Insulin resistance is a two-sided mechanism acting under opposite catabolic and anabolic conditions

The survival of multi-cellular organisms depends on the organism ability to maintain glucose homeostasis for time of low/high nutrient availability or high energy needs, and the ability to fight infections or stress. These effects are realized through the insulin controlled transport of blood glucose into the insulin-responsive cells such as muscle, fat and liver cells. Reduction in the ability of these cells to take glucose from the blood in response to normal circulating levels of insulin is known as insulin resistance (IR). Chronic IR is a key pathological feature of obesity, type 2 diabetes, sepsis and cancer cachexia, however temporal IR are widely met in fasting/ hibernation, pregnancy, anti-bacterial immunity, exercise and stress. Paradoxically, a certain part of the IR-cases is associated with catabolic metabolism, whereas the other is related to anabolic pathways. How can this paradoxical IR-response be explained? What is the metabolic basis of this IR variability and its physiological and pathological impacts? An answer to these questions might be achieved through the hypothesis in which IR is considered as a two-sided mechanism acting under opposite metabolic conditions (catabolism and anabolism) but with the common aim to sustain glucose homeostasis in a wide metabolic range. To test this hypothesis, I examined the main metabolic distinctions between the varied IR-cases and their dependence on the blood glucose concentration, level of the IR-threshold, and catabolic/anabolic activation. On the basis of the established interrelations, a simple model of IR-distribution has been developed. The model revealed the «U-type distribution» form with separation into two main IR-groups, each determined in the catabolic or anabolic conditions with one exception – type 2 diabetes and its paradoxical catabolic activation in anabolic conditions. The dual opposing (or complementary) role for the IR opens a new possibility for better understanding the cause and consequences of transition from adaptive IR-responses to its pathological forms.     

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung

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Haem oxygenase-1 regulates catabolic and anabolic processes in osteoarthritic chondrocytes

Pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and other catabolic factors participate in the pathogenesis of cartilage damage in osteoarthritis (OA). Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) mediate cartilage degradation and might be involved in the progression of OA. Previously, we found that haem oxygenase-1 (HO-1) is down-regulated by pro-inflammatory cytokines and up-regulated by IL-10 in OA chondrocytes. The aim of this study was to determine whether HO-1 can modify the catabolic effects of IL-1beta in OA cartilage and chondrocytes. Up-regulation of HO-1 by cobalt protoporphyrin IX significantly reduced glycosaminoglycan degradation elicited by IL-1beta in OA cartilage explants but increased glycosaminoglycan synthesis and the expression of collagen II in OA chondrocytes in primary culture, as determined by radiometric procedures, immunoblotting and immunocytochemistry. HO-1 decreased the activation of extracellular signal-regulated kinase 1/2. This was accompanied by a significant inhibition in MMP activity and expression of collagenases MMP-1 and MMP-13 at the protein and mRNA levels. In addition, HO-1 induction caused a significant increase in the production of insulin-like growth factor-1 and a reduction in the levels of insulin-like growth factor binding protein-3. We have shown in primary culture of chondrocytes and articular explants from OA patients that HO-1 counteracts the catabolic and anti-anabolic effects of IL-1beta. Our data thus suggest that HO-1 may be a factor regulating the degradation and synthesis of extracellular matrix components in OA.     

Stimulation of Hepatitis C Virus RNA translation by microRNA-122 occurs under different conditions in vivo and in vitro

