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Biomedical subjects

R W Stevenson

Publications and source records attributed to R W Stevenson.

At least 55 records · Page 3Linked to original sources
PubMed1988

Role of gluconeogenesis in sustaining glucose production during hypoglycemia caused by continuous insulin infusion in conscious dogs.

The roles of glycogenolysis and gluconeogenesis in sustaining glucose production during insulin-induced hypoglycemia were assessed in overnight-fasted conscious dogs. Insulin was infused intraportally for 3 h at 5 mU.kg-1.min-1 in five animals, and glycogenolysis and gluconeogenesis were measured by using a combination of tracer [( 3-3H]glucose and [U-14C]alanine) and hepatic arteriovenous difference techniques. In response to the elevated insulin level (263 +/- 39 microU/ml), plasma glucose level fell (41 +/- 3 mg/dl), and levels of the counterregulatory hormones glucagon, epinephrine, norepinephrine, and cortisol increased (91 +/- 29 to 271 +/- 55 pg/ml, 83 +/- 26 to 2356 +/- 632 pg/ml, 128 +/- 31 to 596 +/- 81 pg/ml, and 1.5 +/- 0.4 to 11.1 +/- 1.0 micrograms/dl, respectively; for all, P less than .05). Glucose production fell initially and then doubled (3.1 +/- 0.3 to 6.1 +/- 0.5 mg.kg-1.min-1; P less than .05) by 60 min. Net hepatic gluconeogenic precursor uptake increased approximately eightfold by the end of the hypoglycemic period. By the same time, the efficiency with which the liver converted the gluconeogenic precursors to glucose rose twofold. Five control experiments in which euglycemia was maintained by glucose infusion during insulin administration (5.0 mU.kg-1.min-1) provided baseline data. Glycogenolysis accounted for 69-88% of glucose production during the 1st h of hypoglycemia, whereas gluconeogenesis accounted for 48-88% of glucose production during the 3rd h of hypoglycemia. These data suggest that gluconeogenesis is the key process for the normal counterregulatory response to prolonged and marked hypoglycemia.

Animals↗
PubMed1987

Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog.

In seven insulin-deficient (less than 3 mU/l) pancreatectomised dogs, the direct and glucagon-related indirect effects of intraportal insulin infusion (350 microU/kg-min; 12 +/- 1 mU/l) on glucose production were determined. Insulin was infused for 300 min during which time the plasma glucagon concentration was allowed to fall (314 +/- 94 to 180 +/- 63 ng/l) for 150 min before being replaced by an infusion intraportally at 2.6 ng/kg-min (323 +/- 61 ng/l) for the remaining 150 min. Glucose production and gluconeogenesis were determined using arterio-venous difference and tracer techniques. Insulin infusion shut off net hepatic glucose output and caused the plasma glucose, blood glycerol and plasma non-esterified fatty acid levels to fall. It caused the hepatic fractional extraction of alanine (0.41 +/- 0.10 to 0.21 +/- 0.06) and lactate (0.32 +/- 0.09 to 0.04 +/- 0.03) to fall which increased their concentrations. When glucagon was replaced, all of these changes were fully or partly reversed with the exception of the changes in glycerol and nonesterified fatty acids. Indeed, 70% of the fall in hepatic glucose production and virtually 100% of the changes in lactate and alanine metabolism produced by basal insulin infusion were mediated by a fall in glucagon. However, the fall in hepatic uptake of glycerol was unaffected by changes in glucagon and thus gluconeogenesis from this substrate was inhibited by insulin per se probably as a result of reduced lipolysis. The latter effect of insulin may explain the incomplete restoration of hepatic glucose production when hyperglucagonaemia was re-established during insulin infusion.

Animals↗
PubMed1987

Induction of penile erection by intracavernosal injection: a double-blind comparison of phenoxybenzamine versus papaverine-phentolamine versus saline.

