Accentuated Eccentric Loading and Cluster Set Configurations in the Back Squat: A Kinetic and Kinematic Analysis.

ABSTRACT: Wagle, JP, Cunanan, AJ, Carroll, KM, Sams, ML, Wetmore, A, Bingham, GE, Taber, CB, DeWeese, BH, Sato, K, Stuart, CA, and Stone, MH. Accentuated eccentric loading and cluster set configurations in the back squat: a kinetic and kinematic analysis. J Strength Cond Res 35(2): 420-427, 2021-This study examined the kinetic and kinematic differences between accentuated eccentric loading (AEL) and cluster sets in trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, and back squat to body mass ratio = 1.8 ± 0.3). Four load condition sessions consisted of traditionally loaded (TL) "straight sets," TL cluster (TLC) sets, AEL cluster (AEC) sets, and AEL "straight sets" where only the first repetition had eccentric overload (AEL1). An interrepetition rest interval of 30 seconds was prescribed for both TLC and AEC. Concentric intensity for all load conditions was 80% 1 repetition maximum (1RM). Accentuated eccentric loading was applied to repetitions using weight releasers with total eccentric load equivalent to 105% of concentric 1RM. Traditionally loaded cluster had statistically greater concentric outputs than TL. Furthermore, statistically greater eccentric and concentric outputs were observed during AEC compared with TL with the exception of peak power. Statistically greater concentric characteristics were observed in TLC compared with AEL1, but statistically greater eccentric outputs were observed in AEL1. In the 2 cluster set conditions, statistically greater concentric rate of force development (RFDCON) (d = 0.470, p < 0.001) and average velocity (vavg) (d = 0.560, p < 0.001) in TLC compared with AEC were observed. However, statistically greater eccentric work (WECC) (d = 2.096, p < 0.001) and eccentric RFD (RFDECC) (d = 0.424, p < 0.001) were observed in AEC compared with TLC. Overall, eccentric overload demonstrated efficacy as a means of increasing eccentric work and RFD, but not as a means of potentiating concentric output. Finally, interrepetition rest seems to have the largest influence on concentric power output and RFD.

Preliminary Investigation Into the Effect of ACTN3 and ACE Polymorphisms on Muscle and Performance Characteristics.

ABSTRACT: Wagle, JP, Carroll, KM, Cunanan, AJ, Wetmore, A, Taber, CB, DeWeese, BH, Sato, K, Stuart, CA, and Stone, MH. Preliminary investigation into the effect of ACTN3 and ACE polymorphisms on muscle and performance characteristics. J Strength Cond Res 35(3): 688-694, 2021-The purpose of this investigation was to explore the phenotypic and performance outcomes associated with ACTN3 and ACE polymorphisms. Ten trained men (age = 25.8 ± 3.0 years, height = 183.3 ± 4.1 cm, body mass = 92.3 ± 9.3 kg, and back squat to body mass ratio = 1.8 ± 0.3) participated. Blood samples were analyzed to determine ACTN3 and ACE polymorphisms. Standing ultrasonography images of the vastus lateralis (VL) were collected to determine whole muscle cross-sectional area (CSA-M), and a percutaneous muscle biopsy of the VL was collected to determine type I-specific CSA (CSA-T1), type II-specific CSA (CSA-T2), and type II to type I CSA ratio (CSA-R). Isometric squats were performed on force platforms with data used to determine peak force (IPF), allometrically scaled peak force (IPFa), and rate of force development (RFD) at various timepoints. One repetition maximum back squats were performed, whereby allometrically scaled dynamic strength (DSa) was determined. Cohen's d effect sizes revealed ACTN3 RR and ACE DD tended to result in greater CSA-M but differ in how they contribute to performance. ACTN3 RR's influence seems to be in the type II fibers, altering maximal strength, and ACE DD may influence RFD capabilities through a favorable CSA-R. Although the findings of the current investigation are limited by the sample size, the findings demonstrate the potential influence of ACTN3 and ACE polymorphisms on isometric and dynamic strength testing. This study may serve as a framework to generate hypotheses regarding the effect of genetics on performance.

Pre-Training Muscle Characteristics of Subjects Who Are Obese Determine How Well Exercise Training Will Improve Their Insulin Responsiveness.

