Different absorption of isophane (NPH) insulin from subcutaneous and intramuscular sites suggests a need to reassess recommended insulin injection technique

The absorption of isophane (NPH) insulin from subcutaneous and intramuscular injection sites was measured in seven healthy volunteers using the euglycaemic clamp technique. Human Insulatard (Nordisk, Gentofte, Denmark) was administered in a dose of 0.25 U kg-body-weight-1 into the anterior compartment of the thigh. In random order injections were given either subcutaneously, via 12 mm needle at 45 degrees to the skin into a skinfold, or intramuscularly by 25 mm needle perpendicularly to the skin. Insulin concentrations rose more rapidly after intramuscular injection than after subcutaneous injection, being significantly higher as early as 60 min after injection (19.7 +/- 1.6 (+/- SE) vs 8.7 +/- 1.4 mU l-1; p less than 0.001). Thereafter insulin concentrations remained significantly higher for the remaining 360 min of study, reflected by a significantly greater area under the insulin concentration curve for the 420 min study (IM 8630 +/- 1256 vs SC 4908 +/- 465 mU l-1 min, p less than 0.05). A significantly greater quantity of infused glucose was required to maintain euglycaemia after intramuscular injection than after subcutaneous injection (923 +/- 256 vs 216 +/- 71 mg kg-1 min, p less than 0.05). These results demonstrate a striking difference in the pharmacokinetics of an isophane (NPH) insulin when injected into subcutaneous fat and muscle.     

Exercise augments the absorption of isophane (NPH) insulin

In order to determine the effect of exercise on the rate of absorption of an isophane (NPH) insulin, 7 normal men were studied on two separate occasions using the euglycaemic clamp technique. On one day subjects undertook 60 min of exercise on a treadmill (5 km h-1, 5 degrees slope) 180 min after injection of human isophane (NPH) insulin (0.25 U kg-1), while on the control day they remained at rest throughout the 420 min study. Serum insulin concentrations rose in parallel after injection achieving similar values at 180 min on exercise and control days (13.7 +/- 1.2 (+/- SE) vs 12.0 +/- 1.5 mU l-1; NS), respectively. After the onset of exercise, insulin concentrations rose markedly to a peak of 29.8 +/- 2.2 mU l-1 after 50 min of exercise (p less than 0.001), compared with a slight fall on the control day to 10.4 +/- 1.7 mU l-1 (NS). At the end of the exercise period, serum insulin concentrations returned rapidly to control day values. Glucose infusion requirements rose significantly during the exercise period from 2.8 +/- 0.5 mg kg-1 min-1 to a peak at 235 min of 11.1 +/- 1.2 mg kg-1 min-1 (p less than 0.001), compared with an increase on the control day from 2.0 +/- 0.6 to 2.5 +/- 0.6 mg kg-1 min-1 (NS) over the same period. These results demonstrate an enhanced rate of absorption of an isophane (NPH) insulin during exercise in normal subjects.     

Absorption of NPH (isophane) insulin in resting diabetic patients: evidence for subcutaneous injection in the thigh as the preferred site.

The absorption kinetics of NPH (isophane) insulin injected subcutaneously into the abdominal wall and subcutaneously (SC) and intramuscularly (IM) into the thigh was studied in 11 Type 1 diabetic patients. The thickness of the subcutaneous adipose tissue layer was measured by ultrasound. NPH (isophane) insulin injected IM into the thigh was absorbed faster than NPH insulin injected SC into the thigh (T50%, IM 8.0 +/- 0.6 h and SC 10.3 +/- 0.7 h, p less than 0.05). No difference in T50% values was found for injection into the abdominal wall (9.7 +/- 1.2h) compared with the thigh. The mean absorption rate from 1.5 to 13.5 h after injection was higher after injection IM into the thigh (6.4 +/- 0.3% of initial dose injected absorbed per h) than after SC injection into the thigh (5.2 +/- 0.3% h-1) and SC into the abdominal wall (5.1 +/- 0.3% h-1) (p less than 0.01). The most constant absorption rate was obtained after SC injection into the thigh (within-study day CV of the mean absorption rate 19.9 +/- 3.2% vs 34.4 +/- 3.2% after IM injection into the thigh and 27.1 +/- 4.9% after SC injection into the abdominal wall (p less than 0.02]. The study provides further evidence that the subcutaneous tissue of the thigh is the preferred injection site for NPH insulin.     

