Biomedical subjects

G L Dohm

Publications and source records attributed to G L Dohm.

At least 19 recordsLinked to original sources

PubMed2000

Protein kinase C modulates insulin action in human skeletal muscle.

There is good evidence from cell lines and rodents that elevated protein kinase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/inhibition on insulin-mediated glucose transport in incubated human skeletal muscle and primary adipocytes to discern a potential role for PKC in insulin action. Rectus abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC inhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC activator. PKC inhibition had no effect on basal glucose transport. GF increased (P < 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximately twofold above basal. GF plus insulin also increased (P < 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity approximately 50% (P < 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adipocytes. Further support for the hypothesis that elevated PKC activity is related to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease (P < 0.05) in insulin-stimulated 2-DOG transport. Incubation of insulin-sensitive muscles with GF also resulted in enhanced insulin action ( approximately 3-fold above basal). These data demonstrate that certain PKC inhibitors augment insulin-mediated glucose uptake and suggest that PKC may modulate insulin action in human skeletal muscle.

Abdominal Muscles↗

PubMed2000

Insulin stimulation of muscle protein synthesis in obese Zucker rats is not via a rapamycin-sensitive pathway.

The obese Zucker rat is resistant to insulin for glucose disposal, but it is unknown whether this insulin resistance is accompanied by alterations of insulin-mediated muscle protein synthesis. We examined rates of muscle protein synthesis either with or without insulin in lean and obese Zucker rats with the use of a bilateral hindlimb preparation. Additional experiments examined insulin's effect on protein synthesis with or without rapamycin, an inhibitor of protein synthesis. Protein synthesis in red and white gastrocnemius was stimulated by insulin compared with control (no insulin) in obese (n = 10, P<0.05) but not in lean (n = 10, P>0.05) Zucker rats. In white gastrocnemius, rapamycin significantly reduced rates of protein synthesis compared with control in lean (n = 6) and obese (n = 6) rats; however, in red gastrocnemius, the attenuating effect of rapamycin occurred only in obese rats. The addition of insulin to rapamycin resulted in rates of synthesis that were similar to those for rapamycin alone for lean rats and to those for insulin alone (augmented) for obese rats in both tissues. Our results demonstrate that insulin enhances protein synthesis in muscle that is otherwise characterized as insulin resistant. Furthermore, rapamycin inhibits protein synthesis in muscle of obese Zucker rats; however, stimulation of protein synthesis by insulin is not via a rapamycin-sensitive pathway.

Animals↗

PubMed2000

Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.

This study was conducted to investigate the possible involvement of protein kinase C (PKC) and serine/threonine phosphorylation of the insulin receptor in insulin resistance and/or obesity. Insulin receptor tyrosine kinase activity was depressed in muscle from obese insulin-resistant patients compared with lean insulin-responsive control subjects. Alkaline phosphatase treatment resulted in a significant 48% increase in in vitro insulin-stimulated receptor tyrosine kinase activity in obese but not lean muscle. To investigate the involvement of PKC in skeletal muscle insulin resistance and/or obesity, membrane-associated PKC activity and the protein content of various PKC isoforms were measured in human skeletal muscle from lean, insulin-responsive, and obese insulin-resistant patients. Membrane-associated PKC activity was not changed; however, PKC-beta protein content, assayed by Western blot analysis, was significantly higher, whereas PKC-theta, -eta, and -mu were significantly lower in muscle from obese patients compared with muscle from lean control subjects. Incubation of muscle strips with insulin significantly increased membrane-associated PKC activity in muscle from obese but not lean subjects. PKC-delta, -beta, and -theta were translocated from the cytosol to the membrane fraction in response to insulin treatment. These results suggest that in skeletal muscle from insulin-resistant obese patients, insulin receptor tyrosine kinase activity was reduced because of hyperphosphorylation on serine/threonine residues. Membrane-associated PKC-beta protein was elevated under basal conditions, and membrane-associated total PKC activity was increased under insulin-stimulated conditions in muscle from obese insulin-resistant patients. Thus, we postulate that the decreased tyrosine kinase activity of the insulin receptor may be caused by serine/threonine phosphorylation by PKC.

Adult↗

PubMed1999

Effects of obesity and stable weight reduction on UCP2 and UCP3 gene expression in humans.

