Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients

OBJECTIVE: Insulin Mix25 is a new premixed insulin analog containing 25% insulin lispro and 75% neutral protamine lispro (NPL) suspension (NPL insulin). The aim of the study was to compare serum glucose and insulin responses after breakfast in type 2 diabetic patients who received Mix25, premixed regular/NPH (30%/70%), or NPH insulin before the meal. RESEARCH DESIGN AND METHODS: We studied 22 type 2 diabetic patients of age 62 +/- 1 years, BMI 30 +/- 1 kg/m2, duration of diabetes 15 +/- 2 years, duration of insulin therapy 6 +/- 1 years, insulin dose 65 +/- 6 U/day, and HbA1c 7.9 +/- 0.2%. Ten healthy individuals (age 56 +/- 1 years, BMI 28 +/- 1 kg/m2) served as control subjects. Each patient (except healthy subjects, who were studied once each) was studied three times in a double-blind, randomized fashion. After an overnight fast, the patients received 36 +/- 4 U of test insulin. Ten minutes after insulin injection, the patients ingested a breakfast meal (512 kcal, 60% carbohydrate, 20% fat, and 20% protein), identical in all studies. Blood samples were taken before and at 10- to 30-min intervals for 240 min after the breakfast meal. RESULTS: The peak rise in serum glucose was lower after Mix25 (76 +/- 7 mg/dl) than after 30/70 (94 +/- 5 mg/dl, P < 0.05) or NPH (113 +/- 4 mg/dl, P < 0.005) insulin. The incremental area under the serum glucose curve was 36% smaller after Mix25 than after 30/70 (P < 0.01) and 56% smaller than after NPH (P < 0.005) insulin. The peak rise in serum insulin concentration was higher after Mix25 (103 +/- 18 mU/l) than after 30/70 (87 +/- 13 mU/l, P < 0.05) or NPH (62 +/- 12 mU/l, P < 0.01) insulin. The incremental area under the serum insulin curve was higher after Mix25 than after 30/70 during the first 2-3 h (P < 0.02), but the difference disappeared by the end of the 4-h follow-up period. After Mix25 injection, there was an inverse correlation between the glucose response to a meal and insulin dose (r = -0.56, P < 0.01) or the incremental area under the serum insulin curve (r = -0.39, P < 0.05). No such correlations were observed with the other insulins. CONCLUSIONS: Because of its faster initial absorption rate, the new premixed insulin analog Mix25 reduces blood glucose response to a breakfast meal in type 2 diabetic patients compared with premixed 30/70 (regular/NPH) or NPH insulin.     

Comparison of insulin levels after injection by jet stream and disposable insulin syringe

Intermediate-acting biosynthetic human (NPH) insulin was administered by disposable insulin syringe into the right upper thigh of nine insulin-dependent diabetic youths. Seven days later, the same amount and type of NPH insulin was given in the same anatomic site with a Medi-Jector II, which delivers insulin as a jet stream. Blood was collected before insulin injection and at hourly intervals subsequently for the measurement of glucose and insulin. The total serum insulin measured before the first morning dose with the needle and syringe and the Medi-Jector II was 41.2 +/- 10.7 microU/ml and 46.2 +/- 10.7 microU/ml, respectively. During the next 9 h, the areas under the respective total insulin curves were not different, but the area under the free-insulin curve after jet injection was greater than the free-insulin area after needle injection (P less than .01). The ratio of free/total serum insulin was 0.31 +/- 0.02 after needle injection and 0.40 +/- 0.03 after jet injection (P less than .0025). The peak of total insulin concentration occurred 4.2 h after jet injection of NPH: 1 h earlier than the peak after needle injection. The plasma glucose at time zero was 197 +/- 15 mg/dl before needle injection and 242 +/- 19 mg/dl before jet injection. Although the diet consumed by each subject on the 2nd study day was identical to that of the 1st day, the mean glucose increase was greater after needle-injected insulin than after jet-spray injection. This indicates that the greater amount of free insulin observed after jet-injected insulin had a direct effect in lowering the plasma glucose. Jet injection may reduce insulin requirements by increasing the availability of free insulin.     

