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Biomedical subjects

H Wallberg-Henriksson

Publications and source records attributed to H Wallberg-Henriksson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Improved work capacity but unchanged peak oxygen uptake during primary rehabilitation in tetraplegic patients.

Individuals with cervical spinal cord lesions are characterised by markedly decreased aerobic capacity, accompanied by increased risk of developing cardiovascular disease. The aim of this study was to evaluate the effects of a primary rehabilitation programme that included three sessions of arm cycling per week on the endurance capacity in 10 male tetraplegic subjects (injury level C6-C8; eight ASIA-A and two ASIA-B). Peak oxygen uptake (peak VO2) was measured three times (at T1 approximately 99 +/- 10 days after injury. T2 approximately 2 months after T1, and at T3 approximately 2 months after T2). Ten paraplegic patients admitted to the hospital for primary rehabilitation served as controls. In the tetraplegic patients, mean peak load increased (22 +/- 2, 32 +/- 5, and 32 +/- 7 watt, at T1, T2 and T3 respectively) (P < 0.01), while mean peak VO2 did not change during the study (0.78 +/- 0.07, 0.86 +/- 0.08, and 0.81 +/- 0.06 1 x min-1, at T1, T2 and T3, respectively) (ns). In contrast peak VO2 was significantly higher in the paraplegic control group (1.37 +/- 0.08, 1.64 +/- 0.10 and 1.75 +/- 0.08 1 x min-1, respectively) (P < 0.001), and increased significantly during the study period (P < 0.001). Mean heart rate (HR) and mean stroke volume (SV), measured at corresponding submaximal work loads during the study did not change significantly in the tetraplegic patients. Mean systolic blood pressure (SBP), recorded immediately after peak arm exercise was low at all three tests (93 +/- 8, 89 +/- 6 and 84 +/- 6 mmHg) in the tetraplegic group. However, both muscle strength and 'activities of daily life' index improved significantly during the study period. Our results suggest that functional improvement in tetraplegic patients is not necessarily followed by aerobic metabolic improvement. We conclude that more time should be spent on arm endurance training, or training methods which activate larger muscle groups and/or increases blood pressure.

Adult↗
PubMed1998

Exercise-induced overexpression of key regulatory proteins involved in glucose uptake and metabolism in tetraplegic persons: molecular mechanism for improved glucose homeostasis.

Complete spinal cord lesion leads to profound metabolic abnormalities and striking changes in muscle morphology. Here we assess the effects of electrically stimulated leg cycling (ESLC) on whole body insulin sensitivity, skeletal muscle glucose metabolism, and muscle fiber morphology in five tetraplegic subjects with complete C5-C7 lesions. Physical training (seven ESLC sessions/wk for 8 wk) increased whole body insulin-stimulated glucose uptake by 33+/-13%, concomitant with a 2.1-fold increase in insulin-stimulated (100 microU/ml) 3-O-methylglucose transport in isolated vastus lateralis muscle. Physical training led to a marked increase in protein expression of GLUT4 (378+/-85%), glycogen synthase (526+/-146%), and hexokinase II (204+/-47%) in vastus lateralis muscle, whereas phosphofructokinase expression (282+/-97%) was not significantly changed. Hexokinase II activity was significantly increased, whereas activity of phosphofructokinase, glycogen synthase, and citrate synthase was not changed after training. Muscle fiber type distribution and fiber area were markedly altered compared to able-bodied subjects before ESLC training, with no change noted in either parameter after ECSL training. In conclusion, muscle contraction improves insulin action on whole body and cellular glucose uptake in cervical cord-injured persons through a major increase in protein expression of key genes involved in the regulation of glucose metabolism. Furthermore, improvements in insulin action on glucose metabolism are independent of changes in muscle fiber type distribution.

3-O-Methylglucose↗
PubMed1998

Skeletal muscle insulin resistance after trauma: insulin signaling and glucose transport.

