Acute in Vivo Effects of Low Ethanol Concentration on the Capacity of Urea Synthesis in Rats

We studied the effect of acute exposure, by constant intravenous infusion, to a low blood ethanol concentration (range 8-14 mmol/l) on the in vivo capacity of urea-N synthesis (CUNS), alanine elimination, and the nitrogen retention in fed and fasted rats. Alanine was infused to obtain a constant blood concentration of alpha-amino nitrogen between 7.3 and 11.7 mmol/l, at which concentrations urea synthesis is at maximum. CUNS was calculated after nephrectomy as accumulation of urea in body water, elimination of alanine as alanine infusion rate corrected for accumulation, and nitrogen retention as the difference. In the fed state ethanol decreased CUNS from 7.84 +/- 0.32 mumol N/(min 100 g body weight (BW] (mean +/- SEM) (n = 7) to 6.30 +/- 0.58 (n = 6) (p less than 0.001) and in the fasted state from 8.25 +/- 0.27 mumol N/(min 100 g BW) (n = 10) to 6.90 +/- 0.25 (n = 10) (p less than 0.001). In the fed state ethanol increased the elimination of alanine from 6.49 +/- 0.28 mumol/(min 100 g BW) (n = 7) to 6.95 +/- 0.25 (n = 6) (p less than 0.01), and in the fasted state decreased it from 6.25 +/- 0.12 mumol/(min 100 g BW) (n = 10) to 5.67 +/- 0.20 (n = 10) (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Loss of nitrogen from organs in rats induced by exogenous glucagon

Rats weighing 220 g were injected sc with zinc protamin glucagon 20 micrograms once daily (recurrent hyperglucagonemia) and zinc protamin glucagon 60 micrograms three times daily (chronic hyperglucagonemia); the controls received the vehicle three times daily. In the first group blood glucagon rose to above 200 ng/liter for 5 h every day; in the second group it constantly stayed above 600 ng/liter. After both 2 (n = 5) and 14 (n = 5) days treatment the control total blood alpha-amino-nitrogen (AAN) concentration was 4.3 +/- 0.1 mmol/liter, and the urea nitrogen synthesis rate was 4.9 +/- 0.4 mumol/(min.100 g BW) (mean +/- SEM) in controls. In recurrent hyperglucagonemic rats, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 3.6 +/- 0.2 mmol/liter (P less than 0.05 vs. control) and urea nitrogen synthesis rate 4.5 +/- 0.8 mumol/(min.100 g BW). In chronic hyperglucagonemic, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 2.2 +/- 0.1 mmol/liter (P less than 0.05 vs. control) and UNSR 7.9 +/- 0.8 mumol/(min.100g BW) (P less than 0.05 vs. control). The urea excretion was identical in controls and during recurrent hyperglucagonemia, but it was increased by 50% during chronic hyperglucagonemia. Food intake was the same in all groups. N Balances decreased from 10 mmol/24 h to 5 mmol/24 h (P less than 0.05) by chronic hyperglucagonemia. The total organ N content did not change by recurrent hyperglucagonemia, but in chronic hyperglucagonemia it decreased to 65-85% (P less than 0.01) in carcass, intestines, liver, and kidneys. In conclusion chronic but not recurrent hyperglucagonemia increases the rate of urea synthesis and decreases the blood amino acid concentration. This is suggested to be a reason for the loss of N from organs by chronic hyperglucagonemia.     

