Increased tissue-type plasminogen activator activity in orthotopic but not heterotopic liver transplantation: the role of the anhepatic period.

The major cause of the increased tissue-type plasminogen activator activity during orthotopic liver transplantation is still unclear. Both the lack of hepatic clearance of tissue-type plasminogen activator in the anhepatic period and increased endothelial release from the graft on reperfusion have been proposed as the major causes. Heterotopic liver transplantation avoids the resection of the host liver and is a useful model to help differentiate between these two possibilities. In this study the fibrinolytic system was evaluated in 10 orthotopic liver transplantations, 18 heterotopic liver transplantations and a control group of 10 partial hepatic resections. A marked increment in tissue-type plasminogen activator activity, from 0.2 to 5.2 IU/ml (p less than 0.02), was observed during the anhepatic period of orthotopic liver transplantation, which rapidly normalized after reperfusion. In contrast, tissue-type plasminogen activator activity levels remained normal in heterotopic liver transplantation and partial hepatic resections. In orthotopic liver transplantation and in heterotopic liver transplantation no increase occurred in tissue-type plasminogen activator activity after reperfusion. The first venous hepatic outflow after reperfusion did not contain elevated tissue-type plasminogen activator activity levels. Plasma degradation products of fibrin and fibrinogen increased during the anhepatic period of orthotopic liver transplantation (from 2.60 to 8.80 micrograms/ml [p less than 0.008] and from 0.40 to 1.60 micrograms/ml [p less than 0.04], respectively) and remained elevated thereafter. In heterotopic liver transplantation and partial hepatic resections these levels remained low. In conclusion, the lack of hepatic clearance during the anhepatic period is probably the most important factor in the evolution of increased tissue-type plasminogen activator activity during orthotopic liver transplantation.     

Glucose homeostasis in a diabetic patient during liver transplantation: a case report

A 66-year-old woman with type C hepatitis had been treated for hepatocellular carcinoma (HCC) with transcatheter arterial embolization and radiofrequency ablation. Liver function worsened gradually to decompensated liver cirrhosis. She had recurrence of HCC and was later admitted to Juntendo University Hospital for living-donor liver transplantation. Although blood glucose was high, she had never been diagnosed with diabetes mellitus. No diabetes-related complications were detected at that time. We started treatment with multiple insulin injections. There is a unique time called the anhepatic phase during liver transplantation during which the liver does not exist in the body. Recent reports show that it is not necessary to administer glucose for patients with normal glucose tolerance during the anhepatic phase since plasma glucose could be maintained at normoglycemia to hyperglycemia (100-150 mg/dl). In our patient, plasma glucose concentration was rather high during the anhepatic phase without glucose administration. We analyzed the levels of blood glucose, insulin and various other hormones during the anhepatic phase. This could be the first report on glucose homeostasis during the anhepatic phase in a diabetic patient.     

Renal glucose production and utilization: new aspects in humans

Summary According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25 % of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed. [Diabetologia (1997) 40: 749–757].     

体外静脉－静脉转流在肝移植手术中的应用

使用离心泵行体外静脉－静脉（Ｖ－Ｖ）转流的技术，成功地应用于２例同种异体原位肝移植手术。结果表明：（１）肝移植手术使用Ｖ－Ｖ转流，腹腔内脏及下肢血液循环得到保证，避免了无肝期酸硷平衡失调和开放循环后电解质的紊乱；（２）使用离心泵能较好地控制转流期间体内外血流量的平衡，维持血流动力学的稳定；（３）血液变温器的使用可防止转流中及术后低温；（４）部分肝素化使激活凝血时间（ＡＣＴ）控制在２００秒左右，既可预防转流中循环管道系统凝血，又可避免因全身肝素化使手术出血增加。     

Prediction of rat liver transplantation outcomes using energy metabolites measured by microdialysis

