The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease.

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

The role of ectopic adipose tissue: benefit or deleterious overflow?

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth.

Hypoalbuminemia: Pathogenesis and Clinical Significance.

Hypoalbuminemia is associated with inflammation. Despite being addressed repeatedly in the literature, there is still confusion regarding its pathogenesis and clinical significance. Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin. The half-life of albumin has been shown to shorten, decreasing total albumin mass. These 2 factors lead to hypoalbuminemia despite increased fractional synthesis rates in plasma. Hypoalbuminemia, therefore, results from and reflects the inflammatory state, which interferes with adequate responses to events like surgery or chemotherapy, and is associated with poor quality of life and reduced longevity. Increasing or decreasing serum albumin levels are adequate indicators, respectively, of improvement or deterioration of the clinical state. In the interstitium, albumin acts as the main extracellular scavenger, antioxidative agent, and as supplier of amino acids for cell and matrix synthesis. Albumin infusion has not been shown to diminish fluid requirements, infection rates, and mortality in the intensive care unit, which may imply that there is no body deficit or that the quality of albumin "from the shelf" is unsuitable to play scavenging and antioxidative roles. Management of hypoalbuminaemia should be based on correcting the causes of ongoing inflammation rather than infusion of albumin. After the age of 30 years, muscle mass and function slowly decrease, but this loss is accelerated by comorbidity and associated with decreasing serum albumin levels. Nutrition support cannot fully prevent, but slows down, this chain of events, especially when combined with physical exercise.

Disease or adaptation: another look at the practice of medicine.

The practice of medicine has changed considerably over the past few decades and is now focusing more and more on early intervention strategies. As a result, we tend to consider pre-symptomatic abnormalities, however small, already as a potential target for treatment. In this viewpoint, we argue that we should put more emphasis on pathophysiological thinking as many of the so-called early abnormalities may, in fact, reflect adaptive mechanisms rather than disease. This view should influence medical care and education, emphasizing the importance of knowledge of pathophysiology.

Macronutrient Metabolism in Starvation and Stress.

In starvation and to a lesser extent in stress starvation, the loss of protein mass is spared as much as possible. This metabolic arrangement must have developed under the influence of evolutionary pressure in view of the importance of protein mass for function and longevity. Peripheral adipose tissue mass is only limiting when its mass is extremely small. Protein is the predominant precursor of glucose in (stress) starvation and glucose is an essential substrate for the synthesis and maintenance of cells and matrix and for the control of the redox state. To spare protein, glucose should be used efficiently only for those purposes that cannot be achieved by fat. It is suggested that this is achieved by limiting full glucose oxidation and increasing fatty acid and ketone body oxidation, which most likely can also largely cover energy needs of the central nervous system. In stress states, net negative nitrogen balance (catabolism) largely results from net losses of peripheral protein mass, predominantly muscles, whereas central organs (e.g. the liver), the immune system and wound healing are anabolic. A number of factors are responsible for a net negative nitrogen balance which may ultimately lead to death if stress persists. In stress, the amino acid mix derived from peripheral (predominantly muscle) tissues is modified in interplay with the liver and to a minor extent the kidney. This mix is different in nonstressed conditions, containing substantially increased amounts of the nonessential amino acids glutamine, alanine, glycine and (hydroxy)proline. Part of the amino acid skeletons released by muscles are substrates to produce glucose in the liver and kidney. Glucose and the amino acids produced especially serve as substrates for cell proliferation and matrix deposition. The catabolic processes in peripheral tissues cannot be countered completely by adequate nutritional support as long as stress persists. This metabolic arrangement dictates a nutritional mix containing liberal amounts of protein and carbohydrates and addition of lipids to cover energy requirements.

The Biological Value of Protein.