Recent data suggest that intracavernous injections of phenoxybenzamine in saline, and/or papaverine with phentolamine mesylate in saline, result in erection in otherwise impotent men. A double-blind study using normal saline and normal saline mixed with phenoxybenzamine or papaverine-phenotolamine mesylate showed that none of 11 subjects with organic erection dysfunction responded with appreciable penile swelling to saline injection, but all responded with some degree of penile swelling to the other solutions. The mechanism of penile erection in response to intracavernous injections is still unclear, but it is thought to be related to the alpha-adrenergic blocking and/or smooth muscle relaxant actions of these drugs; the volume of the injection or the normal saline content of the solution are not factors in causing penile tumescence.

Adult↗
PubMed1987

Lack of effect of somatostatin on epinephrine-stimulated glucose production in the dog.

The effects of somatostatin on epinephrine-stimulated hepatic glucose production were assessed in the conscious overnight fasted dog. Glucose production was measured using a primed constant infusion of 3-3H-glucose. Two experiments were performed on each of four animals, each experiment consisting of a tracer equilibration period (80 minutes), a control period (40 minutes), and a test period (180 minutes). In the first experiment, epinephrine was infused at 0.08 microgram/kg/min during the test period so that the plasma concentration rose from 138 +/- 4 to 727 +/- 109 pg/mL. In the second experiment two weeks later, epinephrine was again infused (112 +/- 17 to 727 +/- 148 pg/mL) but with somatostatin (0.8 microgram/kg/min) and intraportal replacement amounts of insulin and glucagon. The pancreatic hormones were administered in such a way as to mimic the insulin and glucagon levels observed during epinephrine infusion in the first experiment. In the first experiment, epinephrine caused changes in insulin and glucagon levels at five minutes of plus 9 +/- 1 microU/mL and minus 1 +/- 3 pg/mL, respectively, and averaged plus 6 +/- 2 microU/mL and minus 9 +/- 5 pg/mL over the first hour. Glucose production peaked at 15 minutes (increment of 0.83 +/- 0.24 mg/kg/min) and increased by an average of 0.38 +/- 0.12 mg/kg/min in the first hour. In the second experiment, intraportal replacement of insulin and glucagon during epinephrine infusion resulted in changes in insulin and glucagon levels at five minutes of plus 8 +/- 3 microU/mL and plus 2 +/- 2 pg/mL, respectively, and averaged plus 4 +/- 2 microU/mL and minus 7 +/- 6 pg/mL over the first hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1987

The synthetic 32-46 fragment of human growth hormone increases insulin and glucagon levels in the conscious dog.

Human growth hormone (hGH, 22 K) has an acute insulinlike effect not observed with the 20 K variant form of hGH that lacks amino acids 32 to 46 (deletion peptide, hGH32-46). The possibility that hGH32-46 increases insulin secretion was examined by infusing hGH32-46 (1.6 nmol/kg/min) or saline in a crossover design study into each of four conscious 16-hour-fasted dogs for three hours (0 to 180 minutes) following a 40-minute control period. At 90 minutes, plasma glucose was raised to and maintained at 170 mg/dL by glucose infusion for three hours (until 270 minutes). After a lag period of 30 minutes hGH32-46 infusion caused glucagon to increase (P less than 0.05) by 67 +/- 20 pg/mL and insulin tended to rise by 8 +/- 3 microU/mL. Saline tended to cause glucagon and insulin to decline slightly (by 17 +/- 8 pg/mL and 6 +/- 2 microU/mL); hGH32-46 increased (P less than 0.05) tracer determined (3H-3-glucose) glucose production by 1.13 +/- 0.66 mg/kg/min while saline had no effect. Neither treatment changed plasma glucose (100 +/- 4 to 105 +/- 3 mg/dL with hGH32-46; 99 +/- 4 to 99 +/- 4 mg/dL with saline). Induction of hyperglycemia (168 +/- 2 mg/dL) caused glucagon concentrations to fall similarly to about 50 pg/mL with and without hGH32-46. Insulin rose in both protocols but to a greater extent (P less than 0.05) with hGH32-46 (+67 +/- 18 v +35 +/- 13 microU/mL at 180 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of somatostatin on glucose homeostasis in conscious long-fasted dogs.