Insulin binding to the cardiopulmonary bypass biomaterials

Hyperglycemia associated with cardiopulmonary bypass (CPB) is an independent predictor of morbidity and mortality. One suggested cause of hyperglycemia during CPB is a decline of serum insulin concentrations. Since plasma C-proteins are not reduced during CPB -suggesting that pancreatic insulin secretion is not affected - the reduction of insulin concentrations is hypothesized to be due to the binding of the insulin protein to the CPB biomaterials. The hypothesis of this study is that insulin binds to the CPB polyvinyl chloride (PVC) tubing and that selected bio-coatings inhibit this process. Human insulin was diluted to a physiologic concentration of 30 microU/mL in saline and exposed to four types of sterile PVC tubing, namely: uncoated, Terumo X-coated, Medtronic Carmeda, and Cobe SMARx T for 30 minutes at 37 degrees C. Insulin concentrations were determined with ELISA. The recovered insulin concentrations were found to be 9.3 +/- 0.6 microU/mL in the uncoated (control), 17.7 +/- 1.9 microU/mL in the X-coating, 17.9 +/- 1.1 microU/mL in the Carmeda, and 14.28 +/- 0.17 microU/mL in the SMARxT coated tubing. These data support the hypothesis that the insulin binding to the PVC tubing can be reduced by 48% and up to 35% with X-coating and Carmeda, and SMARxT coating, respectively. Therefore, the use of coated CPB systems is justified to reduce CPB-associated hyperglycemia.     

Effectiveness of human ultralente versus NPH insulin in providing basal insulin replacement for an insulin lispro multiple daily injection regimen. A double-blind randomized prospective trial. The Canadian Lispro Study Group

OBJECTIVE: To compare human ultralente (UL) insulin with human NPH insulin as basal insulin replacement in patients who use insulin lispro before meals. RESEARCH DESIGN AND METHODS: There were 178 patients with type 1 diabetes who were randomized to receive either human NPH or UL insulin once daily at bedtime in a 1-year double-blind clinical study. Eight-point blood glucose profiles were collected once monthly in the first 4 months, then every 2 months for the remainder of the study. Patients were also asked to perform premeal blood glucose measurements every day throughout the study. If before-supper blood glucose levels consistently exceeded 8 mmol/l despite optimal postprandial control with the lunch dose of insulin lispro, a second dose of basal insulin before breakfast was administered. RESULTS: For the group as a whole, insulin doses before meals and basal insulin doses were similar at baseline. At study's end, meal doses remained the same (30 +/- 1 U/day for UL., 29 +/- 1 U/day for NPH), while basal requirements were somewhat higher for the UL group than the NPH group: 30 +/- 1 U/day vs. 26 +/- 1 U/day, respectively (P < 0.05). The rates of severe hypoglycemia were similar for patients on NPH (0.05 +/- 0.03 per patient every 30 days) and for UL (0.07 +/- 0.04 per patient every 30 days) insulin. There was no significant difference for glycemic control between the NPH and UL groups overall (HbAlc at the end of the study: 7.6 +/- 0.1 vs. 7.7 +/- 0.1%, respectively), and by study's end a similar number of patients in the NPH and the UL groups needed to be switched to twice daily basal insulin (21 and 24%, respectively). Patients requiring twice-daily injections of basal insulin had a longer duration of diabetes (17.8 +/- 1.5 vs. 14.0 +/- 0.8 years, P < 0.05) and a highest baseline HbAlc (8.6 +/- 0.1 vs. 8.0 +/- 0.1%, P < 0.002) and were significantly older (38 +/- 2 vs. 34 +/- 1 years, P < 0.007). Patients who were switched to twice-daily NPH insulin had lower HbAlc levels at study's end compared with those switched to twice-daily UL insulin (7.7 +/- 0.2 vs. 8.2 +/- 0.3%), but this difference was not statistically significant. Distribution of hypoglycemia across the day was also similar in both groups. CONCLUSIONS: UL or NPH insulin, when used as the basal insulin for multiple injection regimens, results in similar glycemic control in patients using insulin lispro before meals. However, in patients who require a second injection of basal insulin, NPH insulin appears to provide lower prebreakfast and prelunch glucose levels compared with UL insulin.     