Background: Warm ischemia jeopardizes graft quality and recipient survival in donation after cardiac death(DCD) transplantation. Currently, there is no system to objectively evaluate the liver quality from DCD. The present study tried to use energy metabolites to evaluate the donor liver quality. Methods: We divided 195 Sprague-Dawley rats into five groups: the control( n = 39), warm ischemic time(WIT) 15 min( n = 39), WIT 30 min( n = 39), WIT 45 min( n = 39), and WIT 60 min( n = 39) groups. Three rats from each group were randomly selected for pretransplant histologic evaluation of warm ischemiarelated damage. The remaining 36 rats were randomly divided into donors and recipients of 18 liver transplantations, and were subjected to postoperative liver function and survival analyses. Between cardiac arrest and cold storage, liver energy metabolites including glucose, lactate, pyruvate, and glycerol were measured by microdialysis. The lactate to pyruvate ratio(LPR) was calculated. Results: The changes in preoperative pathology with warm ischemia were inconspicuous, but the trends in postoperative pathology and aminotransferase levels were consistent with preoperative energy metabolite measurements. The 30-day survival rates of the control and WIT 15, 30, 45, and 60 min groups were 100%, 81.82%, 76.92%, 58.33%, and 25.00%, respectively. The areas under the receiver operating characteristic curves of glucose, lactate, glycerol, and LPR were 0.87, 0.88, 0.88, and 0.92, respectively. Conclusion: Glucose, lactate, glycerol, and LPR are predictors of graft quality and survival outcomes in DCD transplantation.     

Effect of insulin on hyperkalemia during anhepatic stage of liver transplantation

AIM: To investigate the effectiveness of insulin on decreasing serum potassium concentration during anhepatic stage of orthotopic liver transplantation. METHODS: Sixteen patients with serum potassium concentrations greater than 4.0 mmol/L at the onset of anhepatic stage were randomized into two groups. The patients in control group (n = 8) received no treatment, while those in treatment group (n = 8) received an intravenous bolus injection of regular insulin (20 U) 10 min into the anhepatic stage, followed by a glucose infusion (500 mL 50 g/L dextrose) over 15 min. RESULTS: In control group, potassium concentration underwent no changes whereas in treatment group, it decreased from 4.8+/-0.48 mmol/L to 4.19+/-0.55 mmol/L (mean+/-SD) within 15 min and to 3.62+/-0.45 mmol/L 60 min after the therapy. The potassium concentration was lower in treatment group than in control group within 30 min of treatment (3.94+/-0.57 vs 4.47+/-0.42 mmol/L, respectively; P<0.05), and increased similarly 30 s after graft reperfusion in both groups of patients, but remained lower in treatment group (5.81+/-1.78 vs 7.44+/-1.75 mmol/L, respectively; P<0.05). The potassium concentration returned to pre-reperfusion levels within 5 min after graft reperfusion. CONCLUSION: In patients undergoing orthotopic liver transplantation, the administration of insulin rapidly decreases serum potassium concentration even in the absence of the liver, suggesting an important contribution by extrahepatic tissues in insulin-stimulated uptake of potassium.     

Advantages of venous bypass during orthotopic transplantation of the liver

Venous bypass restores normal hemodynamic physiology during the critical anhepatic phase of orthotopic transplantation of the liver. Its routine use in adults undergoing transplantation in Pittsburgh has resulted in lower operative blood losses, a lower frequency of postoperative renal failure, and a greater probability of survival for all but the highest risk patients. Because it allows for a longer anhepatic phase, the surgeon has the option of tailoring the native hepatectomy to the needs of the individual case, even to the point, in difficult cases, of obtaining most of the hemostasis after removal of the native liver, but before sewing in the donor organ. Selective use of bypass in children may offer similar advantages.     

