Search

Normal fasting subjects were used to study the pharmacokinetics of human insulin (recombinant DNA). Purified pork insulin (PPI) was used as a control agent. There was no difference in serum concentrations between neutral regular human insulin and PPI after intravenous administration. When given subcutaneously, peak concentrations are occasionally higher for human insulin than for PPI. The bioavailability indices for the two insulins are essentially the same. NPH human insulin produced a slightly higher serum concentration after 4 h than did NPH PPI. Studies with 70/30 NPH-regular mixtures suggest that the affinity of protamine for human insulin is less than that for PPI. The serum insulin concentrations after lente human insulin and PPI were not different. These studies, and a review of the published clinical pharmacologic literature, indicate that when present the differences between human insulin and PPI are minimal.

An open parallel trial with glipizide or tolbutamide was carried out in a cohort of 29 comparable maturity-onset diabetic patients. Eighteen of these individuals were studied in detail. During six months of active drug therapy the mean decrease in fasting serum glucose levels on glipizide was 25 +/- 2% versus 17 +/- 2% on tolbutamide (p less than 0.025). Decreases in post prandial glucose levels were 12.2 and 10.4%. Glucose disappearance rates (Kg) during the sixth month of treatment with both drugs increased significantly: on glipizide from 0.47 +/- 0.04%/min to 0.85 +/- 0.08%/min(p less than 0.005), and on tolbutamide from 0.47 +/- 0.08%/min to 0.70 +/- 0.11%/min (p less than 0.01). Early and late insulin release (summed increases over basal for 2--10 min and 10--60 min) during intravenous glucose tolerance testing increased during glipizide, but not during tolbutamide therapy. Post prandial insulin increments over basal during an oral glucose tolerance test also increased during glipizide, but not tolbutamide therapy. Both drugs were comparable with regard to efficacy and safety; however, only glipizide had chronic effects upon insulin secretion.

The short-term effects of a weight-maintenance diet high in fiber and carbohydrate (HFHC) was studied in seven very obese individuals with type II diabetes mellitus. Such diets contained 68% of kcal as carbohydrate and total fiber content of 81 g (in contrast to 42% and 28 g during baseline). Fasting glucose concentrations, summed glucose concentrations, and 24-h glucosuria were unaffected in six of seven individuals. Fasting insulin levels decreased (-6.0 +/- 2.0 microU/ml, P less than 0.05), but meal-stimulated insulin concentrations were not altered. Triglyceride and HDL cholesterol concentrations were also unaffected. Total cholesterol concentrations fell in four individuals whose initial values exceeded 200 mg/dl. Basal glucose production rates were similar in the obese diabetic subjects, in five nonobese normal subjects, and in one obese normal individual (2.05 +/- 0.19 versus 2.63 +/- 0.30 and 1.85 mg/kg/min for the obese normal individual) while on baseline diets, and did not change with HFHC. During isoglycemic hyperinsulinemic glucose clamp procedures (maintenance of basal glucose concentrations), 40 mU/m2/min was infused intravenously for 2 h. Glucose disappearance rates increased significantly in the normal-weight control subjects, but did not increase during baseline diets in the obese type II diabetic subjects (4.65 +/- 0.80 versus 0.68 +/- 0.40 mg/kg/min). HFHC diet had no effect on glucose disappearance rates. Plasma insulin levels were 131.0 +/- 11.0, 120.0 +/- 11.0, and 120.0 +/- 5.0 microU/ml during these studies. These studies indicate that short-term HFHC diets without caloric restriction were ineffective in improving glycemic control or lessening insulin resistance in very obese patients with type II diabetes.