The biological value of a protein extends beyond its amino-acid composition and digestibility, and can be influenced by additional factors in a tissue-specific manner. In healthy individuals, the slow appearance of dietary amino acids in the portal vein and subsequently in the systemic circulation in response to bolus protein ingestion improves nitrogen retention and decreases urea production. This is promoted by slow absorption when only protein is ingested (e.g. casein). When a full meal is ingested, whey achieves slightly better nitrogen retention than soy or casein, which is very likely achieved by its high content of essential amino acids (especially leucine). Elderly people exhibit 'anabolic resistance' implying that more protein is required to reach maximal rates of muscle protein synthesis compared to young individuals. Protein utilization in inflammatory or traumatic conditions increases substantially in the splanchnic tissues containing most of the immune system, and in wounds and growing tissues. This happens especially in the elderly, which often suffer from chronic inflammatory activity due to disease, physical inactivity and/or the aging process itself. Consequently, the proportion of protein absorbed in the gut and utilized for muscle protein synthesis decreases in these situations. This compromises dietary-protein-induced stimulation of muscle protein synthesis and ultimately results in increased requirements of protein (∼1.2 g/kg body weight/day) to limit gradual muscle loss with age. To optimally preserve muscle mass, physical exercise is required. Exercise has both direct effects on muscle mass and health, and indirect effects by increasing the utilization of dietary protein (especially whey) to enhance rates of muscle protein synthesis.

Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients.

BACKGROUND: Pancreatic cancer is often accompanied by cachexia, a syndrome of severe weight loss and muscle wasting. A suboptimal response to nutritional support may further aggravate cachexia, yet the influence of nutrition on protein kinetics in cachectic patients is poorly understood. METHODS: Eight cachectic pancreatic cancer patients and seven control patients received a primed continuous intravenous infusion of l-[ring-(2)H5]phenylalanine and l-[3,3-(2)H2]tyrosine for 8 h and ingested sips of water with l-[1-(13)C]phenylalanine every 30 min. After 4 h, oral feeding was started. Whole body protein breakdown, protein synthesis, and net protein balance were calculated. Results are given as median with interquartile range. RESULTS: Baseline protein breakdown and protein synthesis were higher in cachectic patients compared with the controls (breakdown: 67.1 (48.1-79.6) vs. 45.8 (42.6-46.3) µmol/kg lean body mass/h, P = 0.049; and synthesis: 63.0 (44.3-75.6) vs. 41.8 (37.6-42.5) µmol/kg lean body mass/h, P = 0.021). During feeding, protein breakdown decreased significantly to 45.5 (26.9-51.1) µmol/kg lean body mass/h (P = 0.012) in the cachexia group and to 33.7 (17.4-37.1) µmol/kg lean body mass/h (P = 0.018) in the control group. Protein synthesis was not affected by feeding in cachectic patients: 58.4 (46.5-76.1) µmol/kg lean body mass/h, but was stimulated in controls: 47.9 (41.8-56.7) µmol/kg lean body mass/h (P = 0.018). Both groups showed a comparable positive net protein balance during feeding: cachexia: 19.7 (13.1-23.7) and control: 16.3 (13.6-25.4) µmol/kg lean body mass/h (P = 0.908). CONCLUSION: Cachectic pancreatic cancer patients have a higher basal protein turnover. Both cachectic patients and controls show a comparable protein anabolism during feeding, albeit through a different pattern of protein kinetics. In cachectic patients, this is primarily related to reduced protein breakdown, whereas in controls, both protein breakdown and protein synthesis alterations are involved.

Routes for early enteral nutrition after esophagectomy. A systematic review.