Sources of endogenous glucose production in the Goto-Kakizaki diabetic rat

Plasma glucose, insulin and glucose tolerance were quantified in diabetic Goto-Kakizaki (GK) rats (342+/-45 g, n = 5) and compared with weight-matched non-diabetic Wistars (307+/-30 g, n = 8). Compared to Wistars, GK rats had higher fasting plasma insulin (219+/-50 versus 44+/-14 pmol/l, P<0.002) and glucose (9.2+/-2.3 versus 5.5+/-0.5 mmol/l, P<0.025). GK rats showed impaired glucose tolerance (IPGTT 2 h plasma glucose=14+/-1.5 versus 6.4+/-0.1 mmol/l, P<0.001). Endogenous glucose production (EGP) from glycogenolysis, phosphoenolpyruvate (PEP) and glycerol after 6 hours of fasting was quantified by a primed infusion of [U-(13)C]glucose and (2)H(2)O tracers and (2)H/(13)C NMR analysis of plasma glucose. EGP was higher in GK compared to Wistar rats (191+/-16 versus 104+/-27 mumol/kg per min, P<0.005). This was sustained by increased gluconeogenesis from PEP (85+/-12 versus 35+/-4 mumol/kg per min, P<0.02). Gluconeogenesis from glycerol was not different (20+/-3 in Wistar versus 30+/-6 mumol/kg per min for GK), and glycogenolysis fluxes were also not significantly different (76+/-23 mumol/kg per min for GK versus 52+/-19 mumol/kg per min for Wistar). The Cori cycle accounted for most of PEP gluconeogenesis in both Wistar and GK rats (85+/-15% and 77+/-10%, respectively). Therefore, increased gluconeogenesis in GK rats is largely sustained by increased Cori cycling while the maintenance of glycogenolysis indicates a failure in hepatic autoregulation of EGP.     

Kinetics of urea synthesis and alanine uptake by perfused rat livers

Eight livers of 200 g rats were isolated and perfused in a single pass system with a semi-synthetic medium to which alanine was added to concentrations from 0.5 to 15 mmol/l. In each liver, 4-5 sets of urea synthesis rate and alanine uptake rate at different alanine concentrations were measured. The urea synthesis rate in relation to the alanine concentration was compatible with substrate inhibition kinetics. The kinetic constants were (mean +/- SD): Vmax = 10.34 +/- 3.41 mumol urea-N/(min X 100 g b.w.), Km = 1.56 +/- 0.67 mmol/l, and Ki = 5.35 +/- 2.44 mmol/l. The alanine uptake rate followed Michaelis-Menten kinetics with the constants (mean +/- SD) Vmax = 7.51 +/- 1.68 mumol/(min X 100 g b.w.) and Km = 2.14 +/- 1.04 mmol/l. The constants were assessed by non-linear iterative regression analysis. Urea synthesis exceeded alanine uptake at alanine concentrations below 2 mmol/l, and was smaller at higher concentrations. In two experiments, alanine metabolites were measured. The glucose production rate in relation to the alanine concentration suggested substrate inhibition. At high alanine concentrations, ammonia, lactate and pyruvate were released by the livers. The results indicate that whole liver urea synthesis and gluconeogenesis is inhibited by high blood alanine concentrations, in contrast to alanine uptake.     

Metabolic actions of cortisol in a macropodid marsupial Thylogale billardierii

In undisturbed pademelon wallabies (Thylogale billardierii) with indwelling jugular venous catheters, an increase in the plasma cortisol concentration from 0.25 +/- 0.05 to 1.35 +/- 0.15 (S.E.M.) mumol/l in 2 h, during i.v. infusion of cortisol at 1.0 mg/kg per h, caused no significant change in the plasma glucose concentration from the control value of 4.26 +/- 0.25 mmol/l. The rates of appearance (Ra) and metabolic clearance (MCR) of glucose, measured by steady-state isotope dilution, also did not change significantly from the control values of 14.9 +/- 0.7 mumol/kg per min and 3.52 +/- 0.19 ml/kg per min respectively. Twice-daily i.m. injections of 7 mg cortisol/kg for 7 days caused increases in plasma concentrations of cortisol, from 0.26 +/- 0.02 to 0.66 +/- 0.04 mumol/l on day 7, and glucose, from 5.1 +/- 0.1 to 7.2 +/- 0.6 mmol/l by day 5. The concentration of glycogen in the liver of wallabies fasted for 24 h increased from the control level of 1.17 +/- 0.56 to 5.92 +/- 1.14 g/100 g on day 7 (P less than 0.01), but mean glucose Ra and MCR did not change significantly. Plasma concentrations of alpha-amino nitrogen rose from 2.73 +/- 0.13 to 3.22 +/- 0.12 mmol/l on day 1 and remained at this level. Plasma concentrations of urea rose from 8.59 +/- 0.62 to 9.70 +/- 0.32 mmol/l on day 1, but then declined below the control level. Food intake and urinary excretion of nitrogen did not change in undisturbed animals. However, fasting followed by liver biopsy was accompanied by urinary excretion of nitrogen in excess of food intake, persisting until day 2 of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of one month high fructose intake on plasma glucose and lipid levels in non-insulin-dependent diabetes