Briefly trained physicians assistants using protocols (clinical algorithms) for diabetes, hypertension, and related chronic arteriosclerotic and hypertensive heart disease abstrated information from the medical record and obtained history and physical examination data on every patient-visit to a city hospital chronic disease clinic over a 18-month period. The care rendered by the protocol system was compared with care rendered by a "traditional" system in the same clinic in which physicians delegated few clinical tasks. Increased thoroughness in collecting clinical data in the protocol system led to an increase in the recognition of new pathology. Outcome criteria reflected equivalent quality of care in both groups. Efficiency time-motion studies demonstrated a 20 per cent saving in physician time with the protocol system. Coct estimates, based on the time spent with patients by various providers and on the laboratory-test-ordering patterns, demonstrated equivalent costs of the two systems, given optimal staffing patterns. Laboratory tests were a major element of the cost of patient care,and the clinical yield per unit cost of different tests varied widely.

The large-scale clinical trials of human insulin (recombinant DNA) in the United States consisted of a "New Patient" study and a "Transfer" study. The "New Patient" study involved 101 patients (38% type I) who have never received insulin and who were treated with human insulin and followed for 6 mo using NPH insulin alone or in combination with Neutral Regular Insulin (NRI). Shortly after treatment, serum glucose and total glycohemoglobin concentration fell. No patients developed insulin lipoatrophy or insulin allergy. Two patients developed insulin hypertrophy; in one, it was transient. Intradermal tests to varying dilutions of human insulin did not change over 6 mo. In addition, there was no evidence of development of antibodies to Escherichia coli polypeptide. Two-hundred-and-forty-three patients, 91% of whom had type I diabetes, were transferred in a controlled double-blind study from mixed beef-pork or purified pork insulin (PPI) either to human insulin or back to their previous insulin treatment and followed for 3 mo. While insulin dosage did not change, there was a slight increase in fasting serum glucose and a statistically significant increase in fasting ketonuria. There was no change in the frequency of the complications of insulin treatment. These limited data are consistent with the conclusion that NPH human insulin is slightly shorter acting than its animal insulin counterparts. Overall, human insulin is a safe, effective insulin.

[7-3HA1Androstenedione and [4-14C]estrone or [7-3H]testosterone and [14C]estradiol were infused at constant rates into brachial arm veins of 15 normal men. During the infusions blood samples were obtained from the brachial artery, a deep vein draining primarily muscle, and a superficial vein draining primarily adipose tissue of the arm contralateral to the infusion. In seven men the mean +/- SE value for the fractional conversion of androstene tissue. In eight men the mean +/- SE value for the fractional conversion of testosterone to estradiol was 0.0007 +/- 0.0001 for muscle and 0.0012 +/- 0.0002 for adipose tissue. Both of these values were significantly (P less than 0.01) less than the respective values of androstenedione aromatization to estrone. If constancy of tissue aromatization throughout the body is assumed, the muscle accounts for 25-30% and adipose tissue for 10-15% of the total extragonadal aromatization of androgens to estrogens.