Surgical trauma induces peripheral insulin resistance; however, the cellular mechanism has not been fully elucidated. We examined the effects of surgical trauma on insulin receptor signaling and glucose transport in skeletal muscle, a tissue that plays a predominant role in maintaining glucose homeostasis. Surgical trauma was induced by intestinal resection in the rat. Receptor phosphorylation was not altered with surgical trauma. Phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase association was increased by 60 and 82% compared with fasted and fed controls, respectively (P < 0. 05). Similar results were observed for insulin receptor substrate-1-associated PI 3-kinase activity. Insulin-stimulated protein kinase B (Akt kinase) phosphorylation was increased by 2.2-fold after surgical trauma (P < 0.05). The hyperphosphorylation of Akt is likely to reflect amplification of PI 3-kinase after insulin stimulation. Submaximal rates of insulin-stimulated 3-O-methylglucose transport were reduced in trauma vs. fasted rats by 51 and 38% for 100 and 200 microU/ml of insulin, respectively (P < 0.05). In conclusion, insulin resistance in skeletal muscle after surgical trauma is associated with reduced glucose transport but not with impaired insulin signaling to PI 3-kinase or its downstream target, Akt. The surgical trauma model presented in this report provides a useful tool to further elucidate the molecular mechanism(s) underlying the development of insulin resistance after surgical trauma.

Animals↗
PubMed1998

Exercise in the management of non-insulin-dependent diabetes mellitus.

The incidence of non-insulin-dependent diabetes mellitus (NIDDM) has increased worldwide during the last decades, despite the development of effective drug therapy and improved clinical diagnoses. NIDDM is one of the major causes of disability and death due to the complications accompanying this disease. For the well-being of the patient, and from a public healthcare perspective, the development of effective intervention strategies is essential in order to reduce the incidence of NIDDM and its resulting complications. For the patient, and for society at large, early intervention programmes are beneficial, especially from a cost-benefit perspective. Physical activity exerts pronounced effects on substrate utilisation and insulin sensitivity, which in turn potentially lowers blood glucose and lipid levels. Exercise training also improves many other physiological and metabolic abnormalities that are associated with NIDDM such as lowering body fat, reducing blood pressure and normalising dyslipoproteinaemia. Clearly, regular physical activity plays an important role in the prevention and treatment of NIDDM. Since physical activity has been shown in prospective studies to protect against the development of NIDDM, physical training programmes suitable for individuals at risk for NIDDM should be incorporated into the medical care system to a greater extent. One general determinant in a strategy to develop a preventive programme for NIDDM is to establish a testing programme which includes VO2max determinations for individuals who are at risk of developing NIDDM. Before initiating regular physical training for people with NIDDM, a complete physical examination aimed at identifying any long term complications of diabetes is recommended. All individuals above the age of 35 years should perform an exercise stress test before engaging in an exercise programme which includes moderate to vigorously intense exercise. The stress test will identify individuals with previously undiagnosed ischaemic heart disease and abnormal blood pressure responses. It is important to diagnose proliferative retinopathy, microalbuminuria, peripheral and/or autonomic neuropathy in patients with NIDDM before they participate in an exercise programme. If any diabetic complications are present, the exercise protocol should be modified accordingly. The exercise programme should consist of moderate intensity aerobic exercise. Resistance training and high intensity exercises should only be performed by individuals without proliferative retinopathy or hypertension. Once enrolled in the exercise programme, the patient must be educated with regard to proper footwear and daily foot inspections. Fluid intake is of great importance when exercising for prolonged periods or in warm and humid environments. With the proper motivation and medical supervision, people with NIDDM can enjoy regular physical exercise as a means of enhancing metabolic control and improving insulin sensitivity.

Adipose Tissue↗
PubMed1998

Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects.

The serine/threonine kinase Akt (PKB/Rac) has been implicated as playing a role in the insulin-signaling pathway to glucose transport. Little is known regarding the regulation of Akt kinase activity in insulin-sensitive tissues, such as skeletal muscle, or whether this regulation is altered in insulin-resistant states such as NIDDM. We examined the effect of insulin on Akt kinase activity in skeletal muscle from six NIDDM patients and six healthy subjects. Whole-body insulin sensitivity, assessed by the euglycemic-hyperinsulinemic clamp, was significantly lower in NIDDM subjects (P < 0.001), and this was accompanied by impaired in vitro insulin-stimulated glucose transport in skeletal muscle. In both groups, insulin induced a significant increase in Akt kinase activity, but the response to maximal insulin (60 nmol/l) was markedly reduced in skeletal muscle from NIDDM subjects (66% of control levels, P < 0.01). Impaired Akt kinase activity was not accompanied by decreased protein expression of Akt. Instead, a trend toward increased Akt expression was noted in skeletal muscle from NIDDM subjects (P < 0.1). These parallel defects in insulin-stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM.

Biological Transport↗
PubMed1998

Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients.