BACKGROUND: Early enteral feeding following surgery can be given orally, via a jejunostomy or via a nasojejunal tube. However, the best feeding route following esophagectomy is unclear. OBJECTIVES: To determine the best route for enteral nutrition following esophagectomy regarding anastomotic leakage, pneumonia, percentage meeting the nutritional requirements, weight loss, complications of tube feeding, mortality, patient satisfaction and length of hospital stay. DESIGN: A systematic literature review following PRISMA and MOOSE guidelines. RESULTS: There were 17 eligible studies on early oral intake, jejunostomy or nasojejunal tube feeding. Only one nonrandomized study (N = 133) investigated early oral feeding specifically following esophagectomy. Early oral feeding was associated with a reduced length of stay with delayed oral feeding, without increased complication rates. Postoperative nasojejunal tube feeding was not significantly different from jejunostomy tube feeding regarding complications or catheter efficacy in the only randomised trial on this subject (N = 150). Jejunostomy tube feeding outcome was reported in 12 non-comparative studies (N = 3293). It was effective in meeting short-term nutritional requirements, but major tube-related complications necessitated relaparotomy in 0-2.9% of patients. In three non-comparative studies (N = 135) on nasojejunal tube feeding only minor complications were reported, data on nutritional outcome was lacking. Data on patient satisfaction and long-term nutritional outcome were not found for any of the feeding routes investigated. CONCLUSION: It is unclear what the best route for early enteral nutrition is after esophagectomy. Especially data regarding early oral intake are scarce, and phase 2 trials are needed for further investigation. REGISTRATION: International prospective register of systematic reviews, CRD42013004032.

The gut-liver axis.

PURPOSE OF REVIEW: The liver adaptively responds to extra-intestinal and intestinal inflammation. In recent years, the role of the autonomic nervous system, intestinal failure and gut microbiota has been investigated in the development of hepatic, intestinal and extra-intestinal disease. RECENT FINDINGS: The autonomic nervous system can be stimulated via enteral fat leading to cholecystokinin release, stimulating receptors in the gut and in the brain. This promotes bowel integrity, dampening the inflammatory response to food antigens. Consensus exists that intravenously administered long-chain fatty acids can cause liver damage but randomized-controlled trials are lacking. Disruption of the enterohepatic circulation of bile salts can give rise to cholestasis and nonalcoholic fatty liver disease, which may progress to fibrosis and cirrhosis. Reduced intestinal availability of bile salts reduces stimulation of the farnesoid X receptor. This may induce hepatic bile salt overload and associated hepatotoxicity through reduced action of intestinal fibroblast growth factor 19. Evidence is put forward to suggest that the intestinal microbiota is associated with liver abnormalities. SUMMARY: Enteral lipids reduce inflammation and liver damage during stress or systemic inflammation, whereas parenteral lipid is associated with liver damage. Maintaining the enterohepatic circulation of bile salts limits hepatic cholestasis through an farnesoid X receptor feedback pathway. Changes in gut microbiota composition may induce liver disease.

The conditional role of inflammation in pregnancy and cancer.

Cancer growth is characterized by proliferation of tumor cells in conjunction with invasion of all different immune cells that also invade healing wounds. This inflammatory response is necessary for cell proliferation but a second purpose of the inflammatory process is so that a low Th1/Th2 ratio is present with overexpression of IL-10, TGF-ß and IFN-γ. Down regulation of NO activity also shifts the balance between M1 and M2 macrophages. Both aspects allow the antigenous nature of the tumor to escape anti-tumor effects of the host. Support for this view comes from observations in pregnancy in which the placenta exhibits identical immune responses and downregulation of NO production to allow trophoblast cells to invade the uterine tissues without being rejected. Cell proliferation requires a metabolic set-up in which the organism produces adequate substrate for growth. This also bears the characteristics of a systemic inflammatory response delivering a similar substrate mix required for cancer and fetal growth. This arrangement is clearly beneficial in pregnancy and therefore supports the view that cancer growth is facilitated by the organism: the cancerous tumor elicits an immunological response opposing anti-tumor effects and induces the host to produce building blocks for growth.

Adaptive reciprocity of lipid and glucose metabolism in human short-term starvation.

The human organism has tools to cope with metabolic challenges like starvation that are crucial for survival. Lipolysis, lipid oxidation, ketone body synthesis, tailored endogenous glucose production and uptake, and decreased glucose oxidation serve to protect against excessive erosion of protein mass, which is the predominant supplier of carbon chains for synthesis of newly formed glucose. The starvation response shows that the adaptation to energy deficit is very effective and coordinated with different adaptations in different organs. From an evolutionary perspective, this lipid-induced effect on glucose oxidation and uptake is very strong and may therefore help to understand why insulin resistance in obesity and type 2 diabetes mellitus is difficult to treat. The importance of reciprocity in lipid and glucose metabolism during human starvation should be taken into account when studying lipid and glucose metabolism in general and in pathophysiological conditions in particular.