Translation of the Hepatitis C Virus (HCV) positive strand RNA genome is directed by an internal ribosome entry site (IRES) in the viral RNA's 5'-untranslated region (5'-UTR). HCV propagates preferentially in the liver, and HCV translation is stimulated by the liver-specific microRNA-122 (miR-122) acting on two target sites in the 5'-UTR. This stimulation is effective in living cells containing miR-122 and also in the rabbit reticulocyte lysate in vitro-translation system after addition of miR-122. Another RNA sequence located in the Core protein coding sequence can base-pair in a long-range RNA-RNA interaction to the HCV 5'-UTR, overlapping with the miR-122 target sites and the short spacer between them, and thereby inhibits HCV translation. Here we show genetic evidence that in reticulocyte lysate single-stranded miR-122 interferes with this inhibitory long-range RNA-RNA interaction and thereby contributes to enhanced HCV translation, involving not only the 5'-seed sequence of miR-122 but also sequences at its 3'-end. Also RNA oligonucleotides shorter than a typical microRNA stimulate HCV translation, confirming that in the reticulocyte lysate the stimulation of HCV translation functions by displacement of the inhibitory long-range interaction by miR-122. In contrast, in transfected HuH-7 hepatoma cells and in HeLa cells this interference of miR-122 with the inhibitory long-range RNA-RNA interaction plays not a major role, but only duplex miR-122 RNAs of the correct length stimulate HCV translation. These results suggest that: (1) the processing of the microRNA precursors and (2) the events occurring at the HCV RNA differ between cells and reticulocyte lysate.     

The possible role of leucine in modulating glucose homeostasis under distinct catabolic conditions

Branched-chain amino acids (BCAA) (especially leucine) have been shown to activate protein synthesis pathways, decrease proteolysis and increase insulin sensitivity. Furthermore, it appears that leucine can be used as a nutritional therapy to avoid sarcopenia and skeletal muscle atrophy due to immobilization or glucocorticoid treatment. However, it is of note that all of these conditions are related to insulin resistance to varying degrees and affect different tissues, particularly skeletal muscle. Additionally, evidence from recent studies demonstrate that a combination of protein containing high levels of leucine with nutrients containing saturated fatty acids or an excess of leucine are capable of inducing insulin resistance. From this discussion, a few major questions arise. First, what is the role of a combination of macronutrients in inducing insulin resistance? Second, in insulin resistance, does leucine supplementation follow the same path observed under healthy conditions? Finally, what are the dose-dependent outcome and the latency of leucine effect under such conditions? The present article discusses these questions based on data from the literature and experiments performed by our group.     

The possible role of leucine in modulating glucose homeostasis under distinct catabolic conditions

Branched-chain amino acids (BCAA) (especially leucine) have been shown to activate protein synthesis pathways, decrease proteolysis and increase insulin sensitivity. Furthermore, it appears that leucine can be used as a nutritional therapy to avoid sarcopenia and skeletal muscle atrophy due to immobilization or glucocorticoid treatment. However, it is of note that all of these conditions are related to insulin resistance to varying degrees and affect different tissues, particularly skeletal muscle. Additionally, evidence from recent studies demonstrate that a combination of protein containing high levels of leucine with nutrients containing saturated fatty acids or an excess of leucine are capable of inducing insulin resistance. From this discussion, a few major questions arise. First, what is the role of a combination of macronutrients in inducing insulin resistance? Second, in insulin resistance, does leucine supplementation follow the same path observed under healthy conditions? Finally, what are the dose-dependent outcome and the latency of leucine effect under such conditions? The present article discusses these questions based on data from the literature and experiments performed by our group.     

Effects of resistance exercise volume and nutritional supplementation on anabolic and catabolic hormones

Seven resistance-trained men performed six bouts of resistance exercise, each separated by at least 1 week, in a crossover design. High, moderate and low volumes of exercise were used, each performed twice and followed immediately post-exercise by either a placebo or carbohydrate-protein supplementation. All bouts of resistance exercise were performed using a load equal to 100% of each subject's ten-repetition maximum (10-RM), and all rest periods between sets of exercise were 1 min. Blood was obtained before and at intervals after exercise until 120 min post-exercise. Lactate levels were significantly (P<0.05) elevated immediately post-exercise, and to a significantly greater extent after the greatest volume of exercise. Levels of growth hormone rose significantly after the greatest volume of exercise only. Those of insulin and glucose rose significantly after supplementation only. Cortisol levels tended to be higher after the greatest volume of exercise, but the differences were not significant. Supplementation had no effect on the lactate, growth hormone or cortisol responses to resistance exercise. The data indicate that volume of exercise and protein-carbohydrate supplementation can alter the metabolic and hormonal responses to resistance exercise independently. However, cortisol levels remain high after a high volume of resistance exercise, irrespective of whether a post-exercise carbohydrate-protein supplement is used. Electronic Publication     

