To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pg/ml for increments in plasma glucose (the resultant of increments in glucose production and decrements in glucose clearance), blood lactate, blood beta-hydroxybutyrate, and diastolic blood pressure, and greater than 400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steady-state plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (+/-SE) plasma metabolic clearance rate of epinephrine was 52 +/- 4 ml x min-1 x kg-1; this value rose to 89 +/- 6 ml x min-1 x kg-1 (P less than 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We conclude that in human subjects: (a) the plasma epinephrine thresholds for its hemodynamic and metabolic actions lie within the physiologic range, (b) epinephrine and norepinephrine accelerate their own metabolic clearance, and (c) epinephrine is 10 times more potent than norepinephrine.

/pdf/epinephrine-plasma-metabolic-clearance-rates-and-physiologic-2hfv1pwcf4.pdf

Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.

A B S T R A C T To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of0.1, 0.5, 1.0, 2.5, and 5.0,ug/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pglml for increments in plasma glucose (the resultant ofincrements in glucose production and decrements in glucose clearance), blood lactate, blood f3-hydroxybutyrate, and diastolic blood pressure, and >400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steadystate plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (±SE) plasma metabolic clearance rate of epinephrine was 52±4 ml min-l kg-l; this value rose to 89±6 ml * min-' kg-' (P < 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We con

/pdf/rates-and-physiologic-thresholds-for-metabolic-and-53dro9tm02.pdf

Rates and Physiologic Thresholds for Metabolic and Hemodynamic Actions in Man

To delineate the potential role of disordered glucose and glucose-precursor kinetics in the abnormal carbohydrate metabolism of chronic renal failure, alanine and glucose production and utilization and gluconeogenesis from alanine were studied in patients with chronic compensated renal insufficiency and in normal volunteers. With simultaneous primed injection-continuous infusions of radiolabeled alanine and glucose, rates of metabolite turnover and precursor-product interrelationships were calculated from the plateau portion of the appropriate specific activity curves. All subjects were studied in the postabsorption state. In 13 patients with chronic renal failure (creatinine = 10.7±1.2 mg/100 ml; mean±SEM), glucose turnover was found to be 1,035±99.3 μmol/min. This rate was increased 56% (P = 0.003) over that observed in control subjects (664±33.5 μmol/min). Alanine turnover was 474±96.0 μmol/min in azotemic patients. This rate was 191% greater (P = 0.007) than the rate determined in control subjects (163±19.4 μmol/min). Gluconeogenesis from alanine and the percent of glucose production contributed by gluconeogenesis from alanine were increased in patients with chronic renal failure (192% and 169%, respectively) as compared to controls (P < 0.05 for each). Alanine utilization for gluconeogenesis was increased from 40.2±3.86 μmol/min in control subjects to 143±39.0 μmol/min in azotemic patients (P < 0.05). The percent of alanine utilization accounted for by gluconeogenesis was not altered in chronic renal insufficiency. In nondiabetic azotemic subjects, mean fasting glucose and immunoreactive insulin levels were increased 24.3% (P = 0.005) and 130% (P = 0.046), respectively.

These results in patients with chronic renal failure demonstrate (a) increased glucose production and utilization, (b) increased gluconeogenesis from alanine, (c) increased alanine production and utilization, and (d) a relative impairment to glucose disposal. We conclude that chronic azotemia is characterized by increased rates of glucose and glucose precursor flux and by a relative impairment to glucose disposal. These findings may suggest an underlying hepatic and peripheral insensitivity to the metabolic action of insulin in patients with chronic renal insufficiency.

Abnormal Carbohydrate Metabolism in Chronic Renal Failure: THE POTENTIAL ROLE OF ACCELERATED GLUCOSE PRODUCTION, INCREASED GLUCONEOGENESIS, AND IMPAIRED GLUCOSE DISPOSAL

The rate of appearance of unlabelled glucose was calculated from tracer data and compared with the actual rate of infusion of unlabelled glucose into a anaesthetized dog with all sources of endogenous glucose production surgically removed. The mean steady-state rate of appearance of unlabelled glucose calculated from the equilibrium specific radioactivity was insignificantly higher (0.3%) than the actual rate of infusion of unlabelled glucose (n = 6). During non-steady states, a time-variable volume of distribution of glucose (V) was necessary to predict the rate of appearance of unlabelled glucose correctly from the pool-dependent equation described by Steele [(1959) Ann. N.Y. Acad. Sci. 82, 420--430]. Rapid fluctuations in the rate of appearance of glucose could be predicted reasonably well by using a fixed value of V for 40ml/kg, but by using larger fixed values for V (100--160ml/kg) the rates were inaccurate. The pool-dependent two-radiactive-isotope technique described by Issekutz, Issekutz & Elahi [(1974) Can. J. Physiol. Pharmacol. 52, 215--224] predicted single-step increases in the rate of infusion of glucose reasonably accurately, but the Steele (1959) equation was better at predicting sequential changes in the rate of infusion of unlabelled glucose.

/pdf/the-realiability-of-rates-of-glucose-appearance-in-vivo-58rrk8mza5.pdf

The realiability of rates of glucose appearance in vivo calculated from constant tracer infusions

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg−1 min−1) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg−1 min−1; (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg−1 min−1); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg−1 min−1). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls (170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 μU/ml at 90 min. NSGB switched from a net output of 1.71±0.13 to a net uptake of 1.5-1.6 mg kg−1 min−1 due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78±0.13 to 1.6-1.8 mg kg−1 min−1; P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 μU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 μU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 μU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg−1 min−1). Peripheral glucose uptake rose to the same extent as in controls.

It is concluded that: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

/pdf/differential-effects-of-insulin-on-splanchnic-and-peripheral-235ah8mqbb.pdf

Differential Effects of Insulin on Splanchnic and Peripheral Glucose Disposal after an Intravenous Glucose Load in Man

From 57th annual meeting of the Federation of American Societies for Experimental Biology; Atlantic City, New Jersey, USA (15 Apr 1973). An analysis is presented of the one-compartment calculator previously used, and examples are given of its performance in situations where inflow and outflow rates are known. A two-compartment calculator is described, and examples are given of the much improved estimates of inflow and outflow that result from its use. In the two- compartment procedure, preliminary observations are made of plasma glucose specific activity in the steady state, and these are subjected to compartmental analysis. Elements of this two-compartment system are utilized to create the calculator for use in the nonsteady state. The whole procedure can be carried out by hand, using a desk-top machine. (LMT)

Two-compartment calculator for the dog glucose pool in the nonsteady state

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Two-compartment calculator for the dog glucose pool in the nonsteady state