The evolutionary benefit of insulin resistance.

Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in various states such as starvation, immune activation, growth and cancer, to spare glucose for different biosynthetic purposes such as the production of NADPH, nucleotides in the pentose phosphate pathway and oxaloacetate for anaplerosis. In these conditions, total glucose oxidation by the tricarboxylic acid cycle is actually low and energy demands are largely met by fatty acid and ketone body oxidation. This beneficial role of insulin resistance has consequences for treatment and research. Insulin resistance should be investigated at the cellular, tissue and whole organism level. The metabolic pathways discussed here, should be integrated in the accepted and valid mechanistic events of insulin resistance before interfering with them to promote insulin sensitivity at any cost.

Guided treatment improves outcome of patients with enterocutaneous fistulas.

BACKGROUND: The present study was designed to evaluate the effects of guided treatment of patients with an enterocutaneous fistula and to evaluate the effect of prolonged period of convalescence on outcome. METHODS: All consecutive patients with an enterocutaneous fistula treated between 2006 and 2010 were included in this study. Patient information was gathered prospectively. Treatment of patients focused on sepsis control, optimization of nutritional status, wound care, establishing the anatomy of the fistula, timing of surgery, and surgical principles. Outcome included spontaneous and surgical closure, mortality, and postoperative recurrence. The relationship between period of convalescence and recurrence rate was determined by combining the present prospective cohort with a historical cohort from our group. RESULTS: Between 2006 and 2010, 79 patients underwent focused treatment for enterocutaneous fistula. Cox regression analysis showed that period of convalescence related significantly with recurrence of the fistula (hazard ratio 0.99; 95 % confidence interval 0.98-0.999; p = 0.04). Spontaneous closure occurred in 23 (29 %) patients after a median period of convalescence of 39 (range 7-163) days. Forty-nine patients underwent operative repair after median period of 101 (range 7-374) days and achieved closure in 47 (96 %). Overall, eight patients (10 %) died. CONCLUSIONS: Prolonging period of convalescence for patients with enterocutaneous fistulas improves spontaneous closure and reduces recurrence rate.

Absence of post-prandial gut anabolism after intake of a low quality protein meal.

BACKGROUND & AIMS: Gut health relates to a diet with a high digestibility and quality. Limited data are available on the acute effects of low quality foods on gut metabolism and the consequences for liver metabolism. METHODS: A meal with the low quality protein gelatin (tryptophan deficient and low amount of essential amino acids) was compared to a meal with the high quality protein Whey and a tryptophan supplemented gelatin meal (Gel + TRP) in healthy pigs with chronic implanted catheters. In a conscious state, amino acid, ammonia, urea, glucose and lactate fluxes across the portal drained viscera (PDV) and liver were studied for 6 h after administration of the protein meal. RESULTS: The average net portal appearance of amino acids was 99.8 ± 14.6% of the intake in the Gel group as compared to 61.4 ± 9.0% (p = 0.022) in the Whey group. In addition, a net portal appearance of tryptophan was observed in the Gel group (p = 0.005) of about 42% of tryptophan released in the Whey group. Intestinal energy metabolism and citrulline production was not affected. Adding tryptophan to the Gel meal diminished net portal AA appearance to 41.6 ± 24.0% of the intake (p = 0.012), but did not reduce the stimulated liver urea production. CONCLUSIONS: In the post-prandial phase after intake of a low protein quality meal, net anabolism in the healthy intestine is absent. It is likely that the intestine responds with a net breakdown of endogenous (labile) proteins to secure amino acid availability for the body. Addition of the first limiting essential amino acid to this meal improved protein anabolism in the intestine. Protein quality of a meal is related to the anabolic response of the intestine during the meal.