Study of porcine and human isophane (NPH) insulins in normal subjects

Summary The plasma glucose, C-peptide and insulin responses to subcutaneously administered highly purified porcine, semi-synthetic and biosynthetic human isophane (NPH) insulin and diluting medium as control in normal male subjects were evaluated. Porcine and semi-synthetic human NPH insulins were administered at two dose levels of 0.15 and 0.30 U/kg body weight and biosynthetic human NPH at 0.15 U/kg body weight only. At the low dose level the three insulin preparations resulted in a similar maximal hypoglycaemic effect within 3–5 h after administration. However, over the remainder of the 11 h post-injection period, the plasma glucose level was lower after semi-synthetic human insulin. In contrast, at the 0.30 U/kg dose level, there was no difference in the early or late hypoglycaemic response between porcine and semi-synthetic human NPH insulins of equivalent pharmaceutical formulation. The clinical relevance of these findings needs further evaluation. The data suggest that for the intermediate-acting NPH insulin preparations, both the species of insulin, nature and quantity of the retarding protein and their subsequent interaction may determine their time-action characteristics.     

Different insulin concentrations in resuspended vs. unsuspended NPH insulin: Practical aspects of subcutaneous injection in patients with diabetes

Aims

This study measured the insulin concentration (Ins_[C]) of NPH insulin in vials and cartridges from different companies after either resuspension (R+) or not (R?; in the clear/cloudy phases of unsuspended NPH).

Comparison of the effects on glucose and lipid metabolism of equipotent doses of insulin detemir and NPH insulin with a 16-h euglycaemic clamp

Aims/hypothesis The association of insulin detemir with non-esterified fatty acid binding sites on albumin may limit its transfer from the circulation into the extravascular extracellular space in adipose tissue and muscle, due to the capillary endothelial cell barrier. In the liver, the open sinusoids may expose hepatocytes to insulin detemir, enabling it to have a greater effect in the liver than in peripheral tissues.Methods We investigated the effects of equipotent doses of insulin detemir and NPH insulin on hepatic glucose rate of appearance (R_a), peripheral glucose rate of disposal (R_d) and glycerol R_a (a measure of lipolysis) using stable isotope techniques. We also investigated the effects of these insulins on NEFA concentrations in seven healthy volunteers during a 16-h euglycaemic clamp. A higher dose of insulin detemir was also studied.Results There was no difference in the glucose infusion profile between insulin detemir and NPH. Insulin detemir had a greater effect on mean suppression of glucose R_a (mean difference 0.24 mg kg^–1 min^–1; CI 0.09–0.39; p<0.01), and minimum glucose R_a, with minimum low dose detemir –0.10±0.15 mg·kg^–1·min^–1 and minimum NPH 0.17±0.10 mg·kg^–1·min^–1 (p<0.02). However, it had a lesser effect on mean suppression of NEFA concentrations (mean difference –0.10 mmol/l; CI –0.03 to –0.17; ANOVA, p<0.02) than NPH. The effect of insulin detemir on glucose R_d and glycerol R_a was not different from NPH. Following high-dose detemir, total glucose infused and maximum glucose R_d were higher (p<0.02, p<0.03) and plasma NEFA concentrations lower (p<0.01) than with low-dose determir.Conclusions/interpretation This study suggests that insulin detemir, when compared to NPH insulin, has a greater effect on the liver than on peripheral tissues and thus has the potential to restore the physiological insulin gradient.     

The action profiles of human NPH insulin preparations

The complete time-action profiles of four subcutaneously injected human NPH insulin preparations (Protaphane HM/Novo; Insulatard Human/Nordisk; Huminsulin Basal/Eli Lilly; Basal H-Insulin/Hoechst) have been investigated by means of the euglycaemic clamp technique (blood glucose 5.0 mmol l-1). Six normal male subjects were connected to a Biostator on five occasions in randomized order including a control study without insulin injection. A stable basal insulin level of about 10 mU l-1 was established by means of a low dose insulin infusion (0.1 mU kg-1 min-1) which subsequently suppressed C-peptide by 35 +/- 19% (mean +/- SD) to levels of around 0.3 nmol l-1. Twelve units of NPH insulin were injected subcutaneously into the abdominal wall and glucose infusion rates were monitored for 19 h. In the control study, the mean glucose infusion rate was 1.11 +/- 0.60 (range 0.32-1.95) mg kg-1 min-1. Maximal glucose infusion rates, reached 5-7 h after injection, were comparable (4.3-4.9 mg kg-1 min-1) for the four different preparations used. Glucose infusion rates returned to basal rates within the 19 h study period. Mean plasma free insulin levels peaked at 17.5-18.6 mU l-1 3-4.5 h after injection and returned to basal levels within 16 h. The time ranges of greater than 90, greater than 75, greater than 50, and greater than 25% of maximal insulin action (as estimated from glucose infusion rates) revealed no significant differences between the four insulin preparations tested. No significant insulin action was observed beyond 17 h after insulin injection of any preparation.     

