Nawfal W. Istfan

Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1.

To improve our understanding of the metabolic role of cytokines in protein wasting, we estimated the rates of protein synthesis and degradation in muscle and liver tissues in intact rats treated with several doses of recombinant IL 1 and/or tumor necrosis factor (TNF)/cachectin. Protein breakdown in muscle and liver were derived in vivo from the relationship between [14C]leucine distribution and tissue dilution in reference to circulating leucine. Synthesis was derived from the relationship between [14C]leucine appearance in the protein-bound and free-tissue leucine pools. To specifically relate changes in leucine tracer metabolism to protein dynamics, we separately measured the effect of these cytokines on blood flow to different tissues. The increase in dilution of the tissue-free [14C]leucine by TNF and TNF/IL 1 mixture, but not by IL 1 alone, could not be explained by a hemodynamic effect of these cytokines. Rather, this finding indicated that muscle proteolysis is enhanced by TNF and synergistically augmented by the addition of IL 1. Compatible with these data was the finding that more prolonged infusions of recombinant TNF/cachectin and the combination with IL 1 increased urinary nitrogen excretion. Changes in [14C]leucine dilution in the liver were less pronounced than those in skeletal muscle and consistent with net anabolic effect of TNF on liver protein. We conclude that rats exposed systemically to sublethal doses of TNF respond with increasing muscle and decreasing liver proteolysis, similar to that observed in inflammation and in cancer.

Effects of Long-Chain Triglyceride Emulsions on Reticuloendothelial System Function in Humans

Parenteral administration of long-chain triglyceride emulsions has been shown to have deleterious effects on reticuloendothelial system function in animal models. It is unknown whether this interference occurs in humans with clinically relevant doses of intravenous fat. Two studies were done. Eighteen patients were prospectively enrolled for study. Patients received full feeding by continuous total parenteral nutrition (amino acids 1.5 g/kg/day and dextrose 4.5 g/kg/day) with 33.1 kcal/kg/day. Forty-three % of the nonprotein calories were provided as soybean oil emulsion (Travamulsion 20%) and was administered intravenously over 10 hr (0.130 g/kg/hr). Reticuloendothelial system function was determined by measuring the change in the clearance rate of intravenously injected 99mTc-sulfur colloid (TSC) in each patient. In study 1 (n = 10), one day of lipid (10 hr) was infused, with the clearance of 99mTc-sulfur colloid measured before the lipid was infused and then during the last hour of the 10-hr infusion. In study 2 (n = 8), the clearance rates were measured before the lipid emulsion was begun, and then during the last hour of the infusion on the 3rd day. Clearance rates for TSC after 10 hr of lipid infusion in study 1 did not differ (0.27 +/- 1/min to 0.26 +/- 0.1/min, p greater than 0.10). However, after 3 days of lipid infusion (10 hr/day), a statistically significant reduction in TSC was seen (0.46 +/- 0.08/min-0.27 +/- 0.03/min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Parenteral infusion of long- and medium-chain triglycerides and reticuloendothelial system function in man.

Previous study demonstrated that patients who received total parenteral nutrition (TPN) with standard intermittent infusion of long chain triglyceride (LCT) at 0.13 g kg-1hr-1 over 10 hr for each of three days showed a significant decline in 99Tc-sulfur colloid (TSC) clearance rate by the reticuloendothelial system (RES). The present studies evaluated eight patients who received the same total lipid dose of LCT infused continuously as in a three-in-one admixture, and another nine patients receiving the same amount of fat as a medium chain triglyceride (MCT)/LCT (75%/25%) emulsion intermittently over 10 hr at 0.13 g kg-1hr-1 for three consecutive days. Patients were given continuous total parenteral nutrition (TPN) comprised of protein, 1.5 g kg-1day-1, and dextrose, 4.5 g kg-1day-1. RES function was examined by measuring the clearance rates of intravenously injected TSC while receiving TPN containing only protein and dextrose, and again after three days of fat infusion. Mean (+/- SEM) clearance rate constants before and after continuous LCT infusion were 0.38 +/- 0.09 and 0.41 +/- 0.08 min-1, respectively, while those before and after intermittent MCT/LCT infusion were 0.50 +/- 0.18 and 0.73 +/- 0.24 min-1, respectively. In contrast to intermittent LCT infusion, the administration of continuous LCT or an intermittent MCT/LCT mixture does not impair TSC clearance by the RES. These findings suggest that condensing the daily period of LCT infusion at standard dosage may exceed the rate of metabolic utilization, resulting in increased fat removal and diminished TSC uptake by the RES.(ABSTRACT TRUNCATED AT 250 WORDS)

Weight Loss and Health Outcomes in African Americans and Whites After Gastric Bypass Surgery

Objective: The objective was to describe differences in weight loss, dietary intake, and cardiovascular risk factors between white and African‐American patients after gastric bypass (GBP).

