R. Situlin

Metabolic response to injury and sepsis: changes in protein metabolism

The metabolic response to trauma and sepsis involves an increased loss of body proteins. Specific sites of changes of protein and amino acid metabolism have been identified. In skeletal muscle, the rate of proteolysis is accelerated greatly. The rate of protein synthesis also may be increased but not enough to match the increase in degradation. Intramuscular glutamine concentration is decreased because of increased efflux and possibly decreased de novo synthesis. In the liver, the rate of synthesis of selected proteins (i.e., albumin, transferrin, prealbumin, retinol-binding protein, and fibronectin) is decreased, whereas acute phase protein synthesis is accelerated. Tissues characterized by rapidly replicating cells, such as enterocytes, immune cells, granulation tissue, and keratinocytes, exhibit early alterations in the case of decreased protein synthesis capacity. In these tissues, glutamine use is accelerated. Increased stress hormone (cortisol and glucagon) and cytokine secretion, as well as intracellular glutamine depletion, are potential mediators of altered protein metabolism in trauma and sepsis. However, the relative importance of these factors has not been clarified. Therapy of acute protein catabolism may include the use of biosynthetic human growth hormone, possibly in combination with insulin-like growth factor-1, and the administration of metabolites at pharmacologic doses. We recently studied the effects of carnitine and alanyl-glutamine administration in severely traumatized patients. We found that both carnitine and the glutamine dipeptide restrained whole-body nitrogen loss without affecting selected indices of protein metabolism in the skeletal muscle.

Omega-3 fatty acids and protein metabolism: enhancement of anabolic interventions for sarcopenia

Purpose of reviewThe increased age observed in most countries, with the associated higher rates of chronic illnesses and cancer, and a diffuse sedentary lifestyle, will increase the number of patients with clinically relevant anabolic resistance, sarcopenia and its complications. The need for solutions to this major health issue is, therefore, pressing. Recent findingsThe metabolic derangements and other consequences associated with sarcopenia can be slowed or even prevented by specific nutritional interventions. New evidence is available about the efficacy of omega-3 fatty acid dietary supplementation to improve protein metabolism and counteract anabolic resistance through indirect effects. Studies show that the anabolic stimuli from substrates (e.g. amino acids or proteins), hormones (e.g. insulin) and/or physical activity in skeletal muscle can be enhanced by long-term fish oil administration. SummaryThe review of data from recent studies on this topic suggests that dietary omega-3 fatty acid supplementation, in association with an anabolic stimulus, could potentially provide a safe, simple and low-cost intervention to counteract anabolic resistance and sarcopenia. This intervention may contribute to prevent cachexia and disabilities. Supplementation should be given in the earlier stages of sarcopenia (e.g. precachexia). Further research should, however, be performed to better understand the mechanisms involved and the best dosage and timing of administration.

Inverse relationship between "a body shape index" (ABSI) and fat-free mass in women and men: Insights into mechanisms of sarcopenic obesity.

BACKGROUND & AIMS Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro-inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass. METHODS Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index. RESULTS In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (β-coefficients: 0.62 and 0.77, respectively) and ABSI (β-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only. CONCLUSIONS ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals.

Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report.

We have investigated the effects of 24 h human recombinant growth hormone (hGH) administration on leg muscle glutamine exchange and protein kinetics in severely traumatized patients. Muscle amino acid exchange and protein balance were evaluated using the leg arteriovenous balance technique, whereas changes in skeletal muscle free amino acid concentrations were evaluated in biopsy specimens. hGH infusion decreased phenylalanine release from protein degradation by 56 +/- 14%, and the rate of branched chain amino acid catabolism by 51 +/- 10%. Glutamine release from leg muscle was suppressed by 58 +/- 12%. This latter effect was completely accounted for by a hGH-mediated suppression of glutamine synthesis in skeletal muscle. In conclusion, growth hormone administration in trauma patients may restrain protein and amino acid catabolism in skeletal muscle. However, the growth hormone-mediated suppression of glutamine production we have observed in this study could decrease the systemic availability of this amino acid. During growth hormone treatment, this potential side-effect could be prevented by an exogenous glutamine administration.

Slower activation of insulin action in hypertension associated with obesity.

Objective To determine whether kinetic abnormalities in the onset of insulin action contribute to the insulin resistance in obesity-associated hypertension. Design We monitored the rate of increase in glucose infusion during 6 h of hyperinsulinemic (40 mU/m2 per min) euglycemic clamps in hypertensive and normotensive obese subjects. The two groups of hypertensive (n = 9) and normotensive (n = 9) subjects were matched for age (48 ± 2 versus 45 ± 5 years), sex (five males and four females versus four males and five females) and body mass index (42 ± 3 versus 40 ± 2 kg/m2). Results In all subjects, the glucose infusion rate required to maintain euglycemia increased progressively during the clamp studies to achieve maximal, steady-state values within the fifth hour. During the first 2 h of the clamp, mean glucose infusion rate, the traditional approach to assessing insulin sensitivity, was lower in the hypertensive than in the normotensive obese patients (2.04 ± 0.13 versus 3.29 ± 0.41 mg/kg per min, respectively; P < 0.05). In contrast, the maximal steady-state glucose infusion rate, calculated as the mean value during the sixth hour of clamping, was similar in the hypertensive and in the normotensive obese patients (4.48 ± 0.43 versus 4.81 ± 0.45 mg/kg per min, respectively; NS). The time required to reach the half-maximal glucose infusion rate was greater in the hypertensive than normotensive obese patients (91 ± 12 versus 38 ± 5 min, respectively; P < 0.05). Conclusion In obesity, hypertension was associated with a slower rate of activation of the insulin effect on glucose metabolism, whereas the maximal steady-state insulin effects were not altered by elevated blood pressure. Thus, the link between obesity and hypertension may be associated with the kinetics of onset of insulin action.