Two recently described proteins in the mitochondrial uncoupling protein (UCP) family, UCP-2 and UCP-3, have been linked to phenotypes of obesity and NIDDM. We determined the mRNA levels of UCP-2 and UCP-3 in skeletal muscle of NIDDM patients and of healthy control subjects. No difference in the mRNA levels or in the protein expression of UCP-2 was observed between the two groups. In contrast, mRNA levels of UCP-3 were significantly reduced in skeletal muscle of NIDDM patients compared with control subjects. In the NIDDM patients, a positive correlation between UCP-3 expression and whole-body insulin-mediated glucose utilization rate was also noted. These results suggest that UCP-3 regulation may be altered in states of insulin resistance.

Blood Glucose↗
PubMed1998

Insulin action in skeletal muscle from patients with NIDDM.

Insulin resistance in peripheral tissues is a common feature of non insulin-dependent diabetes mellitus (NIDDM). The decrease in insulin-mediated peripheral glucose uptake in NIDDM patients can be localized to defects in insulin action on glucose transport in skeletal muscle. Following short term in vitro exposure to both submaximal and maximal concentrations of insulin, 3-O-methylglucose transport rates are 40-50% lower in isolated skeletal muscle strips from NIDDM patients when compared to muscle strips from nondiabetic subjects. In addition, we have shown that physiological levels of insulin induce a 1.6-2.0 fold increase in GLUT4 content in skeletal muscle plasma membranes from control subjects, whereas no significant increase was noted in NIDDM skeletal muscle. Impaired insulin-stimulated GLUT4 translocation and glucose transport in NIDDM skeletal muscle is associated with reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI3-kinase activity. The reduced IRS-1 phosphorylation cannot be attributed to decreased protein expression, since the IRS-1 protein content is similar between NIDDM subjects and controls. Altered glycemia may contribute to decreased insulin-mediated glucose transport in skeletal muscle from NIDDM patients. We have shown that insulin-stimulated glucose transport is normalized in vitro in the presence of euglycemia, but not in the presence of hyperglycemia. Thus, the circulating level of glucose may independently regulate insulin stimulated glucose transport in skeletal muscle from NIDDM patients via a down regulation of the insulin signaling cascade.

Diabetes Mellitus, Type 2↗
PubMed1997

Differential regulation of phosphoinositide 3-kinase adapter subunit variants by insulin in human skeletal muscle.

The role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signaling was evaluated in human skeletal muscle. Insulin stimulated both antiphosphotyrosine-precipitable PI 3-kinase activity and 3-O-methylglucose transport in isolated skeletal muscle (both approximately 2-3-fold). Insulin stimulation of 3-O-methylglucose transport was inhibited by the PI 3-kinase inhibitor LY294002 (IC50 = 2.5 microM). The PI 3-kinase adapter subunits were purified from muscle lysates using phosphopeptide beads based on the Tyr-751 region of the platelet-derived growth factor receptor. Immunoblotting of the material adsorbed onto the phosphopeptide beads revealed the presence of p85alpha, p85beta, p55(PIK)/p55gamma, and p50 adapter subunit isoforms. In addition, p85alpha-NSH2 antibodies recognized four adapter subunit variants of 54, 53, 48, and 46 kDa, the latter corresponding to the p50 splice variant. Serial immunoprecipitations demonstrated that these four proteins were associated with a large proportion of the total PI 3-kinase activity immunoprecipitated by p85alpha-NSH2 domain antibodies. Antibodies to p85beta, p55(PIK)/p55gamma, and the p50 adapter subunit also immunoprecipitated PI 3-kinase activity from human muscle lysates. A large proportion of the total cellular pool of the 53-kDa variant, p50, and p55(PIK) was present in antiphosphotyrosine immunoprecipitates from unstimulated muscle, whereas these immunoprecipitates contained only a very small proportion of the cellular pool of p85alpha, p85beta, and the 48-kDa variant. Insulin greatly increased the levels of the 48-kDa variant in antiphosphotyrosine immunoprecipitates and caused smaller -fold increases in the levels of p85alpha, p85beta, and the 53-kDa variant. The levels of p50 and p55(PIK) were not significantly changed. These properties indicate mechanisms by which specificity is achieved in the PI 3-kinase signaling system.

3-O-Methylglucose↗
PubMed1997

Involvement of phosphoinositide 3-kinase in insulin stimulation of MAP-kinase and phosphorylation of protein kinase-B in human skeletal muscle: implications for glucose metabolism.