Gut perforation after orthotopic liver transplantation in adults

AIM： To describe cases of gut perforation after orthotopic liver transplantation.
METHODS： Data were colleted from our center database and medical records. Six of 187 patients （3.2%）who underwent orthotopic liver transplantation from January to December 2005 developed gut perforation.All patients were male with an average age of 46 years.Modified piggyback liver transplantation was performed at the Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University.RESULTS： Previous operation, steroid therapy, and prolonged portal venous cross clamp time, poor nutritional status and iatrogenic injury were found to be its ecological factors. The patients with gut perforation were found to have fever, increased leukocytes, mild abdominal pain and tenderness. The median portal venous clamp time was 63 min （range 45-72 min）,median cold ischaemia time was 11.3 h （range 7-15 h）.Median intraoperative blood loss was 500 mL （range 100-1200 mL） and median operation time was 8.8 h （range 6-12 h）. None of the six patients developed acute cellular rejection. White cell count was above 18 × 10^9/L in five patients （neutrophilic leukocytes were above 90%） and 1.5 × 10^9/L in one patient. Bacterial culture in drainage liquid revealed enterococci in five patients. Of the 6 patients undergoing orthotopic liver transplantation, 3 survived and 3 died after modified piggyback liver transplantation.
CONCLUSION： Gut perforation occurs after orthotopic liver transplantation in adults. A careful and minimal dissection during OLT, longer retention of the stomach tube, and reducing the portal clamp time and steroid dose should be taken into consideration. If gut perforation is not prevented, then early diagnosis,preferably through detection of enterococci may ensure better survival.     

老年肝移植术后早期急性肺损伤的观察与分析

目的分析比较中青年及老年肝移植患者术后早期（术后14d内）急性肺损伤（ALI）的发生情况及肺损伤的相关术中危险因素。方法采用回顾性调查的方法,分析比较中青年肝移植组（N=20）和老年肝移植（n=20）围术期的临床资料及术后早期肺损伤的发生情况,同时进行秩相关分析,此外,将所有患者分为ALI组和非ALI组,比较两组的手术时间、无肝期时间、输红细胞量、输血浆量、输晶体量、输胶体量、出血量、输白蛋白量、每分钟没公斤体重出入量、术后重症监护室（ICU）时间、总带管时间、再插管率、住院时间,并进一步多元逐步Logistic回归分析确定术后早期发生ALI的独立危险因素。结果中青年组患者中有8例在术后早期发生ALI,老年组有12例。秩相关分析得出无肝期时间、术中输注的晶体量、胶体量、输血量、每分钟每公斤体重出入量及术后ICU时间均与Au发生相关。Logistic回归分析筛选出术中输注红细胞（OR=2．34,95％CI1．958～2．664）、无肝期时间（OR=1．36,95％CI1．103～1．610）为原位肝移植术后发生ALI的独立危险因素。结论老年肝移植术后早期发生ALI与术中输注红细胞、无肝期时间关系密切。     

Kidney: its impact on glucose homeostasis and hormonal regulation

According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although animal and in vitro studies have documented that the kidney is capable of gluconeogenesis, glucose production by the human kidney has been regarded as negligible. This knowledge is based on net balance measurements across the kidney. Recent studies combining isotopic and balance techniques have demonstrated that the human kidney is involved in the regulation of glucose homeostasis by making glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the postabsorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis actually increases by approximately 2-fold. Following meal ingestion, glucose utilization by the kidney increases. Increased glucose uptake into the kidney may be implicated in diabetic nephropathy. Normally each day, ～ 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium glucose cotransporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and when plasma glucose concentrations exceed a threshold, glucose begins to appear in the urine. Renal glucose release is stimulated by epinephrine and is inhibited by insulin. Handling of glucose by the kidney is altered in type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the postabsorptive and postprandial states, and renal glucose reabsorption is also increased Since renal glucose release is almost exclusively due to gluconeogenesis, it seems that the kidney is as important gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactae glutamine and glycerol.     

