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Biomedical subjects

J D Best

Publications and source records attributed to J D Best.

At least 91 records · Page 5Linked to original sources
PubMed1985

Blood pressure and norepinephrine spillover during propranolol infusion in humans.

To determine whether a reflex increase of sympathetic nervous system activity contributes to maintenance of blood pressure during acute beta-adrenergic blockade, we measured plasma norepinephrine levels and norepinephrine kinetics during propranolol administration. During a 90-min infusion of propranolol (10 mg iv + 80 micrograms/min) in 12 normal subjects, heart rate fell from 56 +/- 2 to 49 +/- 2 (SE) beats/min (P less than 0.001), but there was no fall in mean arterial blood pressure (84 +/- 3 mmHg before and 86 +/- 3 mmHg after propranolol). Arterial plasma norepinephrine levels rose from 183 +/- 20 to 250 +/- 29 pg/ml during propranolol (P less than 0.001), suggesting increased sympathetic vasoconstrictor tone. However, isotope dilution studies using tritiated norepinephrine infusion showed that arterial plasma levels of tritiated norepinephrine rose from 743 +/- 78 to 1,002 +/- 101 dpm/ml during propranolol (P less than 0.001), indicating a reduction in the rate of norepinephrine clearance from plasma. The calculated fall in clearance from 1.90 +/- 0.13 to 1.42 +/- 0.11 1/min (P less than 0.001) entirely accounted for the rise in plasma norepinephrine, since the calculated rate of norepinephrine spillover into plasma remained at the base-line level of 340 +/- 40 ng/min during propranolol. In control studies on four subjects, arterial plasma norepinephrine levels and norepinephrine kinetics did not change from base line during the control period. We conclude that maintenance of blood pressure during propranolol infusion is not due to a reflex generalized increase of sympathetic vasoconstrictor tone.

Adult↗
PubMed1984

Lack of a direct alpha-adrenergic effect of epinephrine on glucose production in human subjects.

To determine whether alpha-adrenergic stimulation can directly increase glucose production in humans, we infused epinephrine plus propranolol in six normal subjects. The contribution of pancreatic islet effects was eliminated by the infusion of somatostatin. Despite high levels of epinephrine (1,234 +/- 255 pg/ml; mean +/- SE), plasma glucose fell from 85 + 1 to 71 +/- 7 mg/dl. Glucose production rate fell from 1.88 +/- 0.06 to 1.50 +/- 0.16 mg X kg-1 X min-1. During control studies in the same subjects (propranolol and somatostatin without epinephrine), plasma glucose fell from 87 +/- 1 to 75 +/- 3 mg/dl and glucose production fell from 1.93 +/- 0.10 to 1.58 +/- 0.13 mg X kg-1 X min-1. Thus, under conditions of suppressed insulin and falling glucose levels, both of which favor a positive response, a high level of alpha-adrenergic stimulation failed to directly increase glucose production. To ensure that the liver was not refractory to other stimuli, glucagon was administered during infusion of epinephrine and propranolol. In these studies, plasma glucose rose to 175 +/- 20 mg/dl and glucose production plateaued at 3.71 +/- 0.30 mg X kg-1 X min-1 (n = 7). These findings were similar to the effects of propranolol, somatostatin, and glucagon without epinephrine on plasma glucose (196 +/- 15 mg/dl) and glucose production (3.65 +/- 0.29 mg X kg-1 X min-1). Thus, although the liver remained responsive to glucagon during alpha-adrenergic stimulation, no alpha-adrenergic augmentation of glucose production was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men.