Accuracy of pen injectors versus insulin syringes in children with type 1 diabetes.

OBJECTIVE: To compare the accuracy and precision of insulin syringes and pen devices used by children with type 1 diabetes and their parents. RESEARCH DESIGN AND METHODS: There were 48 subjects (32 patients, a parent of an additional 16 patients) instructed to measure out morning insulin doses three times from vials and/or cartridges containing saline mixed with small amounts of [14C]glucose (solution used as regular insulin) and [3H]glucose (solution used as NPH insulin) and to dispense the contents into a scintillation vial. Statistical analysis was used to determine the accuracy and precision of both methods of insulin delivery. RESULTS: The absolute error in measuring out doses of regular insulin < 5 U was greater with insulin syringes compared with pen injection devices (9.9 +/- 2.4 vs. 4.9 +/- 1.6%, respectively). Both were comparable for regular insulin doses > 5 U (3.2 +/- 0.6 vs. 2.2 +/- 0.4% for syringes and pens, respectively). The accuracy in drawing up NPH doses was similar for low and high insulin doses (mean percent error of 7.5 +/- 1.5 vs. 5.6 +/- 1.1%). CONCLUSIONS: Pen devices are more accurate than insulin syringes in measuring out insulin at low insulin doses. The accuracy of insulin syringes improves when higher doses of regular insulin are measured out and becomes comparable to pen devices.     

Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime

OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P < 0.05). The bedtime NPH dosage was no different. With lispro + NPH, the mean daily blood glucose was lower than with Hum-R (8.0 +/- 0.1 vs. 8.8 +/- 0.1 mmol/l; P < 0.05), HbA1c was lower (6.34 +/- 0.10 vs. 6.71 +/- 0.11%, mean value over 1 year; P < 0.002), and hypoglycemia (blood glucose < or = 3.8 mmol/l) was less frequent (7.4 +/- 0.5 vs. 11.5 +/- 0.7 episodes/patient-month) and tended to occur more within 90 min after meals than in the postabsorptive state (P < 0.05 vs. Hum-R). After 1 year, plasma adrenaline and symptom responses to experimental, stepped hypoglycemia improved with lispro and were closer to the responses of 12 nondiabetic control subjects versus Hum-R both in terms of thresholds and magnitude (P < 0.05). CONCLUSIONS: We concluded that mealtime injection of lispro + NPH improves the 24-h blood glucose and the percentage HbA1c as compared with Hum-R. The improvement can be maintained long term. Intensive therapy with lispro + NPH results in less frequent hypoglycemia and better awareness and counterregulation of hypoglycemia.     

A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes

OBJECTIVE: Because there are limited data on the comparison of insulin aspart and mixed insulin in type 2 diabetes, this trial was performed to compare the efficacy and safety of preprandial insulin aspart with human soluble insulin (HI) and human premix (70% NPH/30% regular) insulin (MIX). RESEARCH DESIGN AND METHODS: A total of 231 type 2 diabetic patients were randomized to insulin aspart (n = 75), HI (n = 80), or MIX (n = 76) for 3 months. Insulin aspart and HI were administered with or without bedtime NPH insulin. A total of 204 patients completed the trial according to protocol. HbA1c, 7-point blood glucose, insulin dosage, and hypoglycemic episodes were recorded. The primary end point was "change of HbA1c" from baseline to last visit. Analysis for equivalence was performed by t tests with three subtests. RESULTS: HbA1c decreased 0.91 +/- 1.00 for insulin aspart, 0.73 +/- 0.87 for HI, and 0.65 +/- 1.10 for MIX with the following confidence intervals: insulin aspart HI (-0.21 to 0.57, P = 0.025), insulin aspart MIX (-0.17 to 0.69, P = 0.092), and HI-MIX (-0.33 to 0.48, P = 0.006). Postprandial blood glucose decreased in the insulin aspart group: 0.44 mmol/l to >1.67 mmol/l compared with HI and 1.1 mmol/l to >1.67 mmol/l compared with MIX. Preprandial insulin doses were similar in the insulin aspart and HI groups (10-14.5 U). Hypoglycemic events per month were 0.56 HI, 0.40 insulin aspart, and 0.19 MIX. CONCLUSIONS: Statistically, insulin aspart was not equivalent to another treatment in terms of HbA1c reduction. Insulin aspart treatment resulted in improved HbA1c and postprandial blood glucose. The application of insulin aspart was safe and well tolerated.     

