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Biomedical subjects

K S Nair

Publications and source records attributed to K S Nair.

At least 19 recordsLinked to original sources
PubMed2006

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal.

AIMS/HYPOTHESIS: The aim of this study was to test the hypothesis that type 1 diabetes alters renal amino acid, glucose and fatty acid metabolism. MATERIALS AND METHODS: We studied five C-peptide-negative, type 1 diabetic subjects during insulin replacement (glucose 5.6 mmol/l) and insulin deprivation (glucose 15.5 mmol/l) and compared them with six non-diabetic subjects. Leucine, phenylalanine, tyrosine, glucose and palmitate tracers were infused after an overnight fast and samples were obtained from the renal vein, femoral vein and femoral artery. RESULTS: Insulin deprivation significantly increased whole-body fluxes (20-25%) of phenylalanine, tyrosine and leucine, and leucine oxidation (50%). Kidney contributed 5-10% to the whole-body leucine and phenylalanine flux. A net uptake of phenylalanine, conversion of phenylalanine to tyrosine (5 micromol/min) and net release of tyrosine (approximately 5 micromol/min) occurred across the kidney. Whole-body (three-fold) and leg (two-fold) leucine transamination increased but amino acid metabolism in the kidney did not alter with diabetes or insulin deprivation. Insulin deprivation doubled endogenous glucose production, renal glucose production was unaltered by insulin deprivation and diabetes (ranging between 100 and 140 micromol/min). Renal palmitate exchange was unaltered by insulin deprivation. CONCLUSIONS/INTERPRETATION: In conclusion, kidney post-absorptively accounts for 5-10% of whole-body protein turnover, 15-20% of leucine transamination and 10-15% of endogenous glucose production, and actively converts phenylalanine to tyrosine. During insulin deprivation, leg becomes a major site for leucine transamination but insulin deprivation does not affect renal phenylalanine, leucine, palmitate or glucose metabolism. Despite its key metabolic role, insulin deprivation in type 1 diabetic patients does not alter many of these metabolic functions.

Amino Acids↗
PubMed2006

Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs.

AIMS/HYPOTHESIS: In non-diabetic people, insulin levels in the liver are two-fold higher than those in the systemic circulation. In contrast, patients with type 1 diabetes have similar hepatic and systemic insulin levels because insulin is administered peripherally. The aim of this study was to compare the effects of systemic (SI) and pre-portal (PI) insulin administration on energy, glucose and protein metabolism in chronic insulin-dependent ketosis-prone diabetic dogs. MATERIALS AND METHODS: We applied glucose-controlled insulin infusion, indirect calorimetry and stable isotope and radioisotope techniques to measure energy, protein and glucose metabolism. We maintained near-normoglycaemia at identical levels under both study conditions for 20 h. RESULTS: SI was associated with lower oxygen consumption (130+/-13 vs 161+/-8 ml/min), CO(2) production (99+/-10 vs 130+/-8 ml/min), respiratory quotient (0.76+/-0.02 vs 0.81+/-0.01) and energy expenditure (870+/-90 vs 1089+/-60 kcal/24 h) (p<0.05 for all differences). PI increased the respiratory quotient from the insulin-deprived state, whereas SI did not. Glucose kinetics were similar for SI and PI, whereas leucine oxidation (36+/-4 vs 54+/-5 micromol kg(-1) min(-1)) and the fractional synthesis rates of liver tissue protein (0.68+/-0.6 vs 0.83+/-0.07%/h), albumin (0.55+/-0.06 vs 0.68+/-0.4%/h), and fibrinogen (1.73+/-0.23 vs 2.59+/-0.25%/h) were all lower during SI than PI (p<0.05). CONCLUSIONS/INTERPRETATION: The route of insulin administration did not alter glucose metabolism but did affect protein synthesis in the liver. The potential impact of this altered liver protein metabolism on chronic complications needs careful evaluation. A similar decrease in energy expenditure resulting from systemic insulin administration during tight glycaemic control is a potential cause of weight gain.

Amino Acids↗
PubMed2005

Whole body and forearm substrate metabolism in hyperthyroidism: evidence of increased basal muscle protein breakdown.