Isolated skeletal muscle from healthy individuals was used to evaluate the role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signalling pathways regulating mitogen activated protein kinase (MAP-kinase) and protein kinase-B and to investigate whether MAP-kinase was involved in signalling pathways regulating glucose metabolism. Insulin stimulated glycogen synthase activity (approximately 1.7 fold), increased 3-o-methylglucose transport into human skeletal muscle strips (approximately 2 fold) and stimulated phosphorylation of the p42 ERK-2 isoform of MAP-kinase. This phosphorylation of p42 ERK2 was not blocked by the PI 3-kinase inhibitors LY294002 and wortmannin although it was blocked by the MAP-kinase kinase (MEK) inhibitor PD 98059. However, PD98059 (up to 20 micromol/l) did not block insulin activation of glycogen synthase or stimulation of 3-o-methylglucose transport. Wortmannin and LY294002 did block insulin stimulation of protein kinase-B (PKB) phosphorylation and stimulation of 3-o-methylglucose transport was inhibited by wortmannin (IC50 approximately 100 nmol/l). These results indicate that MAP-kinase is activated by insulin in human skeletal muscle by a PI 3-kinase independent pathway. Furthermore this activation is not necessary for insulin stimulation of glucose transport or activation of glycogen synthase in this tissue.

3-O-Methylglucose↗
PubMed1997

Improved body composition after 8 wk of electrically stimulated leg cycling in tetraplegic patients.

The practical aspects of utilizing electrically stimulated leg cycling (ESLC) to counteract alterations in body composition were investigated in five tetraplegic subjects with long-standing complete spinal cord injuries (C5-C7). After a 2-wk adaptation period, the subjects performed seven ESLC sessions per week for 8 wk. No adverse reactions were noted in response to the ESLC program. The ESLC sessions were accompanied by higher lactate concentrations compared with arm exercise. Heart rate and blood pressure response revealed clear, but not serious, signs of autonomic dysreflexia in the beginning of the ESLC sessions. Body temperature increased moderately during the ESLC sessions. Peak oxygen uptake (Vo2) during an ESLC session increased by 70% (P < 0.05) after 8 wk of training. Body composition, evaluated by dual-energy X-ray absorptiometry (DEXA), demonstrated an increase in lean body mass (LBM) from 66.2 +/- 2.6 to 68.2 +/- 2.1% (P < 0.05), with a concomitant decrease in whole body fat (BF) content from 29.7 +/- 2.6 to 27.8 +/- 2.1% (P < 0.05) after training. The cross-sectional area of quadriceps, hamstrings, gluteus maximus, and gluteus medius muscles, measured by computer tomographic scans, increased from 267 +/- 27 to 324 +/- 27 cm2 (P < 0.05) after the training. In conclusion, daily ESLC sessions during a 2-mo period resulted in increased LBM, decreased BF content, and increased muscular endurance in tetraplegic subjects without any noticeable adverse effects.

Absorptiometry, Photon↗
PubMed1997

Effect of insulin on GLUT4 cell surface content and turnover rate in human skeletal muscle as measured by the exofacial bis-mannose photolabeling technique.

Insulin-stimulated glucose transport across the skeletal muscle cell membrane is a major regulatory step in postprandial glucose disposal. To estimate the total molar concentration of GLUT4 as well as the turnover rate of GLUT4 in human vastus lateralis muscles at the cell surface in the basal state and after insulin exposure, we have applied the sensitive exofacial bis-mannose photolabeling technique on in vitro incubated human skeletal muscle strips from healthy subjects. In addition, we have measured 3-O-methylglucose transport in other muscle strips prepared from the same surgically removed human skeletal muscle biopsies to compare glucose transport with cell surface level of GLUT4. Maximal in vitro insulin stimulation (2,400 pmol/l) resulted in a twofold increase compared with basal in both surface GLUT4 content (0.38 +/- 0.05 vs. 0.19 +/- 0.03 pmol/g wet muscle wt, P < 0.005) and 3-O-methylglucose transport (1.24 +/- 0.13 vs. 0.63 +/- 0.08 pmol x ml(-1) x h(-1), P < 0.005). The insulin-induced increment in 3-O-methylglucose transport was strongly correlated with the insulin-induced increase in cell surface GLUT4 content (r2 = 0.91; P < 0.005). The calculated turnover rate of human skeletal muscle GLUT4 amounted to approximately 8 x 10(4) min(-1) at 35 degrees C and was unaffected by insulin. In conclusion, maximal in vitro insulin stimulation of vastus lateralis muscle strips from healthy subjects resulted in a twofold rise in glucose transport as well as in cell surface content, whereas the turnover rate of GLUT4 was unaffected by insulin under the chosen experimental conditions.

