Prevalence and clinical significance of the repetitive ventricular response during sinus rhythm in coronary disease patients

The prevalence of the repetitive ventricular response (RVR) after single and double premature stimulation during sinus rhythm or a paced supraventricular rhythm at a rate of 85 bpm was assessed in 343 patients (group 1: 237 patients studied prospectively who were referred for coronary arteriography and ventriculography; group 2: 44 patients after recent acute myocardial infarction; group 3: 61 patients with documented ventricular tachycardia and/or fibrillation). In group 1 patients, RVR testing was performed from both the right ventricular apex (n = 237) and outflow tract (n = 190), whereas in the remaining patients only the apex was stimulated. In group 1, RVR after a single premature stimulus occurred in 21.9% and after two stimuli in 63.2%. In patients with normal left ventricular (LV) function (n = 63) the prevalence of RVR after a single stimulus was significantly less (9.5%) than in those with LV dysfunction (n = 174;26.4%,p < 0.01). However, after double stimulation, there was no longer any difference. In group 2, the prevalence of RVR was 25% after one and 34.1% after two premature stimuli. In group 3 patients, RVR was observed in only 14.8% after one and in 41% of patients after two premature stimuli. Ventricular tachycardia (≥ 10 QRS) was induced in nine patients during a supraventricular rhythm. Two hundred thirty-seven patients of group 1, who were prospectively studied in order to assess the prognostic significance of the RVR, were followed for a mean period of 27.2 ± 10.7 months. No prognostic significance of the RVR could be shown in this group of patients, 160 of whom had chronic coronary artery disease. In conclusion, premature ventricular stimulation during sinus rhythm with the use of single and double stimuli was not able to provide a clinically useful differentiation between various groups of patients. It had no predictive value for the dentification of patients prone to sudden death or ventricular tachycardia in patients with chronic coronary artery disease.     

Prevalence of late potentials in patients with and without ventricular tachycardia: Correlation with angiographic findings

Late potentials occurring at the end of or after the QRS complex were searched for from the body surface using high gain amplification and signal averaging techniques with filter settings between 100 and 300 hertz. The number of repetitions of the averaging process ranged between 150 and 300. Two hundred thirty-six patients were studied. In 27 control subjects, no late potentials were recorded. Among 146 patients without ventricular tachycardia or fibrillation, late potentials were present in 49 (34 percent). The mean duration of late potentials was 31 ± 15.3 ms (median 25). Of 63 patients with documented ventricular tachycardia or fibrillation, 45 (71 percent) had late potentials (mean duration 51 ± 31.5 ms; median 50) (probability [p] < 0.001). There was a close correlation between the detection of late potentials and left ventricular function. Late potentials occurred more frequently in patients with than in those without ventricular akinesia or aneurysm and in patients with than in those without ventricular tachycardia or fibrillation.

In conclusion, late potentials are a frequent finding in patients with regional contraction abnormalities, both in patients with and in those without documented ventricular tachycardia. The greater prevalence and longer duration of these signals in patients with ventricular tachycardia or fibrillation might be responsible for the greater susceptibility to ventricular tachycardia. Long-term follow-up studies will be necessary to assess the possible prognostic significance of late potentials in patients without previously documented ventricular tachycardia or fibrillation.     

Effect of propafenone in the Wolff-Parkinson-White syndrome: electrophysiologic findings and long-term follow-up