To determine whether islet adaptation during insulin resistance involves increased responsiveness to the level of plasma glucose, insulin resistance was induced in nine normal men by giving dexamethasone (Dex) (3 mg twice daily for 2 days). Plasma insulin and acute insulin responses (AIR) to isoproterenol were measured at three different glucose levels under control and Dex conditions. During Dex there were elevations above control levels of basal glucose (104 +/- 2 vs. 94 +/- 3 mg/dl) and insulin (21 +/- 3 vs. 13 +/- 2 microU/ml, both P less than 0.03). When glucose levels were raised stepwise by matching amounts using glucose clamps, AIR to isoproterenol rose as a linear function of glucose level under both conditions but rose more steeply during Dex. That is, the potentiating effect of glucose (delta AIR/delta glucose) was greater during Dex: 1.3 +/- 0.2 vs. 0.8 +/- 0.2 (P less than 0.01). Similarly, matched increments in glucose level produced greater increments in prestimulus insulin level during Dex (P less than 0.03). We conclude that 48 h of Dex raises the "gain" of the potentiating effect of glucose. Because the direct effect of glucocorticoids on B cell function has been reported to be inhibitory, the observed stimulation is likely to be a result of the insulin resistance caused by Dex.

Adaptation, Physiological↗
PubMed1984

Pentobarbital anesthesia suppresses basal and 2-deoxy-D-glucose-stimulated plasma catecholamines.

Since pentobarbital anesthesia is known to attenuate certain autonomic reflexes, we tested whether pentobarbital would suppress both basal and stimulated levels of plasma catecholamines and whether a large stimulus might counterbalance this suspected suppression. In untrained dogs, sampled by venipuncture, pentobarbital (30 mg/kg iv) decreased the plasma concentration of epinephrine (E) from 146 +/- 9 to 38 +/- 8 (SE) pg/ml (n = 46) and norepinephrine (NE) from 276 +/- 13 to 91 +/- 10 pg/ml (both P less than 0.0005), suggesting that barbiturate anesthesia suppresses sympathetic outflow in these mildly stressed animals. Pentobarbital also had a marked suppressive effect on the lower baseline catecholamines (E, 84 +/- 14 pg/ml; NE, 118 +/- 10 pg/ml; n = 6) of trained, chronically catheterized dogs, suggesting that it was capable of suppressing resting sympathetic outflow as well. To determine whether pentobarbital anesthesia also suppressed reflex activation of the sympathetic nervous system, the plasma catecholamine response to the neuroglucopenic agent, 2-deoxy-D-glucose (2-DG), was measured in conscious and in pentobarbital-anesthetized dogs. In conscious dogs, the administration of 2-DG (100 mg/kg iv) doubled the base-line plasma concentration of E and NE 30 min after the 2-DG injection. In contrast, the administration of 2-DG (100 mg/kg iv) to pentobarbital-anesthetized dogs produced no significant increase of either plasma catecholamine, suggesting marked suppression of this sympathetic reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1984

Effect of pentobarbital anesthesia on plasma norepinephrine kinetics in dogs.

To assess the effect of barbiturate anesthesia on sympathetic nervous system activity, plasma norepinephrine (NE) kinetics were measured in trained dogs with an indwelling right atrial catheter before and during iv administration of pentobarbital sodium (30 mg/kg, iv, plus continuous infusion at 0.1-0.2 mg/kg X min). Plasma NE levels fell by 64 +/- 6% from 103 +/- 22 to 42 +/- 18 pg/ml (mean +/- SEM; n = 6; P less than 0.001) during pentobarbital anesthesia. As measured with the isotope dilution method using steady state kinetics, basal NE spillover rate into plasma was 203 +/- 92 ng/min; this level fell by 91 +/- 2% (P less than 0.001) to 24 +/- 13 ng/min during anesthesia. Clearance of NE from plasma was also impaired by the anesthesia. Before pentobarbital administration, the NE clearance rate from plasma was 1.7 +/- 0.4 liters/min; this rate fell during anesthesia by 71 +/- 6% (P less than 0.001) to 0.5 +/- 0.2 liters/min. During control studies in which no barbiturate was administered, there was no change in plasma NE levels (111 +/- 11 vs. 116 +/- 19 pg/ml; n = 3), NE spillover rate into plasma (209 +/- 56 vs. 204 +/- 61 ng/min), or clearance of NE from plasma (1.8 +/- 0.4 vs. 1.7 +/- 0.2 liters/min). The marked suppression of the NE spillover rate into plasma during pentobarbital administration suggests that this type of anesthesia causes a profound suppression of baseline sympathetic nervous system activity in trained dogs. The observed fall of plasma NE levels underestimated the degree of suppression of sympathetic nervous activity by the anesthesia, since there was a concurrent fall in NE clearance from plasma.

