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Biomedical subjects

W W Lacy

Publications and source records attributed to W W Lacy.

At least 55 records · Page 3Linked to original sources
PubMed1978

Control of hepatic glucose output by glucagon and insulin in the intact dog.

The regulation of hepatic glucose production by glucagon and insulin has been studied in the intact dog. An attempt has been made to evaluate the role of basal physiological concentrations of the hormones in the regulation of glycogenolysis and gluconeogenesis. Somatostatin was infused continuously into postabsorptive dogs to inhibit the secretion of both glucagon and insulin. Either or both hormones were then replaced intraportally by continuous infusion as desired. The main observations were as follows. (1) When both hormones were simultaneously replaced for periods up to 4.5h, plasma insulin and glucagon concentrations, total glucose output (glycogenolysis plus gluconeogenesis), glucose utilization and the plasma glucose concentration closely matched the same parameters in 0.9% NaCl-infused controls. (2) When glucagon alone was infused, thereby creating a selective insulin deficiency, glucose output (primarily glycogenolysis) rapidly increased by as much as threefold. Glycogenolytic glucose production then fell off progressively and returned to the control value within 4h. The gluconeogenic conversion of [14C]alanine and [14C]lactate into [14C]glucose was stimulated markedly and increased progressively throughout the test period. Glucagon therefore converted the liver from an organ largely dependent on glycogenolysis for glucose production to one heavily dependent on gluconeogenesis. The potent inhibitory effect of basal insulin on postabsorptive glucose output was also clearly apparent. (3) When insulin alone was infused, thereby creating a selective glucagon deficiency, glucose output (glycogenolysis) fell abruptly by about 30% and remained decreased. Gluconeogenesis also decreased (20%) after the selective removal of both insulin and glucagon, but it only remained suppressed for 1h. The low glucose output led to a modest fall in the blood glucose concentration. Thus glucagon plays an important role in maintaining basal glucose production. (4) When insulin was infused and the plasma glucose was kept at its control concentration by infusion of glucose in similar experiments to the above, the hepatic output of glucose fell by as much as 75%. This demonstrates the presence of a glucagon-independent metabolic reflex triggered by a low plasma glucose concentration, the purpose of which is to maintain glucose output at a rate capable of preventing castastrophic hypoglycaemia.

Animals↗
PubMed1977

Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man.

To investigate the role of glucagon in regulating hepatic glucose production in man, selective glucagon deficiency was produced in four normal men by infusing somatostatin (0.9 mg/h) and regular pork insulin (150-muU/kg per min) for 2 h. Exogenous glucose was infused to maintain euglycemia. Arterial plasma glucagon levels fell by greater than 50% whereas plasma insulin levels were maintained in the range of 10-14 muU/ml. In response to these hormonal changes, net splanchnic glucose production (NSGP) fell by 75% and remained suppressed for the duration of the study. In contrast, when somatostatin alone was administered to normal men, resulting in combined insulin and glucagon deficiency (euglycemia again maintained), NSGP fell markedly but only transiently, reaching its nadir at 15 min. Thereafter, NSGP rose progressively, reaching the basal rate at 105 min. These data indicate that the induction of selective glucagon deficiency in man (with basal insulin levels maintained) is associated with a marked and sustained fall in hepatic glucose production. We conclude, therefore, that basal glucagon plays an important role in the maintenance of basal hepatic glucose production in normal man.

Adolescent↗
PubMed1977

Insulin-glucagon interaction in controlling splanchnic glucose production in normal man.

The interaction of glucagon and insulin in controlling hepatic glucose production in man has been inferred from studies of immunoreactive glucagon and insulin. This study directly examines the interaction of glucagon and insulin in controlling net splanching glucose production (NSGP) in eight normal men. Glucagon was infused iv at 5 ng/kg/min for 15 min and resultant arterial glucagon levels (1.3 X 10(-10) M) did not exceed the physiologic portal range. In four normal men NSGP increased 2.3-fold by 5 min and remained elevated for 15 min. There was no change in arterial insulin concentration. To study the effect of exogenous insulin on this glucagon-induced increase in NSGP, insulin was infused at 10 mU/kg/min in four normal men to achieve arterial immunoreactive insulin concentrations of 1500 muU/ml (1 X 10(-8) M). Blood glucose was stabilized by glucose infusions. During insulin and glucose administration, NSGP was suppressed and net splanchnic glucose uptake occurred. After 40 min of insulin and glucose pretreatment, a 5 ng/kg/min glucagon infusion resulted in no increase in NSGP (arterial insulin: glucagon molar ratio of approximately 100). In two subjects the glucagon infusion rate was then increased to 15 ng/kg/min (arterial insulin: glucagon molar ratio of approximately 33), resulting in stimulation of NSGP. These studies provide evidence that insulin in high concentration can suppress glucagon-stimulated NSGP in normal man.

Adult↗
PubMed1977

Transient stimulatory effect of sustained hyperglucagonemia on splanchnic glucose production in normal and diabetic man.

Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a couterregulatory action to glucagon. The insulin-dependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachial-artery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng/kg./min. Glucagon levels rose four-to-fivefold in both groups, plateauing at 300-600 pg./ml. In the normals, NSGP rose from 92+/-12 to 211+/-31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19+/-6 to 33+/-11 muU/.ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78+/-24 to a peak of 221+/-33 mg./min. at 30 minutes and then fell sharply to 113+/-15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl. These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.

