Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Effects of species of origin, purification levels, and formulation on insulin immunogenicity.

The immunogenicity of purified pork insulins (PPI) with and without (groups 1 and 2, respectively) trace contamination of beef insulin was contrasted with mixed beef pork insulin of lower purity (MBP, group 3) in 137 patients who had not previously been treated with insulin. Patients and physicians were blinded with regard to the species source of insulin and studies were conducted for a minimum of 1 yr. Antibody development to insulin was assessed by species-specific binding of 125I-insulin by acid charcoal extracted sera, as well as by measurement of insulin prebound to immunoglobulins by a polyethylene glycol precipitation method. NPH- and lente-treated individuals had equivalent antibody responses with regard to the rate of development of antibodies, and maximum immune responses to insulin. In all patient groups, antibody bound insulin as well as species-specific binding of 125I-insulin increased significantly over time (all P less than 0.01 for specific binding of pork and beef insulins SBP and SBB, as well as bound insulin). Maximum bound insulin and SBB as well as bound insulin and SBB over the entire course of the study were significantly greater in group 1 than in group 2 patients (both P less than 0.05). The rate of development and magnitude of antibodies' responses in both PPI-treated groups were significantly less than that seen in the MBP group (all P less than 0.01). New formation of antibeef proinsulin antibodies was seen in one patient from groups 1 and 3, but not in group 2. In all groups, insulin dose per day and fasting serum glucose concentrations increased by about 5 U/day and 10 mg/dl over 1 yr, but groups did not differ. MBP insulin used in these studies proved to be significantly less immunogenic than previously available Argentine pure beef insulin, purified by gel filtration. PPI containing even trace contamination of beef insulin was more immunogenic than PPI alone.

Reduction of insulin clearance during hyperglycemic clamp. Dose-response study in normal humans.

Insulin secretion and clearance were studied in eight normal subjects who underwent hyperglycemic clamp studies at plasma glucose levels of 120, 225, and 300 mg/dl on three occasions. Insulin secretion rates were calculated during a 1-h baseline period and during 3 h of glucose clamping from a two-compartmental analysis of peripheral C-peptide concentrations with individual kinetic parameters derived after intravenous bolus injections of biosynthetic human C-peptide. At the 300-mg/dl clamp level, the insulin secretion rate increased to a value 9.9 +/- 0.7 times that of basal at the end of the clamp (mean +/- SE), whereas over the same period, the peripheral insulin concentrations increased to a greater extent, reaching a value 15.4 +/- 1.2 times that of basal (P = .002). This greater relative increase in the insulin concentration in comparison with the corresponding insulin secretion rate suggests a reduction in the clearance of endogenous insulin. A similar trend was seen at the 225-mg/dl clamp level, but the relative increase in the insulin concentration (9.9 +/- 1.5 times that of basal) was not significantly higher than the relative increase in the insulin secretion rate (8.1 +/- 0.5 times that of basal, P = .17). At the 120-mg/dl clamp level, the relative increases in the insulin secretion rate (2.7 +/- 0.2 times that of basal) and the insulin concentration (2.4 +/- 0.2 times that of basal) were similar (P = .26), indicating no reduction in endogenous insulin clearance during moderate stimulation of insulin secretion. In conclusion, a reduction in endogenous insulin clearance occurs during greater stimulation of insulin secretion at higher glucose-clamp levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Reevaluation of urine C-peptide as measure of insulin secretion.

Urine C-peptide (UCP) has been proposed as a measure of insulin secretion, because insulin and C-peptide are consecreted in equimolar concentrations by the pancreatic beta-cell. The validity of this approach was tested by comparing insulin secretion rates, calculated by application of a two-compartmental analysis of peripheral C-peptide concentrations, with UCP excretion rates. Insulin secretion and UCP excretion with subjects on a mixed diet were simultaneously measured over a 24-h period in 13 patients with noninsulin-dependent diabetes mellitus and in 14 matched nondiabetic control subjects. The fraction of secreted C-peptide that was excreted in the urine (fractional C-peptide excretion) showed considerable intersubject variability in the diabetic (11.3 +/- 1.6%, range 3.9-20.8) and control (8.0 +/- 1.7%, range 1.1-27.9, P = .07) subjects (means +/- SE). UCP clearance demonstrated a similar degree of variability and was not significantly different (P = .07) between diabetic (23.8 +/- 3.0 ml/min) and control (16.5 +/- 2.7 ml/min) subjects. In control subjects, the 24-h insulin secretion rate correlated more closely with the fasting insulin secretion rate (r = .97, P = .0001), fasting C-peptide (r = .81, P = .0005), and fasting insulin (r = .80, P = .0005) concentrations than with the 24-h UCP excretion rate (r = .62, P = .02). Similar results were obtained in the diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin secretion and clearance. Comparison after oral and intravenous glucose.