Anesthesia↗
PubMed1984

Prolonged infusion of somatostatin with glucagon replacement increases plasma glucose and glucose turnover in man.

To determine the effect of isolated beta-cell impairment on glucose turnover, we administered a 46-h infusion of somatostatin (200 micrograms/h) with glucagon replacement (0.75 ng/kg X min) to eight normal men. Fasting plasma insulin levels fell slightly, but significantly, from 8 +/- 2 (+/- SEM; control) to 6 +/- 2 microU/ml 46 h after beginning the infusion (P less than 0.001). Over the same period, fasting plasma glucose rose from 89 +/- 2 to 114 +/- 2 mg/dl (P less than 0.001), and plasma glucagon levels remained unchanged (79 +/- 5 vs. 82 +/- 8 pg/ml P = NS). Glucose turnover was measured by isotope dilution using [3-3H]glucose. The glucose production rate rose consistently from a baseline value of 2.08 +/- 0.04 to 2.45 +/- 0.06 mg/kg X min (P less than 0.01). The glucose disposal rate also rose consistently from 2.11 +/- 0.04 to 2.53 +/- 0.09 mg/kg X min (P less than 0.01). We conclude that prolonged mild selective insulin deficiency produced by infusion of somatostatin with glucagon replacement in normal men causes an elevation of the fasting plasma glucose level, which is maintained by glucose overproduction rather than by glucose underutilization. Overproduction of glucose may also be important in maintaining basal hyperglycemia in patients with noninsulin-dependent diabetes mellitus who have a similar impairment of insulin secretion.

Adolescent↗
PubMed1984

Dose-dependent suppression of norepinephrine appearance rate in plasma by clonidine in man.

Clonidine is an alpha 2-receptor agonist which lowers both blood pressure and plasma norepinephrine (NE) levels in man. To determine whether the clonidine-induced fall in plasma NE is due to decreased NE appearance into plasma or increased NE clearance from plasma, NE infusions [( 3H]NE; 15 microCi/m2 bolus and 0.35 microCi/m2 X min infusion) were performed in 10 normal subjects, aged 25-56 yr. Arterialized plasma samples were obtained for measurements of steady state [3H]NE specific activity and plasma NE to allow calculation of plasma NE appearance rate and NE clearance before and 120-140 min after 1.5 and 5.0 micrograms/kg oral clonidine. Using an identical protocol, responses were compared in 4 subjects after placebo administration. Clonidine produced a dose-related reduction in mean arterial blood pressure, but no significant change in heart rate. The basal supine plasma NE concentration of 204 +/- 21 pg/ml (mean +/- SEM) fell by 27% (P less than 0.02) after low dose clonidine and by 51% (P less than 0.001) after high dose clonidine. There was no change in plasma epinephrine levels. The basal plasma NE appearance rate of 0.25 +/- 0.03 microgram/m2 X min was reduced by 32% (P less than 0.01) after low dose clonidine and by 52% (P less than 0.001) after high dose clonidine. The basal plasma NE clearance of 1.2 +/- 0.08 liters/m2 X min was unchanged after clonidine treatment. There was no change in mean plasma NE levels, plasma NE appearance rate, or mean arterial pressure after placebo administration. These findings demonstrate that the clonidine-induced fall in plasma NE levels is due to a dose-dependent suppression of plasma NE appearance rate and provide evidence for alpha 2-adrenergic inhibition of sympathetic nervous system activity in normotensive subjects.