The effects of a high fructose diet on the control of blood glucose and serum lipids were studied in 10 non-insulin-dependent diabetic patients (mean age 64.4 years, mean duration of diabetes 5.6 years). Comparison was made following 28 days on the usual diabetic diet and 28 days during which 25% of the usual carbohydrate was substituted with fructose. There was no change in mean (+/- SEM) fasting plasma glucose (on usual diet 9.2 +/- 0.5 mmol/l, on fructose diet, 9.1 +/- 0.4 mmol/l), but there was a fall in mean plasma glucose levels at 30, 60, and 120 min in a 75 g OGTT following the fructose diet. There was no significant change in fasting lipids: on usual diet mean serum cholesterol 5.8 +/- 0.2 mmol/l, on fructose diet 5.6 +/- 0.2 mmol/l; serum triglyceride, on usual diet 1.3 +/- 0.1 mmol/l, on fructose diet 1.3 +/- 0.1 mmol/l; HDL cholesterol on usual diet 1.4 +/- 0.1 mmol/l, on fructose diet 1.4 +/- 0.1 mmol/l. Mean body weight did not vary significantly between the two diets. Incorporation of fructose into the diabetic diet may lower post-prandial glucose levels without disturbing serum lipids.     

Insulin and C-peptide responses to 75 g oral glucose load in the healthy man

Plasma insulin and C-peptide levels in the fasting state and after a 2-h 75 g oral glucose tolerance test (OGTT) in a large number of healthy subjects are reported. 247 volunteers (134 males, 113 females), aged 13-69 years, who had a negative history of diabetes, no history of significant disease, normal physical examination, normal body weight, normal glucose tolerance, normal blood tests, and who were taking no drugs were studied. Results, mean +/- SEM (range): fasting glucose concentration = 4.64 +/- 0.03 mmol/l (3.10 - 6.10), 1-h glucose concentration = 5.23 +/- 0.10 mmol/l (2.20 - 9.90), 2-h glucose concentration = 4.11 +/- 0.06 mmol/l (2.00 - 6.80); fasting insulin level = 0.088 +/- 0.002 nmol/l (0.03 - 0.28), 1-h insulin level = 0.45 +/- 0.01 nmol/l (0.06 - 1.63), 2-h insulin level = 0.24 +/- 0.01 nmol/l (0.05 - 1.12); fasting C-peptide concentration = 0.60 +/- 0.01 nmol/l (0.14 - 1.34), 1-h C-peptide concentration = 2.17 +/- 0.05 (0.63 - 8.56), 2-h C-peptide concentration = 1.77 +/- 0.04 nmol/(0.35 - 5.74). Fasting insulin and fasting C-peptide concentrations correlated to post-glucose insulin and C-peptide concentrations, respectively. At each sampling-point insulin concentration correlated to C-peptide concentration. After glucose ingestion, both insulin and C-peptide plasma levels correlated significantly with the corresponding glucose levels. During fasting, C-peptide but no insulin level correlated to glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protein and amino acid metabolism during early starvation as reflected by excretion of urea and methylhistidines