Interferon induction under in vitro conditions

The procedures generally used for the in vitro induction of interferon exploit fibroblast or leucocyte culture suspensions. Several factors and conditions influencing the capacity for IFN induction were studied, with the following results. In contrast to previous findings, optimum IFN induction was obtained at 37 degrees C, rather than 30 degrees C, when human fibroblasts were induced with 100 micrograms/ml of Poly (IC). There was a direct correlation between the dose of the inducing agent applied and the amount of IFN produced. Also, the cells were excellently super-inducible with metabolic inhibitors like actinomycin D and cycloheximine. In addition, priming procedures enhanced IFN induction in human fibroblasts. Comparing different cell types with respect to their ability to be induced for IFN production, we found that different cell types show great differences in their inducer sensitivity. Finally, the response of different cell culture systems was highly variable when induced with different compounds.     

Catabolic effect of anabolic steroid in skeletal muscle under conditions of impaired neurotrophic regulation

Effect of anabolic steroid nandrolone (Phenobolin) on fast (plantar) and slow (soleus) skeletal muscles was studied in guinea pigs with impaired neurotrophic regulation (denervation, axonal transport blockade) or after tenotomy. Immunohistochemical analysis with monoclonal antibodies to fast myosin heavy chains showed that injection of anabolic steroid did not modify the relative content of fast and slow muscle fibers in the studied muscles under all experimental conditions. Injection of anabolic steroid did not modify the weight of the studied muscles and did not prevent its drop after denervation or tenotomy. Axonal transport blockade by colchicine application on the nerve induced the appearance of fast muscle fibers in the slow soleus muscle and an increase in its weight; in the slow muscle, nandrolone did not prevent the induction of fast myosin synthesis. Under conditions of axonal transport blockade, the agent exerted a catabolic effect and considerably reduced the muscle weight. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol.127, No. 5, pp. 569–572, May, 1999     

Molecular mechanisms of the cartilage-specific microRNA-140 in osteoarthritis

Osteoarthritis (OA) is the most widespread chronic degenerative joint disorder, characterized by progressive destruction of articular cartilage, subchondral bone alterations, formation of osteophytes and synovitis. MicroRNAs (miRNAs) are a class of endogenous and non-coding single-strand RNAs with a length of about 22 nucleotides, and many of them are evolutionarily conserved. miRNAs have been implicated in the process of development and pathogenesis of diseases, and tissue-specific miRNA functional studies in mice have revealed both pathogenic and protective functions. miRNA-140 (miR-140) was shown to be specifically expressed in cartilage tissues in developing zebrafish and mouse embryos during the development of both long and flat bones. Recently, miR-140 has been reported in many studies to play significant roles in OA pathogenesis. Although the previous results were not always consistent, the molecular mechanisms of the regulation and dual function of miR-140 in cartilage homeostasis and development have been established in previous studies. Further elucidation of the molecular basis of miR-140 will uncover synergistic inhibitory effects of miR-140 and other factors on OA pathogenesis, and provide a novel means of treating OA disease.     