Adult↗
PubMed1984

Insulin and oral hypoglycaemics.

The management of diabetes involves an individualised diet and exercise programme, patient education about all aspects of diabetes care (including blood or urine tests for glucose) and attention to other risk factors for macrovascular disease such as smoking, hypertension and hypercholesterolaemia. Recent advances in these aspects of diabetes and better understanding of the differences between insulin dependent and noninsulin dependent diabetes have had a major influence on the way insulin and oral hypoglycaemics are now used.

Absorption↗
PubMed1983

Differential changes of autonomic nervous system function with age in man.

To assess the relationship between aging and autonomic nervous system function, cardiovascular and pupillary autonomic nervous system reflexes were measured in subgroups of 103 normal male subjects ranging in age from 19 to 82 years (mean age = 39 years). Both the plasma norepinephrine level, a measure of cardiovascular sympathetic nervous system activity, and the mean arterial blood pressure increased with age (r = 0.68 and 0.67, respectively, both p less than 0.001). In contrast, the plasma epinephrine level, a measure of adrenomedullary sympathetic nervous system activity, was unrelated to age (r = 0.08, p = NS). Respiratory variation of heart rate during beta-adrenergic blockade, an index of cardiac parasympathetic nervous system activity, was reduced in older subjects (r = -0.54, p less than 0.001). Thus, there was evidence of an age-related increase of cardiovascular sympathetic nervous system activity and a reduction of cardiac parasympathetic nervous system activity. These findings are consistent with the hypothesis that there is sympathetic nervous system and parasympathetic nervous system compensation of cardiovascular function in response to an age-related decrease in baroreceptor sensitivity. However, dark-adapted pupil size during parasympathetic nervous system blockade, an index of iris sympathetic nervous system activity, declined with age (r = -0.81, p less than 0.001). The latency time for the pupillary response to a light stimulus, an index of iris parasympathetic nervous system activity, was prolonged in older subjects (r = 0.58, p less than 0.001). Thus, both sympathetic nervous system and parasympathetic nervous system inputs to the iris were diminished in older subjects, findings consistent with the generalized decrease of peripheral somatic nerve function that has been reported with aging in man. It is concluded that autonomic nervous system function also declines with aging, but that other age-related changes such as a decline of baroreceptor sensitivity may lead to compensatory autonomic nervous system response, which could mask underlying functional defects.

Adult↗
PubMed1983

[LeuB24]insulin is an insulin agonist at the liver in vivo.

A mutant insulin isolated from the plasma of a diabetic patient has been reported to antagonize insulin action in vitro and was thought to be [LeuB24]insulin. This study examines the ability of [LeuB24]insulin to antagonize insulin action at the liver in vivo in anesthetized dogs. Antagonism of insulin action was first simulated by decreasing the intraportal insulin infusion 50%. This resulted in a significant increase in both glucose production (Ra) (delta = + 0.30 +/- 0.08 mg X kg-1 X min-1) and the glucose level in arterial plasma (delta = +6.5 +/- 2.8 mg/dl), validating the responsiveness of the preparation to partial insulin antagonism. [LeuB24]insulin was infused intraportally, at molar ratios of 1:1, 1:2, 1:4, and 1:10 (50, 25, 12.5, and 5 ng/min, respectively) with insulin (54 ng/min). Infusion at all but the lowest dose resulted in a significant drop in glucose production (delta = -0.44 +/- 0.07, -0.35 +/- 0.06, and -0.28 +/- 0.08 mg X kg-1 X min-1 for4 analogue infusions of 50, 25, and 12.5 ng/min, respectively) and plasma glucose levels (delta = -7 +/- 3 and -3 +/- 1 mg/dl for analogue infusions of 50 and 25 ng/min, respectively). No change in Rd (glucose disposal) was observed for either insulin withdrawal of [LeuB24]insulin infusion. We conclude that, at the liver in vivo, [LeuB24]insulin does not antagonize insulin action but rather acts as an insulin agonist. Its hepatic effects would not contribute to a diabetic hyperglycemia.