3-O-Methylglucose↗
PubMed1997

Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats.

The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C protein kinase [RAC]) has recently been implicated to play a role in the signaling pathway to glucose transport. However, little is known concerning the regulation of Akt activity in insulin-sensitive tissues such as skeletal muscle. To explore the role of hyperglycemia on Akt kinase activity in skeletal muscle, normal Wistar rats or Goto-Kakizaki (GK) diabetic rats were treated with phlorizin. Phlorizin treatment normalized fasting blood glucose and significantly improved glucose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the compound had no effect on glucose homeostasis. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) Akt kinase activity was reduced by 68% (P < 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with Wistar rats. Importantly, the defects at the level of Akt kinase and glucose transport were completely restored by phlorizin treatment. There was no significant difference in Akt kinase protein expression among the three groups. At a submaximal insulin concentration (2.4 nmol/l), activity of Akt kinase and glucose transport were unaltered. In conclusion, improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin-stimulated activity of Akt kinase and glucose transport. Thus, hyperglycemia may directly contribute to the development of muscle insulin resistance through alterations in insulin action on Akt kinase and glucose transport.

Animals↗
PubMed1996

C-peptide stimulates glucose transport in isolated human skeletal muscle independent of insulin receptor and tyrosine kinase activation.

We have previously demonstrated that C-peptide stimulates glucose transport in skeletal muscle from non-diabetic subjects in a dose-dependent manner. To further elucidate the mechanism by which C-peptide activates glucose transport, we investigated the influence of human recombinant C-peptide on receptor and post-receptor events involved in the glucose transport process. Human skeletal muscle specimens were obtained from the vastus lateralis by means of an open biopsy procedure. Stimulation of isolated muscle strips from healthy control subjects with supra-physiological concentrations of insulin (6,000 pmol/l) and C-peptide (2,500 pmol/l), did not further augment the twofold increase in the rate of 3-o-methylglucose transport induced by either stimulus alone. C-peptide did not displace 125I-insulin binding from partially purified receptors, nor did it activate receptor tyrosine kinase activity. Tyrosine-labelled 125I-C-peptide did not bind specifically to crude membranes prepared from skeletal muscle, or to any serum protein other than albumin. The beta-adrenergic receptor stimulation with isoproterenol inhibited insulin- but not C-peptide-mediated 3-o-methylglucose transport by 63 +/- 18% (p < 0.01), whereas the cyclic AMP analogue, Bt2cAMP, abolished the insulin- and C-peptide-stimulated 3-o-methylglucose transport. C-peptide (600 pmol/l) increased 3-o-methylglucose transport 1.8 +/- 0.2-fold in skeletal muscle specimens from patients with insulin-dependent diabetes mellitus. In conclusion, C-peptide stimulates glucose transport by a mechanism independent of insulin receptor and tyrosine kinase activation. In contrast to the effect on insulin-stimulated glucose transport, catecholamines do not appear to have a counter regulatory action on C-peptide-mediated glucose transport.

3-O-Methylglucose↗
PubMed1996

Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM.

We investigated the response of the glucose transport system to insulin, in the presence of ambient glucose concentrations, in isolated skeletal muscle from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) (age, 55 +/- 3 years, BMI 27.4 +/- 1.8 kg/m2) and seven healthy control subjects (age, 54 +/- 3 years, BMI 26.5 +/- 1.1 kg/m2). Insulin-mediated whole body glucose utilization was similar between the groups when studied in the presence of ambient glucose concentrations (approximately 10 mmol/l for the NIDDM patients and 5 mmol/l for the control subjects). Samples were obtained from the vastus lateralis muscle, by means of an open muscle biopsy procedure, before and after a 40-min insulin infusion. An increase in serum insulin levels from 54 +/- 12 to 588 +/- 42 pmol/l, induced a 1.6 +/- 0.2-fold increase in glucose transporter protein (GLUT4) in skeletal muscle plasma membranes obtained from the control subjects (p < 0.05), whereas no significant increase was noted in plasma membrane fractions prepared from NIDDM muscles, despite a similar increase in serum insulin levels. At concentrations of 5 mmol/l 3-O-methylglucose in vitro, insulin (600 pmol/l) induced a 2.2-fold (p < 0.05) increase in glucose transport in NIDDM muscles and a 3.4-fold (p < 0.001) increase in the control muscles. Insulin-stimulated 3-O-methylglucose transport was positively correlated with whole body insulin-mediated glucose uptake in all participants (r = 0.78, p < 0.001) and negatively correlated with fasting plasma glucose levels in the NIDDM subjects (r = 0.93, p < 0.001). Muscle fibre type distribution and capillarization were similar between the groups. Our results suggest that insulin-stimulated glucose transport in skeletal muscle from patients with NIDDM is down-regulated in the presence of hyperglycaemia. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin-induced gain of GLUT4 at the level of the plasma membrane.