Stuart, CA, Lee, ML, South, MA, Howell, MEA, Cartwright, BM, Ramsey, MW, and Stone, MH. Pre-training muscle characteristics of subjects who are obese determine how well exercise training will improve their insulin responsiveness. J Strength Cond Res 31(3): 798-808, 2017-Only half of prediabetic subjects who are obese who underwent exercise training without weight loss increased their insulin responsiveness. We hypothesized that those who improved their insulin responsiveness might have pretraining characteristics favoring a positive response to exercise training. Thirty nondiabetic subjects who were obese volunteered for 8 weeks of either strength training or endurance training. During training, subjects increased their caloric intake to prevent weight loss. Insulin responsiveness by euglycemic clamps and muscle fiber composition, and expression of muscle key biochemical pathways were quantified. Positive responders initially had 52% higher intermediate muscle fibers (fiber type IIa) with 27% lower slow-twitch fibers (type I) and 23% lower expression of muscle insulin receptors. Whether after weight training or stationary bike training, positive responders' fiber type shifted away from type I and type IIa fibers to an increased proportion of type IIx fibers (fast twitch). Muscle insulin receptor expression and glucose transporter type 4 (GLUT4) expression increased in all trained subjects, but these moderate changes did not consistently translate to improvement in whole-body insulin responsiveness. Exercise training of previously sedentary subjects who are obese can result in muscle remodeling and increased expression of key elements of the insulin pathway, but in the absence of weight loss, insulin sensitivity improvement was modest and limited to about half of the participants. Our data suggest rather than responders being more fit, they may have been less fit, only catching up to the other half of subjects who are obese whose insulin responsiveness did not increase beyond their pretraining baseline.

Myosin content of individual human muscle fibers isolated by laser capture microdissection.

Muscle fiber composition correlates with insulin resistance, and exercise training can increase slow-twitch (type I) fibers and, thereby, mitigate diabetes risk. Human skeletal muscle is made up of three distinct fiber types, but muscle contains many more isoforms of myosin heavy and light chains, which are coded by 15 and 11 different genes, respectively. Laser capture microdissection techniques allow assessment of mRNA and protein content in individual fibers. We found that specific human fiber types contain different mixtures of myosin heavy and light chains. Fast-twitch (type IIx) fibers consistently contained myosin heavy chains 1, 2, and 4 and myosin light chain 1. Type I fibers always contained myosin heavy chains 6 and 7 (MYH6 and MYH7) and myosin light chain 3 (MYL3), whereas MYH6, MYH7, and MYL3 were nearly absent from type IIx fibers. In contrast to cardiomyocytes, where MYH6 (also known as α-myosin heavy chain) is seen solely in fast-twitch cells, only slow-twitch fibers of skeletal muscle contained MYH6. Classical fast myosin heavy chains (MHC1, MHC2, and MHC4) were present in variable proportions in all fiber types, but significant MYH6 and MYH7 expression indicated slow-twitch phenotype, and the absence of these two isoforms determined a fast-twitch phenotype. The mixed myosin heavy and light chain content of type IIa fibers was consistent with its role as a transition between fast and slow phenotypes. These new observations suggest that the presence or absence of MYH6 and MYH7 proteins dictates the slow- or fast-twitch phenotype in skeletal muscle.

Effects of Short-Term Free-Weight and Semiblock Periodization Resistance Training on Metabolic Syndrome.

South, MA, Layne, AS, Stuart, CA, Triplett, NT, Ramsey, MW, Howell, ME, Sands, WA, Mizuguchi, S, Hornsby, WG, Kavanaugh, AA, and Stone, MH. Effects of short-term free-weight and semiblock periodization resistance training on metabolic syndrome. J Strength Cond Res 30(10): 2682-2696, 2016-The effects of short-term resistance training on performance and health variables associated with prolonged sedentary lifestyle and metabolic syndrome (MS) were investigated. Resistance training may alter a number of health-related, physiological, and performance variables. As a result, resistance training can be used as a valuable tool in ameliorating the effects of a sedentary lifestyle including those associated with MS. Nineteen previously sedentary subjects (10 with MS and 9 with nonmetabolic syndrome [NMS]) underwent 8 weeks of supervised resistance training. Maximum strength was measured using an isometric midthigh pull and resulting force-time curve. Vertical jump height (JH) and power were measured using a force plate. The muscle cross-sectional area (CSA) and type were examined using muscle biopsy and standard analysis techniques. Aerobic power was measured on a cycle ergometer using a ParvoMedics 2400 Metabolic system. Endurance was measured as time to exhaustion on a cycle ergometer. After training, maximum isometric strength, JH, jump power, and V[Combining Dot Above]O2peak increased by approximately 10% (or more) in both the metabolic and NMS groups (both male and female subjects). Over 8 weeks of training, body mass did not change statistically, but percent body fat decreased in subjects with the MS and in women, and lean body mass increased in all groups (p ≤ 0.05). Few alterations were noted in the fiber type. Men had larger CSAs compared those of with women, and there was a fiber-specific trend toward hypertrophy over time. In summary, 8 weeks of semiblock free-weight resistance training improved several performance variables and some cardiovascular factors associated with MS.

