Anna G.; Abdul‐Ghani, Muhammad

doi:10.2337/db13-1130

Cited by 72 publications

(66 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Yet, lipid oversupply does not appear to further impair carbohydratesupported maximal coupled or uncoupled respiration within this cohort of subjects across a range of oxidative capacity. This is supported by the work of Daniele et al (11), who demonstrated that reducing circulating FFA levels increases carbohydrate supported ATP production in both type 2 diabetic patients as well as normal-glucose-tolerant subjects. We suggest that mitochondrial performance is not impaired to a greater degree in low-oxidative muscle confounded with obesity (14,23) within the context of excess lipid exposure.…”

Section: Discussionsupporting

confidence: 64%

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Dubé

Coen

Distéfano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Dubé JJ, Coen PM, DiStefano G, Chacon AC, Helbling NL, Desimone ME, Stafanovic-Racic M, Hames KC, Despines AA, Toledo FG, Goodpaster BH. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am J Physiol Endocrinol Metab 307: E1117-E1124, 2014. First published October 28, 2014; doi:10.1152/ajpendo.00257.2014.-We hypothesized that acute lipid-induced insulin resistance would be attenuated in highoxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. lipids; mitochondria; skeletal muscle CHRONIC SUBSTRATE OVERLOAD, coupled with physical inactivity, is a key mediator of the development of obesity and insulin resistance (49). It has been suggested that mitochondrial dysfunction (1, 17), perhaps a result of nutrient oversupply, particularly saturated fatty acids and/or physical inactivity, plays a key role in decreased insulin action observed in the obese state. However, there is evidence to suggest that mitochondrial content and performance are normal in insulinresistant obese subjects (14). Although there is controversy regarding the influence of mitochondrial performance on the development of insulin resistance (17,22), there is little debate that increased physical activity (i.e., aerobic exercise) provides a necessary stimulus for increased mitochondrial content (24), capacity for fat oxidation (6), and improved insulin sensitivity (13). Yet few studies have directly assessed the effects of lipid oversupply on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance in high-vs. lowoxidative muscle (9, 40).Using the exogenous lipid infusion model of insulin resistance (7, 26), we hypothesized that excess fatty acids would be preferentially oxidized in enduranc...

show abstract

Section: Discussionsupporting

confidence: 64%

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Dubé

Coen

Distéfano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Daniele et al (8) conclude that the mitochondrial defect in IR is partially reversible, which is consistent with other interventions, including weight loss and exercise, both of which also have profound effects on FFA metabolism and insulin sensitivity (17). However, this article used an intervention with specific direct FFA-lowering effects.…”

mentioning

confidence: 66%

“…Thus, it is possible that reductions in FFA have disparate effects on mitochondrial O 2 consumption and ATP production, both of which could result in an increased coupling. It is also likely that the longer-term treatment in the study by Daniele et al (8) had a fundamentally different effect on mitochondria. A deeper interrogation of mitochondrial respiratory states (e.g., basal, coupled and uncoupled respiration), in addition to ATP and H 2 O 2 measurements, could have revealed these potentially important effects of FFA reduction.…”

mentioning

confidence: 83%

Improved Mitochondrial Function Is Linked With Improved Insulin Sensitivity Through Reductions in FFA

Goodpaster

Coen

2014

Diabetes

View full text Add to dashboard Cite

Skeletal muscle insulin resistance (IR) is inextricably linked with the etiology of type 2 diabetes (T2D) and is a key target for prevention and treatment strategies. IR likely has many mechanistic origins, but the primary causes remain elusive, particularly in humans. Of the many possible mediators of IR, a considerable body of work has debated the potential roles of mitochondria (1-3), lipid oversupply (i.e., "lipotoxicity") (4,5), and the association between mitochondria, fatty acid metabolism, and intramyocellular lipid accumulation-the subject of this article. Indeed, substantial evidence exists to both support and refute a role for mitochondria in skeletal muscle insulin resistance (6,7).In this issue, Daniele et al. (8) examined the associations among chronic free fatty acid (FFA) levels, intramyocellular lipids, the capacity for skeletal muscle mitochondrial ATP production and IR in human obesity and T2D. These investigators used a 2-week, single-arm, open-label acipimox treatment, which, consistent with this group's previous studies (9,10), significantly reduced circulating FFA levels and presumably availability to muscle and improved insulin sensitivity. The authors' central hypothesis was that chronic reduction in FFA would increase insulin sensitivity and that this would occur despite any change in the capacity for mitochondrial ATP production measured ex vivo in mitochondria isolated from muscle biopsy specimens. Their inherent argument was that this would rule out a role for mitochondria in FFA-induced IR.Daniele et al. conducted a series of elegant ex vivo and in vivo studies in obese insulin-resistant subjects either with or without T2D. Contrary to their initial hypothesis, they found that reduction in elevated FFA in individuals with both T2D and normal glucose tolerance resulted in an increase in maximal carbohydrate and fatty acid-supported ATP production measured in mitochondria fractions isolated from vastus lateralis biopsy specimens. The reduction in FFA, however, did not decrease mitochondrial reactive oxygen species (ROS) measured as H 2 O 2 emission from isolated mitochondrial fractions. Although no explicit hypothesis was stated, previous reports implicate mitochondria ROS in insulin resistance in high-fat diet-fed rodents and obese humans (1). These results are also apparently contradicted by a recent study by Phielix et al. (11), who reported that shorterterm acipimox treatment in patients with T2D did not increase mitochondrial respiration within intact myofibers and actually decreased maximal respiration in isolated mitochondria. Moreover, Phielix et al. (11) reported a decrease in mitochondrial H 2 O 2 production with FFA reduction.The ostensive inconsistency in the effects on mitochondria between these two studies can possibly be explained by the effects of FFA on mitochondrial uncoupling and/or efficiency. High FFA can cause mitochondrial uncoupling (12,13), and UCP3 has mild uncoupling properties and can help protect against FFA-induced oxidative stress (14). Thus, it is poss...