The electrophysiologic and long-term efficacy of propafenone, a relatively new antiarrhythmic agent, was assessed in 47 patients with accessory pathways. In 23 patients (group I), the electrophysiologic effects were assessed initially. In 19 patients in this group and in 24 additional patients (group II), long-term therapy with oral propafenone was initiated. The mean age of the patients was 38 years in group I and 41 years in group II. The duration of a history of tachycardia in both groups was 12 years (mean); 14 patients previously had had attacks of syncope. During the electrophysiologic study in group I, propafenone did not change the spontaneous sinus rate. Corrected sinus node recovery time as well as the AH interval, HV time, QRS duration and effective refractory periods of the atria and ventricles was significantly prolonged. The effective refractory period of the accessory pathway increased from 238 to 322 ms (p less than 0.02). The 1:1 conduction capacity of the accessory pathway decreased from 231 to 176 beats/min (mean; p less than 0.01). Complete block in the anterograde direction occurred in 6 patients. The shortest RR interval during atrial fibrillation increased from 232 to 303 ms (p less than 0.05). The retrograde refractory period of the accessory pathway was prolonged from 245 to 295 ms (p less than 0.01). Complete or 2:1 retrograde block during basic drive occurred in 3 patients and 1 patient, respectively. In 6 of 15 patients, propafenone made sustained supraventricular tachycardia (SVT) either no longer inducible or nonsustained. The cycle length of induced SVT increased from 324 to 395 ms (p less than 0.01). During long-term administration (follow-up duration 2 to 3 years), 17 of 43 patients did not report any episode of symptomatic tachycardia. In another 18 patients, tachycardia was rare, slower and self-terminating. In only 3 patients, the frequency and severity of attacks had not changed. One patient with dilated cardiomyopathy died suddenly. Side effects necessitating discontinuation of medication were observed in only 2 patients. The remaining side effects, if present, were tolerated, and dosage dependent. In conclusion, propafenone is an effective and well-tolerated antiarrhythmic agent in the long-term management of patients with the Wolff-Parkinson-White syndrome.     

Laboratory animals exhibiting obesity and diabetes syndromes

Spontaneous hyperglycemia, hyperinsulinemia and obesity are common features for at least one period of the life-time in some strains of mice. Both genetic and environmental factors are involved in the pathogenesis of the diabetes-like syndrome, making these strains excellent models for studies on both obesity and diabetes-like states. The metabolic peculiarities can be due to a dominant gene, as for the yellow obese, or a single recessive gene, as in the obese and the diabetes mouse; or they can be of polygenic origin, as for the KK and the NZO mouse. However, the severity of the metabolic disorder is due to the interaction of the mutant genes with modifiers in the background genome, rather than being exclusively the manifestation of the mutant genes themselves. Studies on the pathophysiology and biochemistry of these animals have revealed interstrain differences, different patterns of development of the metabolic disorder, and different degrees of severity of the diabetes-like syndrome. Although the primary causes of the syndrome remain unclear in some strains, an involvement of hypothalamic feeding centers has been implicated.     

Prognostic significance of repetitive ventricular response during programmed ventricular stimulation

To determine the incidence and prognostic significance of the repetitive ventricular response, a retrospective study was performed in 65 patients (49 male, 16 female, mean age ± standard deviation 55 ± 11 years) with coronary artery or myocardial disease and a variety of cardiac rhythm disorders. Programmed right ventricular stimulation was performed at a basic pacing rate of 120 beats/min using one (S₂) and two (S₂-S₃) premature stimuli. The data were analyzed as to the presence or absence of a repetitive ventricular response and the patients' outcome ([1] sudden death at 1 hour or less or documented ventricular fibrillation without myocardial infarction; [2] survival or death from noncardiac causes or nonsudden death).A repetitive ventricular response was observed in 23 (35.4 percent) of 65 patients after one and in 31 (48.4 percent) of 64 patients after two premature stimuli. It occurred in 9 of 9 patients with ventricular fibrillation and in 14 (82.4 percent) of 17 patients with ventricular tachycardia. The mean follow-up period was 76 ± 39 weeks. Sixteen patients were classified as dying suddenly; the remaining patients were considered surviving (or dying nonsuddenly). After one premature stimulus, a repetitive ventricular response was observed in 32.7 percent of patients surviving or with nonsudden death and in 43.8 percent of patients with sudden death or malignant ventricular arrhythmias. After two premature stimuli, the incidence of a repetitive ventricular response increased from 40.8 percent in patients surviving or with nonsudden death to 68.8 percent in patients with sudden death; 6 (12.2 percent) of 49 patients surviving or with non-sudden death and 9 (56.3 percent) of 16 patients with sudden death had more than three ventricular echo beats. All nonsurviving patients who demonstrated a repetitive ventricular response had intraventricular reentry. Depending on the rigidity of the criteria used (that is, the number of echo beats), the sensitivity of the test ranged between 37 and 88 percent and specificity ranged between 45 and 92 percent. The proportion of false positive results was high (33 to 66 percent); but the proportion of false negative results was low (8 to 18 percent).This retrospective study showed a correlation between sudden death and the incidence and number of repetitive ventricular responses (depending on the number of premature stimuli) and the type of reentrant beats (bundle branch reentry or intraventricular reentry).     