Skeletal Muscle Fiber Adaptations Following Resistance Training Using Repetition Maximums or Relative Intensity.

The purpose of the study was to compare the physiological responses of skeletal muscle to a resistance training (RT) program using repetition maximum (RM) or relative intensity (RISR). Fifteen well-trained males underwent RT 3 d·wk-1 for 10 weeks in either an RM group (n = 8) or RISR group (n = 7). The RM group achieved a relative maximum each day, while the RISR group trained based on percentages. The RM group exercised until muscular failure on each exercise, while the RISR group did not reach muscular failure throughout the intervention. Percutaneous needle biopsies of the vastus lateralis were obtained pre-post the training intervention, along with ultrasonography measures. Dependent variables were: Fiber type-specific cross-sectional area (CSA); anatomical CSA (ACSA); muscle thickness (MT); mammalian target of rapamycin (mTOR); adenosine monophosphate protein kinase (AMPK); and myosin heavy chains (MHC) specific for type I (MHC1), type IIA (MHC2A), and type IIX (MHC2X). Mixed-design analysis of variance and effect size using Hedge's g were used to assess within- and between-group alterations. RISR statistically increased type I CSA (p = 0.018, g = 0.56), type II CSA (p = 0.012, g = 0.81), ACSA (p = 0.002, g = 0.53), and MT (p < 0.001, g = 1.47). RISR also yielded a significant mTOR reduction (p = 0.031, g = -1.40). Conversely, RM statistically increased only MT (p = 0.003, g = 0.80). Between-group effect sizes supported RISR for type I CSA (g = 0.48), type II CSA (g = 0.50), ACSA (g = 1.03), MT (g = 0.72), MHC2X (g = 0.31), MHC2A (g = 0.87), and MHC1 (g = 0.59); with all other effects being of trivial magnitude (g < 0.20). Our results demonstrated greater adaptations in fiber size, whole-muscle size, and several key contractile proteins when using RISR compared to RM loading paradigms.

Divergent Performance Outcomes Following Resistance Training Using Repetition Maximums or Relative Intensity.

PURPOSE: To compare repetition maximum (RM) to relative intensity using sets and repetitions (RISR) resistance training on measures of training load, vertical jump, and force production in well-trained lifters. METHODS: Fifteen well-trained (isometric peak force = 4403.61 [664.69] N, mean [SD]) males underwent resistance training 3 d/wk for 10 wk in either an RM group (n = 8) or RISR group (n = 7). Weeks 8 to 10 consisted of a tapering period for both groups. The RM group achieved a relative maximum each day, whereas the RISR group trained based on percentages. Testing at 5 time points included unweighted (<1 kg) and 20-kg squat jumps, countermovement jumps, and isometric midthigh pulls. Mixed-design analyses of variance and effect size using Hedge's g were used to assess within- and between-groups alterations. RESULTS: Moderate between-groups effect sizes were observed for all squat-jump and countermovement-jump conditions supporting the RISR group (g = 0.76-1.07). A small between-groups effect size supported RISR for allometrically scaled isometric peak force (g = 0.20). Large and moderate between-groups effect sizes supported RISR for rate of force development from 0 to 50 ms (g = 1.25) and 0 to 100 ms (g = 0.89). Weekly volume load displacement was not different between groups (P > .05); however, training strain was statistically greater in the RM group (P < .05). CONCLUSIONS: Overall, this study demonstrated that RISR training yielded greater improvements in vertical jump, rate of force development, and maximal strength compared with RM training, which may be explained partly by differences in the imposed training stress and the use of failure/nonfailure training in a well-trained population.