Improved serum insulin profiles in diabetic individuals who massaged their insulin injection sites

Eight insulin-dependent diabetic patients were studied on two consecutive mornings when they injected their usual morning mixtures of insulin. One morning they massaged their insulin injection sites 15 min after the injection. Free insulin levels rose 10.14 +/- 9.91 microU/ml higher (P less than 0.05) and serum glucose levels fell 8.3% lower (P less than 0.05) 30 min after massage than on the control study day.     

Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo

OBJECTIVE: To study the pharmacodynamic properties of the subcutaneously injected long-acting insulin analog HOE901 (30 microg/ml zinc) in comparison with those of NPH insulin and placebo. RESEARCH DESIGN AND METHODS: In this single-center double-blind euglycemic glucose clamp study, 15 healthy male volunteers (aged 27 +/- 4 years, BMI 22.2 +/- 1.8 kg/m2) received single subcutaneous injections of 0.4 U/kg body wt of HOE901, NPH insulin, or placebo on 3 study days in a randomized order. The necessary glucose infusion rates (GIRs) to keep blood glucose concentrations constant at 5.0 mmol/l were determined over a 30-h period after administration. RESULTS: The injection of HOE901 did not induce the pronounced peak in metabolic activity observed with NPH insulin (GIRmax 5.3 +/- 1.1 vs. 7.7 +/- 1.3 mg x kg(-1) x min(-1)) (P < 0.05); after an initial rise, metabolic activity was rather constant over the study period. This lack of peak was confirmed by a lower glucose consumption in the first 4 h after injection (area under the curve from 0 to 4 h [AUC(0-4 h)] 1.02 +/- 0.34 vs. 1.48 +/- 0.34 g/kg) (P < 0.001) with HOE901, as compared with NPH insulin. In this single-dose study, the metabolic effect measured over a period of 30 h was lower with HOE901 than with NPH insulin (AUC(0-30 h) 7.93 +/- 1.82 vs. 9.24 +/- 1.29 g/kg) (P < 0.05). CONCLUSIONS: This study shows that the soluble long-acting insulin analog HOE901 induces a smoother metabolic effect than NPH insulin, from which a better substitution of basal insulin requirements may follow.     

Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro mix25 and insulin lispro mix50. Mix50 Study Group.

The objective of this 6-month, open-label, randomized, two-period crossover study was to compare glycemic control when patients were treated with (1) 2 manufactured premixed insulin formulations containing insulin lispro and a novel insulin lispro-protamine formulation, neutral protamine lispro (NPL), and (2) 2 manufactured premixed human insulin formulations, human insulin 50/50 and human insulin 30/70. One hundred individuals, 37 with type 1 diabetes mellitus (12 females, 25 males; mean age, 39.4 years; mean body mass index [BMI], 24.8; mean duration of diabetes, 12.9 years) and 63 with type 2 diabetes mellitus (33 females, 30 males; mean age, 59.0 years; mean BMI, 28.4; mean duration of diabetes, 12.6 years), were treated with insulin lispro mixtures. Insulin lispro Mix50 (50% insulin lispro/50% NPL) and human insulin 50/50 (50% regular insulin/50% neutral protamine Hagedorn [NPH] insulin) were administered before breakfast; insulin lispro Mix25 (25% insulin lispro/75% NPL) and human insulin 30/70 (30% regular insulin/70% NPH) were administered before dinner. Blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG <3.0 mmol/L), insulin dose and timing of dose before meals, and hemoglobin A1c were measured. Mean doses of insulin lispro and human insulin mixtures were similar overall and for both diabetes subgroups. However, compared with human insulin mixtures, twice-daily administration of insulin lispro mixtures resulted in improved postprandial glycemic control, similar overall glycemic control, and less nocturnal hypoglycemia, as well as offering the convenience of dosing closer to meals.     

