[Isolation ward: initial experiences after 4 years]. / Isolierstation: erste Erfahrung nach 4 Jahren.

UNLABELLED: Since October 1988 there has been an isolation ward at Basle Cantonal Hospital. Its purpose is to treat patients with high dose chemotherapy and bone marrow transplantation under protective isolation and by standardized criteria. The isolation ward has two sub-units, viz. the reverse isolation for neutropenic patients (8 single room units) and the LAF unit (5 laminar airflow units) for allogeneic bone marrow transplantation (BMT). Up to July 1992, 287 patients (152 males and 133 females) required 527 hospitalizations. The median age was 41 (5-82) years in the reverse isolation unit and 28 (4-61) years in the LAF unit. Bed occupation was 90% and 82% throughout the period. 71% of patients were from the Basle area and the rest from elsewhere in Switzerland or from other countries. DIAGNOSIS: acute leukemias (112); myelodysplastic or myeloproliferative syndromes (52); severe aplastic anemia or agranulocytosis (46); lymphoproliferative syndromes (50); solid tumors (28). Indications for hospitalisation: BMT (107); complications after BMT (infections, GvHD) (63); chemotherapy on protocols of SAKK (105); other chemotherapies (64); antilymphocyte globulin or growth factor treatment (27); splenectomies (18); neutropenic fever (62); patient work-up (59); terminal care (20). Patients in reverse isolation were hospitalized for a median 17 (1-142) days; in the LAF unit for 52 (1-121) days.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endotoxin on leucine and glucose kinetics in man: contribution of prostaglandin E2 assessed by a cyclooxygenase inhibitor.

The effects of endotoxin (E) administration on whole body protein and glucose metabolism were studied in normal volunteers. Injection of 4 ng/kg Escherichia coli E iv resulted in a relative increase in leucine flux (1-13C-leucine infusion technique) compared to controls [+0.12 +/- 0.10 vs. -0.45 +/- 0.23 mumol/kg.min after 360 min, P = 0.028, analysis of variance (ANOVA)], indicating increased proteolysis. Nonoxidative leucine flux was higher after E than after saline administration (0.08 +/- 0.11 vs. -0.47 +/- 0.18 mumol/kg.min, P = 0.007, ANOVA), suggesting increased amino acid incorporation into proteins. E caused a transient decrease of plasma glucose concentration (by 0.5 +/- 0.1 mmol/L after 150 min; P < 0.004 vs. saline controls) due to a relative increase in disappearance compared to appearance of glucose (6,6 D2-glucose infusion technique). These alterations were associated with increases in plasma concentrations of ACTH, beta-lipoprotein (beta-LPH), GH, cortisol, epinephrine, free fatty acid, beta-hydroxybutyrate, and decreases of plasma insulin. Pretreatment with ibuprofen, a cyclooxygenase inhibitor, blunted the effects of E on whole body leucine flux (P < 0.05 vs. E) and on nonoxidative leucine flux (P < 0.05 vs. E) but enhanced the E-induced decrease of plasma glucose concentration (P < 0.004 vs. E), due to a relative increase in glucose disappearance compared to appearance (P = 0.02). The increases in counterregulatory hormones (ACTH, beta-LPH, GH, cortisol, epinephrine) were also attenuated by ibuprofen. Thus, acute endotoxinemia results in a redistribution of whole body proteins due to an increase in both protein breakdown and amino acid incorporation into proteins and in decreased plasma glucose concentrations. The ibuprofen data suggested that these effects of E on leucine kinetics, but not on glucose metabolism, were prostaglandin E2-mediated.

Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man.