Influence of insulin on blood levels of branched chain keto and amino acids in man

Branched chain keto acids, their corresponding amino acids, glucose, glucagon, growth hormone, C-peptide and gastric inhibitory polypeptide were determined in 8 healthy subjects after an intravenous bolus injection of 0.1 U/kg insulin. Branched chain keto acids declined within 60 min, the corresponding amino acids within 20 min or later. Amino acids tended to return towards normal earlier than their keto acids. Blood glucose levels were normal 2 hr after insulin injection while keto and amino acids remained diminished for more than 3 hr. In 8 healthy controls, given physiological saline instead of insulin, the branched chain keto acids did not decline throughout the test. It is suggested that insulin diminishes blood levels of branched chain keto acids, that the intraorgan flux of branched chain keto acids is different from the flux of branched chain amino acids and that branched chain keto acids may serve to correct for hypoglycemia.     

Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

Increased serum low-density lipoprotein cholesterol in men treated short-term with the diuretic chlorthalidone

The effect of the diuretic chlorthalidone (100 mg/day for 6 weeks) on serum lipoproteins was evaluated in 37 subjects. In 19 men with essential hypertension (aged 41 ± 3 yr), 8 normal men (26 ± 3 yr), or all of these men considered together, chlorthalidone significantly increased serum low density lipoprotein-cholesterol (LDL-C) by 20% (p < 0.05 to <0.01). There was also a tendency for increased LDL-C in seven postmenopausal women (+ 15%) but not in three premenopausal women with essential hypertension. High density lipoprotein-cholesterol was not significantly changed in hypertensive women or normal men and decreased slightly (p < 0.05) in hypertensive men. Apolipoproteins A-I, A-II, and B were not changed significantly in women or men. Diuretic-induced lipoprotein alterations were not associated with altered plasma volume and unrelated to variations in serum potassium, glucose, insulin levels, blood pressure, and body weight. Short-term diuretic therapy with chlorthalidone may increase serum LDL-C in young or middle-aged men with normal or high blood pressure.     

Oral glucose tolerance test: Effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

To evaluate the role of splanchnic metabolism in the disposal of orally ingested glucose and thereby to define the optimal glucose load for glucose tolerance testing, splanchnic glucose output (SGO), as determined by the hepatic-venous catheter technique, was estimated in 16 healthy male volunteers in the basal state and after different glucose loads. Following glucose ingestion of 12.5, 25, 50, 75, and 100 g glucose, mean SGO over 2 hours was 9, 10, 12.3, 20, and 24.7 g above basal hepatic glucose production or 72, 40, 25, 26, and 25 percent of the respective glucose load. Increasing glucose doses represented a greater and more prolonged insulinogenic stimulus as determined by insulin concentrations in hepatic venous plasma. Splanchnic lactate uptake decreased and finally reverted to a net output in most of the subjects studied, whereas pyruvate production increased with rising glucose loads. It is concluded that (1) maximal stimulation of insulin release by administration of 50 to 100 g glucose results in maximal splanchnic extraction (75%) of an ingested glucose load, whereas smaller amounts of glucose are retained to a lesser extent; (2) 100 g of glucose provide optimal conditions for performing an oral glucose tolerance test (OGTT), thereby provoking a relative as well as an absolute maximum of splanchnic glucose extraction; and (3) splanchnic uptake of pyruvate and lactate following ingestion of small amounts of glucose revert to a net output with utilization of increasing glucose loads.     

