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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human adult diseases such as cardiovascular disease, hypertension, and type 2 diabetes have been epidemiologically linked to poor fetal growth and development. Male offspring of rat dams fed a low-protein (LP) diet during pregnancy and lactation develop diabetes with concomitant alterations in their insulin-signaling mechanisms. Such associations have not been studied in female offspring. The aim of this study was to determine whether female LP offspring develop diabetes in later life. Control and LP female offspring groups were obtained from rat dams fed a control (20% protein) or an isocaloric (8% protein) diet, respectively, throughout pregnancy and lactation. Both groups were weaned and maintained on 20% normal laboratory chow until 21 mo of age when they underwent intravenous glucose tolerance testing (IVGTT). Fasting glucose was comparable between the two groups; however, LP fasting insulin was approximately twofold that of controls (P < 0.02). Glucose tolerance during IVGTT was comparable between the two groups; however, LP peak plasma insulin at 4 min was approximately threefold higher than in controls (P < 0.001). LP plasma insulin area under the curve was 1.9-fold higher than controls (P < 0.02). In Western blots, both muscle protein kinase C-zeta expression and p110beta-associated p85alpha in abdominal fat were reduced (P < 0.05) in LPs. Hyperinsulinemia in response to glucose challenge coupled with attenuation of certain insulin-signaling molecules imply the development of insulin resistance in LP muscle and fat. These observations suggest that intrauterine protein restriction leads to insulin resistance in females in old age and, hence, an increased risk of type 2 diabetes.
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PMID:Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring. 1551 5

Atrophy of skeletal muscle is common to a number of conditions, including cancer, sepsis, AIDS, renal failure, diabetes, severe trauma, and burns. In all cases, protein synthesis in skeletal muscle is depressed, whereas protein degradation is increased through an increase in activity and expression of the ubiquitin-proteasome proteolytic pathway. This pathway is not responsive to simple nutritional intervention. Certain agents, including glucocorticoids, cytokines, proteolysis-inducing factor (PIF), and oxidative stress, are thought to be responsible for the induction of the ubiquitin-proteasome pathway in skeletal muscle in catabolic conditions. Insulin suppresses activation of this pathway, and loss of insulin action in diabetes leads to muscle wasting. Cytokines, PIF, and reactive oxygen species (ROS) are thought to induce proteasome expression through activation of the transcription factor nuclear factor kappa B (NF-kappaB). Targets for therapeutic intervention include antagonists of the inducers of proteasome expression, intracellular signaling pathways leading to activation of NF-kappaB, and the enzymes inducing ubiquitin conjugation to the substrate protein (myosin), as well as the proteasome itself. Anticytokine and anti-PIF antibodies are effective in attenuating muscle protein degradation in certain experimental animal models,and glucocorticoid receptor antagonists are effective in the treatment of sepsis. Agents that inhibit NF-kappaB activation, such as resveratrol, thalidomide, ibuprofen, eicosapentaenoic acid, and beta-hydroxy-beta-methylbutyrate, are effective in the preservation of skeletal muscle mass in cachexia. These results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to prevent muscle wasting.
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PMID:The ubiquitin-proteasome pathway as a therapeutic target for muscle wasting. 1591 24

Structural and functional modifications occur in skeletal muscle during aging. These defects lead to impairment in muscle strength, contractile capacity and performance. Among factors implicated in this age-related loss of muscle mass, a dysregulation of protein synthesis and breakdown has frequently been reported. Insulin plays a major role in regulating muscle protein metabolism, since its action contributes to increase net gain of muscle protein in animal and humans. More recently, specific actions of insulin on various muscle proteins, notably mitochondrial proteins, have been demonstrated, suggesting that insulin is also a major regulating factor of mitochondrial oxidative phosphorylation in human skeletal muscle. Insulin resistance develops with aging, classically involving changes in glucose tolerance. However, the effect of insulin on protein metabolism is less well documented, and insulin resistance could be involved in age-related muscle protein loss, progressively leading to sarcopenia. Therefore in a more general concept, insulin resistance found in many clinical settings, could be considered as a contributor to muscle wasting.
Diabetes Metab 2005 Dec
PMID:Insulin resistance: a contributing factor to age-related muscle mass loss? 1641 62