Thyroid hormones have significant metabolic effects, and muscle wasting and weakness are prominent clinical features of chronic hyperthyroidism. To assess the underlying mechanisms, we examined seven hyperthyroid women with Graves' disease before (Ht) and after (Eut) medical treatment and seven control subjects (Ctr). All subjects underwent a 3-h study in the postabsorptive state. After regional catheterization, protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique using [15N]phenylalanine and [2H4]tyrosine. Before treatment, triiodothyronine was elevated (6.6 nmol/l) and whole body protein breakdown was increased 40%. The net forearm release of phenylalanine was increased in hyperthyroidism (microg.100 ml(-1).min(-1)): -7.0 +/- 1.2 Ht vs. -3.8 +/- 0.8 Eut (P = 0.04), -4.2 +/- 0.3 Ctr (P = 0.048). Muscle protein breakdown, assessed by phenylalanine rate of appearance, was increased (microg.100 ml(-1).min(-1)): 15.5 +/- 2.0 Ht vs. 9.6 +/- 1.4 Eut (P = 0.03), 9.9 +/- 0.6 Ctr (P = 0.02). Muscle protein synthesis rate did not differ significantly. Muscle mass and muscle function were decreased 10-20% before treatment. All abnormalities were normalized after therapy. In conclusion, our results show that hyperthyroidism is associated with increased muscle amino acid release resulting from increased muscle protein breakdown. These abnormalities can explain the clinical manifestations of sarcopenia and myopathy.

Adult↗
PubMed2005

AIDS-related discrimination in Asia.

The Asia Pacific Network of People Living with HIV/AIDS (APN+) conducted the first regional documentation of AIDS-related discrimination in Asia. This project was an action-based, peer-implemented study that aimed to develop an understanding of the nature, pattern and extent of AIDS-related discrimination in several Asian countries. Trained HIV-positive people interviewed 764 positive people in four countries (India 302; Indonesia 42; Thailand 338; the Philippines 82) using a structured questionnaire. Findings indicate that the major area of discrimination in each country is within the health sector, where over half of those surveyed experienced some form of discrimination. In all countries, the majority of people did not receive pre-test counselling before being tested for HIV. People who reported coerced testing were significantly more likely than other respondents to face subsequent AIDS-related discrimination. A considerable number of respondents were refused treatment after being diagnosed with HIV and many experienced delayed provision of treatment or health services. Breaches of confidentiality by health workers were common. Within the family and the community, women were significantly more likely to experience discrimination than men, including ridicule and harassment, physical assault and being forced to change their place of residence because of their HIV status. These findings have serious implications, particularly in light of the increasing trend in many countries to test all pregnant women in order to prevent transmission of HIV to their unborn children.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value.

Oesophageal carcinoma remains a disease of poor prognosis. Surgical cure rates are compromised by the fact that most patients are diagnosed at a late stage of disease because of the delayed onset of symptoms, by which time metastases and organ infiltration may have already occurred. Thus, invasion and metastases play a key role in influencing patient survival, and the search for novel treatments may therefore hinge on gaining insight into the mechanisms controlling these processes. It has been established that the initial step in the metastatic cascade is the detachment of tumour cells from the primary tumour via dysregulation of normal cell-cell and cell-matrix interactions. Distinct proteins known as cell adhesion molecules (CAMs) mediate these interactions. In recent years, a plethora of information has contributed to the in depth understanding of these molecules. This review provides a brief description of five families of CAMs (cadherins, integrins, CD44, immunoglobulin superfamily, and selectins) and highlights their altered expression in relation both to prognosis and tumour behaviour in squamous cell carcinoma and adenocarcinoma of the oesophagus.

Adenocarcinoma↗
PubMed2003

Sarcopenia--consequences, mechanisms, and potential therapies.

Increasingly, the worldwide population is growing older. Sarcopenia occurs with age and is characterized by loss of muscle mass, strength and endurance. Mechanisms that underlie this process are beginning to be understood. These include age-related loss and atrophy of individual muscle fibers, decreased synthesis of muscle proteins, and reduced mitochondrial function. The role of decreased anabolic hormone production in causing these changes remains to be clearly defined. Anabolic hormone replacement is a potential strategy currently being investigated for treatment of sarcopenia. Combinations of aerobic, resistance, and stretching exercise programs have well established beneficial effects. Further understanding of the molecular processes involved in the aging of muscle both at the level of gene expression and protein modification will be important for discovering novel treatment strategies.