Endogenous excretion of nitrogenous products was studied during early starvation in six healthy, nonobese subjects after six days on a well-defined diet, designed to achieve net protein balance and an adequate calorie supply. The diet contained 0.5 g myofibrillar-free protein and 35 kcal/kg body weight. The subjects then fasted for three days. Urine was collected for 24-hour periods and analyzed for urea, ammonia, 3-methylhistidine, and 1-methylhistidine. Blood glucose and serum urea levels were measured daily. In a second group of subjects, muscle biopsies for determination of free amino acid concentrations were taken in the overnight fasted state and after three days of fasting. During the period with a balanced diet, urea production fell initially and stabilized after two to three days at a level of 146 +/- 15 mmol/24 h. During the period of fasting, serum urea increased from 3.0 +/- 0.4 to a maximum value of 6.2 +/- 0.7 mmol/L and urea production rose markedly, to a peak of 293 +/- 16 mmol/24 h. Ammonia excretion was 24 +/- 2 mmol/24 h before and 71 +/- 13 mmol/24 h after three days of fasting. 3-Methylhistidine excretion was stable before fasting and then rose from 154 +/- 17 to 198 +/- 17 mumol/24 h. 1-Methylhistidine excretion was unchanged during fasting. Blood glucose levels were stable at 4.8 +/- 0.2 mmol/L before fasting and then fell to 3.7 +/- 0.3 mmol/L. Intracellular concentrations of amino acids in skeletal muscle decreased markedly during fasting; after three days of fasting the glutamine concentration had fallen by 34%.(ABSTRACT TRUNCATED AT 250 WORDS)     

One-shot high-dose pamidronate disodium (APD): effective, simple treatment for hypercalcaemia in haematological malignancy

Fifteen patients with haematological malignancy and hypercalcaemia (mean +/- SEM calcium 3.44 +/- 0.14 mmol/l) received pamidronate (1 mg/kg) by infusion on 17 occasions (two patients were retreated 2 and 6 months after the first dose). After 4 days the plasma calcium had fallen to 2.84 +/- 0.14 mmol/l (P less than 0.001; n = 17), and in 10/17 episodes was less than 2.6 mmol/l. The mean fall was 0.61 mmol/l (95% confidence intervals 0.49-0.72 mmol/l). By 7 days a further decrease to 2.53 +/- 0.10 mmol/l had occurred, continuing to 2.38 +/- 0.11 mmol/l after 14 days. Plasma phosphate fell from 1.18 +/- 0.16 to 0.74 +/- 0.07 mmol/l at 7 days (P less than 0.001; n = 12). In 9 of the 17 episodes plasma creatinine initially exceeded 120 mumol/l (four of these greater than 300 mumol/l). This did not impair the response to pamidronate and there was no significant change in plasma creatinine following treatment. A single large dose of pamidronate was a simple, well-tolerated and very reliable treatment for hypercalcaemia complicating haematological malignancy, irrespective of renal function.     

β-Endorphin and adrenocortical function in obesity

OBJECTIVE: To test the hypothesis that the hyperendorphinaemia in obesity originates from outside the pituitary. DESIGN: Intravenous administration of corticotrophin-releasing hormone (CRH) after overnight suppression with 2 mg of dexamethasone in normal-weight controls and in obese subjects before and after weight reduction. PATIENTS: Eleven obese females, age (mean +/- SEM) 30 +/- 2.1 years, body mass index (BMI) 41.2 +/- 1.9 kg/m2. Eight normal-weight females served as controls, age 26 +/- 2.1 years, BMI 21.4 +/- 0.5 kg/m2. Five obese subjects were also studied after weight loss of 18.4 +/- 1.0% of original weight. MEASUREMENTS: Plasma beta-endorphin, ACTH and cortisol. Cortisol production rate in 24-hour urine. Basal (without dexamethasone suppression) plasma beta-endorphin levels. RESULTS: Basal (without dexamethasone suppression) beta-endorphin levels were 7.7 +/- 0.8 pmol/l in the obese and 3.8 +/- 0.5 pmol/l in the control subjects (P less than 0.005). The degree of suppression of beta-endorphin after dexamethasone was similar in the obese (23.2 +/- 3.7%) and in the control subjects (28.2 +/- 0.12%). Administration of CRH following dexamethasone suppression resulted in a small but significant increase of plasma beta-endorphin in both obese (from 1.55 +/- 0.12 to 2.32 +/- 0.28 pmol/l) and control subjects (from 0.98 +/- 0.24 to 1.69 +/- 0.33 pmol/l). The groups did not differ regarding this response, nor regarding the release of ACTH and cortisol after CRH. Cortisol production rate was higher (P less than 0.001) in the obese (68.7 +/- 3.3 mumol/24 h) than in the controls (40.0 +/- 3.0 mumol/24 h). No correlation between cortisol production rate and basal beta-endorphin levels was found. Weight loss appeared to have no influence on cortisol production rate, basal beta-endorphin levels, or on the responses to dexamethasone or CRH. CONCLUSIONS: Plasma beta-endorphin in obese subjects can be affected by manipulations of the hypothalamic-pituitary-adrenocortical axis; the hypothesis that the hyperendorphinaemia of obesity originates from outside the pituitary cannot be confirmed.     