A comparison of semisynthetic human NPH insulin and porcine NPH insulin in the treatment of insulin-dependent diabetes mellitus

Twenty-two insulin-dependent diabetic patients participated in a double-blind, cross-over study, where treatment with semisynthetic human NPH insulin (Novo Industri) was compared with porcine NPH insulin (Nordisk). Each treatment period lasted 8 weeks. Blood glucose level, glycosylated haemoglobin, insulin requirements, and frequency of hypoglycaemic events were compared. No difference was found in 24-hour blood glucose profiles. Fasting blood glucose level was 8.3 mmol/l during treatment with human insulin and 8.7 mmol/l during treatment with porcine insulin (p less than 0.1). Mean HbA1c was 7.7% at the end of study compared to 9.5% at baseline (p less than 0.01), but this decline in HbA1c was independent of the treatment regimen. Forty-six hypoglycaemic events occurred during treatment with human insulin compared to 39 events during treatment with porcine insulin. No difference was found regarding insulin requirements during the study. It is concluded that semisynthetic human NPH insulin is indistinguishable from porcine NPH insulin with respect to 24-hour blood glucose profile, HbA1c level and insulin dose requirements.     

Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study

Aims/hypothesis  This long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus. Methods  An open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for ≥3 months prior to study entry and a baseline HbA_1c level of 6.0–12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used. Results  Similarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was −1.98% (95% CI −7.02, 3.06%). Other measures of retinopathy—the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema—occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine. Conclusions/interpretation  This study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus. Trial registration  ClinicalTrials.gov NCT00174824 Funding  This study was sponsored by sanofi-aventis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

A comparison of insulin detemir and neutral protamine Hagedorn (isophane) insulin in the treatment of diabetes: a systematic review

The aim of this review is to summarize the clinical efficacy, tolerability and safety data of insulin detemir, and compare its use with that of neutral protamine Hagedorn (NPH) insulin in randomized controlled trials in people with type 1 or type 2 diabetes. A literature search was conducted with PubMed using predefined search terms. Studies were included if they met the following criteria: randomized, controlled trial, comparison of insulin detemir with NPH insulin, non‐hospitalized adults aged ≥18 years with either type 1 or type 2 diabetes, and study duration of ≥12 weeks. The following types of studies were excluded: non‐randomized controlled trials, studies of mixed cohorts of patients with type 1 or type 2 diabetes that did not report results separately, pharmacokinetic/pharmacodynamic studies, reviews, pooled or meta‐analyses or health‐economic analyses. Fourteen publications met the inclusion criteria. Nine studies in people with type 1 diabetes and three studies in people with type 2 diabetes, using insulin detemir in a basal–bolus regimen were included. Two studies were in people with type 2 diabetes using insulin detemir with oral antidiabetes medicines. In 14 studies of people with type 1 or type 2 diabetes, insulin detemir treatment provided similar or better glycaemic control, lower within‐subject variability, similar or lower frequency of hypoglycaemia and less weight gain when compared with NPH insulin.     

Impact of injection sites for soluble insulin on glycaemic control in Type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen

Summary The absorption rate of rapid acting (soluble) insulin is slow from the subcutaneous tissue of the thigh compared to intramuscular injection into the thigh and s.c. injection into the abdominal wall. The aim of the study was to evaluate the impact of soluble insulin injected either intramuscularly into the thigh (IMT), s.c. into the abdominal wall (SCA) or s.c. into the thigh (SCT) on glycaemic control in Type 1 (insulin-dependent) diabetic outpatients treated with the basal bolus insulin delivery regimen. Fifty-five, C-peptide negative Type 1 diabetic outpatients were included in a randomised 3-month intervention study. The insulin doses were adjusted frequently by blinded observers based on the patients' self-monitored blood glucose values and reported hypoglycaemic episodes. The serum fructosamine value was within normal limits in three patients in the IMT group, in six patients in the SCA group and in none of the patients in the SCT group following the intervention period (p<0.01). However, the difference in mean serum fructosamine values did not reach statistical significance (IMT: 1.24 mmol/l (95 % confidence interval; 1.17 to 1.31), SCA: 1.25 mmol/l (1.18 to 1.32), SCT: 1.34 mmol/l (1.26 to 1.41), (p=0.09)). Blood glucose excursions were larger in the SCT group than in the SCA and IMT group from post-lunch to pre-dinner measurements and from pre- to post-dinner measurements. A higher number of measured low nocturnal blood glucose values (less than 4 mmol/l) was observed in the SCT group (34 of 85) than in the IMT (14 of 64) and SCA (21 of 81) group (p<0.05). Three patients in the IMT group, two in the SCA group, and seven in the SCT group experienced severe hypoglycaemic episodes (p=0.14). In conclusion s.c. injection of soluble insulin into the abdominal wall is preferable compared to s.c. injection into the thigh in the basal bolus insulin delivery regimen. Furthermore, soluble insulin injection s.c. into the thigh during daytime has important clinical implications for the development of nocturnal hypoglycaemia independently of the NPH insulin injection at bedtime.     