We postulated that human insulin of recombinant DNA origin would be a poor immunogen and might prove to be less immunogenic than purified pork insulin. Results are reported for 100 diabetic subjects not previously treated with insulin. Individuals completed the first 12 months of a clinical trial of human insulin of recombinant DNA origin. These patients are contrasted with 121 similar individuals who are taking part in a trial of purified pork insulin. Prior to therapy, species-specific binding of 125I human insulin and pork insulins and insulin bound to antibody were undetectable in all individuals. In patients treated with human insulin of recombinant DNA origin, binding of 125I human insulin increased to 10 +/- 1.2% at 12 months versus increases in binding of 125I pork insulin in pork insulin-treated patients to 12.6 +/- 1.4% (NS). Mean percentages of species-specific binding tended to reach a plateau in the human insulin-treated group but continued to increase in the pork insulin group (p less than 0.001). Median bound values were nil throughout in patients treated with human insulin, but increased to 52 mU/l in the pork insulin group with significantly less bound insulin seen in the former group at all visits (p less than 0.001). The percentage of individuals who remained antibody free at 12 months, as indicated by bound insulin, was 56% in the human insulin-treated patients and 40% in the patients treated with pork insulin (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The production and metabolism of dihydrotestosterone (DHT) was studied in 10 normal men using constant infusions of [7-3H]-delta 4 -androstenedione (A)/[4-14C]DHT (6 men) or of [7-3H]testosterone (T)/[4-14C]DHT (4 men) with measurement of radioactivity as precursor and product in the brachial artery, and a superficial vein (draining primarily adipose tissue) and deep vein (draining primarily muscle) in the arm opposite to the infusion. The metabolic clearance rates (MCR) were (mean +/- SE) 560 +/- 55, 1620 +/- 80, and 790 +/- 65, 1/day for DHT, A and T respectively. The overall conversions (percent of A or T infused which was measured as DHT in arterial blood) were 2.3 +/- 0.8% and 2.7 +/- 0.5% for A to DHT and T to DHT. Of the DHT entering the adipose tissue 13.8 +/- 3.4% was metabolized and of that entering muscle 5.8 +/- 1.8% was metabolized. On the basis of assumed blood flows, adipose tissue and muscle metabolism each carry out approx. 7-8% of the overall metabolism of DHT. Of the A entering the forearm adipose tissue 1.9 +/- 0.5% was converted to DHT. Extrapolated to the body's adipose tissue, this represents 14% of the total A converted to DHT. Of the T entering the forearm adipose tissue 1.2 +/- 0.3% was converted to DHT. Extrapolated to the body's adipose tissue, this represents 6% of the total T converted to DHT. In three out of six subjects infused with A/DHT and in three out of four subjects infused with T/DHT small gradients indicating conversion of A and T to DHT by tissues drained by the deep vein were found. The mean value for the conversion of A to DHT across the deep vein tissues was 0.84 +/- 0.51% and for T to DHT was 0.28 +/- 0.12%. Both adipose tissue and muscle metabolize DHT but only adipose tissue appears to play a role in the conversion of A and T to DHT.

3H and 14C-Labeled estrone, estradiol, and estrone sulfate were infused at constant rates into brachial arm veins of normal men. In any one experiment, subjects generally received two estrogens, one 3H-labeled and one 14C-labeled. During the infusions, blood samples were obtained from the brachial artery, a deep vein draining primarily muscle and a superficial vein draining primarily adipose tissue of the arm contralateral to the infusion. In 11 men the mean +/- SE value for the metabolism of estrone by muscle, rho1,0A,M(rho1,0A,M = fraction of estrone in arterial blood which is metabolized by muscle) is 0.17 +/- 0.02 which is not (P greater than 0.1) significantly different from the mean +/- SE value for the metabolism of estrone by adipose tissue, rho1,0A,AT, 0.22 +/- 0.02. Both tissues convert estrone to estradiol, rho1,2A,M(rho1,2A,M = fraction of estrone in arterial blood which is measured as estradiol in venous blood draining muscle) is 0.026 +/- 0.005 and rho1,2A,AT is 0.022 +/- 0.005. Both tissues metabolized estradiol, rho2,0A,M = 0.09 +/- 0.01 and rho2,0A,AT = 0.12 +/- 0.03, and for each tissue the metabolism of estradiol was significantly less than that of estrone (P less than 0.01). Estradiol was converted to estrone by both tissues; rho2,1A,M = 0.007 +/- 0.003 and rho 2,1A,AT = 0.017 +/- 0.003. For estrone sulfate, tissue metabolism could be demonstrated in only 2 of 5 infusions; the values being 0.04 and 0.03, and 0.04 and 0.03 in muscle and adipose tissue, respectively. In only 1 of 3 infusions was evidence obtained for the conversion, by muscle, of estrone sulfate to estrone, rhoS,1A,M = 0.003 and only in one of the 5 subjects was adipose tissue active in this conversion. In no instance were we able to show conversion of estrone sulfate to estradiol by either tissue. In only 1 of 3 infusions could we measure demonstrable conversion of estrone to estrone sulfate by adipose tissue, rho1,SA,AT = 0.02, and we could not demonstrate conversion of estrone to estrone sulfate by muscle or of estradiol to estrone sulfate by either tissue. Both muscle and adipose tissue metabolize and interconvert the free estrogens, estrone and estradiol. The total metabolism by both tissues accounts for 5-10% of the overall metabolic clearance rate of each steroid. The formation of estrone sulfate from estrone and estradiol and the hydrolysis of estrone sulfate occurs to only a minor extent in these tissues.