The metabolic effects of recombinant human insulin-like growth factor-I (IGF-I) were assessed in five groups of normal male overnight-fasted volunteers receiving infusions of either 0, 5, 7.5, 15, or 30 micrograms/kg.h IGF-I during 8 h, resulting in total plasma IGF-I concentrations 127 +/- 7, 247 +/- 30, 389 +/- 39, 573 +/- 62, 620 +/- 105 ng/ml, respectively. Glucose consumption (euglycemic glucose clamp) increased dose dependently during IGF-I infusion (P < 0.001) up to 6.7 +/- 1.3 mg/kg. min in the 30 micrograms/kg.h group. Plasma triglyceride concentrations decreased with increasing doses of IGF-I (P < 0.03); the fall was 43% in the 30 micrograms/kg.h group. Plasma free fatty acid concentrations decreased during 7.5, 15, and 30 micrograms/kg.h IGF-I by 23%, 34%, and 48%, respectively. IGF-I lowered plasma beta-hydroxybutyrate concentrations in a dose-dependent manner (P < 0.025). Plasma concentrations of leucine and alpha-ketoisocaproate decreased dose dependently (P < 0.001 and P < 0.015). Whole body leucine flux (1-13C-leucine infusion technique) decreased with increasing doses of IGF-I by 41% during 30 micrograms/kg.h, indicating decreased whole body protein breakdown. Leucine oxidation into 13CO2 decreased with increasing doses of IGF-I (P < 0.045) by 57% in the 30 micrograms/kg.h group, suggesting inhibition of irreversible loss of leucine. Plasma C-peptide and insulin concentrations decreased dose dependently (P < 0.005 and P < 0.02), indicating diminished insulin secretion. Thus, acute elevation of plasma IGF-I concentrations in man results in metabolic effects which are qualitatively similar to those described previously of insulin.

Effect of acute acidosis and alkalosis on leucine kinetics in man.

The effects of acute pH changes on whole body leucine kinetics (1-13C-leucine infusion technique) were determined in normal subjects. Plasma insulin, glucagon, and growth hormone concentrations were kept constant by somatostatin and replacement infusions of the three hormones. When acidosis was produced by ingestion of NH4Cl (4 mmol kg-1 p.os; n = 8) arterialized pH decreased within 3 h from 7.39 +/- 0.01 to 7.31 +/- 0.01 (P less than 0.001) and leucine plasma appearance increased by 0.13 +/- 0.04 mumol kg-1 min-1 (P less than 0.02); in contrast, when alkalosis was produced by intravenous infusion of 4 mmol kg-1 NaHCO3 (n = 7, pH 7.47 +/- 0.01), leucine plasma appearance decreased by -0.09 +/- 0.04 mumol kg-1 min-1 (P less than 0.01 vs. acidosis). Whole body leucine flux also increased during acidosis compared to alkalosis (P less than 0.05), suggesting an increase in whole body protein breakdown during acidosis. Apparent leucine oxidation increased during acidosis compared to alkalosis (P = 0.05). Net forearm leucine exchange remained unaffected by acute pH changes. Plasma FFA concentrations decreased during acidosis by -107 +/- 67 mumol l-1 (P less than 0.05) and plasma glucose increased by 1.90 +/- 0.25 mmol l-1 (P less than 0.02); in contrast, alkalosis resulted in an increase in plasma FFA by 83 +/- 40 mumol l-1 (P less than 0.02; P less than 0.01 vs. acidosis), suggesting an increase in lipolysis; plasma glucose decreased compared to acidosis (P less than 0.01). The data demonstrate that acute metabolic acidosis and alkalosis, as they occur in clinical conditions, influence protein breakdown, and in the opposite direction, lipolysis.

Protein metabolism assessed by 1-13C leucine infusions in patients undergoing bone marrow transplantation.

Patients receiving cytoreductive therapy and bone marrow transplantation (BMT) are known to develop marked protein catabolism. To assess the contribution of whole body protein breakdown, amino acid oxidation and incorporation into proteins, plasma leucine kinetics (1-13C-leucine infusion technique) were determined in six patients five times within 14 days before and after cytoreductive therapy (Cyclophosphamide and total body irradiation) and marrow transplantation. Nitrogen balance became negative (-0.20 +/- 0.04 g/Kg/24 hr) after cyclophosphamide (p less than 0.01) and was -0.25 +/- 0.05 g/Kg/24 hr 7 days after BMT in spite of total parenteral nutrition. Plasma leucine concentration increased after BMT by 67% (p less than 0.0015). Leucine plasma appearance was 1.20 +/- 0.15 mumol/kg/min before treatment, it increased slightly and transiently after cyclophosphamide, and increased again from day 5 to day 7 after BMT (p less than 0.01), suggesting increased protein break-down. Leucine oxidation increased from 0.27 +/- 0.07 before therapy to 0.97 +/- 0.16 mumol/kg/min (p less than 0.02) after cyclophosphamide and BMT. Nonoxidative leucine disappearance rate decreased slightly from 0.92 +/- 0.08 to 0.75 +/- 0.16 mumol/kg/min after BMT (ns). Leucine metabolic clearance rate decreased from 11.8 +/- 1.65 before therapy to 6.9 +/- 0.70 ml/kg/min (p less than 0.02) after cytoreductive therapy. After BMT it increased again to 9.9 +/- 1.5 ml/kg/min (p less than 0.02). The results demonstrate that patients undergoing cytoreductive therapy and bone marrow transplantation develop negative nitrogen balance due to increased protein breakdown associated with increased leucine oxidation and increased metabolic clearance rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevation of plasma epinephrine concentrations inhibits proteolysis and leucine oxidation in man via beta-adrenergic mechanisms.