Insulin secretion and clearance in response to the administration of oral and intravenous glucose was investigated in nine normal men. C-peptide metabolic kinetics were calculated by analysis of individual C-peptide decay curves after the bolus injection of biosynthetic human C-peptide. Glucose was administered to the subjects on three occasions: as a 75-g oral dose, a 75-g i.v. infusion, and an intravenous glucose infusion at a variable rate adjusted to mimic the peripheral glucose levels obtained after the oral glucose load (matching experiment). Glucose, insulin, and C-peptide concentrations were measured for the subsequent 5 h. The glucose level after the oral glucose load (115.9 +/- 2.6 mg/dl, mean +/- SE) closely approximated that after the matching experiment (120.5 +/- 2.5 mg/dl) but was significantly lower than after 75 g i.v. glucose (127.7 +/- 3.4 mg/dl, P less than .05). Analysis of the areas under the peripheral concentration curves (60-360 min) showed that the responses of both insulin (52.7 +/- 5.6 and 46.5 +/- 4.5 pmol.ml-1.300 min-1) and C-peptide (252.7 +/- 27.5 and 267.0 +/- 21.6 pmol.ml-1.300 min-1) were not significantly different after the oral and 75-g i.v. glucose studies, respectively, whereas in the matching experiment, both the insulin (26.1 +/- 3.9 pmol.ml-1.300 min-1) and C-peptide (178.0 +/- 18.9 pmol.ml-1.300 min-1) responses were lower (P less than .05) than in the other two studies. Insulin secretory rates were derived from peripheral C-peptide concentrations with an open two-compartment model and individually derived model parameters. (ABSTRACT TRUNCATED AT 250 WORDS)

Immunologic aspects of human proinsulin therapy.

We investigated the immunogenicity of human proinsulin (HPI) when used as the sole or principal insulin agonist in insulin-naive patients with insulin-dependent (type I) and non-insulin-dependent (type II) diabetes mellitus. Sixty-one patients (13 type I, 48 type II) were treated with rDNA human insulin (NPH HI with or without regular HI) and 53 were treated with HPI (8 type I, 45 type II). At 6 mo, virtually identical levels of HbA1c (5.2 vs. 5.3%, P = NS) were achieved. However, regular HI was added less often to the treatment regimen in HPI-treated patients (16 vs. 32 patients, P less than .001). Overall, there was no significant increase in proinsulin-specific antibodies in either treatment group. However, 8 of 51 (1 transiently) patients in the HPI group developed low levels of binding of HPI (highest percentage bound was 5%). Two patients in the HI group developed very low levels of HPI binding (1.2 and 1.9%). Binding of HI (greater than 2.4%) was seen in both treatment groups; however, the prevalence of HI binding was less in the HPI group at 6 mo (39 of 60 in HI group vs. 20 of 51 in HPI group, P = .008). Concomitant treatment with regular HI did not affect the prevalence or level of binding of HPI or HI. We conclude that human proinsulin is a weak immunogen when used as the principal insulin agonist and may reduce both the formation of anti-HI antibodies and the need for concomitant therapy with regular HI.

In vivo deactivation of proinsulin action on glucose disposal and hepatic glucose production in normal man.

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 microgram/m2/min) or proinsulin (2.75 micrograms/m2/min), achieving steady-state serum levels of 32 +/- 3 microU/ml (equivalent to 0.23 +/- 0.02 pmol/ml) and 3.7 +/- 0.2 pmol/ml, respectively. Suppression of HGO was similar (83-84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 +/- 0.43 versus 1.98 +/- 0.28 mg/kg/min, P less than 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.

Insulin treatment for the early 80s: facts and questions about old and new insulins and their usage.

Recent data now emphasize the importance of blood glucose control as a means of forestalling diabetic microvascular disease. As a result, attempts are being made to optimize conventional insulin therapy, and new modes of insulin delivery (e.g., pumps) are being adopted. Also, improvements in manufacturing technology have resulted in the commercial availability of porcine insulin, which is highly effective in preventing the complications of insulin therapy in those patients receiving only this material. Human insulin, produced biosynthetically in bacteria using recombinant DNA technology, is now being tested. While these developments in insulin and its administration offer great promise to the diabetic patient, many more studies will be needed to determine their absolute clinical benefits.

New directions in drug development: mixtures, analogues, and modeling.