IGF-1 controls GLUT3 expression in muscle via the transcriptional factor Sp1.

Glucose transporter 3 (GLUT3), while first found in human fetal muscle, is predominantly expressed in brain and neural tissue. By several independent techniques we have previously shown that GLUT3 is expressed in human skeletal muscle cells. The structure of the human GLUT3 gene has not been previously reported nor has there been any evaluation of the 5'-untranslated region (UTR). To this end, we have cloned and sequenced the human GLUT3 gene. Insulin-like growth factor-1 (IGF-1) increased endogenous Glut3 protein in cultured L6 myotubes, and similarly stimulated luciferase activity in a construct of the human GLUT3 5'-UTR linked to a luciferase reporter gene. Actinomycin D, an inhibitor of mRNA synthesis, prevented IGF-1 stimulation of Glut3 protein. Transfection of L6 cells with Sp1 increased Glut3 and augmented IGF-1 stimulation of Glut3 expression. Knockdown of Glut3 expression in cultured L6 muscle cells using small interference RNA (siRNA) specific for Glut3 significantly reduced myocyte glucose uptake. DNAse footprinting and gel shift assays showed Sp1 specifically bound to the human GLUT3 5'-UTR. Substitution mutants of the human GLUT3 5'-UTR luciferase construct indicated that only one of three Sp1 site clusters was involved in IGF-1 action. These data, using both a human GLUT3 5'-UTR construct and L6 cells' endogenous promoter, suggest that IGF-1 plays a role in maintaining muscle GLUT3 expression and basal glucose uptake via the transcriptional factor Sp1.

Repetition-to-Repetition Differences Using Cluster and Accentuated Eccentric Loading in the Back Squat.

The current investigation was an examination of the repetition-to-repetition magnitudes and changes in kinetic and kinematic characteristics of the back squat using accentuated eccentric loading (AEL) and cluster sets. Trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, back squat to body mass ratio = 1.8 ± 0.3) completed four load condition sessions, each consisting of three sets of five repetitions of either traditionally loaded straight sets (TL), traditionally loaded cluster sets (TLC), AEL cluster sets (AEC), and AEL straight sets where only the initial repetition had eccentric overload (AEL1). Eccentric overload was applied using weight releasers, creating a total eccentric load equivalent to 105% of concentric one repetition maximum (1RM). Concentric load was 80% 1RM for all load conditions. Using straight sets (TL and AEL1) tended to decrease peak power (PP) (d = −1.90 to −0.76), concentric rate of force development (RFDCON) (d = −1.59 to −0.27), and average velocity (MV) (d = −3.91 to −1.29), with moderate decreases in MV using cluster sets (d = −0.81 to −0.62). Greater magnitude eccentric rate of force development (RFDECC) was observed using AEC at repetition three (R3) and five (R5) compared to all load conditions (d = 0.21⁻0.65). Large within-condition changes in RFDECC from repetition one to repetition three (∆REP1⁻3) were present using AEL1 (d = 1.51), demonstrating that RFDECC remained elevated for at least three repetitions despite overload only present on the initial repetition. Overall, cluster sets appear to permit higher magnitude and improved maintenance of concentric outputs throughout a set. Eccentric overload with the loading protocol used in the current study does not appear to potentiate concentric output regardless of set configuration but may cause greater RFDECC compared to traditional loading.

Muscle hypertrophy in prediabetic men after 16 wk of resistance training.

Resistance training of healthy young men typically results in muscle hypertrophy and a shift in vastus lateralis composition away from type IIx fibers to an increase in IIa fiber content. Our previous studies of 8 wk of resistance training found that many metabolic syndrome men and women paradoxically increased IIx fibers with a decrease in IIa fibers. To confirm the hypothesis that obese subjects might have muscle remodeling after resistance training very different from healthy lean subjects, we subjected a group of nine obese male volunteers to progressive resistance training for a total of 16 wk. In these studies, weight loss was discouraged so that muscle changes would be attributed to the training alone. Detailed assessments included comparisons of histological examinations of needle biopsies of vastus lateralis muscle pretraining and at 8 and 16 wk. Prolonging the training from 8 to 16 wk resulted in increased strength, improved body composition, and more muscle fiber hypertrophy, but euglycemic clamp-quantified insulin responsiveness did not improve. Similar to prior studies, muscle fiber composition shifted toward more fast-twitch type IIx fibers (23 to 42%). Eight weeks of resistance training increased the muscle expression of phosphorylated Akt2 and mTOR. Muscle GLUT4 expression increased, although insulin receptor and IRS-1 expression did not change. We conclude that resistance training of prediabetic obese subjects is effective at changing muscle, resulting in fiber hypertrophy and increased type IIx fiber content, and these changes continue up to 16 wk of training.NEW & NOTEWORTHY Obese, insulin-resistant men responded to 16 wk of progressive resistance training with muscle hypertrophy and increased strength and a shift in muscle fiber composition toward fast-twitch, type IIx fibers. Activation of muscle mTOR was increased by 8 wk but did not increase further at 16 wk despite continued augmentation of peak power and rate of force generation.