Type 2 diabetes (T2DM) subjects failing diet treatment are characterized by hyperinsulinemia and insulin resistance leading to fasting and postprandial hyperglycemia and hyperlipidemia. Energy is essential for allowing the process of protein synthesis to proceed. Additionally, insulin can stimulate protein synthesis in human muscle. The aims of this study were to determine if poorly controlled T2DM affects postabsorptive muscle protein anabolism, and if the muscle anabolic response to hyperinsulinemia with high energy availability is maintained. Control (n = 6) and T2DM subjects (n = 6) were studied in the postabsorptive state and during an isoenergetic high nutritional energy clamp (relative to postabsorptive state). Muscle protein synthesis and breakdown (nmol . min(-1) . 100 g leg muscle(-1)) were assessed using stable isotope methodology, femoral arterio-venous sampling, muscle biopsies, and a three-pool model to calculate protein turnover. Postabsorptive phenylalanine net balance and whole body rate of appearance (Ra) were not different between groups; however, basal muscle protein breakdown was higher in T2DM (94 +/- 9) than in controls (58 +/- 12) (P < 0.05) and muscle protein synthesis tended (P = 0.07) to be elevated in T2DM (66 +/- 14) compared with controls (39 +/- 6). During the clamp, net balance increased, whole body Ra and muscle protein breakdown decreased (P < 0.05), and muscle protein synthesis tended to decrease (P = 0.08) to a similar extent in both groups. We conclude that postabsorptive muscle protein turnover is elevated in poorly controlled T2DM, however, there is no excessive loss of muscle protein because net balance is not different from controls. Moreover, the anabolic response to increased insulin and energy availability is maintained in T2DM.
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PMID:Skeletal muscle protein anabolic response to increased energy and insulin is preserved in poorly controlled type 2 diabetes. 1661 12

This paper reviews present understanding of the role played by the sarcolemmal glutamine transporter, system N(m), in control of intramuscular glutamine concentration. Glutamine transport in skeletal muscle is a saturable, stereospecific, Na dependent and insulin sensitive process. The activity of system N(m) is subject to modification during muscle denervation, diabetes and exposure to bacterial products in a manner consistent with the observed negative glutamine balance exhibited by muscle during such circumstances. The modification in transporter activity appears to be dependent on factors influencing the distribution of Na across the sarcolemma, the resting membrane potential and the active carrier population in the sarcolemma (possibly through up or down regulation of the number of transporter molecules). Derangements in net membrane glutamine transport during pathophysiological conditions may help, partly, to account for the loss in muscle glutamine which in turn may influence control of protein and carbohydrate metabolism in muscle. The free intramuscular glutamine concentration appears to act as a positive signal in the control of muscle protein turnover and glycogen synthesis, a finding that may have important therapeutic implications for limiting muscle wasting. The kinetic properties of the glutamine transporter and the dipeptidase activity in the muscle vascular bed allow the intramuscular glutamine pool to be repleted following administration of glutamine dipeptides (such as Ala-Gln) with the result that a net anabolic shift in protein balance and an amelioration in muscle glutamine efflux takes place.
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PMID:Role of membrane transport in the regulation of skeletal muscle glutamine turnover. 1683 53

Insulin deficiency is known to be associated with a state of increased muscle protein breakdown; this process is mediated by the ubiquitin-proteasome pathway. Convincing in vitro data are further supported by extensive studies in humans with insulin deprivation and are further substantiated by reversal of muscle protein breakdown with insulin treatment. In patients with end-stage renal disease (ESRD) and diabetes mellitus (DM), muscle protein breakdown is enhanced in both acute and chronic conditions. Recent data also point to the potential protein catabolic effects of insulin resistance combined with insulin deficiency. Because ESRD is associated with a state of insulin resistance, uremic muscle wasting may also be mediated by this pathway.
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PMID:Effects of glucose homeostasis on protein metabolism in patients with advanced chronic kidney disease. 1719 26

Muscle protein metabolism is resistant to insulin's anabolic effect in healthy older subjects. This is associated with reduced insulin vasodilation. We hypothesized that aerobic exercise restores muscle protein anabolism in response to insulin by improving vasodilation in older subjects. We measured blood flow, endothelin-1, Akt/mammalian target of rapamycin (mTOR) signaling, and muscle protein kinetics in response to physiological local hyperinsulinemia in two groups of older subjects following a bout of aerobic exercise (EX group: aged 70 +/- 2 years; 45-min treadmill walk, 70% heart rate max) or rest (CTRL group: aged 68 +/- 1 years). Baseline endothelin-1 was lower and blood flow tended to be higher in the EX group, but protein kinetics was not different between groups. Insulin decreased endothelin-1 (P < 0.05) in both groups, but endothelin-1 remained higher in the CTRL group (P < 0.05) and blood flow increased only in the EX group (EX group: 3.8 +/- 0.7 to 5.3 +/- 0.8; CTRL group: 2.5 +/- 0.2 to 2.6 +/- 0.2 ml x min(-1) x 100 ml leg(-1)). Insulin improved Akt phosphorylation in the EX group and increased mTOR/S6 kinase 1 phosphorylation and muscle protein synthesis (EX group: 49 +/- 11 to 89 +/- 23; CTRL group: 58 +/- 8 to 57 +/- 12 nmol x min(-1) x 100 ml leg(-1)) in the EX group only (P < 0.05). Because breakdown did not change, net muscle protein balance became positive only in the EX group (P < 0.05). In conclusion, a bout of aerobic exercise restores the anabolic response of muscle proteins to insulin by improving endothelial function and Akt/mTOR signaling in older subjects.
Diabetes 2007 Jun
PMID:Aerobic exercise overcomes the age-related insulin resistance of muscle protein metabolism by improving endothelial function and Akt/mammalian target of rapamycin signaling. 1735 Nov 47

