Biomedical subjects
Publications and source records attributed to B C Sinclair-Smith.
We used ear oximetry in combination with maneuvers of hypoxic breathing, exercise, and hyperoxic breathing to assess the cardiopulmonary function of a patient with Eisenmenger's syndrome. The results showed that mild alveolar hypoxia decreased O2 SAT moderately, that exercise alone decreased O2 SAT markedly, and that oxygenation was improved with increased inspired oxygen fraction.
Four normal and five insulin dependent diabetic men received a 2 h pharmacologic glucagon infusion (50 ng/kg/min) resulting in plasma glucagon levels (4400 pg/ml) similar to those seen in glucagonoma patients. In normal subjects in whom plasma insulin concentrations rose significantly (239 uU/ml) and the blood level of 15 of the 18 amino acids measured fell significantly. In contrast, in the diabetic men who secreted no insulin in response to glucagon (no rise in C-peptide levels), only 10 of 18 amino acid levels fell significantly. The branched chain amino acids valine, leucine and isoleucine, as well as tyrosine and phenylalanine were among the 8 amino acids which showed no change in response to glucagon in the diabetics. Thus, glucagon appears to have no acute affect on branched chain amino acid levels in man.
We have determined the effect of insulin infused at 1 and 5 mU/kg/min on gluconeogenesis from alanine in 48-hr fasted men. The conversion of alanine to glucose was measured by the arterial-hepatic venous catheterization technique combined with the infusion of 14C-alanine. During insulin infusion, euglycemia was maintained by variable glucose infusion. When insulin was infused at 1 mU/kg/min the net splanchnic production of 14C-glucose was suppressed by 80% but glucagon infused at the end of the study resulted in substantial release of 14C-glucose from the liver suggesting marked accumulation of labeled glucose in glycogen. When insulin was infused at 5 mU/kg/min the splanchnic release of 14C-glucose was also markedly suppressed but in contrast to the lower insulin dose very little labeled glucose accumulated in glycogen. Neither the high nor the low dose insulin infusion had any effect on net splanchnic alanine uptake and plasma glucagon levels fell by 35% in both protocols. These data demonstrate that in 48-hr fasted man, (1) a small increment in insulin concentration will suppress glucose production but mostly by diverting the newly formed glucose into glycogen; (2) at higher concentrations, insulin will inhibit glucose production mainly by suppressing glucoeogenesis; and (3) this insulin-induced suppression of gluconeogenesis is due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine.
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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.
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.
Tricuspid regurgitation developed in two patients after inferior wall myocardial infarction. Neither patient had preexisting valvular heart disease or evidence of endocarditis, and neither had suffered chest trauma. Because abnormalities in right ventricular function may occur after inferior infarction, and because other known causes of tricuspid incompetence were not present, we postulate that these patients developed valvular regurgitation from dysfunction of the papillary muscle complex controlling tricuspid valve function, a mechanism similar to that proposed to explain mitral regurgitation seen with inferior wall ischemia.
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.
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.
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.
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