OBJECTIVES: The molecular determinants of energy expenditure are presently unknown. Recently, two uncoupling protein homologues, UCP2 and UCP3, have been identified. UCP2 is expressed widely, and UCP3 is expressed abundantly in skeletal muscle. Both could be important regulators of energy balance. In this paper, we investigated whether altered UCP2 and UCP3 mRNA levels are associated with obesity or weight reduction. RESEARCH METHODS AND PROCEDURES: UCP2, UCP3 long and short mRNA levels were examined in skeletal muscle and in white adipose tissue of lean, obese, and weight-reduced individuals by RNase protection assay. RESULTS: Expression of UCP2, UCP3S, and UCP3L mRNA in skeletal muscle was similar in lean individuals and in individuals with obesity at stable weight. In contrast, UCP3L and UCP3S mRNAs were decreased by 38% (p<0.0059) and 48% (p<0.0047), respectively, in 20% weight-reduced patients with obesity at stable weight. In contrast, UCP2 mRNA levels were increased by 30% in skeletal muscle of 20% weight-reduced subjects with obesity. In a different set of patients, mostly lean, UCP3L mRNA in skeletal muscle was decreased by 28% (p = 0.0425) after 10% weight reduction at stable weight. Expression of UCP2 mRNA in subcutaneous adipose tissue was similar in lean individuals and in individuals with obesity, and was increased by 58% during active weight loss. DISCUSSION: Stabilization at reduced body weight in humans is associated with a decrease in UCP3 mRNA in muscle. It is possible that reduced UCP3 expression could contribute to decreased energy expenditure in weight-stable, weight-reduced individuals.

Adipose Tissue↗

PubMed1999

Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats.

Serine/threonine phosphorylation of insulin receptor has been implicated in the development of insulin resistance. To investigate whether dephosphorylation of serine/threonine residues of the insulin receptor may restore the decreased insulin-stimulated receptor tyrosine kinase activity in skeletal muscle of obese Zucker rats, insulin receptor tyrosine kinase activity was measured before and after alkaline phosphatase treatment. Compared to lean controls, insulin-stimulated glucose transport was depressed by 61% (p < 0.05) in obese Zucker rats. The insulin receptor and insulin receptor substrate-1 contents were decreased by 14% (p < 0.05) and 16% (p < 0.05), respectively, in skeletal muscle of obese Zucker rats. In vivo insulin-induced tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 was depressed by 82% (p < 0.05) and 86% (p < 0.05), respectively. In the meantime, in vitro insulin-stimulated receptor tyrosine kinase activity in obese rats was decreased by 39% (p < 0.05). Dephosphorylation of the insulin receptor by prior alkaline phosphatase treatment increased insulin-stimulated receptor tyrosine kinase activity in both lean and obese Zucker rats, but the increase was three times greater in obese Zucker rats (p < 0.05). These findings suggest that excessive serine/threonine phosphorylation of the insulin receptor in obese Zucker rats may be a cause for insulin resistance in skeletal muscle.

Animals↗

PubMed1999

Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation.

The factors that regulate gene expression of uncoupling proteins 2 and 3 (UCP-2 and UCP-3) in skeletal muscle are poorly understood, but both genes are clearly responsive to the metabolic state of the organism. Therefore, we tested the hypothesis that denervation and acute and/or chronic exercise (factors that profoundly affect metabolism) would alter UCP-2 and UCP-3 gene expression. For the denervation studies, the sciatic nerve of rat and mouse hindlimb was sectioned in one leg while the contralateral limb served as control. Northern blot analysis revealed that denervation was associated with a 331% increase (P < 0.001) in UCP-3 mRNA and a 200% increase (P < 0. 01) in UCP-2 mRNA levels in rat mixed gastrocnemius (MG) muscle. In contrast, denervation caused a 53% decrease (P < 0.001) in UCP-3 and a 63% increase (P < 0.01) in UCP-2 mRNA levels in mouse MG. After acute exercise (2-h treadmill running), rat UCP-3 mRNA levels were elevated (vs. sedentary control) 252% (P < 0.0001) in white gastrocnemius and 63% (P < 0.05) in red gastrocnemius muscles, whereas UCP-2 levels were unaffected. To a lesser extent, elevations in UCP-3 mRNA (22%; P < 0.01) and UCP-2 mRNA (55%; P < 0.01) levels were observed after acute exercise in the mouse MG. There were no changes in either UCP-2 or UCP-3 mRNA levels after chronic exercise (9 wk of wheel running). These results indicate that acute exercise and denervation regulate gene expression of skeletal muscle UCPs.