Dexamethasone does not increase IGF-I and IGFBP-3 levels in man in the absence of endogenous GH

It has been previously shown that short-term glucocorticoid administration increases circulating IGF-I and IGFBP-3 levels both in men and rats. An increase in endogenous GH secretion or a direct hepatic effect have been suggested as possible mechanisms. The aim of this study was to investigate the effect of short-term dexamethasone administration (3 mg orally during 7 days) in 8 patients with Sheehan's syndrome in replacement therapy. All patients had GH values <2.5 pg/l after clonidine administration. Before treatment IGF-I values were 9.3 3.6 microg/l (mean +/- SE) and IGFBP-3 levels were 1,195 +/- 208 microg/l. After dexamethasone administration there were no significant changes either in IGF-I or IGFBP-3 values (10.7 +/- 4.1 and 1,110 +/- 214 microg/l, respectively). A significant increase in insulin values was observed after dexamethasone administration (before: 120 +/- 10 micromol/l; after: 175 +/- 27 pmol/l; p<0.05), while glucose levels did not reach statistical significance (before: 4.6 +/- 0.3 mmol/l; after: 5.9 +/- 1.0 mmol/l). Our data suggest that dexamethasone is unable to increase circulating IGF-I and IGFBP-3 levels in man in the absence of endogenous GH.     

Endothelin-like immunoreactivity in rat models of diabetes mellitus.

The factors associated with high concentrations of circulating plasma immunoreactive endothelin in patients with diabetes mellitus are unknown. Plasma and tissue (lung and kidney) immunoreactive endothelin levels were therefore measured by radioimmunoassay in three animal models of diabetes mellitus: dexamethasone-treated rats (2 mg/kg per day for 12 days), streptozotocin-treated rats (100 mg/kg, 4 days before being killed) and rats treated with both dexamethasone and streptozotocin. Plasma concentrations of immunoreactive endothelin in the dexamethasone-treated rats (3.13 +/- 0.28 pmol/l, mean +/- S.E.M., n = 15) were significantly (P less than 0.005) higher than those in controls (1.33 +/- 0.18 pmol/l, n = 15), while plasma concentrations of immunoreactive endothelin in streptozotocin-treated rats (n = 8) and rats treated with both dexamethasone and streptozotocin (n = 14) were undetectable (less than 0.5 pmol/l). Fast protein liquid chromatographic analysis of the plasma immunoreactive endothelin of dexamethasone-treated rats showed four peaks: one in the void volume, one eluting before endothelin-3, one eluting after endothelin-3 and before endothelin-1 and one eluting in a position identical with that of endothelin-1. Pulmonary concentrations of immunoreactive endothelin in the three groups of rats with diabetes mellitus were lower (P less than 0.005) but no significant change was found in renal immunoreactive endothelin. These findings indicate that short-term dexamethasone treatment increases plasma levels of immunoreactive endothelin while streptozotocin treatment decreases them. Thus, multiple factors may influence plasma concentrations of immunoreactive endothelin in diabetes mellitus.     

Hyperinsulinemia suppresses glucose utilization in specific brain regions: in vivo studies using the euglycemic clamp in the rat