Intensive therapy with inhaled insulin via the AERx insulin diabetes management system: a 12-week proof-of-concept trial in patients with type 2 diabetes

OBJECTIVE: To compare the glycemic control of inhaled insulin via the AERx insulin diabetes management system (iDMS) with that of subcutaneous (SC) insulin, both combined with NPH insulin at bedtime, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The AERx iDMS uses a liquid insulin formulation to achieve flexible precise mealtime dosing (with increments corresponding to 1 IU administered subcutaneously) and ensures insulin delivery only when the breathing technique is optimal. This trial in patients with type 2 diabetes compared the glycemic control (HbA(1c)) achieved by inhaled insulin administered via AERx iDMS with that using SC insulin. This was a randomized, 12-week, open-label, parallel, multicenter, multinational trial in 107 nonsmoking patients with type 2 diabetes (mean age 59 years, mean duration of diabetes 11.9 years). Patients were randomized to receive either inhaled fast-acting human insulin via AERx iDMS immediately before meals or SC fast-acting human insulin administered 30 min before meals, both in combination with evening NPH insulin. RESULTS: Baseline and demographic characteristics were similar between the two groups. There was no statistically significant difference in HbA(1c) between the AERx and SC groups after 12 weeks of treatment (7.84 +/- 0.77 vs. 7.76 +/- 0.77%, P = 0.60). Fasting serum glucose was significantly lower in the AERx group compared with the SC group by the end of the trial (8.9 +/- 3.8 vs. 10.8 +/- 3.7 mmol/l, P = 0.01) with a similar NPH dose in the two groups (0.23 vs. 0.23 IU/kg, P = 0.93). There were no statistically significant differences between the two groups in the intra-subject variability of fasting or prandial blood glucose increment. Adverse events were similar in the two groups. No major safety concerns were raised during the trial. CONCLUSIONS: In patients with type 2 diabetes, preprandial inhaled insulin via AERx iDMS is as effective as preprandial SC insulin injection in achieving glycemic control with similar tolerability.     

Improved postprandial glycemic control with Humalog Mix75/25 after a standard test meal in patients with type 2 diabetes mellitus

OBJECTIVE: This double-blind study was designed to compare the postprandial glucodynamic profile of Humalog Mix75/25, a new premixed insulin analogue containing 75% neutral protamine lispro and 25% insulin lispro with that of human insulin 70/30 (70% neutral protamine Hagedorn insulin and 30% regular human insulin) in patients with type 2 diabetes mellitus. BACKGROUND: Insulin lispro Mix75/25 (Mix75/25) is the first available insulin formulation in which both the rapid-acting and basal components are insulin analogues. METHODS: This randomized, multicenter, double-blind, crossover study monitored patients' postprandial glucodynamic response to Mix75/25 and human insulin 70/30 (70/30) after a standard test meal. Eighty-four patients with type 2 diabetes participated in this study and were randomly assigned to 1 of 2 treatment sequence groups. Patients received an identical test meal on 4 occasions, completing 2 test meals for each treatment. Equal doses of Mix75/25 or 70/30 were administered 5 minutes before each of the 2 test meals, with doses individualized for each patient. Blood samples were collected for 4 hours after the meal for measurement of plasma glucose. From these plasma glucose measurements, fasting plasma glucose, 2-hour postprandial glucose (2pp), 2-hour postprandial glucose excursion (2pp(ex)), maximum glucose excursion (Gex(max)), the area under the glucose concentration versus time curve from 0 to 4 hours (AUC4), and the area under the glucose excursion versus time curve from 0 to 4 hours (AUCex4) were calculated. RESULTS: Because of significant differences in the baseline fasting plasma glucose levels between Mix75/25 and 70/30 (Mix75/25: 8.9+/-2.2 mmol/L [160.2+/-39.6 mg/dL]; 70/30: 8.6+/-1.9 mmol/L [154+/-34 mg/dL), analyses of the excursion parameters provide a truer comparison of the glucodynamic response between insulin formulations. Mix75/25 resulted in significantly lower values for 2pp(ex) (3.35+/-2.28 vs 4.13+/-2.26 mmol/L), Gex(max) (4.51+/-1.88 vs 5.19+/-1.98 mmol/L), and AUCex4 (8.01+/-7.02 vs 10.6+/-6.47 mmol x h/L) compared with 70/30. CONCLUSIONS: In patients with type 2 diabetes mellitus, premeal injection of Mix75/25 resulted in better postprandial glycemic control than did premeal injection of 70/30 in the 4 hours after a standard meal. Mix75/25 is a valuable option for managing postprandial blood glucose in patients with type 2 diabetes mellitus who require insulin.     