Comparison of the Relationship between Lying and Standing Ultrasonography Measures of Muscle Morphology with Isometric and Dynamic Force Production Capabilities.

The purpose of the current study was (1) to examine the differences between standing and lying measures of vastus lateralis (VL), muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA) using ultrasonography; and (2) to explore the relationships between lying and standing measures with isometric and dynamic assessments of force production-specifically peak force, rate of force development (RFD), impulse, and one-repetition maximum back squat. Fourteen resistance-trained subjects (age = 26.8 ± 4.0 years, height = 181.4 ± 6.0 cm, body mass = 89.8 ± 10.7 kg, back squat to body mass ratio = 1.84 ± 0.34) agreed to participate. Lying and standing ultrasonography images of the right VL were collected following 48 hours of rest. Isometric squat assessments followed ultrasonography, and were performed on force platforms with data used to determine isometric peak force (IPF), as well as RFD and impulse at various time points. Forty-eight hours later, one-repetition maximum back squats were performed by each subject. Paired-samples t-tests revealed statistically significant differences between standing and lying measurements of MT (p < 0.001), PA (p < 0.001), and CSA (p ≤ 0.05), with standing values larger in all cases. Further, standing measures were correlated more strongly and abundantly to isometric and dynamic performance. These results suggest that if practitioners intend to gain insight into strength-power potential based on ultrasonography measurements, performing the measurement collection with the athlete in a standing posture may be preferred.

Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans.

We evaluated insulin action in skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) in 5 extremely obese women with acanthosis nigricans (AN), who had normal oral glucose tolerance, and 5 healthy lean subjects, by using a 5-stage pancreatic clamp and stable isotopically labeled tracer infusion. Basal plasma insulin concentration was much greater in obese subjects with AN than lean subjects (54.8 +/- 4.5 vs 8.0 +/- 1.3 microU/mL, P < .001), but basal glucose and free fatty acid concentrations were similar in both groups. During stage 1 of the clamp, glucose rate of appearance (R(a)) (2.6 +/- 0.3 vs 3.7 +/- 0.3 micromol x kg FFM(-1) x min(-1), P = .02) and palmitate R(a) (2.4 +/- 0.6 vs 7.0 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < .05) were greater in obese subjects with AN than lean subjects despite slightly greater plasma insulin concentration in subjects with AN (3.0 +/- 0.7 vs 1.1 +/- 0.4 microU/mL, P < .05). The area under the curve for palmitate R(a) (1867 +/- 501 vs 663 +/- 75 micromol x kg FFM(-1) x 600 min(-1), P = .03) and glucose R(a) (1920 +/- 374 vs 1032 +/- 88 micromol x kg FFM(-1) x 600 min(-1), P = .02) during the entire clamp procedure was greater in subjects with AN than lean subjects. During intermediate insulin conditions (plasma insulin, approximately 35 microU/mL), palmitate R(a) was 5-fold greater in subjects with AN than in lean subjects (2.6 +/- 1.1 vs 0.5 +/- 0.2 micromol x kg FFM(-1) x min(-1), P = .05). Maximal glucose disposal was markedly lower in obese subjects with AN than in lean subjects (13.0 +/- 0.8 vs 23.4 +/- 1.8 mg x kg FFM(-1) x min(-1), P = .01) despite greater peak plasma insulin concentration (1842 +/- 254 vs 598 +/- 38 microU/mL, P < .05). These data demonstrate obese young adults with AN have marked insulin resistance in multiple tissues. However, marked insulin hypersecretion can compensate for impaired insulin action, resulting in normal glucose and fatty acid metabolism during basal conditions.