Cytokines, muscle proteolysis, and the catabolic response to infection and inflammation.

Apart from fever, the most striking characteristic of infection to the layman and the professional alike are the development of anorexia and associated weight loss. Although the unintentional weight loss is composed of both fat and lean tissue, it is the loss of the lean tissue representing protein (nitrogen) that has the greatest clinical impact. The relationship among inflammation and infection, protein metabolism, and endogenous mediators has been both a general research interest for others and a personal one of this laboratory for some time. Early studies demonstrated a catabolic nitrogen response to fever and infection (1, 2). Still other investigators reported that factors derived from white blood cells, which were at that time collectively termed leukocyte endogenous mediator (LEM), could be identified and postulated their role in these responses (3, 4). LEM was considered to be a group of low molecular weight, heat-labile proteins that were synthesized and released by circulating and fixed monocytes of the reticuloendothelial system in response to inflammation and infection (4, 5). In the study of the role of these factors in the protein metabolic response to inflammation and injury, initial work employed the amino acid analogs aminoisobutyric acid and 1-aminocyclopenta-necarboxylic acid to show a direct hepatic effect of LEM to take up, transport, and incorporate amino acids into protein, specifically acute phase globulin (6–8). Our initial experimental work with LEM and its effect on protein metabolism employed a relatively crude product produced by intraperitoneal injection of shellfish glycogen into rabbits and harvesting a cell-free supernatant (9).

Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects

OBJECTIVE High fat, low carbohydrate (HFLC) diets have become popular tools for weight management. We sought to determine the effects of a HFLC diet compared to a low fat high carbohydrate (LFHC) diet on the change in weight loss, cardiovascular risk factors and inflammation in subjects with obesity. METHODS Obese subjects (29.0-44.6 kg/m2) recruited from Boston Medical Center were randomized to a hypocaloric LFHC (n=26) or HFLC (n=29) diet for 12 weeks. RESULTS The age range of subjects was 21-62 years. As a percentage of daily calories, the HFLC group consumed 33.5% protein, 56.0% fat and 9.6% carbohydrate and the LFHC group consumed 22.0% protein, 25.0% fat and 55.7% carbohydrate. The change in percent body weight, lean and fat mass, blood pressure, flow mediated dilation, hip:waist ratio, hemoglobin A1C, fasting insulin and glucose, and glucose and insulin response to a 2h oral glucose tolerance test did not differ (P>0.05) between diets after 12 weeks. The HFLC group had greater mean decreases in serum triglyceride (P=0.07), and hs-CRP (P=0.03), and greater mean increases in HDL cholesterol (P=0.004), and total adiponectin (P=0.045) relative to the LFHC. Secreted adipose tissue adiponectin or TNF-α did not differ after weight loss for either diet. CONCLUSIONS Relative to the LFHC group, the HFLC group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets.

Effects of different lipid sources in total parenteral nutrition on whole body protein kinetics and tumor growth.

This study examined the short-term effects of three total parenteral nutrition solutions, each containing a different lipid source, on host and tumor protein metabolism in a rat cancer model. Each diet contained 220 kcal/kg per day, including 2 g of nitrogen/kg per day and 50% of nonprotein calories as either a structured lipid of medium-chain triglycerides and fish oil, a physical mix of medium-chain triglycerides and fish oil, or Liposyn II, a long-chain triglyceride. A 3-day intravenous feeding infusion began on day 7 after tumor implantation. Tumor growth rate, nitrogen balance, energy expenditure, and plasma albumin, glucose, and free fatty acids were measured, and whole body protein kinetics and fractional synthetic rates in liver, muscle, and tumor tissues were assessed using a constant infusion of 14C-leucine. The results revealed that tumor growth rate was slowed in structured lipid-fed animals (p = .06, one-way analysis of variance) with significant increases in rates of tumor protein synthesis and tumor protein breakdown (p < .001, one-way analysis of variance). Although muscle fractional synthetic rates were significantly decreased in tumor-bearing animals (p < .05, two-way analysis of variance), the rates in structured lipid-fed animals were restored. Nitrogen balance improved significantly in structured lipid-fed animals. The results demonstrate that the source of lipid in total parenteral nutrition solutions can influence tumor and host protein metabolism, and that a structured lipid composed of medium-chain triglycerides and fish oil seems to improve protein metabolism in host tissue without stimulating tumor growth.