To study the immunologic effects of transfer of patients from animal insulins to human insulin (recombinant DNA), a double-blind comparative trial was begun in over 300 patients. Preliminary results are reported in 116 individuals. After maintenance on purified pork or mixed beef-pork insulins (PPI or MBP) for a minimum of 6 mo, 116 patients were either switched to human insulin or maintained on their previous insulin. Antibody levels were assessed at a baseline visit and then monthly. In PPI-maintained individuals as well as those switched to human insulin there was a significant decrease in qualitative antibody binding as indicated by species-specific binding of 125I beef and human insulins (SBB and SBH), both P less than 0.005. Quantitative binding, as indicated by bound insulin levels, decreased to a much greater extent in patients switched to human insulin, 52% versus 31%, P less than 0.005. Parameters derived from formal antibody titration did not change. In patients maintained on MBP, bound insulin decreased (-36% at 6 mo, P less than 0.002). When switched from MBP to human insulin, there was a marked reduction in all parameters of binding, both qualitative and quantitative: SBP, -68%; SBH, -61%; SBB, -57%; bound insulin, -67% (all P less than 0.001) and decreases in high- and low-affinity binding capacities (P less than 0.02). Thus, for patients treated previously with nonhomologous insulins, transfer to human insulin may result in significant immunologic improvement in anti-insulin antibody levels.

Eating does not modify benoxaprofen blood concentrations. Combining benoxaprofen with tolbutamide does not significantly change plasma glucose, insulin, or tolbutamide concentrations. Probenecid, by blocking renal tubular secretion of benoxaprofen, increases the benoxaprofen half-life and decreases its renal clearance and urinary excretion. Excretion rate is halved in patients with severe renal impairment. Hemodialysis inefficiently lowers benoxaprofen plasma concentrations. Neither glomerular nor renal tubular function is affected by benoxaprofen, even after five years of therapy. The incidence in urine of microscopic spheroids (benoxaprofen glucuronide complexes) is related to urinary drug concentration and osmolality; increasing the fluid intake decreases incidence.

Insulin antibodies and immune complexes (ICs) are present in most patients with diabetes after initiation of conventional insulin therapy. We studied the ability of bovine insulin, porcine insulin, and human insulin ICs to stimulate the procoagulant activity (PCA) of human blood monocytes (HBMs) and human umbilical vein endothelium (HUVE) in vitro. Polyclonal insulin antibodies from patients with insulin antibody-mediated resistance were isolated by immunoabsorption. PCA expressed by isolated adherent HBMs or cultured HUVE was quantified by radioimmunoassay of fibrinopeptide A with a 1:80 dilution of human plasma. Beef, pork, and human insulin, in quantities determined from titration curves, were added to fixed amounts of antibody to obtain equivalent amounts of ICs. For four different antibodies, the ratios of PCA (expressed by HBMs exposed to ICs or to antibodies alone and normalized for cell numbers) to activity expressed by tissue culture medium were as follows: beef insulin ICs, 2.55 +/- 0.41; por insulin ICs, 1.47 +/- 0.16; human insulin ICs, 1.28 +/- 0.19; and antibody, 1.28 +/- 0.32. The differences between beef and pork insulin ICs and antibody controls were significant. For a fifth antibody, a dose response between beef insulin ICs and PCA expression was demonstrated. For a sixth antibody, HBMs could express PCA when stimulated with antibody of a relatively low binding capacity (0.35 ng bovine insulin per microgram of antibody) only in the presence of lymphocytes. Conditioned medium from these cells significantly stimulated endothelial cell procoagulant activity. These observations raise the possibility that insulin ICs, that is, beef insulin ICs, may generate increased PCA and thereby contribute to the vascular complications of diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