Hemodynamics and vasoactive substance levels during renal congestion that occurs in the anhepatic phase of liver transplantation

AIM: To explore hemodynamics and vasoactive substance levels during renal vein congestion that occurs in the anhepatic phase of liver transplantation.METHODS: New Zealand rabbits received ligation of the hepatic pedicle, supra-hepatic vena cava and infrahepatic vena cava [anhepatic phase group(APH); n = 8], the renal veins(RVL; n = 8), renal veins and hepatic pedicle [with the inferior vena cava left open)(RVHP; n = 8)], or a sham operation(SOP; n = 8). Hemodynamic parameters(systolic, diastolic, and mean arterial blood pressures) and the levels of serum bradykinin(BK) and angiotensin Ⅱ(ANGII) were measured at baseline(0 min), and 10 min, 20 min, 30 min, and 45 min after the surgery. Correlation analyses were performed to evaluate the associations between hemodynamic parameters and levels of vasoactive substances.RESULTS:All experimental groups(APH,RVL,and RVHP)showed significant decreases in hemodynamic parameters(systolic,diastolic,and mean arterial blood pressures)compared to baseline levels,as well as compared to the SOP controls(P0.05 for all).In contrast,BK levels were significantly increased compared to baseline in the APH,RVL,and RVHP groups at all time points measured(P0.05 for all),whereas no change was observed in the SOP controls.There were no significant differences among the experimental groups for any measure at any time point.Further analyses revealed that systolic,diastolic,and mean arterial blood pressures were all negatively correlated with BK levels,and positively correlated with ANGII levels in the APH,RVL,and RVHP groups(P0.05 for all).CONCLUSION:In the anhepatic phase of orthotopic liver transplantation,renal vein congestion significantly impacts hemodynamic parameters,which correlate with serum BK and ANGII levels.     

Comprehensive and innovative techniques for liver transplantation in rats: A surgical guide

AIM: To investigate our learning curves of orthotopic liver transplantation (OLT) in rats and the most important factor for successful surgery. METHODS: We describe the surgical procedures for our rat OLT model, and determined the operator learning curves. The various factors that contributed to successful surgery were determined. The most important surgical factors were evaluated between successful and unsuccessful surgeries.RESULTS: Learning curve data indicated that 50 cases were required for operator tr...     

EVIDENCE THAT THYROID HORMONES REGULATE GLUCONEOGENESIS FROM GLYCEROL IN MAN

We have previously reported that glucose production assessed using radioiso-topic methods is 50% increased in hyperthyroidism but 30% decreased in hypothyroidism. These studies, however, do not distinguish between glycogenolysis and gluconeogenesis. In fasting man more than 80% of circulating glycerol is cleared by the liver and enters the gluconeogenic pathway. We have therefore measured glycerol clearance following bolus intravenous glycerol administration as an indirect assessment of gluconeogenic capacity. Hyperthyroid and hypothyroid subjects were compared with separate matched controls after an overnight fast. In hyperthyroid subjects blood glucose and blood glycerol were increased but lactate, pyruvate, and alanine concentrations were normal. Glycerol clearance was increased in hyperthyroidism and followed a double exponential decay with a shortened second component half-time. Endogenous glycerol production was increased three-fold. In hypothyroidism fasting circulating levels of glucose, lactate, pyruvate, alanine, and glycerol were normal but glycerol clearance was diminished. Both first and second component half-times were prolonged in hypothyroidism and endogenous glycerol production was decreased by 50%. Thus in hyperthyroidism glycerol clearance is greatly enhanced whilst in hypothyroidism glycerol clearance is diminished. The magnitude of the changes suggests that alterations in gluconeogenesis are probably the major factors concerned in the reported increase and decrease in glucose production in hyperthyroidism and hypothyroidism respectively.     