Cyclic AMP↗
PubMed1977

Gluconeogenesis: methodological approaches in vivo.

The complexity of the process of gluconeogenesis makes it very difficult to study in vivo. Of the many approaches used to study this process, none have proven ideal. The arterial-hepatic venous catheterization technique can provide accurate determination of the net splanchnic uptake of the various gluconeogenic precursors but gives no information as to their fate once extracted. The infusion of a labeled precursor, such as [14C]alanine, will provide qualitative information about the fate of the labeled substrate but, without complicated kinetic analysis, will not provide quantitative information on the conversion of the precursor to glucose. Though each of these individual techniques has major limitations in the study of gluconeogenesis, various combinations of these methods can provide further insight into the regulation of this complicated process. By combining the arterial-hepatic venous catheterization technique with the infusion of a labeled precursor, the splanchnic extraction of the precursor can be measured as well as the amount of the extracted precursor that is converted to glucose. The concomitant infusion of two isotopes (a 14C-labeled gluconeogenic precursor to assess substrate conversion to glucose and 3H-labeled glucose to measure glucose turnover) can also provide an accurate determination of the amount of circulating precursor that is converted to glucose. The latter technique provides no information on the splanchnic extraction of the precursor but has the advantage of being less invasive and, therefore, more applicable to man. The last two techniques measure accurately the direct conversion of the circulating precursor to glucose and, therefore, provide reliable index of gluconeogenesis.

Alanine↗
PubMed1976

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.

Animals↗
PubMed1976

Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs.

The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin's effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.

Alanine↗
PubMed1975

Gluconeogenesis from alanine in normal postabsorptive man. Intrahepatic stimulatory effect of glucagon.

Although the stimulatory effect of glucagon on gluconeogenesis has been well demonstrated in certain systems in vitro, this effect has never been established in man. The present study was undertaken, therefore, to determine whether glucagon could stimulate gluconeogenesis from alanine in normal fasting man. Glucagon might stimulate this process by increasing the hepatic alanine uptake and/or by shunting the extracted alanine within the liver into the gluconeogenic pathway. In order to be able to examine these two aspects of gluconeogenesis, we combined the hepatic vein-brachial artery catheterization technic with an istopic infusion of alanine-14C. Alanine-14C specific activity was measured in whole blood and plasma by use of a rapid chromatographic technic. Since plasma contributed 93 per cent of the alanine extracted by the splanchnic bed with a specific activity three times that of the red blood cells, plasma alanine specific activity was used to study the conversion of alanine to glucose. A constant infusion of alanine-14C achieved a relatively stable arterial specific activity by forty minutes. The administration of glucagon by constant infusion (15-50 ng./kg./min.) had no affect on thf splanchnic extraction of alanine. Net splanchnic glucose-14C production, however, doubled during the glucagon infusion, and the conversion of alanine to glucose increased from 30 plus or minus 2 to 58 plus or minus 9 mumol/min. These data (1) demonstrate that in normal man fasted twelve to fourteen hours, glucagon at supraphysiologic levels can double the rate of gluconeogenesis from alanine and (2) indicate that this stimulatory effect of glucagon is exerted within the liver by shunting the extracted alanine toward new glucose formation rather than by increasing the hepatic extraction of alanine.

Abdomen↗
PubMed1974

Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men.

The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/ml. In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P=<0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.

Diabetes Mellitus↗
PubMed1974

Effect of glucagon on net splanchnic cyclic AMP production in normal and diabetic men.

Glucagon activates hepatic adenylate cyclase, thereby increasing acutely the liver content of cyclic AMP (cAMP) as well as the release of cAMP into the hepatic vein. Insulin, on the other hand, antagonizes this glucagon-mediated cAMP production, thus providing a hypothetical mechanism through which insulin might correct some of the metabolic abnormalities of diabetes. To study this hormonal interaction in man, net splanchnic cAMP production (NScAMPP) was investigated in normal and insulin-dependent diabetic men under basal conditions and in response to intravenous glucagon, 50 ng/kg/min for 2 h. In normals (n=19), basal hepatic vein cAMP concentration was 23.6+/-1.1 nM and NScAMPP was 1.7+/-0.6 nmol/min. Glucagon stimulated NScAMPP in four normal subjects to a peak of 99.6+/-43 nmol/min at 25 min with a subsequent fall to 12.4+/-5.1 nmol/min by 90 min despite continuing glucagon infusion. Endogenous insulin secretion was stimulated as indicated by rising levels of immunoreactive insulin and C-peptide (connecting peptide) immunoreactivity, raising the possibility that endogenous insulin might be responsible for the fall in NScAMPP that followed the initial spike. In the diabetics (n=8), basal hepatic vein cAMP concentration was 24.7+/-1.2 nM and NScAMPP was undetectable. Glucagon stimulated NScAMPP in five diabetics to a peak of 169.9+/-42.6 with a subsequent fall to 17.4+/-3.9 nmol/min by 90 min even though endogenous insulin secretion was not stimulated (no rise in C-peptide immunoreactivity). Although the mean increase in NScAMPP was greater in the diabetics, the two groups did not differ significantly.Conclusions. In normal resting man the liver is a significant source of circulating cAMP. Diabetics do not release abnormally large amounts of hepatic cAMP under basal conditions. Glucagon markedly enhances hepatic cAMP release with a spike-decline pattern in both normal and diabetic men. The decline in hepatic cAMP release despite continuing glucagon stimulation is due to factors other than a stimulation of insulin secretion.

Adolescent↗