Animals↗

PubMed1999

Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice.

Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/ob mice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus, leptin decreased glycogen synthesis 36-46% (P < 0.05), increased oleate oxidation 26% (P < 0.05), decreased oleate incorporation into TAG 32% (P < 0.05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% (P < 0.05). Insulin decreased oleate oxidation 31% (P < 0.05), increased oleate incorporation into TAG 46% (P < 0.05), and increased the partitioning ratio 125% (P < 0.01). Adding leptin diminished insulin's antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M. , G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol 3-kinase inhibitor wortmannin blocked insulin's effects on lipid metabolism but only attenuated leptin's effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulin's promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.

Animals↗

PubMed1999

Effect of endurance exercise on myosin heavy chain gene regulation in human skeletal muscle.

The purpose of this study was to determine the effect of endurance-oriented exercise on myosin heavy chain (MHC) isoform regulation in human skeletal muscle. Exercise consisted of 1 h of cycle ergometer work per day at 75% maximal oxygen consumption for seven consecutive days. Muscle was obtained before the first bout of exercise, 3 h after the first bout of exercise, and before and 3 h after the final exercise bout on day 7 (n = 9 subjects). No changes in MHC mRNA (I, IIa, IIx) were evident after the first exercise period. There was, however, a significant (P < 0.05) decline (-30%) in MHC IIx mRNA 3 h after the final training bout. An interesting finding was that a higher pretraining level of MHC IIx mRNA was associated with a greater decline in the transcript before (r = 0.68, P < 0.05) and 3 h after (r = 0.82, P < 0.05) the final exercise bout. These findings suggest that MHC IIx mRNA is downregulated during the early phase of endurance-oriented exercise training in human skeletal muscle but only after repeated contractile activity. Pretraining MHC IIx mRNA content may influence the magnitude of this response.

Adult↗

PubMed1999

Impact of hyperinsulinemia on myosin heavy chain gene regulation.

The purpose of this study was to determine whether hyperinsulinemia alters myosin heavy chain (MHC) gene expression in human skeletal muscle. A biopsy from the vastus lateralis was obtained in young, lean [age 24.6 +/- 1.0 (SE) yr, body fat 11.9 +/- 1.9%, body mass index 26.1 +/- 1.1 kg/m2; n = 10] men before and after 3 h of hyperinsulinemia (hyperinsulinemic-euglycemic clamp). Muscle was analyzed for mRNA of type I, IIa, and IIx MHC isoforms. Hyperinsulinemia (mean of 1,065.7 +/- 9.8 pmol/l during minutes 20 to 180) did not change (P > 0.05) the mRNA concentration of either the type I MHC or type IIA MHC isoforms. In contrast, type IIX MHC mRNA increased (P < 0.05) with hyperinsulinemia compared with the fasted condition. These data indicate that hyperinsulinemia rapidly increases type IIx MHC mRNA in human skeletal muscle.

Adult↗

PubMed1999

Effect of aging on response to exercise training in humans: skeletal muscle GLUT-4 and insulin sensitivity.

The purpose of this study was to compare the effects of short-term exercise training on insulin-responsive glucose transporter (GLUT-4) concentration and insulin sensitivity in young and older individuals. Young and older women [22.4 +/- 0.8 (SE) yr, n = 9; and 60.9 +/- 1. 0 yr, n = 10] and men (20.9 +/- 0.9, n = 9; 56.5 +/- 1.9 yr, n = 8), respectively, were studied before and after 7 consecutive days of exercise training (1 h/day, approximately 75% maximal oxygen uptake). The older groups had more adipose tissue, increased central adiposity, and a lower maximal oxygen uptake. Despite these differences, increases in whole body insulin action (insulin sensitivity index, determined with an intravenous glucose tolerance test and minimal-model analysis) with training were similar regardless of age, in both the women and men (mean increase of 2.2 +/- 0.3-fold). This was accompanied by similar relative increases in muscle (vastus lateralis) GLUT-4 protein concentration, irrespective of age (mean increase of 3.1 +/- 0.7-fold). Body mass did not change with training in any of the groups. These data suggest that older human skeletal muscle retains the ability to rapidly increase muscle GLUT-4 and improve insulin action with endurance training.