Absorption and miscibility of regular porcine insulin after subcutaneous injection of insulin-treated diabetic patients

The absorption and miscibility of subcutaneously injected 125I-regular porcine insulin was examined in 20 insulin-treated diabetic patients. The disappearance half-life (t1/2) was 2.1 +/- 0.8 h (SD) after injection of regular insulin (40 U/ml) and 2.3 +/- 0.7 h when mixed with porcine NPH insulin (NS). A significant inverse relation was demonstrated between insulin concentration and absorption, as t1/2 was 1.8 +/- 0.7 h (P less than 0.05) when using 20 U/ml. The interindividual coefficients of variation for absorption of regular insulin were 30.9-41.6% and independent of the presence of NPH insulin. The intrapatient variability, however, was much smaller, 14.5-23.6%.     

Double-blind crossover trial of isophane (NPH)- and lente-based insulin regimens

Isophane (NPH) and lente insulin preparations have been the basis of insulin-injection regimens for many decades but were never formally compared. After a 2-mo run-in period, 82 patients were randomized to NPH (Protaphane) or lente (Monotard) insulin preparations given together with Actrapid as a twice-daily injection regimen in a double-blind study. Patients were seen monthly and crossed over after 5 mo of treatment. Control as assessed by glycosylated hemoglobin (NPH 9.2 +/- 0.1%, lente 9.3 +/- 0.1%, mean +/- SE) and fructosamine (1.55 +/- 0.02 and 1.57 +/- 0.02 mM) concentrations was identical for the two regimens as were home-collected laboratory-measured fasting blood glucose (BG) (NPH 8.8 +/- 0.5 mM, lente 9.0 +/- 0.5 mM) and mean BG (8.2 +/- 0.3 and 7.6 +/- 0.3 mM) concentrations. For both regimens, the major control problem was the BG concentration before and after breakfast. Total insulin dosage was similar (NPH 56.3 +/- 0.6 U/day, lente 57.2 +/- 0.6 U/day) with no tendency for a difference in the evening intermediate-acting dose (NPH 17.0 +/- 0.3 U/day, lente 17.0 +/- 0.3 U/day) to counter fasting hyperglycemia. Serum lipid concentrations and body weight confirmed the equivalence of control. Hypoglycemic events were recorded in personal diaries and graded by predetermined criteria. Self-treated, relative-assisted, and hospital/doctor-treated hypoglycemic events did not differ in frequency. We conclude that lente- and NPH-based twice-daily human insulin regimens give indistinguishable metabolic control.     

Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Humalog Mix25 Study Group.