The effects of somatostatin plus intraportal insulin and glucagon replacement (pancreatic clamp) on carbohydrate metabolism were studied in conscious dogs fasted for 7 days so that gluconeogenesis was a major contributor to total glucose production. By use of [3-3H]glucose, glucose production (Ra) and utilization (Rd) and glucose clearance were assessed before and after implementation of the pancreatic clamp. After an initial control period, somatostatin (0.8 microgram . kg-1 . min-1) was infused with intraportal replacement amounts of glucagon (0.42 ng . kg-1 . min-1) and insulin. The insulin infusion rate was varied to maintain euglycemia and then kept constant (68 +/- 16 microU . kg-1 . min-1) for 250 min. Plasma glucagon was similar (84 +/- 14 and 89 +/- 19 pg/ml) before and during somatostatin infusion, while plasma insulin was lower (9.3 +/- 0.9 and 6.6 +/- 0.5 microU/ml, P less than 0.05). Plasma glucose levels remained similar (89 +/- 2 and 96 +/- 9 mg/dl), while Ra and Rd and the ratio of glucose clearance to plasma insulin were significantly (P less than 0.05) increased (from 2.18 +/- 0.12 to 3.21 +/- 0.35 and 2.30 +/- 0.09 to 3.26 +/- 0.38 mg . kg-1 . min-1, and 0.30 +/- 0.03 to 0.59 +/- 0.11, respectively). Net hepatic lactate uptake and [14C]alanine plus [14C]lactate conversion to [14C]glucose increased (P greater than 0.05) (from 9.32 +/- 0.47 to 16.54 +/- 2.97 mumol . kg-1 . min-1 and 100 to 263 +/- 37%, respectively). In conclusion, somatostatin alters glucose clearance in 7-day fasted dogs, resulting in changes in several indices of carbohydrate metabolism.

Alanine↗
PubMed1987

Lactate as substrate for glycogen resynthesis after exercise.

Muscle glycogen levels in the perfused rat hemicorpus preparation were reduced two-thirds by electrical stimulation plus exposure to epinephrine (10(-7) M) for 30 min. During the contraction period muscle lactate concentrations increased from a control level of 3.6 +/- 0.6 to a final value of 24.1 +/- 1.6 mumol/g muscle. To determine whether the lactate that had accumulated in muscle during contraction could be used to resynthesize glycogen, glycogen levels were determined after 1-3 h of recovery from the contraction period during which time the perfusion medium (flow-through system) contained low (1.3 mmol/l) or high (10.5 or 18 mmol/l) lactate concentrations but no glucose. With the low perfusate lactate concentration, muscle lactate levels declined to 7.2 +/- 0.8 mumol/g muscle by 3 h after the contraction period and muscle glycogen levels did not increase (1.28 +/- 0.07 at 3 h vs. 1.35 +/- 0.09 mg glucosyl U/g at end of exercise). Lactate disappearance from muscle was accounted for entirely by output into the venous effluent. With the high perfusate lactate concentrations, muscle lactate levels remained high (13.7 +/- 1.7 and 19.3 +/- 2.0 mumol/g) and glycogen levels increased by 1.11 and 0.86 mg glucosyl U/g, respectively, after 1 h of recovery from exercise. No more glycogen was synthesized when the recovery period was extended. Therefore, it appears that limited resynthesis of glycogen from lactate can occur after the contraction period but only when arterial lactate concentrations are high; otherwise the lactate that builds up in muscle during contraction will diffuse into the bloodstream.

Animals↗
PubMed1987

Importance of the route of intravenous glucose delivery to hepatic glucose balance in the conscious dog.