The role of elevated plasma epinephrine concentrations in the regulation of plasma leucine kinetics and the contribution of beta-receptors were assessed in man. Epinephrine (50 ng/kg per min) was infused either alone or combined with propranolol (beta-blockade) into groups of six subjects fasted overnight; leucine flux, oxidation, and net plasma leucine forearm balance were determined during 180 min. Constant plasma insulin and glucagon concentrations were maintained in all studies by infusing somatostatin combined with insulin and glucagon replacements. Plasma leucine concentrations decreased from baseline during epinephrine infusion by 27 +/- 5 mumol/liter (P less than 0.02) due to a 22 +/- 6% decrease in leucine flux (P less than 0.05 vs. controls receiving saline) and to an increase in the metabolic clearance rate of leucine (P less than 0.02). Leucine oxidation decreased by 36 +/- 8% (P less than 0.01 vs. controls). beta-Blockade abolished the effect of epinephrine on leucine flux and oxidation. Net forearm release of leucine increased during epinephrine (P less than 0.01), suggesting increased muscle proteolysis; the fall of total body leucine flux was therefore due to diminished proteolysis in nonmuscle tissues, such as splanchnic organs. Nonoxidative leucine disappearance as a parameter of protein synthesis was not significantly influenced by epinephrine. Plasma glucose and FFA concentrations increased via beta-adrenergic mechanisms (P less than 0.001). The results suggest that elevation of plasma epinephrine concentrations similar to those observed in severe stress results in redistribution of body proteins and exerts a whole body protein-sparing effect; this may counteract catabolic effects of other hormones during severe stress.

Human ketone body production and utilization studied using tracer techniques: regulation by free fatty acids, insulin, catecholamines, and thyroid hormones.

Ketone body concentrations fluctuate markedly during physiological and pathological conditions. Tracer techniques have been developed in recent years to study production, utilization, and the metabolic clearance rate of ketone bodies. This review describes data on the roles of insulin, catecholamines, and thyroid hormones in the regulation of ketone body kinetics. The data indicate that insulin lowers ketone body concentrations by three independent mechanisms: first, it inhibits lipolysis, and thus lowers free fatty acid availability for ketogenesis; second, it restrains ketone body production within the liver; third, it enhances peripheral ketone body utilization. To assess these effects in humans in vivo, experimental models were developed to study insulin effects with controlled concentrations of free fatty acids, insulin, glucagon, and ketone bodies. Presently available data also support an important role of catecholamines in increasing ketone body concentrations. Evidence was presented that norepinephrine increases ketogenesis not only by stimulating lipolysis, and thus releasing free fatty acids, but also by increasing intrahepatic ketogenesis. Thyroid hormone availability was associated with lipolysis and ketogenesis. Ketone body concentrations after an overnight fast were only modestly elevated in hyperthyroidism resulting from increased peripheral ketone body clearance. There was a significant correlation between serum triiodothyronine levels and the ketone body metabolic clearance rate. Thus, ketone body homeostasis in human subjects resulted from the interaction of hormones such as insulin, catecholamines, and thyroid hormones regulating lipolysis, intrahepatic ketogenesis, and peripheral ketone body utilization.

Contribution of alpha- and beta-receptors to ketogenic and lipolytic effects of norepinephrine in humans.