Aged↗
PubMed2002

Effects of lowering circulating free fatty acid levels on protein metabolism in adult growth hormone deficient patients.

Our study was conducted to define the roles of lowering circulating free fatty acids (FFA) and of growth hormone (GH) replacement on protein metabolism in GH deficient patients. To isolate the specific effects of FFA and GH we studied seven adult subjects with GH deficiency four times: (A) with administration of GH and Acipimox (an inhibitor of lipolysis), (B) with GH, without Acipimox, (C) without GH, with Acipimox and (D) without either. Each study included a 3 h basal period and a 3 h euglycemic clamp. Amino acid metabolism was assessed by stable isotope dilution technique at the whole body level and across the forearm. Overall, we saw no intervention effect on protein metabolism, but when the two situations in which Acipimox was given were combined, Acipimox decreased basal plasma FFA concentrations by 75% and increased serum urea concentrations by 20%, whole body appearance rates (reflecting protein degradation) of phenylalanine (by 7%) and tyrosine (by 11%) and protein synthesis rates for phenylalanine (by 7%), whereas phenylalanine-to-tyrosine conversion was unaffected. Acipimox more than doubled net forearm phenylalanine release during the clamp and increased basal forearm phenylalanine disappearance (reflecting muscle protein synthesis). During the clamp whole body amino acid fluxes and phenylalanine-to-tyrosine conversion decreased together with a decrease in forearm protein breakdown. GH replacement did not affect any of these metabolic parameters. Although we failed to show any role for GH, the results show that lowering of FFA concentrations with Acipimox has pronounced effects on protein metabolism, including increased whole body and forearm protein breakdown, together with increased protein synthesis systemically and locally in the forearm. The increase in serum urea and a doubling of net forearm phenylalanine release after lowering of FFA strongly indicate that the overall effect is catabolic and supports a pivotal protein conserving role of lipids.

Adult↗
PubMed2002

Insulin effect on leucine kinetics in type 2 diabetes mellitus.

Insulin-induced glucose disposal is impaired in Type 2 diabetes mellitus (T2DM). To determine whether insulin-induced suppression of protein breakdown also is impaired, we measured leucine flux (an index of protein breakdown) in diabetic and nondiabetic subjects during a hyperinsulinemic euglycemic clamp. To avoid the confounding effects of a difference in baseline glucose, glucose concentration in the diabetic subjects was normalized by means of an overnight insulin infusion. Despite higher plasma insulin levels (33.5+/-0.05 vs 132+/-2.7 pmol/l, p<01) diabetic subjects had similar amino acid concentrations and leucine flux (96.9+/-5.8 vs 93.4+/-3.7 micromol/kg/h) as nondiabetic subjects. Infusion of insulin (0.5 mU/kg/min) increased insulin levels (p<0.01) to identical levels in both groups (218+/-16 vs 222+/-19), but the glucose infusion required to maintain euglycemia was higher (p<0.01) in nondiabetic than in diabetic subjects, indicating insulin resistance to glucose disposal in the diabetic subjects. In contrast, leucine flux (81.3+/-4.8 vs 81.6+/-3.4 micromol/kg/h) reached identical levels in both groups. The individual and total amino acid levels also were comparable in both groups. We conclude that suppression of whole body protein turnover in response to an acute increase in insulin is normal in people with T2DM. However, chronic adaptation to high insulin levels occurs, thereby enabling protein breakdown and amino acid concentration to remain within the normal range in people with T2DM.

Blood Glucose↗
PubMed2002

Muscle changes in aging.

This review summarizes the recent studies to understand the mechanisms of sarcopenia of aging. A decrease in mitochondrial and nuclear gene transcriptions in skeletal muscle is likely to be responsible for reduced synthesis rates of muscle mitochondrial protein, myosin heavy chain (MHC) and actin. A decrease in muscle mitochondrial protein synthesis could contribute to reduced mitochondrial function. A decrease in synthesis rate of MHC and actin, the key contractile proteins could be responsible for reduced muscle strength. The MHC synthesis rate seems to result from a selective decrease in transcription of MHC isoforms (MHCIIa and IIx) responsible for fast-twitch fibers. Resistance training increases MHC-I isoform mRNA levels with an overall increase in MHC synthesis rate. Aerobic training increases muscle oxidative enzymes equally in young and old but its impact on overall mitochondrial function remains to be clearly defined. Long-term studies are needed to determine the potential benefits and undesirable effects of replacements of various hormones that decline with aging. An individualized exercise prescription involving both aerobic and resistance training is definitely helpful to overcome many aging-related muscle dysfunctions.