To assess the importance of the route of glucose delivery in determining net hepatic glucose balance (NHGB) eight conscious overnight-fasted dogs were given glucose via the portal or a peripheral vein. NHGB was measured using the arteriovenous difference technique during a control and two 90-min glucose infusion periods. The sequence of infusions was randomized. Insulin and glucagon were held at constant basal levels using somatostatin and intraportal insulin and glucagon infusions during the control, portal, and peripheral glucose infusion periods (7 +/- 1, 7 +/- 1, 7 +/- 1 microU/ml; 100 +/- 3, 101 +/- 6, 101 +/- 3 pg/ml, respectively). In the three periods the hepatic blood flow, glucose infusion rate, arterial glucose level, hepatic glucose load, arterial-portal glucose difference and NHGB were 37 +/- 1, 34 +/- 1, 32 +/- 3 ml/kg per min; 0 +/- 0, 4.51 +/- 0.57, 4.23 +/- 0.34 mg/kg per min; 101 +/- 5, 200 +/- 15, 217 +/- 13 mg/dl; 28.5 +/- 3.5, 57.2 +/- 6.7, 54.0 +/- 6.4 mg/kg per min; +2 +/- 1, -22 +/- 3, +4 +/- 1 mg/dl; and 2.22 +/- 0.28, -1.41 +/- 0.31, and 0.08 +/- 0.23 mg/kg per min, respectively. Thus when glucose was delivered via a peripheral vein the liver did not take up glucose but when a similar glucose load was delivered intraportally the liver took up 32% (P less than 0.01) of it. In conclusion portal glucose delivery provides a signal important for the normal hepatic-peripheral distribution of a glucose load.

Animals↗
PubMed1987

Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo.

This study was undertaken to determine whether the dose-dependent effect of glucagon on gluconeogenesis parallels its effect on hepatic glycogenolysis in conscious overnight-fasted dogs. Endogenous insulin and glucagon secretion were inhibited by somatostatin (0.8 micrograms X kg-1 X min-1), and intraportal replacement infusions of insulin (213 +/- 28 microU X kg-1 X min-1) and glucagon (0.65 ng X kg-1 X min-1) were given to maintain basal hormone concentrations for 2 h (12 +/- 2 microU/ml and 108 +/- 23 pg/ml, respectively). The glucagon infusion was then increased 2-, 4-, 8-, or 12-fold for 3 h, whereas the rate of insulin infusion was left unchanged. Glucose production (GP) was determined with 3-[3H]glucose, and gluconeogenesis (GNG) was assessed with tracer (U-[14C]alanine conversion to [14C]glucose) and arteriovenous difference (hepatic fractional extraction of alanine, FEA) techniques. Increases in plasma glucagon of 53 +/- 8, 199 +/- 48, 402 +/- 28, and 697 +/- 149 pg/ml resulted in initial (15-30 min) increases in GP of 1.1 +/- 0.4 (N = 4), 4.9 +/- 0.5 (N = 4), 6.5 +/- 0.6 (N = 6), and 7.7 +/- 1.4 (N = 4) mg X kg-1 X min-1, respectively; increases in GNG (approximately 3 h) of 48 +/- 19, 151 +/- 50, 161 +/- 25, and 157 +/- 7%, respectively; and increases in FEA (3 h) of 0.14 +/- 0.07, 0.37 +/- 0.05, 0.42 +/- 0.04, and 0.40 +/- 0.17, respectively. In conclusion, GNG and glycogenolysis were similarly sensitive to stimulation by glucagon in vivo, and the dose-response curves were markedly parallel.

Alanine↗
PubMed1985

Intracellular digestion of saturated and unsaturated phospholipid liposomes by mucosal cells. Possible mechanism of transport of liposomally entrapped macromolecules across the isolated vascularly perfused rabbit ileum.