To assess the effects of alpha- and beta-adrenergic-receptor activation on ketone body kinetics and lipolysis in humans, five groups of overnight-fasted subjects were studied. Group 1 (n = 7) received norepinephrine (NE) to activate alpha- and beta-receptors, resulting in plasma NE concentrations of 1.5 +/- 0.19 ng/ml; group 2 (n = 7) received NE plus beta-blockade; group 3 (n = 7) NE plus alpha-blockade; group 4 (n = 6) NE plus alpha- and beta-blockade; and group 5 (n = 6) saline. Plasma insulin and glucagon concentrations were maintained constant by infusion of somatostatin with insulin and glucagon replacements. Infusion of NE for 170 min resulted in an increase in total ketone body production ([3-14C]acetoacetate infusions) to 8.5 +/- 1.3 vs. 3.9 +/- 0.6 mumol.kg-1.min-1 (P less than .01) in saline controls and in an increase in plasma free fatty acids (FFAs) to 1120 +/- 102 vs. 526 +/- 115 microM (P less than .01) in controls. alpha-Blockade during NE infusion enhanced the lipolytic effect of NE, because plasma FFA increased to 1981 +/- 204 vs. 1301 +/- 146 microM after 45 min (P less than .002), and the ketogenic effect was augmented (14.3 +/- 1.7 vs. 5.6 +/- 0.9 mumol.kg-1.min-1) after 60 min (P less than .001). In contrast, beta-blockade abolished the ketogenic and lipolytic effects of NE to those observed in saline controls. Combined alpha- and beta-blockade during NE infusion was without significant effect on ketone body kinetics and plasma FFA.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty acid-independent inhibition of hepatic ketone body production by insulin in humans.

To investigate whether elevated plasma insulin or glucagon concentrations are capable of modifying hepatic ketogenesis independently of plasma free fatty acid (FFA) concentrations, ketone body production was determined by [3-14C]acetoacetate infusions in overnight-fasted normal subjects during exogenous supply of FFA (Intralipid and heparin infusion). When plasma FFA concentrations were elevated from 0.73 +/- 0.07 to 1.53 +/- 0.16 mmol/l during low insulin concentrations (approximately equal to 13 microU/ml) in group A (n = 7), total ketone body production increased from 3.6 +/- 0.6 to 8.2 +/- 1.0 mumol.kg-1.min-1 (P less than 0.001). When plasma FFA were similarly elevated during raised plasma insulin concentrations (approximately equal to 110 microU/ml) in group B (n = 5), total ketone body production was only 3.8 +/- 0.8 mumol.kg-1.min-1 (P less than 0.01 vs. group A). Low plasma FFA and low insulin concentrations resulted in total ketone body production of 0.70 +/- 0.18 mumol.kg-1.min-1 in group C (n = 7; P less than 0.01 vs. groups A and B). Elevation of plasma glucagon during Intralipid infusion in group D (n = 7) failed to affect ketogenesis, but the beta-hydroxybutyrate-to-acetoacetate concentration ratio decreased significantly (P less than 0.01). The data indicate that elevation of plasma insulin to high physiological concentrations restrains FFA-induced ketogenesis.

Interaction of cortisol and epinephrine in the regulation of leucine kinetics in man.

To assess the interaction of the two major stress hormones epinephrine and cortisol in the regulation of leucine kinetics in man, epinephrine (50 ng/kg/min) was infused either alone or in combination with cortisol (2 micrograms/kg/min) into two groups of 6 postabsorptive normal male subjects during 180 min. Plasma leucine concentrations decreased by 28% (p less than 0.05) from baseline during epinephrine treatment (plasma levels 515 pg/ml); this was due to a decrease of leucine appearance (determined by 1-13C-leucine infusions) by 23% (p less than 0.025); leucine oxidation decreased by 29% (p less than 0.05). However, when plasma cortisol concentrations were elevated to supraphysiological levels (16.3 mumol/l) during epinephrine administration, the decreases of leucine plasma concentrations, appearance and oxidation were abolished. Plasma glucose and FFA concentrations were similarly elevated during both kinds of treatment. Since leucine appearance represents a measurement of total body protein breakdown and leucine disappearance into non-oxidative pathways reflects protein synthesis, the data indicate that plasma epinephrine concentrations during severe stress exert a protein anabolic effect in man which may counteract catabolic properties of elevated plasma cortisol.