The therapeutic efficacy of human insulin (recombinant DNA) was compared with that of purified porcine insulin (PPI) in seven male subjects with previously treated insulin-dependent diabetes mellitus. In a random crossover design the patients received either PPI or human insulin during one of two consecutive 7-day periods of intensive insulin therapy. Control was evaluated on days 6 and 13. Tissue sensitivity and responsiveness to the study insulins were determined by insulin dose-response studies performed using the euglycemic glucose clamp on days 7 and 14. Insulin dose and all measures of control on days 6 and 13 were not statistically different between treatments. When the insulin dose-response studies during each treatment were compared there were no differences between them. Thus, in previously treated patients with insulin-dependent diabetes, undergoing brief but intensive insulin therapy with continuous subcutaneous insulin infusion, human insulin is as clinically efficacious as PPI. Furthermore, insulin sensitivity and responsiveness, as assessed by dose-response studies during the euglycemic glucose clamp were equivalent for both insulins.

The acute effects of glucagon (mol. wt. 3500) and its interactions with insulin were studied in the forearm during eight studies in seven normal, post-absorptive males. The protocol consisted of a 2 h baseline, 1 h glucagon perfusion (mean glucagon increment, 691 +/- 50 pg/ml), 1 h perfusion of both insulin and glucagon (mean insulin increment of 105 insulin and glucagon (mean insulin increment of 105 /- 13 mU/l) and a 30 min recovery period. Simultaneous arterial (A), deep venous (DV), and superficial venous (SV) blood samples were obtained at 30 min intervals. Perfusion of glucagon resulted in a decrease in (A-DV) non-esterified fatty acids of -0.128 +/- 0.057 mmol/l (n = 7, p less than 0.05) and (A-SV) non-esterified fatty acids of -0.081 +/- 0.36 mol/l (n = 7, p less than 0.05), as well as a change in deep compartment uptake of glycerol after 60 min of -0.044 +/- 0.019 mumol/min/100 ml of forearm tissue (n=6, p less than 0.05), indicating increased lipolysis. There was also a decrease in net glucose uptake as reflected by a change in (A-Dids of -0.081 +/- 0.36 mol/l (n = 7, p less than 0.05), as well as a change in deep compartment uptake of glycerol after 60 min of -0.044 +/- 0.019 mumol/min/100 ml of forearm tissue (n=6, p less than 0.05), indicating increased lipolysis. There was also a decrease in net glucose uptake as reflected by a change in (A-Dids of -0.081 +/- 0.36 mol/l (n = 7, p less than 0.05), as well as a change in deep compartment uptake of glycerol after 60 min of -0.044 +/- 0.019 mumol/min/100 ml of forearm tissue (n=6, p less than 0.05), indicating increased lipolysis. There was also a decrease in net glucose uptake as reflected by a change in (A-DV) of -0.24 +/- 0.09 mmol/l (n = 7, p less than 0.025) and (A-SV) of 0.10 +/- 0.05 mmol/l (n = 7, p less than 0.05). There was also a net decrease in deep arteriovenous differences of potassium in six of seven subjects. Insulin levels, similar to those found after a meal, rapidly reversed the effects of glucagon on non-esterified fatty acid, glucose and potassium. These effects persisted throughout the recovery period.

The incidence of diabetic retinopathy was determined in 38 diabetics and 31 sexual ateliotic dwarfs deficient only in human growth hormone (HGH). The age and sex distribution were approximately the same in each group. The incidence and pattern of glucose intolerance were similar in diabetics and HGH-deficient dwarfs. The majority of diabetics (21 of 38) and HGH-deficient dwarfs (26 of 31) exhibited insulinopenia after glucose, mixed glucose-beef meals, and the infusion of l-arginine. A smaller number of HGH-deficient dwarfs (5 of 31) and diabetics (8 of 38) had normal or augmented absolute insulin responses to these same provocative stimuli. Hypercholesterolemia and hypertriglyceridemia occurred with greater frequency in both diabetics and HGH-deficient dwarfs than in normal controls. 8 of 21 diabetics and 6 of 21 sexual ateliotics exhibited significant hypertriglyceridemia. Five diabetics and six sexual ateliotics had significantly greater than normal serum cholesterol levels. Nearly half of the diabetics (16 of 38) had significant pathological abnormalities of the retina, but these changes were conspicuously absent in HGH-deficient dwarfs. No retinal lesions were detected in any HGH-deficient dwarf.