The Association between Hematological Parameters and Insulin Resistance Is Modified by Body Mass Index – Results from the North-East Italy MoMa Population Study

Objective Increments in red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) levels are reportedly associated with higher insulin resistance (IR). Obesity may cause IR, but underlying factors remain incompletely defined, and interactions between obesity, hematological parameters and IR are incompletely understood. We therefore determined whether: 1) BMI and obesity per se are independently associated with higher RBC, hemoglobin and hematocrit; 2) hematological parameters independently predict insulin resistance in obese individuals. Design and Methods We investigated the associations between BMI, hematological parameters and insulin resistance as reflected by homeostasis model assessment (HOMA) in a general population cohort from the North-East Italy MoMa epidemiological study (M/F = 865/971, age = 49±1). Results In all subjects, age-, sex- and smoking-adjusted hematological parameters were positively associated with BMI in linear regression (P<0.05), but not after adjustment for HOMA or waist circumference (WC) and potential metabolic confounders. No associations were found between hematological parameters and BMI in lean, overweight or obese subgroups. Associations between hematological parameters and HOMA were conversely independent of BMI in all subjects and in lean and overweight subgroups (P<0.01), but not in obese subjects alone. Conclusions In a North-East Italy general population cohort, obesity per se is not independently associated with altered RBC, Hb and Ht, and the association between BMI and hematological parameters is mediated by their associations with abdominal fat and insulin resistance markers. High hematological parameters could contribute to identify insulin resistance in non-obese individual, but they do not appear to be reliable insulin resistance biomarkers in obese subjects.

Relationship between Whole-Body Protein Turnover and Serum Creatinine in Chronically Uremic Patients

To investigate the relationship between decline in renal function and alterations of protein metabolism we determined the rate of whole-body protein turnover in a group of 15 postabsorptive chronically uremic patients (9 males and 6 females) with different levels of serum creatinine concentrations (average 5.7 ± 0.4 (SE) mg·dl–1; range 3.3–9.1). Patients’ age and body mass index were 53 ± 4 years (range 26–73) and 24.7 ± 0.6 kg/m2 (range 20.3–28.7), respectively. Nutritional status (plasma albumin 3.6 ± 0.4 g·dl–1) and acid-base equilibrium (arterial pH 7.38 ± 0.01) were fairly controlled by therapy. Whole-body leucine rate of appearance (Ra), an index of whole-body protein turnover, was assessed using a stable isotope technique. L-[1-13C]leucine was continuously infused and plasma [1-13C]α-ketoisocaproic acid enrichment was determined in steady-state conditions as a marker of the intracellular leucine enrichment. The average leucine Ra was 2.03 ± 0.13 µmol·kg–1·min–1 (range 1.29–3.19). Using simple linear regression analysis, the coefficient of correlation between the individual values of serum creatinine concentration and leucine Ra was 0.59 (n = 15; p = 0.02). Leucine Ra did not significantly correlate with blood pH or plasma albumin. In conclusion, we found a positive linear relationship between the values of plasma creatinine concentration and the rate of whole-body protein degradation. This correlation suggests that the progression of renal insufficiency is associated with accelerated rates of turnover of body proteins.

Cathepsin B and D activity in human skeletal muscle in disease states.

The effects of nutrition and disease state on whole body protein metabolism have been widely studied in recent years, but the distribution of changes among the various body tissues is less known. It is, therefore, important to establish the contribution made by skeletal muscle to whole body protein metabolism in disease state, because skeletal muscle is quantitatively and metabolically the most important body protein “store”1 and remains a good marker of protein-energy malnutrition (PEM) when the protein pools of other tissues and organs become metabolically una vailable 1-3.

Muscle Cathepsin D Activity, and RNA, DNA and Protein Content in Maintenance Hemodialysis Patients

In man, skeletal muscle is the largest protein pool in the body. Muscle losses in response to undernutrition, inactivity, endocrine abnormalities, trauma, severe infection, fever etc. can be very extensive, as a consequence of reduced muscle protein synthesis and/or increased degradation1–8. The rate of muscle protein degradation can paradoxically increase or decrease during wasting, and its changes are accompanied by changes of proteinase activity in muscle9.

Body weight and its association with impulsivity in middle and old age individuals

&NA; Impulsivity, conceptualized as impulsive personality trait, poor inhibitory control and enhanced reward sensitivity, has been strongly linked to obesity. In particular, a disequilibrium between cognitive control and reward sensitivity has been observed in obese individuals in both behavioural and imaging studies. While this issue has been widely investigated in children and adults, it has received little attention in older adults. Here, obese and non‐obese participants aged between 40 and 70 years completed the Barratt Impulsiveness scale (assessing motor, non‐planning and attentional impulsiveness), a Go/no‐go task with foods and non‐foods (assessing inhibitory control) and a reward sensitivity battery with high and low caloric foods (assessing liking, wanting, tastiness and frequency of consumption). We observed that participants with higher BMI reported increased wanting for high calorie foods, but did not show poorer inhibitory control. Interestingly, participants who scored lower on the MMSE reported to consume high calorie more than low calorie foods. Finally, those who presented low scores on non‐planning and motor impulsiveness subscales reported higher tastiness ratings for low calorie foods. These results show that increased reward sensitivity but not reduced inhibitory control may characterize higher BMI during aging. Importantly, they also highlight new findings concerning food preferences among older adults.