Adolescent↗

PubMed1998

Role of transverse tubules (T-tubules) in muscle glucose transport.

The first data to demonstrate glucose transporter translocation in muscle used membranes enriched in sarcolemma because it was assumed that this was the equivalent of the cell membrane of adipocytes. We studied translocation in intact human muscle using immunogold labeling of the GLUT4 transporter but found very little labeling on the sarcolemma. In contrast, there was abundant gold-labeling associated with the T-tubules and we proposed that glucose transport occurred across this membrane system. In a subsequent study using an entirely different technique, we labeled cell surface glucose transporters of rat muscle with a cell impermeant photolabel and demonstrated that a majority of the glucose transporters were translocated to T-tubules, not to the sarcolemma, in response to insulin. In this report we show for the first time that in insulin-plus contraction stimulated muscle, GLUT4 glucose transporters are associated with an area that we call the SCT complex (Sarcolemmal, Caveoli, T-tubule complex). This SCT complex may play an important role in delivering metabolites to the muscle under conditions, such as muscle contraction, when there is a very high requirement for glucose transport. From our data, and supporting data from other labs, we propose that the T-tubule membrane system plays a very important role in delivering nutrients to the center of skeletal muscle cells. Substrates can be quickly carried to the center of the muscle fiber where there are proteins to transport glucose (and presumably other substrates) across the T-tubule membrane to the site where it can be immediately utilized or stored. This hypothesis deserves serious consideration and experimental testing.

Animals↗

PubMed1998

A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?

SUMMARY BACKGROUND DATA: We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy. Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year. This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor. METHODS: Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity. RESULTS: Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group. CONCLUSIONS: Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut.

Adult↗

PubMed1998

Regulation of glucose transporters GLUT-4 and GLUT-1 gene transcription in denervated skeletal muscle.

Because GLUT-4 expression is decreased whereas GLUT-1 expression is increased in denervated skeletal muscle, we examined the effects of denervation on GLUT-4 and GLUT-1 gene transcription. The right hindlimb skeletal muscle of male transgenic mice containing sequential truncations (2,400, 1,639, 1,154, and 730 bp) of the human GLUT-4 promoter linked to the chloramphenacol acyl transferase (CAT) gene was denervated, and the contralateral hindlimb was sham operated. RNase protection analysis revealed that after 72 h denervation decreased CAT mRNA and GLUT-4 mRNA levels 64-85%, respectively (P < 0.05), in the gastrocnemius muscles. In contrast, denervation of the right hindlimb of male rats increased GLUT-1 gene transcription and GLUT-1 mRNA levels by 94 and 213%, respectively (P < 0.05). In conclusion, GLUT-4 transcription is decreased but GLUT-1 transcription is increased in denervated skeletal muscle, suggesting that the effects of denervation on GLUT-4 and GLUT-1 expression are, in part, transcriptionally mediated. Furthermore, these data indicate that a DNA sequence regulated by denervation is located within 730 bp of the 5'-flanking promoter region of the human GLUT-4 gene.

Animals↗

PubMed1998

Membrane glycoprotein PC-1 and insulin resistance.

Peripheral resistance to insulin is a major component of non-insulin dependent diabetes mellitus. Defects in insulin receptor tyrosine kinase activity have been demonstrated in several tissues from insulin resistant subjects, but mutations in the insulin receptor gene occur in only a small fraction of cases. Therefore, other molecules that are capable of modulating the function of the insulin receptor are likely candidates in the search for the cellular mechanisms of insulin resistance. We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined.

Animals↗

PubMed1997

Vanadate stimulation of 2-deoxyglucose transport is not mediated by PI 3-kinase in human skeletal muscle.