It has been suggested that insulin acts centrally by altering brain glucose uptake. Previous studies of the effect of insulin on brain glucose metabolism have been difficult to interpret due to lack of steady state conditions for glucose and/or insulin. To determine whether insulin per se alters brain glucose metabolism, we measured glucose utilization rates, using the deoxyglucose method, in the medial basal hypothalamus, locus coeruleus, and motor cortex of conscious, unrestrained rats undergoing 2-h euglycemic clamps (blood glucose, 4.1 +/- 0.1 mmol/liter) at increasing insulin infusion rates. Plateau insulin levels were 29 +/- 5 mU/liter (controls) and 48 +/- 4, 146 +/- 8, 670 +/- 40, and 7560 +/- 410 mU/liter (clamped). Glucose utilization rates in the medial basal hypothalamus fell significantly from 60 +/- 4 mumol/100 g X min (controls) to 46 +/- 3, 39 +/- 2, 35 +/- 2, and 39 +/- 3 mumol/100 g X min in respective insulin-infused animals (P less than 0.01 vs. controls). Similar falls of up to 39% and 48% were seen in the locus coeruleus and motor cortex, respectively. A significant inverse correlation was found between the glucose utilization rate in each brain region and the log plasma insulin level. The reduction in glucose utilization rate was associated with marked increases in serum corticosterone levels (995 +/- 157 vs. 91 +/- 31 nmol/liter in controls, P less than 0.001). Serum potassium was significantly lower in clamped animals (5.2 +/- 0.3 to 5.9 +/- 0.3 mmol/liter) than in controls (7.0 +/- 0.4 mmol/liter, P less than 0.01). However, the inverse correlation between regional brain glucose utilization and log plasma insulin was independent of changes in serum potassium, while there was no independent correlation with serum potassium. The data reveal reduced glucose utilization in specific brain regions in the presence of insulin levels both equal to and above those found in the postabsorptive state and support a direct effect of insulin in suppressing regional brain glucose utilization.     

Effect of polymer coating on faecal recovery of ingested 5-amino salicylic acid in patients with ulcerative colitis.

It has been suggested that polymer coating might retard jejunal absorption of 5-amino salicylic acid (5-ASA) and thus promote delivery to its colonic site of action. Twenty three patients with active (nine), or quiescent (14) ulcerative colitis were given either uncoated or coated 5-ASA (Asacol) 400 mg qds for one to three weeks, after which they ingested five 1.5 ml dialysis membrane sachets which were recovered from the stool in the next 72 hours. After one week of treatment the concentration of 5-ASA in the faecal dialysate, urine, and fasting plasma in those receiving the coated and uncoated preparations were respectively: 25.4 +/- 5.1 compared with 1.2 +/- 0.4 mmol/l (p less than 0.001); 0.34 +/- 0.21 compared with 0.70 +/- 0.29 mmol/24h (NS) and 11.1 +/- 4.2 compared with 0.07 +/- 0.03 mumol/l (p less than 0.02). Faecal excretion of the drug appeared to be greater in patients with active colitis than in those with quiescent disease. Thus coating with pH dependent methacrylic acid copolymer B is a very effective method of promoting delivery of 5-ASA to the colon, stool dialysate concentrations being 20 fold more than those in controls. Increased trough plasma concentrations in the polymer coating group probably reflect delayed intestinal absorption but no evidence of plasma accumulation after 21 days of therapy was found.     

The metabolic response of the canine neonate to twenty-four hours of fasting

The metabolic effects of 24 hours of neonatal fasting in unanesthetized dogs were compared to fasting for three hours during the first day of life. Blood glucose, lactate, and ketones were unaltered while FFA (0.94 +/- 0.07 v 0.70 +/- 0.04 mmol/L, P less than .01), glycerol (0.21 +/- 0.01 v 0.12 +/- 0.01 mmol/L, P less than .01), and triglycerides (0.41 +/- 0.03 v 0.23 +/- 0.03 mmol/L, P less than .01) were lower at 24 hours. Glucose production and lactate and alanine turnover were unaffected while palmitate turnover declined (8.8 +/- 0.7 v 5.1 +/- 0.5 mumol/kg/min, P less than .01). Oxygen consumption decreased (6.9 +/- 0.4 v 6.0 +/- 0.3 mL/kg/min, P less than .02) while RQ increased (0.79 +/- 0.02 v 0.86 +/- 0.03, P less than 0.05) at 24 hours. Hepatic glycogen content declined (575 +/- 37 to 266 +/- 32 mumol/g, P less than .001) and could account for a GP of 12 mumol/kg/min between 3 and 24 hours of age. Both gluconeogenesis from lactate and alanine increased, together accounting for 7% and 21% of glucose production at 3 and 24 hours. The increment in gluconeogenesis may be facilitated by augmented hepatic cytosolic phosphoenolpyruvate carboxykinase at 24 hours (1.8 +/- 0.2 v 14.1 +/- 0.8 nmol/min mg protein, P less than .01). Despite the decline in VO2, hepatic ATP and energy charge were unaltered by 24 hours of fasting. These data suggest that FFA availability diminishes during a prolonged neonatal canine fast resulting in lower VO2. Furthermore, as FFA availability declines, glucose utilization becomes the predominant precursor for energy production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Net hepatic lactate balance following mixed meal feeding in the four-day fasted conscious dog