Illnesses associated with insulin resistance exhibit increases in whole-body protein degradation and amino acid oxidation. However, the mechanisms stimulating muscle catabolism under these conditions are not clear. Because insulin resistance is associated with accumulation of lipids in muscle, we measured protein degradation in muscles of mice fed a high-fat diet. Muscle protein catabolism was accelerated on the high-fat diet, and this was associated with an increase in plasma free fatty acid and a decrease in plasma levels of the adipocyte-derived cytokine adiponectin. To evaluate how free fatty acids influence adiponectin-mediated changes in muscle protein breakdown we examined C2C12 skeletal muscle cells exposed to free fatty acids. Both saturated fatty acids (palmitate) and unsaturated fatty acids (oleate) increased protein degradation (25 and 18%, respectively) in part by activating the E3 ubiquitin ligases. Adenovirus-mediated overexpression of adiponectin blocked fatty acid-induced protein degradation in C2C12 cells. Palmitate activated the E3 ubiquitin ligases by suppressing insulin receptor substrate-1/Akt signaling in the C2C12 muscle cells, whereas adiponectin attenuated the E3 ubiquitin ligase activation by increasing both insulin receptor substrate-1 tyrosine phosphorylation and Akt Ser473 phosphorylation. In related experiments, adiponectin overexpression decreased TNFalpha and IL-6 expression in 3T3-L1 adipocytes, whereas exposure to free fatty acids had the opposite effect. We conclude that the balance between free fatty acids and adiponectin impacts muscle proteolysis in insulin-resistant conditions and suggest a role for adipose tissue-muscle cross talk in diabetes and obesity.
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PMID:Evidence for adipose-muscle cross talk: opposing regulation of muscle proteolysis by adiponectin and Fatty acids. 1776 67

Protein ingestion stimulates muscle protein synthesis and improves net muscle protein balance. Insulin resistance has been suggested to result in a reduced muscle protein synthetic response to food intake. As such, we hypothesized that type 2 diabetes patients have a impaired muscle protein synthetic response to food ingestion. To test this hypothesis, 10 male type 2 diabetes patients using their normal oral glucose-lowering medication (68 +/- 2 y) and 10 matched, normoglycemic men (65 +/- 2 y) were randomly assigned to 2 crossover treatments in which whole body and muscle protein synthesis were measured following the consumption of either carbohydrate (CHO) or carbohydrate with a protein hydrolysate (CHO+PRO). Primed, continuous infusions with L-[ring-13C6]phenylalanine and L-[ring-2H2]tyrosine were applied and blood and muscle samples were collected to assess whole-body protein balance and mixed muscle protein fractional synthetic rate over a 6-h period. Whole-body phenylalanine and tyrosine flux were higher after the CHO+PRO treatment compared with the CHO treatment in the diabetes and control group (P < 0.01). Protein balance was negative following CHO but positive following CHO+PRO treatment in both groups. Muscle protein synthesis rates were higher in both groups following the CHO+PRO (0.086 +/- 0.014%/h) treatment than in the CHO treatment (0.040 +/- 0.003%/h; P < 0.01) with no difference between the diabetes patients and normoglycemic controls. We conclude that the muscle protein synthetic response to CHO or CHO+PRO ingestion is not substantially impaired in longstanding, type 2 diabetes patients treated with oral blood glucose-lowering medication.
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PMID:The muscle protein synthetic response to carbohydrate and protein ingestion is not impaired in men with longstanding type 2 diabetes. 1849 37

OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IkappaB/NFkappaB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS- TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IkappaB/NFkappaB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS- Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
Diabetes 2008 Oct
PMID:Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. 1933 85


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