Barazzoni, Rocco

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years. Methods A working group ( n = 43 members) conducted a literature search spanning 2019–2024 using the keywords “Global Leadership Initiative on Malnutrition or GLIM.” Prior GLIM guidance activities for using the criteria on muscle mass and inflammation were reviewed. Successive rounds of revision and review were used to achieve consensus. Results More than 400 scientific reports were published in peer‐reviewed journals, forming the basis of 10 systematic reviews, some including meta‐analyses of GLIM validity that indicate strong construct and predictive validity. Limitations and future priorities are discussed. Working group findings suggest that assessment of low muscle mass should be guided by experience and available technological resources. Clinical judgment may suffice to evaluate the inflammation/disease burden etiologic criterion. No revisions of the weight loss, low BMI, or reduced food intake/assimilation criteria are suggested. After two rounds of review and revision, the working group secured 100% agreement with the conclusions reported in the 5‐year update. Conclusion Ongoing initiatives target priorities that include malnutrition risk screening procedures, GLIM adaptation to the intensive care setting, assessment in support of the reduced food intake/assimilation criterion, and determination of malnutrition in obesity.

AbstractThe role of long‐term parenteral support in patients with underlying benign conditions who do not have intestinal failure (IF) is contentious, not least since there are clear benefits in utilising the oral or enteral route for nutritional support. Furthermore, the risks of long‐term home parenteral nutrition (HPN) are significant, with significant impacts on morbidity and mortality. There has, however, been a recent upsurge of the use of HPN in patients with conditions such as gastro‐intestinal neuromuscular disorders, opioid bowel dysfunction, disorders of gut–brain interaction and possibly eating disorders, who do not have IF. As a result, the European Society of Clinical Nutrition and Metabolism (ESPEN), the European Society of Neuro‐gastroenterology and Motility (ESNM) and the Rome Foundation for Disorders of Gut Brain Interaction felt that a position statement is required to clarify – and hopefully reduce the potential for harm associated with – the use of long‐term parenteral support in patients without IF. Consensus opinion is that HPN should not be prescribed for patients without IF, where the oral and/or enteral route can be utilised. On the rare occasions that PN commencement is required to treat life‐threatening malnutrition in conditions such as those listed above, it should only be prescribed for a time‐limited period to achieve nutritional safety, while the wider multi‐disciplinary team focus on more appropriate biopsychosocial holistic and rehabilitative approaches to manage the patient's primary underlying condition.

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) approach to malnutrition diagnosis is based on assessment of three phenotypic (weight loss, low body mass index, and reduced skeletal muscle mass) and two etiologic (reduced food intake/assimilation and disease burden/inflammation) criteria, with diagnosis confirmed by fulfillment of any combination of at least one phenotypic and at least one etiologic criterion. The original GLIM description provided limited guidance regarding assessment of inflammation, and this has been a factor impeding further implementation of the GLIM criteria. We now seek to provide practical guidance for assessment of inflammation. Methods A GLIM‐constituted working group with 36 participants developed consensus‐based guidance through a modified Delphi review. A multiround review and revision process served to develop seven guidance statements. Results The final round of review was highly favorable, with 99% overall “agree” or “strongly agree” responses. The presence of acute or chronic disease, infection, or injury that is usually associated with inflammatory activity may be used to fulfill the GLIM disease burden/inflammation criterion, without the need for laboratory confirmation. However, we recommend that recognition of underlying medical conditions commonly associated with inflammation be supported by C‐reactive protein (CRP) measurements when the contribution of inflammatory components is uncertain. Interpretation of CRP requires that consideration be given to the method, reference values, and units (milligrams per deciliter or milligram per liter) for the clinical laboratory that is being used. Conclusion Confirmation of inflammation should be guided by clinical judgment based on underlying diagnosis or condition, clinical signs, or CRP.

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.

Triiodothyronine (T3) increases O2 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 T3 for 14 days. Relative to saline-treated controls, T3 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 T3 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 T3 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 T3 group. We conclude that T3 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.