Urinary ammonia excretion increases acutely during living donor liver transplantation

Introduction: Arterial ammonia concentrations increase acutely during the anhepatic phase of a liver transplantation (LTx) and return to baseline within 1 h after reperfusion of a functioning liver graft. So far, this return to baseline has solely been attributed to hepatic ammonia clearance. No data exist on the potential contribution of altered renal ammonia handling to peritransplantation ammonia homoeostasis. Aim: The present study investigated the consequences of a hepatectomy and subsequent implantation of a partial liver graft on arterial ammonia concentrations and urinary ammonia excretion during a living donor liver transplantation (LDLTx). Methods: Patients with end‐stage liver disease undergoing LDLTx were selected. Samples of arterial blood and urine were taken before, during and 2 h after the anhepatic phase. Differences were tested using Wilcoxon's test. Results are given as median and range. Results: Eleven adult patients undergoing an LDLTx were included. Before hepatectomy, arterial ammonia concentrations were 89 μM (40–156 μM), increasing to 146 μM (102–229 μM) (P<0.001) during the anhepatic phase and returning to 79 μM (46–111 μM) (P<0.01) after reperfusion. Urinary ammonia excretion was initially 1.06 mmol/h (0.02–6.00 mmol/h), increasing to 3.81 mmol/h (0.32–12.55 mmol/h) (P=0.004) during the anhepatic phase and further increasing to 4.00 mmol/h (0.79–9.51 mmol/h) (P=0.013) after reperfusion. Conclusion: The kidney significantly increased urinary ammonia excretion during the anhepatic phase, which was sustained after reperfusion, contributing to the rapid decrease of ammonia concentrations. Accordingly, the plasma ammonia concentrations measured directly after LTx cannot simply be used as a read‐out of initial liver graft function.     

Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.     

Coagulation changes and the influence of the early perfusate in the course of orthotopic liver transplantation (OLT) when aprotinin is used intra-operatively.

The changes in relevant haemostatic parameters during the course of ten orthotopic liver transplantation were studied when aprotinin was given intra-operatively. Increases of tissue-type (P = 0.008) and urokinase-type (P = 0.009) plasminogen activators during the anhepatic phase could be correlated with hyperfibrinolysis. Thrombin-antithrombin III complexes (TAT) increased after revascularization of the liver graft (P = 0.003). Parallel studies in the perfusate showed that TAT concentrations were 350% and protease inhibitor activities (antithrombin III, protein C) only 52% of the systemic circulation before reperfusion, suggesting that thrombin activation together with protease inhibitor consumption occurs during graft liver reperfusion. The relatively smaller increases in profibrinolytic parameters and a lower blood loss when compared with other groups may be explained by aprotinin administration in our patients.     

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.     

The influence of preconditioning on metabolic changes in the pig liver before, during, and after warm liver ischemia measured by microdialysis

Purpose  Ischemia-reperfusion injury induced by the Pringle maneuver is a well-known problem after liver surgery. The aim of this study was to monitor metabolic changes in the pig liver during warm ischemia and the following reperfusion preceded by ischemic preconditioning (IPC). Methods  Eight Landrace pigs underwent laparotomy. Two microdialysis catheters were inserted in the liver, one in the left lobe and another in the right lobe. A reference catheter was inserted in the right biceps femoris muscle. Microdialysis samples were collected every 30 min during the study. After 2 h of baseline measurement, IPC was performed by subjecting pigs to 10 min of ischemia, followed by 10 min of reperfusion. Total ischemia for 60 min was followed by 3 h of reperfusion. The samples were analyzed for glucose, lactate, pyruvate, and glycerol. Blood samples were drawn three times to determine standard liver parameters. Results  All parameters remained stable during baseline. Glycerol and glucose levels increased significantly during ischemia, followed by a decrease from the start of reperfusion. During the ischemic period, lactate levels increased significantly and decreased during reperfusion. The lactate–pyruvate ratio increased significantly during ischemia and decreased rapidly during reperfusion. Only minor changes were observed in standard liver parameters. Conclusions  The present study demonstrated profound metabolic changes before, during, and after warm liver ischemia under the influence of IPC. Compared with a similar study without IPC, the metabolic changes seem to be unaffected by preconditioning.     