Gene silencing using small interference RNA in mast cells.

Small interfering RNA (siRNA) is a potent and specific method of inducing gene silencing through induction of RNA interference. siRNAs can be allowed for in vitro and in vivo applications. siRNAs have been successfully studied in vitro, but little is known about its efficacy in vivo. We have successfully applied the siRNA technique for silencing glucose transporter 3 in cultured L6 muscle cells. The siRNA technique has been used efficiently to silence RasGRP4 expression in mast cells.

Stimulation of lipolysis by tumor necrosis factor-alpha in 3T3-L1 adipocytes is glucose dependent: implications for long-term regulation of lipolysis.

Tumor necrosis factor-alpha (TNF-alpha) and hyperglycemia both impair insulin sensitivity in vivo. This may be secondary to stimulation of adipose tissue lipolysis and consequent increased circulating free fatty acids (FFAs). Here we report that neither TNF-alpha nor glucose alone has a pronounced effect on lipolysis in 3T3-L1 adipocytes. However, the combination of TNF-alpha plus glucose markedly stimulates lipolysis. Glucose does not affect the ability of isoproterenol to stimulate lipolysis. Alternative substrates such as acetate, pyruvate, and lactate do not allow the TNF-alpha effect. Mannose was almost as effective as glucose; fructose was marginally effective, but galactose was ineffective. The effectiveness of the sugars corresponded with production of lactate, i.e., the cells readily produced lactate from glucose or mannose, slightly from fructose, and not at all from galactose. The ability of TNF-alpha to phosphorylate extracellular signal-regulated kinase 1 (ERK1) and ERK2 and to downregulate perilipin (which has been implicated in the lipolytic effect of TNF-alpha) was not affected by glucose. We conclude that the lipolytic action of TNF-alpha is influenced by glucose in 3T3-L1 adipocytes. The findings suggest that glucose metabolism is required for the lipolytic response to TNF-alpha but not for early signaling events. These findings suggest novel mechanisms by which TNF-alpha and hyperglycemia raise FFA levels and induce insulin resistance.

Angiopoietin-1 inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating fas expression and via the PI3K/Akt pathway.

Angiopoietin-1 (Ang-1) is essential for the maturation of blood vessels during vasculogenesis. Besides angiogenesis, recent publications indicate that Ang-1 is also a potent survival factor for endothelial cells; however, the mechanisms by which pathways remain elusive. Doxorubicin (DOX) is a powerful anticancer drug, but its use is severely restricted by its cardiotoxicity. The authors report here that Ang-1 inhibits DOX-induced cell death in human umbilical vein endothelial cells (HUVECs). Interestingly, the DOX-induced up-regulation in Fas (CD95/APO-1) and Fas ligand expression could be blocked by Ang-1, indicating a pivotal role of Ang-1 in DOX-induced Fas and Fas ligand expression. In addition, the prevention of cell death in this model system seems to be dependent on the activation of phosphatidylinositol 3-kinase (PI3K)/Akt, as Ang-1 fails to inhibit DOX-induced cell death while PI3K/Akt pathway was blocked by the PI3K inhibitor LY294002. Moreover, Ang-1 inhibits DOX-induced up-regulation of p53 through PI3K/Akt. Therefore, Ang-1 is a potent inhibitor for DOX-induced cell death through Fas and PI3K/Akt-mediated pathways.

Insulinoma in a patient with tuberous sclerosis: is there an association?

OBJECTIVE: To describe a patient with tuberous sclerosis who, on initial assessment, had neurologic symptoms, which were ultimately found to be caused by an insulinoma. METHODS: We present a case report with clinical, laboratory, and radiologic data. The literature is reviewed relative to tuberous sclerosis and islet cell tumors, and a possible association is discussed. RESULTS: A 43-year-old man with a history of tuberous sclerosis required medical attention because of mental confusion and slurred speech and was found to have hypoglycemia. Neuroradiologic imaging showed no new lesions to account for his symptoms. His physical examination was striking for a large abdominal mass, which showed increased uptake on octreotide scanning. After surgical resection, the mass measured 21 cm and was found to be an insulinoma. Blood glucose values were normal postoperatively and on follow-up, and the patient had no recurrence of the symptoms. CONCLUSION: From this report, we emphasize two findings. First, we draw clinicians' attention to the possibility of an association between islet cell tumors and tuberous sclerosis and suggest consideration of this diagnosis in patients with tuberous sclerosis who have new or worsening neurologic symptoms. Second, the insulinoma we describe is, to our knowledge, the largest to be reported thus far in the literature.