OBJECTIVE: Humalog Mix25 is a manufactured premixed insulin formulation containing insulin lispro and a novel insulin lispro-protamine formulation (NPL) in a ratio of 25:75%. The objective of this study was to compare Humalog Mix25 to human insulin 30/70 (30% regular insulin/70% NPH) with respect to glycemic control. RESEARCH DESIGN AND METHODS: Humalog Mix25 was compared with human insulin 30/70 in 89 individuals with type 2 diabetes during a 6-month randomized open-label two-period crossover study. Each insulin was administered twice daily, before the morning and evening meals. Information regarding self-monitored blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG < or = 3.0 mmol/l), insulin dose, and HbA1c was collected. RESULTS: Treatment with Humalog Mix25 resulted in better postprandial glycemic control after the morning and evening meals compared with treatment with human insulin 30/70. Overall glycemic control and the incidence of hypoglycemia were comparable between the treatments. CONCLUSIONS: In comparison to treatment with human insulin 30/70, twice daily administration of Humalog Mix25 resulted in improved postprandial glycemic control, similar overall glycemic control, and the convenience of dosing immediately before meals.     

Miscibility of human semisynthetic regular and lente insulin and human biosynthetic regular and NPH insulin

The miscibility of human semisynthetic regular and lente insulins (Actrapid human/Monotard human) and human biosynthetic regular and NPH insulins (Humulin regular/Humulin NPH) was studied in vitro and in 16 insulin-dependent diabetic patients. In vitro a decrease of regular insulin was found immediately after mixture with semisynthetic lente insulin in proportions 1:4, 1:3, 1:2, 1:1, and 2:1. This was not found after mixture with human biosynthetic regular and NPH insulins. Free insulin and blood glucose were determined over 8 h after the morning injection of regular/lente (n = 9) or regular/NPH (n = 7) insulins in proportions used by the patients (approximately 1:2) mixed in one syringe or in separate syringes. Mixing the regular/lente preparations in one syringe immediately before injection resulted in a significant loss of the early rise in free insulin (P less than .01), with a tendency to a higher free insulin in the afternoon. A corresponding change in the blood glucose profile was seen. No changes were observed in free insulin or blood glucose after mixing regular and NPH preparations compared with separate injections. We conclude that mixing human semisynthetic regular and lente insulins (Actrapid human/Monotard human) instantly results in a decrease of regular insulin, probably due to formation of a longer-acting preparation, whereas no such changes occur with human biosynthetic regular and NPH insulins (Humulin regular/Humulin NPH).     

Lispro or regular insulin for multiple injection therapy in adolescence. Differences in free insulin and glucose levels overnight.

OBJECTIVE: Regular insulin given with the evening meal could contribute to the risk of nocturnal hypoglycemia in adolescents with type 1 diabetes using a multiple injection regimen. To test this hypothesis, we compared glucodynamics and free insulin levels on two separate study nights. RESEARCH DESIGN AND METHODS: A total of 14 adolescents were recruited. On both nights, identical doses of regular insulin or insulin lispro were administered 30 min or 10 min, respectively, before the evening meal, using a double-blind randomized crossover study design. Doses of NPH insulin and carbohydrate content of the evening meal and snack were kept identical. Blood samples were taken every 15 min for blood glucose and every 60 min for free insulin and ketones. RESULTS: After insulin lispro administration, glucose levels were significantly lower between the evening meal and the bedtime snack (analysis of variance [ANOVA] P = 0.02), and four hypoglycemic episodes were recorded. This corresponded to a higher (458 +/- 48 vs. 305 +/- 33 pmol/l, P = 0.02), earlier (64 +/- 4.6 vs. 103 +/- 12 min, P = 0.01), and shorter-lasting (245 +/- 21 vs. 365 +/- 39 min, P = 0.01) insulin peak in contrast to regular insulin. After the bedtime snack, glucose levels increased dramatically during the lispro night and stayed higher, up to 0300 in the morning (ANOVA P = 0.01), corresponding to lower mean insulin levels (146 +/- 20 vs. 184 +/- 27 pmol/l, P = 0.04). No differences were seen in glucose and insulin levels between 0300 and 0800. Four episodes of nocturnal hypoglycemia were documented after the bedtime snack during the regular insulin night, in contrast to one episode after insulin lispro. No differences in ketone levels were observed. CONCLUSIONS: The replacement of regular insulin with insulin lispro may reduce the risk of late hypoglycemia, but redistribution of the evening carbohydrate may be needed to ensure good metabolic control and prevent early postprandial hypoglycemia.     

Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes: a single-center, randomized, single-blind, 5-way crossover study

OBJECTIVE: This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus. METHODS: This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique. RESULTS: The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05). CONCLUSIONS: In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.     

Effect of conventional and intensified insulin therapy on free-insulin profiles and glycemic control in NIDDM.

OBJECTIVE--To investigate the effects on 24-h insulin and glucose profiles of two- and four-dose insulin regimens in patients with non-insulin-dependent diabetes mellitus (NIDDM) who have failed oral agent therapy. RESEARCH DESIGN AND METHODS--Ten patients with NIDDM and 10 matched nondiabetic control subjects took part in the study, a randomized crossover trial with 8-wk treatment periods. We determined 24-h profiles of blood glucose and free insulin in control subjects and patients when they were taking oral agents and at the end of each treatment period. The two-dose regimen was mixed (15% regular, 85% NPH) insulin given before breakfast and dinner, and the four-dose regimen was regular insulin given before meals and NPH given at 2200. RESULTS--Patients taking oral agents had higher mean blood glucose than control subjects (mean +/- SE 12.6 +/- 0.6 vs. 4.5 +/- 0.1 mM, P less than 0.0001) and similar 24-h insulin concentrations but lower postprandial insulin concentrations (at breakfast, 87.6 +/- 13.8 vs. 228.6 +/- 29.4 pM, P less than 0.01). Mean 24-h insulin concentrations were the same on two- and four-dose regimens, and both regimens caused basal hyperinsulinemia. Glycemic control also improved. Postprandial insulin peaks were higher at lunch and dinner on the four-dose regimen, and postprandial blood glucose was lower. Fasting proinsulin was elevated in patients compared with the control subjects (25.1 +/- 4.7 pM vs. 5.0 +/- 0.9 pM, P less than 0.001) and was suppressed to normal during insulin treatment. CONCLUSIONS--Two- and four-dose insulin regimens can achieve similar glycemic control. Both regimens cause basal hyperinsulinemia but normalize the hyperproinsulinemia observed during failure of oral agent therapy. Four-dose insulin regimens offer few advantages to the glycemic control achieved with two-dose regimens but may be more physiological.     

Effects of human insulin on insulin binding antibody production in nondiabetic subjects.

OBJECTIVE--To test the hypothesis that human insulin may have a low immunogenicity and that short-term exposure may not cause endogenous insulin antibody production. RESEARCH DESIGN AND METHODS--Randomized double-blind prospective study. Serum samples collected for insulin binding antibodies and measured by a sensitive immunochemical assay. Subjects were seven healthy nondiabetic patients who had never received exogenous insulin. Each subject received 6 separate monthly injections of human insulin. On four occasions, both regular and NPH insulin were administered. On the other two occasions, either NPH or regular insulin was administered alone. RESULTS--Mean +/- SE basal insulin antibody levels (1.2 +/- 0.2 micrograms/L) increased to a maximal level of 4.5 +/- 0.8 micrograms/L after four injections. Thereafter, antibody levels declined to an end-of-study value of 2.5 +/- 0.3 micrograms/L. This represented a highly significant overall increase (P less than 0.001). A control group of six insulin-dependent diabetic subjects treated with human insulin over the same period as the test subjects demonstrated no change in insulin antibody concentrations (2.8 +/- 0.7-2.7 +/- 0.6 micrograms/L). CONCLUSIONS--These results suggest that human insulin preparations, when administered subcutaneously, may be more immunogenic than previously considered. The antigenic response was rapid, because only four subcutaneous injections were sufficient to produce insulin antibody levels in nondiabetic patients similar to those observed in insulin-dependent diabetic patients receiving chronic insulin replacement therapy.