Inhibition of carnitine palmitoyltransferase 1 by phenylalkyloxiranecarboxylic acid and its influence on lipolysis and glucose metabolism in isolated,perfused hearts of streptozotocin-diabetic rats

The metabolic action of the new hypoglycemic compound, sodium-2-(5-[cRlorpRenyl]-pentyl)-oxirane carboxylate (POCA), was studied in isolated perfused hearts of control and streptozotocin-diabetic rats. Perfusion with POCA selectively inhibited the activity of carnitine palmitoyltransferase 1, but had no influence on the activities of carnitine palmitoyltransferase 2, pyruvate dehydrogenase, and triglyceride lipase. Perfusing the hearts of streptozotocin-diabetic rats with POCA (10 μmol/L) reduced myocardial lipolysis and accelerated the rate of pyruvate and lactate outflow as well as pyruvate oxidation. The insulin sensitivity of the diabetic hearts with respect to lactate production and glucose oxidation was restored by perfusion with POCA. In contrast, defective glycogen synthesis in the diabetic hearts was not influenced by POCA. These data suggest that: (1) The insulin resistance of the glucose-perfused diabetic heart results from two different post-insulin-receptor defects. Whereas the disturbances of glucose oxidation are mediated by the excessive metabolism of endogenous triglycerides, the reason for the disturbed glycogen synthesis remains unclear. (2) Since in vitro perfusion with POCA partially restored the insulin sensitivity of the diabetic hearts, insulin-receptor defects should be of minor importance for the insulin resistance of diabetic hearts. (3) Since POCA inhibited carnitine palmitoyltransferase 1 and reduced the rate of lipolysis but had no effect on triglyceride lipase activity, we assume that product inhibiton plays an important role in the regulation of myocardial lipolysis. In summary, inhibition of carntine palmitoyltransferase 1 by POCA is suggested to be a useful approach for restoring insulin sensitivity depressed by an excessive metabolism of lipids.     

Effect of prolonged exercise on serum lipids and lipoproteins

It has been shown that physical exercise lowers serum triglyceride levels and may increase high density lipoprotein-cholesterol levels. Understanding of the mechanisms responsible for these beneficial adaptations is still incomplete. Twenty-six men, who played soccer continuously for 64 hours to establish a world's record, were monitored for acute changes in lipid metabolism. Food intake was determined before and during the exercise period. Blood specimens were taken before and repeatedly during the match for the measurement of triglycerides (TG), total cholesterol (CH), glycerol, apolipoprotein A-I (apoA-I), and cholesterol in various lipoprotein fractions (quantitative lipoprotein electrophoresis). During exercise TG levels decreased from 116 +/- 26 to 66 +/- 13 mg/dL and CH from 180 +/- 22 to 135 +/- 25 mg/dL. Both TG and glycerol showed an initial increase followed by a continuous decrease. Alpha-CH increased by 19% whereas beta-CH and pre-beta-CH decreased markedly (39% and 78%, respectively). In contrast to alpha-CH, apo A-1 fell only slightly by 10%. These results indicate that the effect of chronic exercise on lipids and lipoproteins can be mimicked by acute prolonged exercise. Similar mechanisms may be involved in these adaptations. Moreover, the extreme length of physical exertion substantially lowered CH.     

Reversal of diuretic-induced increases in serum low-density-lipoprotein cholesterol by the betablocker pindolol

Seventeen patients with mild to moderate essential hypertension received during three consecutive 4 wk periods a matched placebo, the thiazide-like diuretic, clopamide in a low dosage of 5 mg/day, or this diuretic combined with the betablocker, pindolol in a low dosage of 10 mg/day. Compared to placebo conditions, clopamide monotherapy significantly increased serum low-density lipoprotein cholesterol (LDL-C) by 13% (p < 0.025). Following addition of pindolol, serum LDL-C was restored to control values. These variations in serum LDL-C were unrelated to concomitant changes in blood pressure, plasma potassium, renin activity or aldosterone levels. Blood pressure in the supine position was reduced from $\text{152}\text{99}\text{±}\text{13}\text{9}\text{mm Hg (+SD)}$ to $\text{141}\text{93}\text{±}\text{15}\text{7}\text{mm Hg}$ following diuretic-monotherapy and to $\text{139}\text{90}\text{±}\text{12}\text{9}\text{mm Hg}$ following diuretic-betablocker combination treatment. These findings suggest that antihypertensive combination treatment with low doses of clopamide and pindolol is not only effective and well tolerated, but may also avoid the increase in serum LDL-C levels occurring when the thiazide-like diuretic is given alone.     