Effect of dietary sodium on fluid/electrolyte regulation during bed rest.

BACKGROUND: A negative fluid balance during bed rest (BR) is accompanied by decreased plasma volume (PV) which contributes to cardiovascular deconditioning. HYPOTHESIS: We hypothesized that increasing dietary sodium while controlling fluid intake would increase plasma osmolality (POSM), stimulate fluid conserving hormones, and reduce fluid/electrolyte (F/E) losses during BR; conversely, decreasing dietary sodium would decrease POSM, suppress fluid conserving hormones, and increase F/E losses. METHODS: We controlled fluid intake (30 ml x kg(-1) x d(-1)) in 17 men who consumed either a 4.0 +/- 0.06 g x d(-1) (174 mmol x d(-1)) (CONT; n = 6), 1.0 +/- 0.02 g x d(-1) (43 mmol x d(-1)) (LS; n = 6), or 10.0 +/- 0.04 g x d(-1) (430 mmol x d(-1)) (HS; n = 5) sodium diet before, during, and after 21 d of 6 degrees head-down BR. PV, total body water, urine volume and osmolality, POSM, and F/E controlling hormone concentrations were measured. RESULTS: In HS subjects, plasma renin activity (-92%), plasma/urinary aldosterone (-59%; -64%), and PV (-15.0%; 6.0 ml x kg(-1); p < 0.05) decreased while plasma atrial natriuretic peptide (+34%) and urine antidiuretic hormone (+24%) increased during BR (p < 0.05) compared with CONT. In LS, plasma renin activity (+166%), plasma aldosterone (+167%), plasma antidiuretic hormone (+19%), and urinary aldosterone (+335%) increased with no change in PV compared with CONT (p < 0.05). Total body water did not change in any of the subjects. CONCLUSIONS: Contrary to our hypothesis, increasing dietary sodium while controlling fluid intake during BR resulted in a greater loss of PV compared with the CONT subjects. Reducing dietary sodium while controlling fluid intake did not alter the PV response during BR compared with CONT subjects.

Insulin resistance and muscle insulin receptor substrate-1 serine hyperphosphorylation.

Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin-responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate-1 (IRS-1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS-1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS-1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS-1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS-1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c-Jun N-terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS-1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS-1 diminishes the transmission of the insulin signal and thereby decreases the insulin-stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS-1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss.

Insulin responsiveness in metabolic syndrome after eight weeks of cycle training.

INTRODUCTION: Insulin resistance in obesity is decreased after successful diet and exercise. Aerobic exercise training alone was evaluated as an intervention in subjects with the metabolic syndrome. METHODS: Eighteen nondiabetic, sedentary subjects, 11 with the metabolic syndrome, participated in 8 wk of increasing intensity stationary cycle training. RESULTS: Cycle training without weight loss did not change insulin resistance in metabolic syndrome subjects or sedentary control subjects. Maximal oxygen consumption (V·O 2max), activated muscle AMP-dependent kinase, and muscle mitochondrial marker ATP synthase all increased. Strength, lean body mass, and fat mass did not change. The activated mammalian target of rapamycin was not different after training. Training induced a shift in muscle fiber composition in both groups but in opposite directions. The proportion of type 2× fibers decreased with a concomitant increase in type 2a mixed fibers in the control subjects, but in metabolic syndrome, type 2× fiber proportion increased and type 1 fibers decreased. Muscle fiber diameters increased in all three fiber types in metabolic syndrome subjects. Muscle insulin receptor expression increased in both groups, and GLUT4 expression increased in the metabolic syndrome subjects. The excess phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser337 in metabolic syndrome muscle tended to increase further after training in spite of a decrease in total IRS-1. CONCLUSIONS: In the absence of weight loss, the cycle training of metabolic syndrome subjects resulted in enhanced mitochondrial biogenesis and increased the expression of insulin receptors and GLUT4 in muscle but did not decrease the insulin resistance. The failure for the insulin signal to proceed past IRS-1 tyrosine phosphorylation may be related to excess serine phosphorylation at IRS-1 Ser337, and this is not ameliorated by 8 wk of endurance exercise training.