3-O-Methylglucose↗
PubMed1996

C-peptide revisited--new physiological effects and therapeutic implications.

Recent studies have demonstrated that replacement of C-peptide to normal physiological concentrations in insulin-dependent diabetic (IDDM) patients on a short-term basis (1-3 h) results in decreased glomerular hyperfiltration, augmented glucose utilization and improved autonomic nervous function. More prolonged administration (1-3 months) of C-peptide to IDDM patients is accompanied by improvements in both renal and autonomic nervous function. Moreover, both in-vitro and in-vivo studies indicate that C-peptide may have a role in the regulation of insulin secretion. The effects of C-peptide may in part be explained by its ability to stimulate Na+,K(+)-ATPase activity. In conclusion, the combined findings indicate that C-peptide is a biologically active hormone. The possibility that C-peptide therapy in IDDM patients may be beneficial should be considered.

Animals↗
PubMed1996

Intact glucose transport in morphologically altered denervated skeletal muscle from quadriplegic patients.

The present study was undertaken to investigate the nature of the whole body insulin resistance that characterizes patients with complete cervical spinal cord lesion. Nine patients with C5-C7 lesions and ten age-matched healthy individuals were studied. Whole body insulin-mediated glucose utilization was reduced by 43% in the quadriplegic patients compared with the controls (P < 0.001). In the quadriplegic patients, lean body mass corresponded to 66 +/- 3% of total body mass. Despite whole body insulin resistance, in isolated vastus lateralis muscle, basal and insulin-stimulated 3-O-methylglucose transport, as well as protein expression of the insulin or exercise-regulatable glucose transporter, GLUT-4, and glycogen content were comparable between the patients and controls. Strikingly, muscle fiber area was reduced by 44% (P < 0.05), percentage of type IIb fibers was increased (P < 0.01), and there was a complete loss of type I fibers in the patients. In conclusion, the dissociation between whole body insulin-mediated glucose uptake and skeletal muscle glucose transport in quadriplegic patients primarily reflects the decreased muscle mass. Furthermore, these findings demonstrate a remarkable capacity of skeletal muscle to maintain an intact glucose transport system despite severe morphological alterations.

Adult↗
PubMed1996

Transgenic mice with muscle-specific insulin resistance develop increased adiposity, impaired glucose tolerance, and dyslipidemia.

Impaired skeletal muscle insulin receptor function is a feature of common forms of insulin resistance, including obesity and noninsulin-dependent diabetes mellitus. However, the extent to which this defect accounts for impaired muscle glucose disposal or altered in vivo glucose homeostasis remains to be established. We recently showed that transgenic mice that overexpress dominant-negative insulin receptors specifically in striated muscle have a severe defect in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here we performed hindlimb perfusion studies to determine the impact of this defect on muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle 3-O-methylglucose transport were reduced by 32-40% in transgenic mice with proportional defects involving total hindlimb [14C]glucose uptake, lactate production, and muscle glycogen synthesis. To address the hypothesis that muscle insulin resistance could promote an increase in the accretion of body fat, carcass analysis was performed using two independent lines of transgenic mice. Although body weights were normal, transgenic mice had a 22-38% increase in body fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad weight was also increased in transgenic mice. Skeletal muscle histology and fiber type distribution were not affected. To determine whether muscle-specific insulin resistance was sufficient to cause impaired glucose tolerance, oral glucose tolerance tests were performed with 6-month-old transgenic and control mice. Fasting glucose levels were increased by 25%, and peak values were 22-40% higher in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate levels and modest increases in levels of plasma triglycerides and FFA (29% and 15%, respectively). We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle-specific insulin resistance can contribute to the development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose disposal is sufficient to result in impaired glucose tolerance and other features of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia.

Adipose Tissue↗