Comparative study of two methods of estimating sinoatrial conduction time in man

Programmed premature atrial stimulation has been widely used to estimate sinoatrial conduction time in man. A proposed new approach uses continuous atrial pacing just above the spontaneous cycle length. Sinoatrial conduction time is represented by the difference between the first cycle after pacing and the spontaneous cycle length, assuming that sinus nodal automaticity is undisturbed by continuous atrial pacing.

Both techniques were compared in 23 consecutive patients. Mean (± standard deviation) sinoatrial conduction time was 113 ± 27 msec estimated with the premature stimulus technique and 96 ± 48 msec when estimated with the continuous pacing technique. In about 30 percent of cases the two values corresponded well with each other. In the remaining patients sinoatrial conduction time estimated with the premature stimulus technique was longer than the time estimated with continuous atrial pacing. Additionally, the latter was estimated at two different rates of pacing in which the cycle length was 30 and 60 msec, respectively, shorter than the previous cycle length. The estimate then increased to 119 ± 39 and 136 ± 40 msec, respectively. Sinoatrial conduction time estimated with continuous atrial pacing did not depend on spontaneous cycle length and did not correlate with sinus nodal recovery time. The cycles after the first pause were slightly longer than the spontaneous cycle length.

The results suggest that data from the two techniques cannot be easily compared and that premature atrial stimulation may exert a more depressive effect on sinus nodal automaticity than continuous atrial pacing. The observed differences in results may also be due to a more pronounced delay of retrograde conduction during premature atrial stimulation than during continuous atrial pacing. It is also possible that continuous atrial pacing leads to some overdrive exciting effect on the sinus node, although the opposite effect is suggested by the response of the cycles after the first postpacing cycle. A final conclusion regarding the validity of each technique cannot be reached on the basis of these clinical data.     

Effect of buformin on splanchnic carbohydrate and substrate metabolism in healthy man

The effect of buformin (100 mg b.i.d. for 5 days) on carbohydrate metabolism, both splanchnic glucose output (SGO) and net substrate exchange were studied in 6 healthy male volunteers in the basal state and following glucose ingestion (100 g). Control studies without buformin were also performed in 5 men. Splanchnic glucose and substrate exchange was determined by means of the hepatic venous catheter technique. SGO was 154 ± 18 (SEM) mg/min in the postabsorptive state and increased 33.3 ± 2.8 g above the basal level during the 150 min period following glucose ingestion. Buformin administration did not alter basal SGO (157 ± 26 mg/min), nor the splanchnic exchange of pyruvate, alanine, glycerol, OH-butyrate and acetoacetate. Splanchnic lactate balance was altered by buformin and net lactate output occurred. Following glucose ingestion the rise in splanchnic lactate output was increased, whereas no change in SGO ($\text{32.9 ± 3.5 g}\text{150 min}$) and splanchnic exchange of the other substrates was observed. The increase in arterial blood glucose concentration following oral glucose loading was reduced by buformin pretreatment (p < 0.0005). The insulin production rate (basal, 16 ± 2 mU/min; following oral glucose, $\text{13 ± 2 U}\text{150 min}$) as calculated from C-peptide release from the splanchnic area was unchanged by buformin. Except for a marked rise in splanchnic lactate production, buformin did not alter splanchnic carbohydrate metabolism after orally ingested glucose in healthy man. The diminished increase in arterial blood glucose concentration associated with unaltered insulin production suggests that buformin facilitates glucose utilization by peripheral tissues.     