Fructose consumption and cancer: is there a connection?

Purpose of reviewCancer cell metabolism is characterized by high rates of glucose uptake and anaerobic glycolysis. Sugar consumption has increased dramatically in the industrialized world, with refined fructose intake skyrocketing upwards in the USA over the past 30 years. Fructose provides an alternative carbon source for glycolysis, entering downstream of glucose and bypassing two key rate-limiting steps. Considering that glycolysis is the major pathway which fuels cancer growth, this review will focus on regulation and flux of glucose versus fructose through this pathway, and consider whether epidemiologic and experimental data support a mechanism whereby fructose might potentiate cancer growth in transformed cells.Box 1. no caption available Recent findingsFructose intake is associated with increased risk of pancreatic and small intestinal cancers, and possibly others. Fructose promotes flux through the pentose phosphate, which enhances protein synthesis and may indirectly increase tumor growth. Fructose treatment is associated with more aggressive cancer behavior and may promote metastasis. SummaryWhereas glucose favors overall growth kinetics, fructose enhances protein synthesis and appears to promote a more aggressive cancer phenotype. Fructose has become ubiquitous in our food supply, with the highest consumers being teens and young adults. Therefore, understanding the potential health consequences of fructose and its role in chronic disease development is of critical importance.

Racial/Ethnic Differences in Insulin Resistance and Beta Cell Function: Relationship to Racial Disparities in Type 2 Diabetes among African Americans versus Caucasians

Both biological and sociocultural factors have been implicated in the well-documented racial disparity in incidence and prevalence of type 2 diabetes (T2D) between African Americans (AA) and non-Hispanic whites (NHW). This review examines the extent to which biological differences in glucose metabolism, specifically insulin resistance and beta cell function (BCF), contribute to this disparity. The majority of available data suggests that AA are more insulin resistant and have upregulated BCF compared to NHW. Increasing evidence implicates high insulin secretion as a cause rather than consequence of T2D; therefore, upregulated BCF in AA may specifically confer increased risk of T2D in this cohort. Racial disparities in the metabolic characteristics of T2D have direct implications for the treatment and health consequences of this disease; therefore, future research is needed to determine whether strategies to reduce insulin secretion in AA may prevent or delay T2D and lessen racial health disparities.

Preoperative weight gain might increase risk of gastric bypass surgery

BACKGROUND Weight loss improves the cardiovascular and metabolic risk associated with obesity. However, insufficient data are available about the health effects of weight gain, separate from the obesity itself. We sought to determine whether the changes in body weight before open gastric bypass surgery (OGB) would have a significant effect on the immediate perioperative hospital course. METHODS A retrospective chart review of 100 consecutive patients was performed to examine the effects of co-morbidities and body weight changes in the immediate preoperative period on the hospital length of stay and the rate of admission to the surgical intensive care unit (SICU). RESULTS Of our class III obese patients undergoing OGB, 95% had ≥1 co-morbid condition and an overall SICU admission rate of 18%. Compared with the patients with no perioperative SICU admission, the patients admitted to the SICU had a greater degree of insulin resistance (homeostatic model analysis-insulin resistance 10.8 ± 1.3 versus 5.9 ± 0.5, P = .001), greater serum triglyceride levels (225 ± 47 versus 143 ± 8 mg/dL, P = .003), and had gained more weight preoperatively (.52 ± .13 versus .06 ± .06 lb/wk, P = .003). The multivariate analyses showed that preoperative weight gain was a risk factor for a longer length of stay and more SICU admissions lasting ≥3 days, as were a diagnosis of sleep apnea and an elevated serum triglyceride concentration. CONCLUSION The results of the present retrospective study suggest that weight gain increases the risk of perioperative SICU admission associated with OGB, independent of the body mass index. Sleep apnea and elevated serum triglyceride levels were also important determinants of perioperative morbidity. In view of the increasing epidemic of obesity and the popularity of bariatric surgical procedures, we propose that additional clinical and metabolic research focusing on the understanding of the complex relationship among obesity, positive energy balance, weight gain, and perioperative morbidity is needed.