Success in modern medical research is achieved when basic and clinical information about a given disorder converges, either intentionally or fortuitously, with the availability of technology or other means to design and apply interventions for the disorder in question. A prime example is the discovery of insulin and its replacement in patients with IDDM in 1923. Seven decades later, the focus of diabetes management is on improvement in metabolic control to forestall the chronic complications of the disease and improve the quality of life of patients with the disease. Metabolic control is being addressed through the development of insulin analogues using sophisticated techniques to understand the chemistry of insulin and to modify it using rDNA technology. The objective of these efforts is to simulate normal insulin secretion with subcutaneously injected agonists. Quality-of-life needs are being addressed with delivery devices, insulin mixtures, and insulin analogues. Although none of these improvements parallel the discovery of insulin, they do provide an optimistic outlook for patients with diabetes mellitus.

Treatment of NIDDM with insulin agonists or substitutes.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common disorder occurring in 3-6% of adults in most western populations. In the United States, 29% of patients with diabetes take insulin; of these, 76% have NIDDM. Insulin therapy is usually required at some time in NIDDM. Insulin therapy improves the abnormalities of NIDDM (reduced beta-cell function, increased hepatic glucose production, reduced peripheral glucose disposal, lipid abnormalities). Insulin and sulfonylurea agents have comparable effects on mild forms of NIDDM, but for more severe forms, insulin is usually superior. Combination insulin-sulfonylurea treatment may improve the response to sulfonylureas, although long-term well-controlled trials have not been conducted. Short-term insulin treatment may restore response to sulfonylureas. Other promising treatments (human proinsulin, nasal insulin, somatostatin) have not shown any advantage over conventional insulin therapy. Insulin causes hypoglycemia and peripheral hyperinsulinemia. The hazards of hyperinsulinemia, e.g., weight gain and hypoglycemia, have been overstated, and questions about its atherogenic effects remain to be resolved. The effect of glycemic control on macro- and microvascular complications has not been established; however, maintaining fasting blood glucose levels of less than 6.7 mM may protect against progression of retinopathy, neuropathy, and nephropathy and reduce the severity of ischemic stroke. Dosage algorithms generally use intermediate- or long-acting insulin to control basal glycemia, with regular insulin added before meals if needed to control postprandial glycemia. Effective therapy depends on the patient being informed, cooperative, and willing to self-monitor blood glucose. Insulin treatment intermittency increases the risk for immune complications (resistance and allergy). Overall, patients with NIDDM can benefit from insulin therapy.

Factors in the survival of patients with insulin-requiring diabetes for 50 years.

Ninety-seven diabetic patients who had taken insulin for 50 yr and longer were surveyed by questionnaire to identify factors that might explain their unusual longevity. The analysis suggested that the long survival of this group was related to the following: maintenance of normal or near normal body weight, regular contact with a personal physician, periodic blood glucose determinations, frequent urine testing, regular exercise, and longevity of the parents and grandparents. The results support the conclusion that careful management of diabetes favors longevity.

Development of IgE antibodies to human (recombinant DNA), porcine, and bovine insulins in diabetic subjects.

Thirty-one previously untreated diabetic individuals received only human insulin (recombinant DNA) for 1 yr with no adverse reactions. The development of serum IgE antibodies to human, porcine, and bovine insulins was assessed by a sepharose radioallergoabsorbent test (RAST). Immunoglobulin (total Ig antibody) binding was assessed by a nonabsorbed species-specific radioimmunoassay. During therapy 2 patients developed IgE antibodies to human insulin as well as increased total Ig binding. The IgE antibodies to human insulin cross-reacted with porcine and bovine insulins, were transient, and were not accompanied by insulin allergy. Ig binding to insulin developed and persisted in 11 of the human insulin-treated diabetics. In comparison, 62 previously untreated diabetic persons received only purified porcine insulin (PPI, less than 5 ppm proinsulin, N = 40) or a mixed bovine-porcine insulin (proinsulin less than 50 ppm, N = 21). Increased Ig antibody developed in 16 of 21 patients receiving mixed bovine-porcine insulin and 25 of 41 PPI-treated patients (P less than 0.05). Seven of 41 PPI-treated patients and 4 of 21 mixed bovine-porcine-treated patients developed anti-insulin IgE antibodies, which were transient in 4 and persisted in 6 diabetic patients. IgE antibody levels did not correlate with total Ig antibody. These data suggest that IgE and total Ig antibodies develop less often after human insulin treatment. Also, the immunoregulation mechanisms responsible for anti-insulin IgE antibody synthesis differ from those regulating other Ig that bind to insulins. Since none of the patients in this study have developed clinical manifestations of insulin allergy or resistance, the clinical relevance of the antibody data must remain speculative.

Immunological and metabolic responses of patients with history of antibody-induced beef insulin resistance to treatment with beef, pork, human, and sulfated beef insulin.

