No abstract

Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (approximately 120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU.kg-1.min-1) and either no glucagon (CONT), basal glucagon (0.7 ng.kg-1.min-1; BasG), or elevated glucagon (2.4 ng.kg-1.min-1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG+I) received elevated insulin (1 mU.kg-1.min-1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10+/-2, 9+/-1, 7+/-1, and 24+/-4 microU/ml, and 24+/-5, 39+/-3, 80+/-11, and 79+/-5 pg/ml, CONT, BasG, HiG, and HiG+I, respectively. Glucagon infusion decreased the glucose requirements (9.3+/-0.1, 4.6+/-1.2, 0.9+/-0.4, and 11.3+/-1.0 mg.kg-1.min-1). Glucose uptake by both hepatic (5.1+/-0.4, 1.7+/-0.9, -1.0+/-0.4, and 1.2+/-0.4 mg.kg-1.min-1) and nonhepatic (4.2+/-0.3, 2.9+/-0.7, 1.9+/-0.3, and 10.2+/-1.0 mg.kg-1.min-1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.

Kupffer cells (KC) become activated in response to lipopolysaccharide (LPS) and produce a variety of mediators. Among them, TNF alpha is known to injure the liver. Here we report that TNF alpha mediates apoptosis in KC and sinusoidal endothelial cells. After stimulation for 24 h with LPS (0-10 micrograms/mL), apoptosis in KC detected by TUNEL TdT-mediated dUTP-biotin nick end labelling (TUNEL) increased in a concentration-dependent manner (0 micrograms/mL, 12 +/- 4%; 0.1 microgram/mL, 36 +/- 11%; 1.0 micrograms/mL, 65 +/- 9%; 10 micrograms/mL, 78 +/- 15%). In contrast, co-incubation of endothelial cells with LPS-stimulated KC resulted in a marked increase in TUNEL-positive endothelial cells. TNF alpha antibody blocked apoptosis in both KC and endothelial cells. Apoptosis was observed in cells adjacent to or in contact with KC. Reducing transmembrane TNF alpha expressed on KC also led to a decrease in endothelial cell apoptosis, suggesting that transmembrane TNF alpha is implicated in the cell-to-cell contact mechanism of induction of apoptosis. Thus, TNF alpha mediates apoptosis in KC and endothelial cells.

During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) and net hepatic lactate release (NHLR) are markedly reduced (downward arrow approximately 45 and approximately 65%, respectively) with infection. Because small quantities of fructose are known to augment hepatic glucose uptake and lactate release in normal fasted animals, the aim of this work was to determine whether acute fructose infusion with TPN could correct the impairments in NHGU and NHLR during infection. Chronically catheterized conscious dogs received TPN for 5 days via the inferior vena cava at a rate designed to match daily basal energy requirements. On the third day of TPN administration, a sterile (SHAM, n = 12) or Escherichia coli-containing (INF, n = 11) fibrin clot was implanted in the peritoneal cavity. Forty-two hours later, somatostatin was infused with intraportal replacement of insulin (12 +/- 2 vs. 24 +/- 2 microU/ml, SHAM vs. INF, respectively) and glucagon (24 +/- 4 vs. 92 +/- 5 pg/ml) to match concentrations previously observed in sham and infected animals. After a 120-min basal period, animals received either saline (Sham+S, n = 6; Inf+S, n = 6) or intraportal fructose (0.7 mg x kg(-1) x min(-1); Sham+F, n = 6; Inf+F, n = 5) infusion for 180 min. Isoglycemia of 120 mg/dl was maintained with a variable glucose infusion. Combined tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism. Acute fructose infusion with TPN augmented NHGU by 2.9 +/- 0.4 and 2.5 +/- 0.3 mg x kg(-1) x min(-1) in Sham+F and Inf+F, respectively. The majority of liver glucose uptake was stored as glycogen, and NHLR did not increase substantially. Therefore, despite an infection-induced impairment in NHGU and different hormonal environments, small amounts of fructose enhanced NHGU similarly in sham and infected animals. Glycogen storage, not lactate release, was the preferential fate of the fructose-induced increase in hepatic glucose disposal in animals adapted to TPN.

Background: Dynamin-related protein 1 (Drp1) plays important roles in tumorigenesis, including lung cancer. However, the effect of Drp1 in lung cancer remains unclear. The present study was aimed to investigate the clinical significance and effect of Drp1 on prognosis of lung cancer. Methods: Oncomine and The Cancer Genome Atlas (TCGA) databases were selected to predict the differential expression levels of Drp1 in lung cancer. Then, 70 cases of lung cancer and normal tissues were collected and immunohistochemistry was used to detect the expression of Drp1. In addition, Kaplan–Meier Plotter database and TCGA database were used to verify the correlation between Drp1 expression and the clinical prognosis in lung cancer patients. Results: Drp1 was significantly overexpressed in lung cancer tissues based on Oncomine and TCGA databases (P < .05). Moreover, results from immunohistochemistry showed that Drp1 protein level in lung cancer was also significantly higher than that in the matched normal tissues (P < .05). Prognostic analysis from Kaplan–Meier Plotter database with the chosen probe IDs of 203105_s_at suggested that Drp1 was negatively correlated to overall survival (OS) of lung cancer patients (HR = 1.16, 95% CI: 1.02–1.31; P = .025), but not in the probe IDs of 226154_at (HR = 0.86, 95% CI: 0.73–1.01; P = .069). However, prognosis from TCGA database showed inconsistent results in which high expression of Drp1 was correlated with worse survival probability of all, male, female in lung adenocarcinoma (P < .05), but not in LUSC (P > .05). Conclusion: Drp1 was highly expressed in lung cancer based on bioinformatics analysis and tissue microarray, but there was a lot of inconsistency in prognosis depending on different levels of Drp1 from the bioinformatics analysis.