Basal concentrations of anabolic and catabolic hormones in relation to endurance exercise after short-term changes in diet

Summary This study aimed to use a classical model to analyse whether alterations in performance due to shortterm changes in diet are reflected in peripheral basal anabolic and catabolic hormone concentrations. Six healthy students (two women and four men) performed a cross-over study including three test situations. The reference test was preceded by each subject's normal unrestricted diet of western type (N). After this, three of the subject's were provided a carbohydrate-rich diet (CHO) for 3 days followed by the second test. Following this test, a carbohydrate deficient, protein/fat rich diet (F) was provided for another 3 days followed by the third test. The remaining three subjects had these diets in reverse order. Basal concentrations of cortisol (C), sex hormone-binding globulin (SHBG), insulin-like growth factor (IGF-I), total-testosterone and non-SHBG-bound-testosterone (NST), the NST:C ratio and an ergometer cycle endurance test with measurements of submaximal as well as measurements of maximal oxygen uptake, heart rate, respiratory exchange ratio (R), free fatty acids (FFA), glycerol and lactate were investigated. All the subjects were involved in athletics for recreation and during the study they performed daily physical exercise according to their normal routine. After the F diet only two of the subjects completed the test. One woman dropped out after 16 min, two men dropped out after 14 min and one after 13 min of cycling. After the CHO diet all six subjects completed the ergometer cycle test. Considering the whole group, there were no significant differences in lactate or glycerol concentrations during the study. The FFA concentrations were significantly higher after consuming the F diet compared to the CHO diet; and correspondingly R was significantly increased after consuming the CHO diet compared to the F diet. These changes in physiological characteristics due to short-term dietary changes were not reflected in concomitant alterations in the concentrations of anabolic or catabolic hormones, or SHBG.     

Simultaneous anabolic and catabolic responses of human chondrocytes seeded in collagen hydrogels to long-term continuous dynamic compression

Cartilage repair strategies increasingly focus on the in vitro development of cartilaginous tissues that mimic the biological and mechanical properties of native articular cartilage. However, current approaches still face problems in the reproducible and standardized generation of cartilaginous tissues that are both biomechanically adequate for joint integration and biochemically rich in extracellular matrix constituents. In this regard, the present study investigated whether long-term continuous compressive loading would enhance the mechanical and biological properties of such tissues. Human chondrocytes were harvested from 8 knee joints (n=8) of patients having undergone total knee replacement and seeded into a collagen type I hydrogel at low density of 2×10(5)cells/ml gel. Cell-seeded hydrogels were cut to disks and subjected to mechanical stimulation for 28 days with 10% continuous cyclic compressive loading at a frequency of 0.3 Hz. Histological and histomorphometric evaluation revealed long-term mechanical stimulation to significantly increase collagen type II and proteoglycan staining homogenously throughout the samples as compared to unstimulated controls. Gene expression analyses revealed a significant increase in collagen type II, collagen type I and MMP-13 gene expression under stimulation conditions, while aggrecan gene expression was decreased and no significant changes were observed in the collagen type II/collagen type I mRNA ratio. Mechanical propertywise, the average value of elastic stiffness increased in the stimulated samples. In conclusion, long-term mechanical preconditioning of human chondrocytes seeded in collagen type I hydrogels considerably improves biological and biomechanical properties of the constructs, corroborating the clinical potential of mechanical stimulation in matrix-associated autologous chondrocyte transplantation (MACT) procedures.     

Regulation of histidine decarboxylase activity in rat hypothalamusin vitro by ATP and cyclic AMP: Enzyme inactivation under phosphorylating conditions

In vitro, hypothalamic HD¹ from rat, could strikingly be inhibited by ATP and cyclic AMP. The enzyme inhibition is partially dependent upon Mg²⁺ and the circumstances favourable for a cAMP-dependent phosphorylation. An almost complete inhibition could be achieved by incubating the homogenate of the hypothalamus under phosphorylating conditions (ATP, cAMP, Mg²⁺ and IBMX) in the presence of a cAMP-dependent protein kinase (obtained from bovine thymus). Cyclic nucleotides and ATP alone elicit only moderate inhibitions on the hypothalamic HD activity. Neither ATP, nor cAMP, added alone or in combinations, alter the total brain or the hypothalamic HNMT from guinea-pigs or rats in concentrations up to 10^–3 M.Results suggest that hypothalamic HD is regulated through a cAMP-dependent process, probable a direct phosphorylation, via a cAMP-dependent protein kinase.