Muscle insulin resistance resulting from impaired microvascular insulin sensitivity in Sprague Dawley rats

Premilovac, Dino; Bradley, EA; Ng, Huei L.H.; Richards, Stephen M.; Rattigan, Stephen; Keske, Michelle A.

doi:10.1093/cvr/cvt015

Cited by 36 publications

(86 citation statements)

References 44 publications

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“…Surgery was performed as previously outlined [23]. Following surgery, an infusion of insulin (10 mU kg…”

Section: Study 1: Euglycaemic-hyperinsulinaemic Clampmentioning

confidence: 99%

“…Rate of muscle glucose uptake (R′g) was determined using 2-deoxy-D- [1-14 C]-glucose (2DG; 740 kBq; PerkinElmer) as previously described [23,28]. Ser 473 -Akt phosphorylation was determined using western blot as previously outlined [23].…”

Section: Study 1: Euglycaemic-hyperinsulinaemic Clampmentioning

confidence: 99%

“…We have previously used this method to demonstrate myocyte-specific insulin resistance in obese Zucker [32] and fat-fed [23] rats.…”

Section: Study 2: Isolated Constant-flow Hindlimb Perfusionmentioning

confidence: 99%

“…Surgery was performed to isolate one hindlimb as previously described [33,34]. Immediately following surgery the animals were killed with an intracardiac injection of pentobarbital sodium and a single hindlimb perfusion was carried out as previously described [23].…”

Section: Study 2: Isolated Constant-flow Hindlimb Perfusionmentioning

confidence: 99%

“…In healthy humans [17] and experimental animals [18][19][20] insulin increases microvascular recruitment. This action is markedly attenuated during states of insulin resistance (high-fat diet/obesity) and is closely associated with decreased muscle glucose uptake in vivo [17,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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A vascular mechanism for high-sodium-induced insulin resistance in rats

et al. 2014

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Aims/hypothesis High sodium (HS) effects on hypertension are well established. Recent evidence implicates a relationship between HS intake and insulin resistance, even in the absence of hypertension. The aim of the current study was to determine whether loss of the vascular actions of insulin may be the driving factor linking HS intake to insulin resistance. Methods Sprague Dawley rats were fed a control (0.31% wt/wt NaCl) or HS (8.00% wt/wt NaCl) diet for 4 weeks and subjected to euglycaemic-hyperinsulinaemic clamp (10 mU min) or constant-flow pump-perfused hindlimb studies following an overnight fast. A separate group of HS rats was given quinapril during the dietary intervention and subjected to euglycaemichyperinsulinaemic clamp as above. Results HS intake had no effect on body weight or fat mass or on fasting glucose, insulin, endothelin-1 or NEFA concentrations. However, HS impaired whole body and skeletal muscle glucose uptake, in addition to a loss of insulin-stimulated microvascular recruitment. These effects were present despite enhanced insulin signalling (Akt) in both liver and skeletal muscle. Constant-flow pump-perfused hindlimb experiments revealed normal insulin-stimulated myocyte glucose uptake in HS-fed rats. Quinapril treatment restored insulin-mediated microvascular recruitment and muscle glucose uptake in vivo.Conclusions/interpretation HS-induced insulin resistance is driven by impaired microvascular responsiveness to insulin, and is not due to metabolic or signalling defects within myocytes or liver. These results imply that reducing sodium intake may be important not only for management of hypertension but also for insulin resistance, and highlight the vasculature as a potential therapeutic target in the prevention of insulin resistance.

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“…Surgery was performed as previously outlined [23]. Following surgery, an infusion of insulin (10 mU kg…”

Section: Study 1: Euglycaemic-hyperinsulinaemic Clampmentioning

confidence: 99%

Section: Study 1: Euglycaemic-hyperinsulinaemic Clampmentioning

confidence: 99%

“…We have previously used this method to demonstrate myocyte-specific insulin resistance in obese Zucker [32] and fat-fed [23] rats.…”

Section: Study 2: Isolated Constant-flow Hindlimb Perfusionmentioning

confidence: 99%

Section: Study 2: Isolated Constant-flow Hindlimb Perfusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A vascular mechanism for high-sodium-induced insulin resistance in rats

et al. 2014

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Role of skeletal muscle perfusion and insulin resistance in the effect of dietary sodium on heart function in overweight

et al. 2021

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Aims Weight excess and insulin resistance predispose to heart failure. High sodium consumption may contribute to the development of cardiac impairment in insulin‐resistant individuals by promoting inadequate skeletal muscle microvascular perfusion response to insulin. We sought to investigate the association of dietary sodium reduction with muscle perfusion, insulin sensitivity, and cardiac function in overweight/obese insulin‐resistant (O‐IR) normotensive subjects. Methods and results Fifty O‐IR individuals with higher than recommended sodium intake were randomized to usual or reduced sodium diet for 8 weeks; 25 lean, healthy subjects served as controls for pre‐intervention measurements. Echocardiography and muscle perfusion were performed during fasting and under stable euglycaemic–hyperinsulinaemic clamp conditions. O‐IR patients demonstrated subclinical cardiac dysfunction as evidenced by lower left ventricular global longitudinal strain (GLS), e′ tissue velocity, and left atrial strain and reduced muscle perfusion. The intervention arm showed improvements in insulin resistance [glucose infusion rate (GIR)], GLS, e′, atrial strain, and muscle perfusion in fasting conditions, as well as improved responses of GLS and muscle perfusion to insulin during clamp. Significant interactions were found between the allocation to low‐salt diet and improvement in muscle perfusion on change in GIR at follow‐up (P = 0.030), and between improvement in muscle perfusion and change in GIR on change in GLS response to insulin at follow‐up (P = 0.026). Mediation analysis revealed that the relationship between the reduction of sodium intake and improvement in GLS was mediated by improvements in muscle perfusion and GIR (decrease in beta coefficient from −0.29 to −0.16 after the inclusion of mediator variables to the model). Conclusions The reduction of dietary sodium in the normotensive O‐IR population improves cardiac function, and this effect may be associated with the concomitant improvements in skeletal muscle perfusion and insulin resistance. These findings might contribute to refining heart failure preventive strategies.

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The contributory role of vascular health in age‐related anabolic resistance

Banks

Rogers

Church

et al. 2021

J cachexia sarcopenia muscle

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Sarcopenia, or the age‐related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli—a phenomenon that has been termed anabolic resistance (AR)—which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age‐related impairments in vascular health may impede nutrient‐stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age‐related AR, review the influence of nitric oxide and endothelin‐1 on age‐related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age‐related AR.

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Muscle insulin resistance resulting from impaired microvascular insulin sensitivity in Sprague Dawley rats

Cited by 36 publications

References 44 publications

A vascular mechanism for high-sodium-induced insulin resistance in rats

A vascular mechanism for high-sodium-induced insulin resistance in rats

Role of skeletal muscle perfusion and insulin resistance in the effect of dietary sodium on heart function in overweight

The contributory role of vascular health in age‐related anabolic resistance

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