The mechanism of intestinal absorption of liposomally entrapped [14C]inulin and 125I-labelled poly(vinylpyrrolidone) was studied using the isolated rabbit intestinal loop with intact perfused vasculature, a system more closely resembling an in vivo system than the everted sac technique. [14C]Inulin or 125I-poly(vinylpyrrolidone) was entrapped in liposomes prepared from unsaturated egg phosphatidylcholine and soya phosphatidylcholine, and saturated distearoylphosphatidylcholine (18:0), dipalmitoylphosphatidylcholine (16:0) and dimyrostoylphosphatidylcholine (14:0). Free and liposomally entrapped macromolecules were introduced in the ileum and the transport of liposomes and entrapped macromolecules into the venous effluent was monitored by measuring the presence of the aqueous marker 125I-poly(vinylpyrrolidone) or [14C]inulin, and lipid marker [3H]cholesterol. The results show that intact liposomes are not transported across intestine into the venous effluent, but they are taken up by mucosal cells and digested intracellularly, releasing the entrapped markers 125I-poly(vinylpyrrolidone) and [14C]inulin. These markers are then transported into the venous effluent as free molecules. The absorption of liposomally entrapped [14C]inulin into the venous effluent is biphasic, first slow for 30 min (i.e., a lag period of 30 min), followed by a rapid linear increase. The duration of the lag period and the rate of absorption of the entrapped [14C]inulin are dependent on the degree of saturation and the transition temperature of the phospholipids used to prepare liposomes. The possible explanation of the lag period based on the evidence presented here is that it is the time required for the liposomes to be taken up by mucosal cells and digested intracellularly. Intracellular digestion of liposomes prepared from saturated phospholipids is more rapid than from those prepared from unsaturated phospholipids, and the greater the fatty acid chain length of the saturated phospholipids the more rapid the intracellular degradation of liposomes.

Animals↗
PubMed1985

Mechanism of epinephrine's glycogenolytic effect in isolated canine hepatocytes.

Epinephrine (10(-7) mol/L) addition to isolated canine hepatocytes activates glycogen phosphorylase from 12.3 +/- 0.4 to 28.6 +/- 2.6 U/g and glucose output from 42 +/- 3 to 170 +/- 24 nmol/mg/h. Preincubation of hepatocytes with propranolol (2 X 10(-5) mol/L) caused a 73% inhibition of phosphorylase activation and a 77% inhibition of the stimulation of glucose output by epinephrine. Phentolamine (2 X 10(-5) mol/L) on the other hand, caused a 16% inhibition of phosphorylase activation and a 27% inhibition of the stimulation of glucose output by epinephrine. These results were unaffected by the sex of the animal. In the dog the glycogenolytic effects of epinephrine appear to be mediated primarily by a beta-adrenergic mechanism.

Animals↗
PubMed1985

The relationship between plasma concentration and disappearance rate of immunoreactive insulin in the conscious dog.

The relationship between plasma concentration and disappearance (infusion) rate of insulin was determined during infusion of insulin via the portal circulation of 14 normal euglycaemic dogs when somatostatin was infused to block endogenous insulin secretion. The relationship could be represented by one straight line over the plasma immunoreactive insulin range 0 to 110 microU/ml (r = 0.99) but above 110 microU/ml the fractional insulin disappearance rate declined. The results indicate the existence in the dog of a saturable pathway of insulin degradation that could conceivably be located in liver and which may become saturated only at insulin concentrations in the portal vein exceeding approximately 330 microU/ml.

Animals↗
PubMed1985

Regulation of ketogenesis by epinephrine and norepinephrine in the overnight-fasted, conscious dog.