Effect of insulin on ketone body clearance studied by a ketone body "clamp" technique in normal man.

The effect of elevated plasma insulin concentration (55 +/- 2 mU/l) on peripheral clearance and production of total ketone bodies was determined using 3-14C-acetoacetate tracer infusions. Nine normal subjects were studied twice, once during insulin infusion (20 mU.m-2.min-1), once during basal plasma insulin concentrations (controls). Blood total ketone body concentrations (sum of acetone, acetoacetate and beta-hydroxybutyrate) were maintained in both studies at 2 mmol/l by feedback-controlled sodium acetoacetate infusions. The coefficient of variation of total ketone body concentrations during the two clamp studies was 10 and 11% respectively. The sodium acetoacetate infusion rate required during the clamp was 55 +/- 4% higher during hyperinsulinaemia than in controls (p less than 0.005). This was due to increased total ketone body clearance (8.4 +/- 0.7 vs 6.7 +/- 0.4 ml.kg-1.min-1, p less than 0.015), and to enhanced suppression of ketone body production (p less than 0.01). Hyperketonaemia alone decreased ketone body production by 42% and diminished ketone body clearance by 46%, the former being enhanced, the latter being in part antagonised by insulin. Since the plasma insulin concentrations were within those observed in patients treated for diabetic ketoacidosis, the data suggest that the antiketotic effect of insulin therapy results in part from an increase in peripheral ketone body disposal.

The effect of cyproheptadine on insulin biosynthesis.

The effect of a potent antiserotonin-antihistaminic compound, cyproheptadine (CPH) on insulin biosynthesis was studied in pancreatic islets isolated from CPH-treated rats. Though insulin content of islets was markedly reduced in CPH-treated rats, the incorporation of radiolabeled leucine into proinsulin and insulin fractions was not affected with respect to the rate and amount. It is concluded that CPH may deplete insulin content of the islets through causing the leakage of insulin.

Stimulatory effect of norepinephrine on ketogenesis in normal and insulin-deficient humans.

Elevation of plasma norepinephrine concentrations to stress levels (1,800 pg/ml) resulted in normal subjects in a significant increase in ketone body production by 155% (determined by use of [14C]acetoacetate infusions), in a decrease of the metabolic clearance rate by 38%, hyperketonemia, and in increased plasma free fatty acid (FFA) levels by 57% after 75 min. Norepinephrine infusion during somatostatin-induced insulin deficiency resulted in an augmented and sustained increase in ketone body concentrations due to increased production and decreased peripheral clearance of ketone bodies. Norepinephrine's stimulatory effect on lipolysis waned with time, and its effect on ketogenesis in normal subjects was greater than its influence on plasma FFA levels, and thus presumably on hepatic FFA uptake, suggesting a direct stimulatory effect on hepatic ketogenesis. The data demonstrate that in normal humans the hyperketonemic effect of elevated plasma norepinephrine concentrations results from a combination of three factors: increased ketone body production from augmented FFA supply to the liver; accelerated hepatic ketogenesis; and modestly decreased metabolic clearance of ketone bodies. Acute insulin deficiency augments all these effects and results in progressive ketosis.

Effect of epinephrine and somatostatin-induced insulin deficiency on ketone body kinetics and lipolysis in man.