Glucose transport in mammalian skeletal muscle is stimulated by insulin, hypoxia and tyrosine protein phosphatase inhibitors such as vanadate. However, it is unknown whether the vanadate signaling mechanism shares a common or separate pathway with insulin or hypoxia. Therefore, experiments were conducted on incubated human muscle strips to compare the effects of vanadate with insulin and hypoxia stimulated 2-deoxyglucose transport (2-DOG). We also used the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin to examine whether PI 3-kinase is a common step by which each stimulate glucose transport. Results demonstrate that whereas the effects of vanadate and hypoxia were additive with insulin stimulated glucose transport, the effect of vanadate plus hypoxia was not. In addition, wortmannin significantly (P < 0.05) reduced insulin but not vanadate or hypoxia stimulated 2-DOG transport. Moreover, PI 3-kinase activity was significantly elevated (P < 0.05) in the presence of insulin but not vanadate. In conclusion, these data suggest that vanadate and hypoxia stimulate glucose transport via a similar signaling pathway which is distinct from insulin and that the vanadate signaling pathway is not mediated by PI 3-kinase in human skeletal muscle.

Analysis of Variance↗

PubMed1997

Transcriptional regulation of hexokinase II in denervated rat skeletal muscle.

Hexokinase II protein is augmented in denervated skeletal muscle; therefore, we determined if hexokinase II gene transcription rates and mRNA levels are increased with denervation. The right hindlimb skeletal muscles of male rats were denervated while the left hindlimbs were sham operated. Seventy-two h following surgery, rats were sacrificed and the gastrocnemius and soleus muscles were harvested for nuclear and RNA isolation. Nuclear run-on and ribonuclease protection analyses indicated that denervation increased hexokinase II transcription rates and mRNA levels 42% and 88%, respectively (p < 0.05). Total hexokinase activity rose 23% in denervated gastrocnemius muscle. In conclusion, the increase in hexokinase II gene transcription and mRNA may account for the increase in hexokinase II protein and the subsequent rise in total hexokinase activity in denervated rat skeletal muscle.

Animals↗

PubMed1997

Treadmill running increases phosphatidylinostol 3-kinase activity in rat skeletal muscle.

Exercise has been shown to increase insulin-stimulated skeletal muscle glucose transport. Activation of phosphatidylinostol 3-kinase (PI 3-kinase) is required for insulin to stimulate glucose transport. The present study was designed to investigate whether treadmill running (60 min, 8% grade, 30 m/min) augments insulin-stimulated activation of PI 3-kinase. Insulin dramatically increased insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (p < 0.05). Treadmill running did not induce IRS-1 tyrosine phosphorylation, not did it alter insulin-stimulated IRS-1 tyrosine phosphorylation. Insulin increased PI 3-kinase activity by 3.0-fold (over basal activity) in white muscle and 5.2-fold in red muscle (p < 0.05). Exercise did not alter basal PI 3-kinase activity in either white or red muscle. However, in response to exercise, insulin-stimulated PI 3-kinase activity was significantly increased in both muscle fibers (p < 0.05). These results suggest that increased insulin responsiveness induced by exercise may be due, in part, to enhanced insulin-stimulated PI 3-kinase activity.

Animals↗

PubMed1997

Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes.

Obese human subjects have increased protein-tyrosine phosphatase (PTPase) activity in adipose tissue that can dephosphorylate and inactivate the insulin receptor kinase. To extend these findings to skeletal muscle, we measured PTPase activity in the skeletal muscle particulate fraction and cytosol from a series of lean controls, insulin-resistant obese (body mass index > 30) nondiabetic subjects, and obese individuals with non-insulin-dependent diabetes. PTPase activities in subcellular fractions from the nondiabetic obese subjects were increased to 140-170% of the level in lean controls (P < 0.05). In contrast, PTPase activity in both fractions from the obese subjects with non-insulin-dependent diabetes was significantly decreased to 39% of the level in controls (P < 0.05). By immunoblot analysis, leukocyte antigen related (LAR) and protein-tyrosine phosphatase 1B had the greatest increase (threefold) in the particulate fraction from obese, nondiabetic subjects, and immunodepletion of this fraction using an affinity-purified antibody directed at the cytoplasmic domain of leukocyte antigen related normalized the PTPase activity when compared to the activity from control subjects. These findings provide further support for negative regulation of insulin action by specific PTPases in the pathogenesis of insulin resistance in human obesity, while other regulatory mechanisms may be operative in the diabetic state.

Adult↗