A group of 32 sexual ateliotic dwarfs with an isolated deficiency of human growth hormone (HGH) were shown previously to resemble subjects with genetic diabetes mellitus in terms of hyperlipemia, carbohydrate intolerance, and patterns of insulin secretion. 11 of these dwarfs had needle biopsies of the quadriceps femoris carried out and tissue fixed for electron microscopy. Capillary basement membrane thickness was measured and compared with measurements previously obtained in diabetics and normal controls. Measurements were similar in controls and dwarfs (1080 +/-27 A and 1086 +/-90 A, respectively) and significantly less than in diabetics (2403 +/-119 A). Placed in juxtaposition with the absence of retinopathy in dwarfs and the high incidence in the diabetic group (41%), the data support the thesis that these anatomical abnormalities are largely independent of serum lipid and carbohydrate abnormalities. The data are consistent with a supportive, if not causative role of growth hormone in the pathogenesis of these lesions.

Five subjects were studied by the forearm perfusion technique with proinsulin at a final plasma conceintration of 1.76 x 10(-9) millimole per milliliter. Two of these subjects were studied with single-component insulin at a concentration of 1.96 x 10(-9) millimole per milliliter. Proinsulin is, in general, biologically less potent than single-component insulin. In contrast to insulin, its effects upon adipose tissue are for the most part greater than upon muscle.

To clarify the role of insulin and growth hormone (HGH) in regulating substrate production for body fuel during prolonged starvation, 6 normal subjects and 10 HGH-deficient dwarfs were fasted for 6 days. Four of these dwarfs received HGH during the fast. Blood glucose concentration decreased a mean 15 mg/100 ml in both controls and HGH-treated dwarfs, but decreased 50 mg/100 ml in untreated dwarfs. The final level at which the blood glucose stabilized was significantly higher in the former two groups (65 +/-1.0 mg/100 ml and 88 +/-19 mg/100 ml, respectively, versus 39.0 +/-4.0 mg/100 ml in the untreated dwarfs). The decline in plasma insulin concentration showed a comparable pattern, decreasing from a similar basal level to 7.7 +/-0.4 muU/ml in controls, 8.8 +/-1.1 muU/ml in dwarfs treated with HGH, and to a significantly lower level of 3.8 +/-1.1 muU/ml in untreated dwarfs. When glucose concentrations were plotted against paired insulin values, the correlation in both dwarfs and normals was significant. In normals, no correlation existed at any time between plasma HGH levels and plasma concentration of either glucose or free fatty acid. Free fatty acid, beta-hydroxybutyrate, and acetoacetate increased respectively in normals to peak concentrations in plasma of 1.55 +/-0.11, 2.87 +/-0.23, and 0.77 +/-0.09 mmoles/liter. Untreated dwarfs had significantly greater values of all three (mean maximal concentration: FFA = 2.16 +/-0.17 mmoles/liter, beta-hydroxybutyrate = 4.11 +/-0.34 mmoles/liter, and acetoacetate = 1.16 +/-0.10 mmoles/liter). Values returned toward normal in HGH-treated dwarfs. The cahnges in plasma concentrations of beta-hydroxybutyrate and acetoacetate were not due to changes in renal excretion. In starvation, the relation between insulin on the one hand and glucose and free fatty acid on the other hand is maintained in the absence of HGH. However, the setting of blood glucose concentration at which this relation takes place is decreased in the absence of HGH. This results in a lower than normal insulin level and, consequently, in a higher than normal free fatty acid concentration.