The effect of elevated plasma epinephrine concentrations (approximately equal to 800 pg/ml) on ketone body kinetics was determined in postabsorptive normal subjects using primed-continuous infusions of 3-14C-acetoacetate. Infusion of epinephrine (60 ng/kg/min) resulted in a transient increase in total ketone body production to a maximum of 2.5-fold the basal rate within 45 min (P less than 0.01 versus controls). Ketone body uptake increased with a delay, compared with production, causing a 2.8-fold increase in total ketone body concentrations (P less than 0.05 versus controls). Plasma free fatty acid (FFA) and blood glycerol concentrations increased transiently during epinephrine; their course was similar to that of ketone body production. Epinephrine administration resulted in hyperglycemia, hyperlactatemia, and a modest increase in plasma insulin and glucagon concentrations. To assess epinephrine's effect on ketone body kinetics during lack of insulin, and to avoid epinephrine-induced alterations in plasma insulin and glucagon concentrations, epinephrine was also infused combined with somatostatin (6.5 micrograms/kg/h). During somatostatin infusion, epinephrine administration resulted in an enhanced and sustained elevation of total ketone body production from 4.4 +/- 0.8 to 15.1 +/- 1.2 mumol/kg/min (P less than 0.01 versus somatostatin alone). Ketone body concentrations increased markedly from 310 +/- 63 to 1763 +/- 137 mumol/L (P less than 0.01 versus somatostatin alone); the ketonemic effect was enhanced due to a 40% decrease of the metabolic clearance rate associated with somatostatin infusion. The increase in plasma FFA and blood glycerol concentrations during somatostatin-induced insulin deficiency was transiently enhanced by epinephrine, such that they increased to 3.2- and 5.6-fold their basal values after 45 min, respectively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the splanchnic bed in extracting circulating adrenaline and noradrenaline in normal subjects and in patients with cirrhosis of the liver.

Splanchnic extraction rates of adrenaline and noradrenaline were determined in seven normal subjects and in nine patients with cirrhosis of the liver using arterial-hepatic venous catherization . Both catecholamines were effectively removed when the blood passed through the splanchnic area: splanchnic fractional uptake of adrenaline in normal subjects was 90 +/- 3%, and lower for noradrenaline, 68 +/- 4% (P less than 0.001). Net splanchnic extraction rates were higher for noradrenaline (126 +/- 16 ng/min) than for adrenaline (40 +/- 10 ng/min, P less than 0.001), probably due to the higher arterial plasma levels of noradrenaline. Resting arterial adrenaline and noradrenaline levels were significantly higher in cirrhotic patients than in normal subjects (adrenaline: 121 +/- 27 vs 54 +/- 8 pg/ml, P less than 0.05; noradrenaline: 678 +/- 89 vs 251 +/- 26 pg/ml, P less than 0.005). Net splanchnic catecholamine uptake was increased in cirrhotic patients. The results demonstrate that the splanchnic bed in normal and cirrhotic subjects extracts plasma catecholamines efficiently; they suggest that elevated plasma catecholamines in cirrhosis are not the result of impaired splanchnic catecholamine removal.

Effect of physiological elevation of plasma growth hormone levels on ketone body kinetics and lipolysis in normal and acutely insulin-deficient man.

The effect of physiological elevation of growth hormone levels on ketone body kinetics was determined using a 14C-ketone body tracer technique in normal and acutely insulin-deficient man. Changes of ketone body production and metabolic clearance rates during growth hormone infusion (plasma levels of approximately 25 micrograms/1) were measured during basal conditions and during heparin-induced elevation of non-esterified fatty acid levels. Growth hormone administration to six subjects fasted overnight resulted in an increase in ketone body production which exceeded that observed in nine control subjects (5.5 +/- 0.5 versus 3.1 +/- 0.1 mumol X kg-1 X min-1, p less than 0.025) after elevation of plasma non-esterified fatty acids. Growth hormone infusion increased glycerol and non-esterified fatty acid concentrations indicating enhanced lipolysis. During somatostatin-induced acute insulin deficiency (n = 7), growth hormone enhanced the increase in total ketone body production observed in six subjects receiving somatostatin alone (8.4 +/- 0.8 versus 4.1 +/- 0.7 mumol X kg-1 X min-1, p less than 0.01). Total ketone body metabolic clearance decreased by 50% during somatostatin and remained uninfluenced by growth hormone. Non-esterified fatty acids and glycerol levels increased during somatostatin, and growth hormone failed to alter non-esterified fatty acid levels significantly. The results demonstrate a stimulatory effect of high physiological growth hormone levels on ketogenesis which is largely explained by an enhancement of lipolysis and thus increase in substrate supply for ketogenesis. Growth hormone administration during acute insulin deficiency enhanced ketogenesis in the absence of alterations in plasma non-esterified fatty acid levels, suggesting a direct hepatic ketogenic effect.

Role of glucagon in enhancing ketone body production in ketotic diabetic man.