OBJECTIVE: We evaluated immunological and metabolic responses during therapy with beef (B), pork (P), human (H, rDNA), and sulfated beef (SB) insulins in patients with insulin-antibody-mediated insulin resistance. RESEARCH DESIGN AND METHODS: A randomized double-blind sequential crossover study was performed with each insulin administered for 56 days unless dose reached 200 U/day or allergy developed. Participants were 26 individuals with history of B-P insulin dosage greater than or equal to 200 U/day and insulin binding capacities greater than 0.216 nM (30 mU/ml serum). Twenty-one participants completed the study. Insulin dosage/day, fasting plasma glucose, percentage HbA1, insulin antibody binding capacity (IABC), bound insulin (BI), percentage binding of 125I-labeled B, P, and H insulins, and receptor inhibition factor (RIF) were assessed. RESULTS: Mean insulin dosage (U/day) was significantly greater on B (88.9) than on P (29.2), H (29.4), or SB (29.6). On B, dosage increased in 12 individuals and reached 200 U/day in 6 individuals. Mean fasting plasma glucose (12.1 mM) and HbA1 (11%) were significantly higher on B than on P, H, and SB. Mean IABC, bound insulin, RIF, and percentage of B, P, and H bound were significantly higher on B than on P, H, and SB. Prolonged treatment with SB before entry into the study (greater than 5 wk) resulted in a blunted anamnestic response to B insulin. CONCLUSIONS: Rechallenge with B results in anamnestic immunological response and deterioration of metabolic control. SB, H, and P insulins have equivalent effects in patients with insulin antibody-mediated immunologic resistance.

Immunologic improvement resulting from the transfer of animal insulin-treated diabetic subjects to human insulin (recombinant DNA).

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.

The plasma glucose response of normal fasting subjects to neutral regular and NPH biosynthetic human and purified pork insulins.

Using doses of 0.1 and 0.15 U/kg, the hypoglycemic activities of neutral regular and NPH biosynthetic human insulin (BHI) and purified pork insulin were compared in normal fasting subjects. Neutral regular insulin was administered by the intravenous and subcutaneous routes and NPH subcutaneously. Comparison of the plasma glucose curves disclosed no statistically significant differences between the maximum effects and the length of time to achieve the maximum effect. Moreover, a dose-response difference between 0.1 and 0.15 U/kg could not established. It is concluded that the hypoglycemic activities of neutral regular and NPH BHI and purified pork insulin are the same.

Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience.

OBJECTIVE: To describe the rationale for the preclinical and clinical developmental course of human proinsulin (HPI), the second product after human insulin for the treatment of diabetes mellitus to be manufactured by DNA technology. RESEARCH DESIGN AND METHODS: The relevant and available published and unpublished preclinical and clinical information generated on pork proinsulin and human proinsulin has been integrated to demonstrate how certain clinically attractive features of pork proinsulin (a soluble intermediate-acting and possibly hepatospecific insulin agonist) led to the development of HPI. RESULTS: Clinical pharmacology studies demonstrated that HPI was definitely, although marginally, hepatospecific. More striking was the finding that the intrasubject/patient coefficient of variation of response to HPI was significantly less than that observed with NPH insulin. However, the fact that unique efficacy in controlled multicenter studies was not demonstrated suggested that these pharmacological features were not translated into clinical benefit. In one multicenter new patient study there were six myocardial infarctions, including two deaths, in patients treated for greater than or equal to 1 yr with HPI and none in the control group. CONCLUSIONS: To obtain an independent review of the risks and benefits of HPI, in February 1988, Lilly convened a consultant group that examined all relevant information on HPI available. These experts shared our concerns about the safety of HPI in light of the failure to demonstrate unique efficacy. Accordingly, clinical trials with HPI were suspended in February 1988. Experience with HPI demonstrates the challenge associated with the development of new drugs in general and insulin agonists in particular.

Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures.

Normal fasting subjects received regular insulin and mixtures of regular with NPH or lente to assess the effects of the combinations on serum insulin concentrations (SIC) and blood glucose responses (BGR). In addition, the influence of concentration, depth, and method and site of administration was investigated. In studies of mixtures of regular with NPH and with lente, it was observed that the regular: lente ratio needed to achieve peak SIC was higher than with the regular: NPH combination. Increased SIC, including either the peak and/or the time interval required to achieve the peak, were related to the depth and site (deltoid and abdominal greater than anterior thigh or buttocks). Assuming linear kinetics of absorption, significant quantities of insulin fail to reach the serum. Marked intra- and intersubject variations in SIC and BGR to regular, NPH, and lente insulins were observed.

The U.S. "new patient" and "transfer" studies.

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.

Clinical pharmacologic studies with human insulin (recombinant DNA).

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.

The therapeutic efficacy of human insulin (recombinant DNA) in patients with insulin-dependent diabetes mellitus: a comparative study with purified porcine insulin.

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.