Animals↗
PubMed1983

Suppression of glucagon secretion during a tolbutamide infusion in normal and noninsulin-dependent diabetic subjects.

To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.

Adult↗
PubMed1983

Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man.

To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 +/- 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2-5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg . min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg . min EPI (high EPI; 69 +/- 15, 76 +/- 13, and 142 +/- 22 pg/ml, respectively; n = 8; P less than 0.003). With glucose levels matched at 256 +/- 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 +/- 12 pg/ml; low EPI, 63 +/- 5 pg/ml; high EPI, 130 +/- 20 pg/ml; P less than 0.008). During control infusions, raising the glucose level from 102 +/- 2 to 166 +/- 5 to 256 +/- 5 mg/dl suppressed AGR from 77 +/- 17 to 69 +/- 15 to 53 +/- 12 pg/ml (P less than 0.002). During low EPI, the same glycemic increments lowered GR from 108 +/- 19 to 76 +/- 13 to 63 +/- 5 pg/ml (P less than 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 +/- 2 mg/dl during control infusions, AGR was 77 +/- 17 pg/ml, compared to only 76 +/- 13 pg/ml during low EPI with the glucose level higher (166 +/- 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P less than 0.0001). These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation.

Adult↗
PubMed1983

Hyperglycemia and beta-cell adaptation during prolonged somatostatin infusion with glucagon replacement in man.

To assess the relationship between beta-cell function and the level and duration of hyperglycemia during generalized beta-cell impairment, we studied the effects of acute and prolonged infusion of somatostatin in seven normal men. Twenty minutes after beginning an acute infusion of somatostatin (200 microgram/h) plus glucagon replacement (0.75 ng/kg/min), plasma glucose (PG) remained unchanged, but plasma insulin (IRI) and acute insulin response to isoproterenol had fallen markedly. Seventy minutes after beginning somatostatin-plus-glucagon, a rise in PG was associated with an increase in the acute insulin response to isoproterenol, though not to the control level. In a separate study, after 46 h of the somatostatin-plus-glucagon infusion, at a glucose level similar to the 70-min level, plasma insulin had returned nearly to the control level and the acute insulin response to isoproterenol had returned completely to the control level. Such increases inb basal and stimulated insulin secretion most likely represent a time-dependent adaptation by the beta-cells to the persistent hyperglycemia. First- and second-phase insulin responses to intravenous glucose were markedly inhibited after 46 h of somatostatin-plus-glucagon. In summary, a 46-h infusion of somatostatin with glucagon replacement in humans leads to hyperglycemia, a slightly diminished basal insulin level, markedly decreased insulin responses to glucose, and an insulin response to isoproterenol maintained at a normal level by acute and probably chronic adaptation to the hyperglycemia. We speculate that beta-cell adaptation to hyperglycemia may explain the similar abnormalities of islet function observed in patients with NIDDM.

Adaptation, Physiological↗
PubMed1983

The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia.

The effects of treatment on plasma total triglyceride, total cholesterol, and plasma postheparin lipase activities have not been evaluated in non-insulin-dependent diabetic (NIDD) subjects without a coexisting familial lipid disorder. In 49 untreated NIDD subjects, there was a linear relationship between glycosylated hemoglobin (GHb) and triglyceride (r = 0.35, P less than 0.02). This correlation was improved after adjusting for the effects of obesity by a partial correlation analysis. After therapy, there was a significant relationship between the change in GHb and the change in triglyceride. To determine whether changes in lipid removal from plasma may contribute to the decrease in plasma lipid concentrations during treatment, the plasma postheparin lipoprotein lipase and hepatic lipase activities were evaluated in a subgroup (N = 8) of these NIDD subjects before and after 1 and 3 mo of therapy. Plasma postheparin hepatic lipase activity in the NIDD subjects was not different from that observed in six normal control subjects and did not change during therapy. In contrast, plasma postheparin lipoprotein lipase activity was lower in the untreated NIDD subjects than in the control subjects. Analysis of the two phases (early and late) of the postheparin lipoprotein lipase activity in plasma showed that the abnormal early phase in untreated NIDD corrected to normal values in less than a month, but the late phase was not corrected until the 3-mo measurement. These findings suggest that some NIDD subjects have a defect in heparin releasable lipoprotein lipase activity, which is reversed with improved glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