To assess the role of endogenous glucagon in regulating hepatic ketone body production in ketotic insulin-withdrawn diabetic subjects, ketone body kinetics were determined in two groups of C-peptide-negative diabetics 6 h after interruption of a s.c. insulin infusion. In group 1 (N = 5), glucagon levels were suppressed by infusion of somatostatin (SRIF), whereas in group 2 (N = 6) glucagon was replaced during SRIF by infusing glucagon at 2 ng/kg/min. Ketone body production rates as determined by primed-continuous infusion of [3-14C]acetoacetate declined from 19.5 +/- 0.8 to 16.4 +/- 0.4 mumol/kg/min (P less than 0.01) during 105 min of SRIF-induced glucagon suppression, whereas they remained unchanged (+0.2 +/- 0.4 mumol/kg/min, P less than 0.01 compared with SRIF) during glucagon replacement. Total ketone body concentrations remained unchanged during SRIF infusion but increased from 2.2 +/- 0.3 to 2.9 +/- 0.2 mmol/L (P less than 0.01) during glucagon replacement. The metabolic clearance rate of total ketone bodies declined significantly (P less than 0.01) by 27% and 21% in the two groups. Plasma free fatty acid and glycerol concentrations remained unchanged in both groups whereas plasma glucose decreased by 3.2 +/- 0.5 mmol/L during SRIF (P less than 0.01). Thus, endogenous glucagon contributed significantly to the maintenance of ketone body production rates in ketotic insulin-deficient diabetics. Since ketogenesis was altered in the absence of changes in free fatty acid levels, the results suggested that glucagon enhanced ketogenesis by an intrahepatic effect.

Failure of glucagon to stimulate ketone body production during acute insulin deficiency or insulin replacement in man.

To assess the role of glucagon and insulin in the acute regulation of ketone body kinetics in man, somatostatin was administered with various combinations of these hormones by replacement infusions in groups of six to seven normal subjects. Somatostatin-induced insulin and glucagon deficiency produced a threefold increase in total ketone body concentrations within 2 h. This increase was the combined result of enhanced production (71%), and decreased metabolic clearance (32%), as determined by 14C-acetoacetate infusions. An associated elevation of non-esterified fatty acids (66%) and glycerol levels occurred. Glucagon replacement (2 ng . kg-1 . min-1) during insulin deficiency failed to enhance ketogenesis or lipolysis but lowered the beta-hydroxybutyrate/acetoacetate concentration ratios. Hyperglycaemia, observed during glucagon administration and insulin deficiency, did not diminish ketone body production or lipolysis. In contrast, insulin replacement (150 microunits . kg-1 . min-1) diminished lipolysis, lowered ketone production, and elevated the metabolic clearance rate of ketone bodies. Glucagon infusions (2 and 4 ng . kg-1 . min-1) during somatostatin and insulin replacement did not accelerate ketone body production or raise non-esterified fatty acid levels, but produced a dose-dependent elevation of blood glucose levels. The results suggest that glucagon is not an important ketogenic hormone under the conditions studied.

[The effect of salmon calcitonin on pancreatic enzymes and hormones before and after retrograde cholangiopancreatography]. / Der Einfluss von Salm-Calcitonin auf die Enzyme und Hormone des Pankreas vor und nach retrograder Choledocho-Pankreatographie.

The effect of salmon calcitonin (SMC) on pancreatic enzymes and hormones was investigated following retrograde choledocho-pancreatography (ERCP). 40 patients were randomly divided in two groups and 2.5 micrograms/h SMC or sodium chloride was infused intravenously for 28 hours. Infusion was started 4 hours before endoscopic procedure and amylase, lipase, glucose, insulin, glucagon and gastrin plasma concentrations were measured before and 2, 12 and 24 hours after the end of the ERCP. According to the radiological findings of pancreatography two additional groups were formed: group 1 with visualization of the main duct and its branches and group 2 with additional visualization of the pancreatic parenchyma. No change in glucose, insulin, glucagon and gastrin was found in any of the groups analyzed. Amylase and lipase showed a significant increase after 2 hours and 24 hours later, values were reached which were not significantly different to baseline levels. The time course of the plasma concentrations was identical in the patients treated by SMC or sodium chloride and showed no significant difference at the various time intervals. Therefore, inhibition of the known increase in pancreatic enzymes following ERCP was not found with SMC treatment.