show abstract

“…The authors of this study also observed FFA rebound, occurring between acipimox doses, and pointed to this as the probable cause of the failure of long-term acipimox treatment to improve glycemia in the patients. A recent study confi rmed insulin sensitization in association with FFA lowering during short, intensive acipimox therapy, despite failure to reduce lipid accumulation in skeletal muscle ( 39 ). We hypothesize that to fully realize the potential of FFA lowering on improving glucose control, net FFA lowering must be achieved, and to do that the FFA rebound issue has to be solved (see below).…”

Section: Discussionmentioning

confidence: 99%

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Kroon

Kjellstedt

Thalén

et al. 2015

Journal of Lipid Research

View full text Add to dashboard Cite

explored and provide evidence supporting this concept. This includes inactivation of hormone sensitive lipase (HSL) ( 5, 6 ) and A 1 -adenosine receptor agonists ( 7 ). In addition, several other G protein-coupled receptors (GPRs) are involved in controlling adipocyte FFA release, including GPR43, GPR81, and GPR109A ( 8-10 ).The GPR109A agonist nicotinic acid (NiAc) has been used clinically ever since its antidyslipidemic effects (HDL elevation and reductions of total cholesterol, LDL-cholesterol, and TG) were discovered more than 50 years ago ( 11-15 ). Although NiAc potently lowers FFA acutely, large-scale clinical studies, with repeated oral NiAc administration, often report increased levels of fasting glycemia ( 16-19 ). NiAc has not been optimized to achieve durable and therapeutically meaningful FFA lowering. By this, we specifi cally mean reducing around-the-clock FFA area under the curve (AUC). In theory, this might be achieved by sustained NiAc exposure; however, the FFA-lowering effect seen initially appears to be lost over time despite maintained NiAc exposure (tolerance development) ( 20 ). Time-dependent loss of both FFA lowering and glucose control improvement also occur in patients with type 2 diabetes, treated with the NiAc analog acipimox ( 21,22 ). To avoid tolerance development, drug holidays are needed. However, at the end of each NiAc exposure period, there is the risk of FFA rebound (here referring to the situation where FFA overshoots pretreatment levels in connection with NiAc decline) due to the short NiAc plasma half-life ( 23 ). FFA rebound is associated with impaired glucose control ( 24, 25 ). The question of whether there might be an optimal balance between periods of continuous exposure (which would minimize rebound) and drug holidays (which would minimize tolerance) in order to achieve maximal FFA lowering has not been addressed. Lipid overload in nonadipose tissues has been linked to the pathogenesis of insulin resistance and atherogenesis ( 1-4 ). A potential means for reversing peripheral lipid overload is to restrict the release of FFAs from adipose tissues. A number of independent mechanisms have been N.D. Oakes, P. Thalén, and A. Kjellstedt Abbreviations: ATGL, adipocyte triglyceride lipase; AUC, area under the curve; ER, extended release; GIR, glucose infusion rate; GPR, G protein-coupled receptor; HOMA-IR, homeostasis model assessment for insulin resistance; HSL, hormone sensitive lipase; NiAc, nicotinic acid; PDE-3B, phosphodiesterase-3B .

show abstract

Chronic Reduction of Plasma Free Fatty Acid Improves Mitochondrial Function and Whole-Body Insulin Sensitivity in Obese and Type 2 Diabetic Individuals

Cited by 72 publications

References 27 publications

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Improved Mitochondrial Function Is Linked With Improved Insulin Sensitivity Through Reductions in FFA

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Contact Info

Product

Resources

About