The present experiments were undertaken to determine whether four days of fasting and marked hepatic glycogen depletion would alter the effect of mixed meal feeding on net hepatic lactate balance in the conscious dog. Dogs were fasted for four days and were then fed a mixed meal over a ten-minute period. Net hepatic glucose and lactate balance were monitored for the next eight hours using the A-V difference technique. The arterial plasma glucose level rose to a maximum of 121 +/- 3 mg/dL three hours after feeding and then decreased. Net hepatic glucose output declined to 0.44 +/- 0.44 mg/kg/min but the liver never became a net consumer of glucose. The arterial blood lactate level rose from 678 +/- 71 to 1000 +/- 158 mumol/L as the liver switched from net lactate uptake (12.2 +/- 2.0 mumol/kg/min) to net lactate production (4.3 +/- 1.7 mumol/kg/min). Over the course of the eight-hour postprandial period 25 g of glycogen were deposited in the liver. The net hepatic uptake of the gluconeogenic amino acids rose from 6.1 +/- 1.2 mumol/kg/min to a peak of 15.4 +/- 4.3 mumol/kg/min one hour after feeding. Net hepatic uptake of glycerol fell from 3.0 +/- 0.3 mumol/kg/min to an average of 1.5 +/- 0.4 mumol/kg/min. The plasma insulin level increased from 13 +/- 2 microU/mL at 3.5 hours and fell to 32 +/- 7 microU/mL by 8 hours. The plasma glucagon level rose from 22 +/- 3 pg/mL to 93 +/- 12 pg/mL 1.5 hours after feeding and fell to 68 +/- 6 pg/mL 8 hours after feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impairment of glucose tolerance in hyperthyroid cats

Intravenous glucose tolerance tests were performed in eight adult cats before and after a 4-week treatment with thyroxine. The untreated cats had a mean fasting blood glucose concentration of 7.7 +/- 0.3 mmol/l and a mean fasting insulin concentration of 88 +/- 31 pmol/l which were not significantly different from mean fasting glucose and insulin concentrations after 4 weeks of thyroxine administration (6.9 +/- 0.2 mmol/l and 101 +/- 28 pmol/l respectively). At 120 min after glucose injection, the glucose concentration in untreated cats returned to baseline concentrations as did the insulin concentration. However, in the hyperthyroid cats both glucose and insulin concentrations were significantly (P less than 0.001) higher (13.6 +/- 0.8 mmol/l and 245 +/- 17 pmol/l respectively) in comparison with the baseline and untreated cats. The t1/2 for glucose disappearance was significantly higher in the cats rendered hyperthyroid, and the glucose disposal rate constant (K) was significantly lower in this group. It is concluded that hyperthyroidism in cats leads to impairment of glucose tolerance possibly due to peripheral insulin resistance.     