Journal Article↗
PubMed2001

Adhesion of neutrophils to fibronectin: role of the cd66 antigens.

Adhesion of neutrophils to substrate is initiated by receptor-ligand interactions that induce outside-in signaling. Inside-out signals and lateral interactions between surface molecules further fine tune the response. This study investigates the role of CD66 in adhesion of neutrophils to fibronectin, using domain-mapped monoclonal antibodies to CD66. Neutrophils express CD66a, CD66b, and CD66c on their surface. The neutrophil surface molecules that bind to fibronectin are the alpha(4)beta(1) and alpha(5)beta(1) integrins. Our results show that the monoclonal antibody Kat4c, which recognizes the AB domain of CD66a, b, and c and the polyclonal anti-CD66 (anti-carcinoembryonic antigen), augments neutrophil adhesion to fibronectin, while monoclonal antibodies to the individual CD66 antigens, the Fab fragment of Kat4c, and a mixture of the individual antibodies to CD66 antigens were unable to affect the adhesion. Thus heterodimerization of CD66a, b, and c is required for promoting neutrophil adhesion to fibronectin. The increased adhesion in presence of Kat4c was inhibited by antibodies to the beta(1) and beta(2) integrins. Antibody ligation of CD66 antigens causes their clustering and concomitant coclustering of the alpha(M) subunit of the beta(2) integrin, thereby activating the integrin. The sugar alpha-methyl mannoside inhibited anti-CD66-mediated clustering, indicating that a carbohydrate-lectin interaction may exist between CD66 and alpha(M) integrin. It also reduced the increased adhesion of neutrophils to fibronectin, suggesting that beta(2) integrin activation precedes beta(1) integrin activation. Further, the anti-CD66-mediated adhesion to fibronectin is accompanied by increased localization of Src family kinases (lyn and hck) to the cytoskeleton and an increase in their kinase activity. These results suggest that crosslinking of CD66a, CD66b, and CD66c promotes activation of the beta(2) integrin and in turn an alteration in the affinity of the beta(1) integrin, which enhances the adhesion of neutrophils to fibronectin.

Antibodies, Monoclonal↗
PubMed2001

Sarcopenia.

Sarcopenia is a term utilized to define the loss of muscle mass and strength that occurs with aging. Sarcopenia is believed to play a major role in the pathogenesis of frailty and functional impairment that occurs with old age. Progressive muscle wasting occurs with aging. The prevalence of clinically significant sarcopenia is estimated to range from 8.8% in young old women to 17.5% in old old men. Persons who are obese and sarcopenic (the "fat frail") have worse outcomes than those who are sarcopenic and non-obese. There is a disproportionate atrophy of type IIa muscle fibers with aging. There is also evidence of an age-related decrease in the synthesis rate of myosin heavy chain proteins, the major anabolic protein. Motor units innervating muscle decline with aging, and there is increased irregularity of muscle unit firing. There are indications that cytokines-especially interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6-play a role in the pathogenesis of sarcopenia. Similarly, the decline in anabolic hormones-namely, testosterone, dehydroepiandrosterone growth hormone, and insulin-like growth factor-I-is also implicated in the sarcopenic process. The role of the physiologic anorexia of aging remains to be determined. Decreased physical activity with aging appears to be the key factor involved in producing sarcopenia. An increased research emphasis on the factors involved in the pathogenesis of sarcopenia is needed.

Aging↗
PubMed2001

Does aging adversely affect muscle mitochondrial function?

Muscle oxidative function appears to decline with aging, and evidence suggests that this is related to reduced synthesis of mitochondrial and other muscle proteins. Causes for these events may include mtDNA damage or reduced mtDNA copy numbers, reduced oxidative enzyme activities and ATP production, and increased proton leak.

Adenosine Triphosphate↗
PubMed2001

Muscle protein metabolism and the sarcopenia of aging.