No abstract

The liver is a major site of glucose disposal during chronic (5 day) total parenteral (TPN) and enteral (TEN) nutrition. Net hepatic glucose uptake (NHGU) is dependent on the route of delivery when only glucose is delivered acutely; however, the hepatic response to chronic TPN and TEN is very similar. We aimed to determine whether the route of nutrient delivery altered the acute (first 8 h) response of the liver and whether chronic enteral delivery of glucose alone could augment the adaptive response to TPN. Chronically catheterized conscious dogs received either TPN or TEN containing glucose, Intralipid, and Travasol for either 8 h or 5 days. Another group received TPN for 5 days, but ϳ50% of the glucose in the nutrition was given via the enteral route (TPNϩEG). Hepatic metabolism was assessed with tracer and arteriovenous difference techniques. In the presence of similar arterial plasma glucose levels (ϳ6 mM), NHGU and net hepatic lactate release increased approximately twofold between 8 h and 5 days in TPN and TEN. NHGU (26 Ϯ 1 vs. 23 Ϯ 3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and net hepatic lactate release (44 Ϯ 1 vs. 34 Ϯ 6 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in TPNϩEG were similar to results for TPN, despite lower insulin levels (96 Ϯ 6 vs. 58 Ϯ 16 pM, TPN vs. TPNϩEG). TEN does not acutely enhance NHGU or disposition above that seen with TPN. However, partial delivery of enteral glucose is effective in decreasing the insulin requirement during chronic TPN.intestine; glycogen IN STRESSED STATES (trauma, injury, or infection) nutritional support is often provided to patients either via the parenteral (TPN) or enteral (TEN) route. Prior studies suggest that when the nutrition (either TPN or TEN) is given continuously for 5 days liver glucose uptake is markedly augmented; the liver removes ϳ45% of the exogenous glucose (1). Even more surprisingly, substantial liver glucose uptake occurred in the absence of hyperglycemia (ϳ6.7 mmol/l) and in only mild hyperinsulinemia (102 pmol/l) (1). Recently, our group (3) observed that the enhancement in the capacity of the liver to take up glucose (i.e., adaptive response) begins within 5 h after initiation of TPN and is nearly fully manifest by 24 h.The enteral route is the preferred route for delivery of exogenous nutrients (12,14). In postsurgical and stressed patients, isocaloric enteral nutrition can be given without significant accompanying hyperglycemia (22, 23) compared with that shown with TPN. A potential benefit of the enteral route is that when only glucose is delivered via the enteral route in the acute setting it enhances net hepatic glucose uptake (NHGU) to a greater extent than when glucose is delivered via a peripheral route; this route-dependent effect has been termed the "portal signal" (7,20). The portal signal can rapidly (Ͻ15 min) augment NHGU; it does not require the presence of hyperglycemia or hyperinsulinemia (11). Surprisingly, when TEN is administered chronically in unstressed animals, which should activate the portal signal, NHGU is not any greater than that seen with TPN...

In response to chronic (5 days) TPN, the liver becomes a major site of glucose disposal, removing approximately 45% (4.5 mg.kg(-1).min(-1)) of exogenous glucose. Moreover, approximately 70% of glucose is not stored but released as lactate. We aimed to determine in chronically catheterized conscious dogs the time course of adaptation to TPN and the glycogen depletion impact on early time course. After an 18-h (n = 5) fast, TPN was infused into the inferior vena cava for 8 (n = 5) or 24 h (n = 6). A third group, of 42-h-fasted animals (n = 6), was infused with TPN for 8 h. TPN was infused at a rate designed to match the dog's calculated basal energy and nitrogen requirements. NHGU (-2.3 +/- 0.1 to 2.2 +/- 0.7 to 3.9 +/- 0.6 vs. -1.7 +/- 0.3 to 1.1 +/- 0.5 to 2.9 +/- 0.4 mg.kg(-1).min(-1), basal to 4 to 8 h, 18 vs. 42 h) and net hepatic lactate release (0.7 +/- 0.3 to 0.6 +/- 0.1 to 1.4 +/- 0.2 vs. -0.6 +/- 0.1 to 0.1 +/- 0.1 to 0.8 +/- 0.1 mg.kg(-1).min(-1), basal to 4 to 8 h) increased progressively. Net hepatic glycogen repletion and tracer determined that glycogen syntheses were similar. After 24 h of TPN, NHGU (5.4 +/- 0.6 mg.kg(-1).min(-1)) and net hepatic lactate release (2.6 +/- 0.4 mg.kg(-1).min(-1)) increased further. In summary, 1) most hepatic adaptation to TPN occurs within 24 h after initiation of TPN, and 2) prior glycogen depletion does not augment hepatic adaptation rate.