The effects on ketogenesis and lipolysis of a norepinephrine (0.04 microgram/kg-min), epinephrine (0.04 microgram/kg-min), or saline infusion were examined in the overnight-fasted, conscious dog. Plasma insulin and glucagon levels were maintained constant by means of a somatostatin infusion (0.8 microgram/kg-min) and intraportal replacement infusions of insulin and glucagon. In saline-infused dogs, plasma epinephrine (62 +/- 8 pg/ml), norepinephrine (92 +/- 29 pg/ml), blood glycerol (87 +/- 10 microM), and plasma nonesterified fatty acid (NEFA) (0.82 +/- 0.17 mM) levels did not change. Total blood ketone body levels tended to rise (62 +/- 10 to 83 +/- 11 microM) by 3 h as did total ketone body production (1.5 +/- 0.4 to 2.2 +/- 0.4 mumol/kg-min) over the same time interval. Norepinephrine infusion to produce plasma levels of 447 +/- 86 pg/ml caused a sustained 50% rise in glycerol levels (66 +/- 17 to 99 +/- 15 mumol/L, P less than 0.05) and 53% rise in nonesterified fatty acids (0.53 +/- 0.07 to 0.81 +/- 0.15 mumol/L, P less than 0.05). Total ketone body levels rose by 43% (51 +/- 8 to 73 +/- 10 mumol/L) and ketone body production rose by a similar proportion (1.5 +/- 0.2 to 2.2 +/- 0.3 mumol/kg-min), changes that did not differ significantly from control animals. A similar increment in plasma epinephrine levels (75 +/- 15 to 475 +/- 60 pg/ml) caused glycerol levels to rise by 82% (105 +/- 23 to 191 +/- 26 mumol/L) in 30 min, but this rise was not sustained and the level fell to 146 +/- 14 mumol/L by 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Lack of effect of somatostatin on the stimulation of hepatic glycogenolysis by epinephrine in isolated canine hepatocytes.

The effects of somatostatin on epinephrine's ability to stimulate glucose output have been examined in hepatocytes isolated from dogs fasted overnight. Half-maximal stimulation of phosphorylase a activity and glucose output occurred at an epinephrine concentration of approx. 5 X 10(-9) M. Somatostatin at 10, 100 or 1000 ng/ml had no effect on the ability of a maximal (1 X 10(-7) M) and a submaximal (1 X 10(-8) M) dose of epinephrine to activate phosphorylase at 2 min, or to stimulate glucose output over 20 min. Since the doses of somatostatin used in the present study are up to 50-fold higher than the blood concentrations commonly found when somatostatin is used in vivo to inhibit pancreatic hormone secretion, it seems unlikely that use of somatostatin in this way would affect stimulation of hepatic glycogenolysis by epinephrine in vivo.

Animals↗
PubMed1984

Effect of epinephrine on glycogenolysis and gluconeogenesis in conscious overnight-fasted dogs.

The aim of this study was to assess the importance of epinephrine as a gluconeogenic hormone in the conscious 18-h-fasted dog. Glucose production ([3H]glucose turnover) and gluconeogenesis [( 14C]alanine conversion to [14C]glucose; and transhepatic gluconeogenic substrate balances) were assessed during epinephrine infusion (0.04 microgram X kg-1 X min-1). Insulin and glucagon were fixed at basal levels (13 +/- 1 microU/ml and 138 +/- 16 pg/ml, respectively) using a pancreatic clamp [somatostatin (0.8 microgram X kg-1 X min-1) plus intraportal insulin (233 microU X kg-1 X min-1) and glucagon (0.65 ng X kg-1 X min-1)]. Plasma epinephrine levels increased to 424 +/- 48 pg/ml. Glucose production increased rapidly (15 min) from 2.7 +/- 0.3 to 3.7 +/- 0.4 mg X kg-1 X min-1 (P less than 0.01) but then returned to base line (2 h). The plasma glucose level rose progressively from 115 +/- 16 to 160 +/- 16 mg/dl (P less than 0.01) at 3 h, whereas glucose clearance fell by 28% (P less than 0.05). Plasma alanine rose from 340 +/- 20 to 497 +/- 50 microM, and blood lactate increased from 640 +/- 135 to 1,910 +/- 241 microM. Net hepatic alanine and lactate uptake increased to maxima of 4.0 +/- 0.3 and 9.3 +/- 2.0 mumol X kg-1 X min-1, respectively. The conversion of alanine to glucose increased by a maximum of 163 +/- 56% (vs. 49 +/- 16% in controls not given epinephrine), whereas the efficiency with which the liver converted alanine to glucose rose by 84 +/- 27% (vs. 82 +/- 12% in controls not given epinephrine).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