Loss of muscle mass, strength, and oxidative capacity accompanies normal aging in humans. The mechanisms responsible for these changes remain to be clearly defined. Muscle protein mass and function depend on protein turnover. Synthesis rate of the major muscle contractile protein, myosin heavy chain (MHC), and transcript levels of fast MHC isoforms decrease in association with strength reductions, while mitochondrial protein synthesis rate declines in parallel with activities of mitochondrial enzymes and maximal oxidative capacity (VO2max). Resistance exercise training increases the synthesis rate of MHC and transcript levels of the slow MHC isoform in older humans, along with increasing muscle strength. The relationship between the synthesis of muscle proteins, and muscle size and function, with aging and exercise training are discussed in this review.

Aged↗
PubMed2001

Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise.

Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20-27 yr), 12 middle-aged (47-60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46-79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% (P < 0.05) from young to middle age and further decreased 50% (P < 0.05) from middle to old age. MHCIIx decreased 84% (P < 0.05) from young to middle age and 48% from middle to old age (P < 0.05). Exercise increased FSR of MHC by 47% (P < 0.01) and mixed muscle protein by 56% (P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.

Adult↗
PubMed2001

Changes in uncoupling protein-2 and -3 expression in aging rat skeletal muscle, liver, and heart.

Uncoupling protein (UCP)-2 and -3 mediate mitochondrial (mt) proton leak in vitro and are potential regulators of energy expenditure and ATP production. Aging is associated with alteration of tissue functions, suggesting impaired mtATP production. To determine whether age-related changes in UCP expression occur, we measured the transcript levels of UCP-2 and -3 in skeletal muscle, liver, and heart in 6- and 27-mo-old rats. UCP-2 transcripts were higher in old animals in the white (+100%) and red (+70%, both P < 0.04) gastrocnemius muscle and in the liver (+300%, P < 0.03), whereas they were comparable in the heart in both age groups. UCP-2 transcript levels correlated positively with mitochondrial-encoded cytochrome c oxidase transcripts normalized for mtDNA (P < 0.01) and negatively with mtDNA copy number (P < 0.001). UCP-3 transcripts were lower in the less oxidative white (-50%, P < 0.04) and unchanged in the more oxidative red (-15%, P = 0.41) gastrocnemius muscle in old animals. Similar changes at protein level were confirmed by UCP-2 protein in aging liver (+300%, P < 0.01) and UCP-2 (+85%, P < 0.05) and UCP-3 (-30%, P = 0.4) protein in aging mixed gastrocnemius muscle. Aging is thus associated with tissue-specific changes of UCP-2 and -3 gene expression. Increased UCP-2 expression may limit ATP production and is related to mitochondrial gene expression in aging muscles and liver. Different age-related changes may reflect differential regulation of UCP-2 and -3 in skeletal muscle. The current data suggest a potential role of uncoupling proteins to alter energy production in aging tissues.

Adenosine Triphosphate↗
PubMed2001

T(3) increases mitochondrial ATP production in oxidative muscle despite increased expression of UCP2 and -3.

Triiodothyronine (T(3)) increases O(2) and nutrient flux through mitochondria (Mito) of many tissues, but it is unclear whether ATP synthesis is increased, particularly in different types of skeletal muscle, because variable changes in uncoupling proteins (UCP) and enzymes have been reported. Thus Mito ATP production was measured in oxidative and glycolytic muscles, as well as in liver and heart, in rats administered T(3) for 14 days. Relative to saline-treated controls, T(3) rats had 80, 168, and 62% higher ATP production in soleus muscle, liver, and heart, respectively, as well as higher activities of citrate synthase (CS; 63, 90, 25%) and cytochrome c oxidase (COX; 119, 225, 52%) in the same tissues (all P < 0.01). In plantaris muscle of T(3) rats, CS was only slightly higher (17%, P < 0.05) than in controls, and ATP production and COX were unaffected. mRNA levels of COX I and III were 33 and 47% higher in soleus of T(3) rats (P < 0.01), but there were no differences in plantaris. In contrast, UCP2 and -3 mRNAs were 2.5- to 14-fold higher, and protein levels were 3- to 10-fold higher in both plantaris and soleus of the T(3) group. We conclude that T(3) increases oxidative enzymes and Mito ATP production and Mito-encoded transcripts in oxidative but not glycolytic rodent tissues. Despite large increases in UCP expression, ATP production was enhanced in oxidative tissues and maintained in glycolytic muscle of hyperthyroid rats.

Adenosine Triphosphate↗