Regulation of splanchnic and renal substrate supply by insulin in humans

To determine the effects of peripheral insulin infusion on total, hepatic, and renal glucose production and on the percent contribution to glucose production of gluconeogenesis versus glycogenolysis, 10 healthy subjects had arterialized hand and hepatic vein catheterization after an overnight fast and the results were compared with data from 12 age- and weight-matched subjects with renal vein catheterization during a 180-minute infusion of either insulin (0.25 mU/kg x min) with dextrose, or saline. Endogenous, hepatic, and renal glucose production was measured with [6,6(-2)H2]glucose, regional lactate, alanine, and glycerol balance by arteriovenous difference; hepatic blood flow by indocyanine green clearance; and renal blood flow by p-aminohippurate clearance, before and every 30 minutes during each infusion period. Insulin increased from about 42 to 98 pmol/L and blood glucose remained constant in all studies (3.8 +/- 0.2 v4.4 +/- 0.1 micromol/ml, hepatic vrenal vein). In response to insulin infusion, endogenous, hepatic, and renal glucose production decreased immediately (30 minutes) and reached a lower plateau value (10.8 +/- 0.8 v6.4 +/- 0.7, 10.4 +/- 1.1 v7.8 +/- 1.0, and 2.8 +/- 0.6 v 1.5 +/- 0.6 micromol/kg x min, respectively) between 120 and 180 minutes (all P < .05). Net renal uptake of lactate (2.4 +/- 0.4 v0.9 +/- 0.6) decreased earlier (30 minutes) and returned to baseline between 120 and 180 minutes (2.4 +/- 0.5 micromol/kg x min), whereas net splanchnic uptake of lactate (5.7 +/- 0.7 v 0.7 +/- 0.6) and alanine (1.8 +/- 0.1 v 1.0 +/- 0.5 micromol/kg x min) decreased later (120 to 180 minutes). Net renal (0.3 +/- 0.1 v 0.1 +/- 0.1) and splanchnic (0.7 +/- 0.3 v 0.4 +/- 0.2 micromol/kg x min) glycerol uptake decreased 90 to 180 minutes after insulin and increased (P < .05) with saline infusion (0.4 +/- 0.1 v0.6 +/- 0.3 and 1.0 +/- 0.5 v1.8 +/- 0.4 micromol/kg x min, respectively). These data indicate that the rapid suppression of endogenous glucose production by insulin reflects primarily a decrease in hepatic glucose release, most likely due to inhibition of net glycogenolysis, combined with suppression of renal gluconeogenesis. Inhibition of hepatic gluconeogenesis presumably occurs later during hyperinsulinemia. We conclude that peripheral insulin, in addition to its inhibition of glycogen degradation, regulates endogenous glucose production, in part, by modifying the splanchnic and renal substrate supply.     

The effects of cortisol treatment on carbohydrate and protein metabolism in Fundulus heteroclitus

In male Fundulus heteroclitus captured during the fall, 5 daily injections of cortisol (200 μg/fish or approximately 20 μg/g body wt) produced significant elevations in serum cortisol and hyperglycemia in both fed and fasted fish. Only fasted fish responded with an increase in liver glycogen. No consistent changes attributable to hormone injection occurred in serum protein, amino acid, liver protein, liver amino acids, or liver alanine aminotrasferase. A single cortisol injection (20 μg/g body wt) in fasted fish produced elevated blood glucose levels which persisted for 48 hr and followed serum cortisol changes closely. Again, no significant changes were seen in liver glycogen or in protein metabolism. We conclude that in F. heteroclitus, blood glucose is the major carbohydrate reservoir influenced by cortisol elevation. Protein catabolism appears not to be the source of the glucose elevation. Reduced peripheral glucose utilization and gluconeogenesis from lactate or glycerol are suggested as alternative sources.