Immune reactions in infective endocarditis. II. Relevance of circulating immune complexes, serum inhibition factors, lymphocytotoxic reactions, and antibody-dependent cellular cytotoxicity against cardiac target cells

Circulating immune complexes (IC) were detected in 35 out of 41 patients (85%) with infective endocarditis of known bacterial origin in contrast to only 9 out of 20 patients (45%) with endocarditis but negative blood cultures (p less than 0.05). Peak IC levels of 33.25 +/- 24.33 micrograms/ml in the early period fell significantly to 8.38 +/- 13.37 micrograms/ml after antibiotic treatment (p less than 0.001). High levels of IC coincided with relative hypocomplementemia. Erythrocyturia was observed in 51 of 58 IC-positive patients demonstrating peripheral sequelae of circulating IC. Incidence and concentrations of IC correlated neither with the mere presence of the rheumatoid factor nor with the titers of antimyolemmal antibodies, nor with antibody mediated cytolysis in the presence of complement. Serum inhibition factors (SIF) and E-rosette inhibitory factors (RIF) were not demonstrated, indicating that IC in endocarditis do not suppress phytohemagglutinin-induced lymphocyte proliferation or the E-rosetting of T cells. Significant lymphocytotoxicity against heterologous cardiac target cells without serum (LC) could be demonstrated in 11 out of 23 patients (48%) with endocarditis as compared to its absence in controls (n = 33, p less than 0.01). In assays of antibody-dependent cellular cytotoxicity (ADCC), either enhancement or blocking of lymphocytotoxicity by autologous serum or both was observed. The modulation of lymphocytotoxicity was most likely due to antimyolemmal antibodies, to IC, or to both, although effects of other serum factors cannot be ruled out completely.     

Metabolites of the aminoacetone pathway in blood after exercise

The following article reports (A) data on glyoxalase I activity in skeletal muscle of untrained men and endurance—trained athletes, and (B) the presence at rest and the rise in blood after exercise of two metabolites of the aminoacetone pathway of amino acid degradation in man. Glyoxalase I showed an average activity of 191 ± 38 U/g wet weight (37°C) in bioptic samples of m.vastus medialis quadricipitis of young adults whereas this was of 235 ± 64 U/g (p < 0.15) in athletes. After an ergometer exercise test with increasing intensity (50 to 400 Watt (W), 3 min-steps) by well trained cyclists, blood L-(+)-lactate increased to 10.12 mmole/liter, whereas methylglyoxal rose by 48.4% and D-(-)-lactate by 70% (resting levels 92 and 110/μmole/liter, respectively). The possible physiologic significance of the assumed aminoacetone pathway was discussed with respect to muscular activity.     

Insulin pharmacokinetics following continuous infusion and bolus injection of regular porcine and human insulin in healthy man

To determine the pharmacokinetics of insulin administered by intravenous (IV) and subcutaneous (SC) pump treatment as well as by the conventional subcutaneous route, six insulin preparations of either porcine or human amino acid sequence were investigated intraindividually following IV or SC insulin infusion at two different rates (Study I) and three preparations were investigated after SC bolus injection (Study II) in healthy men. Insulin release was suppressed in Study I by IV administration of somatostatin (500 μg/hr) to avoid interference by endogenous insulin with the measurement of exogenous insulin. Hypoglycemia was prevented by IV administration of glucose. The data obtained demonstrated (1) greater serum concentrations of immunoreactive insulin (IRI) during continuous IV insulin infusion (141 ± 10 (SEM) pmole/liter) than during SC insulin infusion (54 ± 3 pmole/liter; P < 0.0005) (0.8 U/hr); (2) return of serum IRI to baseline values following a 17-minute square wave insulin infusion (12.8 U/hr; time: 0 to 17 minutes) within 40 minutes after IV insulin infusion but not before 180 minutes after the end of SC insulin infusion; (3) peak serum IRI at 60 to 90 minutes after conventional SC insulin injection returning to baseline values at 300 minutes; and (4) identity of the pharmacokinetics of pumped human and porcine insulin within a given group as well as of the accompanying metabolic dynamics of blood glucose and nonesterified fatty acids, but heterogeneity of serum insulin after its SC bolus injection. We conclude that (1) the pharmacokinetic behavior of regular insulin depends primarily on its route of administration; (2) continuous IV infusion of an insulin dose causes significantly higher serum insulin levels than the SC administration of the identical insulin dose, and (3) hyperinsulinemia caused by a square wave insulin infusion (12.8 U/hr; time: 0 to 17 minutes) requires more than four times longer to return to baseline levels following SC administration than after IV administration of the insulin. These differences in the pharmacokinetic behavior of insulin cause a reduced bioavailability of SC administered insulin and have to be taken into account when instituting insulin treatment by various routes.