An evaluation of dynamic pituitary function tests in patients with pituitary tumours.

In a prospective study of 26 patients with macroadenoma of the pituitary (14 secretory and 12 non-secretory), basal and stimulated pituitary hormone levels were used to detect hypothalamic dysfunction and to examine pituitary hormone secretion before and after hypophysectomy. Suprasellar tumour extention with hypothalamic compression occurred in 18 patients but was not consistently associated with hormonal tests indicative of hypothalamic dysfunction. In patients with secretory tumours, secretory activity was adequately assessed by basal hormone levels alone, which showed that surgery reduced hormone levels by a mean 85% in acromegaly and by a mean 55% in prolactinomas. Preoperatively, pituitary reserve of hormones not being hypersecreted was often normal, despite large tumour size and hypothalamic compression. Even after apparently complete pituitary removal at surgery, normal responses to stimulatory tests could sometimes be detected. Conventional dynamic tests are only of limited value in the assessment of hypothalamo-pituitary dysfunction in patients with large pituitary tumours and should not be used indiscriminately in such individuals requiring surgery.

Acromegaly↗
PubMed1982

Release and clearance rates of epinephrine in man: importance of arterial measurements.

Previous estimates of catecholamine kinetics in human subjects have been based on the measurement of the catecholamine levels in forearm venous plasma. However, the use of forearm venous measurements may introduce considerable error, since venous catecholamine levels may primarily reflect metabolism in the organ drained rather than in the total body. In this study, arterial levels of epinephrine were found to significantly exceed forearm venous levels, both basally (mean +/- SEM, 71 +/- 13 vs. 50 +/- 7 pg/ml; n = 6; P less than 0.05) and during infusions of epinephrine [0.1 microgram/min (112 +/- 9 vs. 77 +/- 11 pg/ml; P less than 0.005) or 2 micrograms/min (862 +/- 71 vs. 437 +/- 66 pg/ml; P less than 0.001)]. During the 2 micrograms/min epinephrine infusion, arterial plasma norepinephrine rose from 191 +/- 37 to 386 +/- 78 pg/ml (P less than 0.001), while venous norepinephrine levels did not change significantly. Fractional extraction (arterial - venous + arterial X 100) of epinephrine across the forearm was 26 +/- 8% in the basal state and increased to 33 +/- 6% and further to 51 +/- 4% during the epinephrine infusions. The addition of propranolol (5 mg, iv, plus an 80 micrograms/min infusion) reduced fractional extraction from 51 +/- 4% to 35 +/- 5%. Whole body clearance of epinephrine, calculated from arterial measurements, was 33 +/- 3 ml/kg . min during the 0.1 microgram/min infusion and 35 +/- 3 ml/kg . min during the 2 micrograms/min epinephrine infusion, values 50% lower than the clearance rates calculated from venous measurements. Propranolol infusion resulted in a fall in whole body clearance to 20 +/- 2 ml/kg . min (P less than 0.001), suggesting that epinephrine clearance is partly dependent on a beta-adrenergic mechanism. Basal endogenous release rate (clearance X basal epinephrine level) was estimated to be approximately 0.18 microgram/min, a value much less than that reported in studies using venous measurements. We conclude that arterial rather than venous measurements should be used to estimate catecholamine kinetics in vivo.

Arteries↗
PubMed1982

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose.

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.

Aged↗