In human protein turnover studies with isotopically labeled leucine (Leu) as a tracer, plasma ketoisocaproate (KIC) enrichment is extensively used as a surrogate measure of intracellular leucine enrichment. To test how accurately arterial ketoisocaproate (A-KIC) represents leucine isotopic enrichment in the hepatic (HV) and femoral veins (FV), which drain liver and muscle beds, we measured Leu and KIC enrichments in samples collected from HV, FV, and femoral artery (A) in 24 control and 6 type I diabetic subjects after a primed, continuous infusion ofl-[1-13C,15N]-Leu. Studies were performed during insulin deprivation or insulin replacement in the diabetic group, whereas the effect of normal saline or three different doses of insulin infusion (0.25, 0.50, and 1 mU ⋅ kg−1⋅ min−1) were assessed in healthy controls. The ratios of baseline isotopic enrichments of A-KIC to HV Leu and FV Leu were 0.93 ± 0.01 and 0.94 ± 0.02, respectively, in normal subjects and 1.07 ± 0.04 and 1.05 ± 0.03, respectively, in diabetic subjects ( P < 0.01, diabetic vs. normal subjects). Insulin did not change A-KIC-to-HV Leu ratios in either group, but the A-KIC-to-FV Leu ratio decreased during insulin infusion in normal subjects ( P < 0.05). In conclusion, A-KIC represents a reliable surrogate measure of HV Leu enrichment at different levels of circulating insulin in humans. The present data support the use of A-KIC as a surrogate precursor pool for hepatic protein synthesis.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurments confirmed the changes in transcript levels of cytochrome- c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

High-fat diets are reported to increase oxidative stress in a variety of tissues, whereas antioxidant supplementation prevents many diseases attributed to high-fat diet. Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage. We hypothesized that the effects of a high-fat diet on skeletal muscle DNA functions would be attenuated or partially reversed by antioxidant supplementation. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. The high-fat diet altered transcript levels of 18 genes of 800 surveyed compared with the control-fed rats. Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes. The magnitude of these alterations due to high-fat diet was reduced by antioxidant supplementation. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome c oxidase subunit III and superoxide dismutase-1 and -2 noted by microarray approach. Mitochondrial ATP production was unaltered by dietary changes or antioxidant supplemention. It is concluded that the high-fat diet increases the transcription of genes involved in stress response but reduces those of free-radical scavenger enzymes, resulting in reduced DNA repair/metabolism (increased DNA damage). Antioxidants partially prevent these changes. Mitochondrial functions in skeletal muscle remain unaltered by the dietary intervention due to many adaptive changes in gene transcription.

Systemic insulin administration causes hypoaminoacidemia by inhibiting protein degradation, which may in turn inhibit muscle protein synthesis (PS). Insulin enhances muscle mitochondrial PS and ATP production when hypoaminoacidemia is prevented by exogenous amino acid (AA) replacement. We determined whether insulin would stimulate mitochondrial PS and ATP production in the absence of AA replacement. Using l-[1,2-13C]leucine as a tracer, we measured the fractional synthetic rate of mitochondrial as well as sarcoplasmic and mixed muscle proteins in 18 participants during sustained (7-h) insulin or saline infusion ( n = 9 each). We also measured muscle ATP production, mitochondrial enzyme activities, mRNA levels of mitochondrial genes, and phosphorylation of signaling proteins regulating protein synthesis. The concentration of circulating essential AA decreased during insulin infusion. Mitochondrial, sarcoplasmic, and mixed muscle PS rates were also lower during insulin (2–7 h) than during saline infusions despite increased mRNA levels of selected mitochondrial genes. Under these conditions, insulin did not alter mitochondrial enzyme activities and ATP production. These effects were associated with enhanced phosphorylation of Akt but not of protein synthesis activators mTOR, p70S6K, and 4EBP1. In conclusion, sustained physiological hyperinsulinemia without AA replacement did not stimulate PS of mixed muscle or protein subfractions and did not alter muscle mitochondrial ATP production in healthy humans. These results support that insulin and AA act in conjunction to stimulate muscle mitochondrial function and mitochondrial protein synthesis.