Reproducibility of the glucagon test

The influence of the fasting blood glucose (FBG) concentration on the beta-cell responsiveness to glucagon was studied twice in 9 insulin-dependent diabetic patients with residual beta-cell function. At a FBG of 7.7 +/- 0.3 mmol/l (mean +/- SEM) all patients displayed a preserved beta-cell function with a plasma C-peptide concentration of 0.25 +/- 0.03 nmol/l 6 min after an i.v. injection of glucagon. In contrast, at a FBG of 3.2 +/- 0.01 mmol/l 4 out of 9 patients would have been classified as not having an endogenous insulin secretion. All the patients had the lowest 6 min C-peptide concentration 0.06 +/- 0.01 nmol/l on the day with the lowest blood glucose concentration. The reproducibility of the glucagon test was assessed by comparing the results from two test days in 12 insulin-dependent, 9 non-insulin-dependent diabetic patients and 6 normal subjects. The 6 min plasma C-peptide concentration, the peak plasma C-peptide concentration, and the area under the plasma C-peptide curves were not different on the two test days in any subgroup. In all diabetic patients and normal subjects, the 6 min plasma C-peptide concentration (r = 0.93, coefficient of variation (CV) = 0.16), the peak plasma C-peptide concentration (r = 0.93, CV = 0.16) and the area under the plasma C-peptide curve (r = 0.94, CV = 0.16) were all significantly correlated. The results show that the prevailing FBG significantly affects the outcome of the glucagon test and confirm its reproducibility.     

The mechanism of the prolonged stimulatory effect of corticotrophin on pregnenolone production by guinea-pig adrenocortical mitochondria

The postulated prolonged stimulatory influence of ACTH on the adrenocortical mitochondrial synthesis of pregnenolone in response to ACTH was studied in adrenal mitochondria isolated from control guinea-pigs and from animals treated s.c. with 100 micrograms ACTH(1-24) twice daily on the day before the animals were killed. The animals from both groups were injected with 100 micrograms ACTH s.c. 30 min before killing. The mitochondrial production of pregnenolone (expressed in nmol per mg mitochondrial protein after 10-min incubation) increased from 1.52 +/- 0.46 (S.E.M.) in the control group to 4.50 +/- 0.59 for mitochondria from ACTH-treated animals, despite a similar free cholesterol content in the mitochondria, even when determined after a previous in-vivo treatment with aminoglutethimide to block further metabolism of cholesterol into pregnenolone. In addition, in the presence of an excess of exogenous cholesterol (100 mumol/l), the production of pregnenolone remained higher for mitochondria from ACTH-treated animals. In contrast, when the calcium concentration in the incubation medium was raised to 1 mmol/l, with subsequent enhancement in pregnenolone synthesis, the mitochondrial pregnenolone production became similar for both groups (8.28 +/- 1.11 nmol in the ACTH-treated group and 9.55 +/- 1.90 nmol in the control group), even in the presence of 100 mumol cholesterol/l (13.5 +/- 1.80 nmol in ACTH-treated animals and 14.8 +/- 1.93 nmol in controls). Cycloheximide treatment administered on the day before the animals were killed was without any effect on pregnenolone production in control animals (3.51 +/- 0.43 nmol before and 3.65 +/- 0.63 nmol after cycloheximide treatment).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of secretin release and pancreatic bicarbonate secretion by somatostatin infusion in man.

Five healthy students were investigated on two different days with or without a constant infusion of somatostatin (500 microgram/h) into an arm vein a fluoroscopically placed Lagerl?f tube was used for the collection of gastric and duodenal juice. After 30-min basal period, 40 ml 100 mmol/l HCl was infused into the midpart of the duodenum over 5 min through a thin catheter attached to the tube. Plasma immunoreactive secretin was measured by radioimmunoassay employing 125I-labelled synthetic secretin, antibody against synthetic secretin, and standards prepared from pure natural porcine secretin. Secretin levels without somatostatin infusion were 4.6+/-0.7 pmol/l (mean+/-S.E.M.) basally and rose to a peak of 21.8+/-6.2 pmol/l after duodenal acidification (p less than 0.05) and with somatostatin infusion were 4.4+/-0.4 pmol/l basally and rose to a peak of 6.7+/-1.7 pmol/l (n.s.) after duodenal acidification. Pancreatic bicarbonate output increased from 8.0+/-2.5 mumol/min (mean+/-S.E.M.) to 283+/-44 mumol/min without somatostatin infusion (p less than 0.05) and from 6.7+/-2.1 mumol/min to 70+/-13 mumol/min somatostatin (p less than 0.05). This study shows that somatostatin (500 microgram/h can inhibit the release of secretin and the pancreatic bicarbonate secretion after duodenal acidification in man.