Basal activity profiles of NPH and [Nɛ-palmitoyl Lys (B29)] human insulins in subjects with IDDM

Summary [N^e-palmitoyl Lys (B29)] human insulin is a fatty acid-acylated derivative of insulin with extended action compared to unmodified insulin when infused intravenously (i. v.) secondary to its binding to circulating albumin. The duration and activity profile of the acylated (A) and NPH (B) insulins were assessed following subcutaneous (s. c.) doses of (A) 6 nmol/kg and (B) 1.2 nmol/kg (equivalent to 0.2 U/kg) in 9 subjects with IDDM. After overnight i.v infusion of regular human insulin, morning glucose was (A) 6.9 ± 0.1 and (B) 6.8 ± 0.1 mmol/l. After the s. c. injection, i. v. human insulin or glucose was infused to maintain near-basal glycaemia and tracer glucose to assess hepatic glucose production (HGP). An activity profile was deduced for each study by expressing the glucose infusion rate at each time point, as a fraction (%) of the basal (measured) HGP, and the i. v. insulin infusion rate as a fraction (%) of the basal requirement. The two fractions are combined by adding the fractional glucose infusion rate and subtracting the fractional insulin infusion rate. Infusion rates of i. v. insulin in the morning were (A) 0.96 ± 0.096 and (B) 1.22 ± 0.09 pmol · kg^–1· min^–1. After insulin injection, i.v insulin requirements decreased and were below 10 % of basal between 100 and 150 min. A constant activity profile of 0 % represents a perfect substitution of the basal i. v. insulin infusion by the s. c. dose. The actual profile is defined by deviations from this (above) and was –17 ± 11, 7 ± 10, –9 ± 6 and –18 ± 18 % for [N^e-palmitoyl Lys (B29)] human insulin and 17 ± 12, 5 ± 6, –9 ± 15, 22 ± 18 % for NPH insulin at 3, 6, 9 and 12 h after s. c. injection. HGP was similar for the two insulins, demonstrating similar metabolic actions and profiles both peripherally and at the liver. [Diabetologia (1998) 41: 116–120] Received: 6 August 1997 and in revised form: 13 October 1997     

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique

Aims/hypothesis This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique.Methods In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments.Results In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC_{0–24 h}) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported.Conclusions/interpretation Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.     

Comparison of two twice-daily insulin regimens: Ultralente/soluble and soluble/isophane

Summary The relative efficacy of two twice-daily insulin regimens using highly purified insulins, once daily Ultratard with twice daily Actrapid (ultralente/soluble) and twice daily Actrapid with twice daily Retard (soluble/isophane), has been studied in 12 diabetics in a cross-over study. Control was optimised as an out-patient, and assessed by in-patient 24 hour profiles. Similar day-time glucose control was achieved, but the mean overnight plasma glucose concentrations were more steady on ultralente/soluble (0100, 0300, 0500, 0700, 0800 h values 5.6, 5.3, 5.8, 7.8, 10.4 mmol/l) than on soluble/isophane (4.3, 3.4, 5.2, 7.5, 12.2 mmol/l). The minimum overnight plasma glucose concentrations were lower (p < 0.05) on soluble/isophane (mean 2.8 mmol/l) than on ultralente/soluble (mean 4.8 mmol/l), associated with higher (p < 0.05) nocturnal free plasma insulin levels after the evening soluble/isophane injection. The plasma glucose rise between 0700 and 0800 h was greater (p < 0.05) on soluble/isophane than on ultralente/soluble. The morning insulin injection should probably be taken immediately on rising, to prevent the pre-breakfast plasma glucose rise. The ultralente/ soluble combination gave similar day-time plasma glucose control to soluble/isophane with less nocturnal hypoglycaemia.     

口服降糖药血糖控制不佳的2型糖尿病患者加用地特胰岛素或中效胰岛素治疗的疗效比较

目的 评估口服降糖药血糖控制不佳的T2DM患者联合地特胰岛素（Det）或中效胰岛素（NPH）治疗的有效性和安全性。方法80例血糖控制不佳的T2DM患者随机分为Det组和NPH组。在16周治疗期调整胰岛素剂量至FPG≤6．0mmol／L。记录治疗前后FPG、HbA,c、低血糖事件及体重。结果治疗16周,两组FPG及HbA-c均较基线下降,差异无统计学意义。Det组的体重增加明显低于NPH组,且低血糖风险减少42％。结论相比NPH,Det在有效控制血糖的同时,能降低低血糖发生风险及减少体重增加。     

Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients

Aims A European, randomized, 29‐centre, open‐label study compared the safety and efficacy of two formulations of insulin glargine and neutral protamine Hagedorn (NPH) human insulin, in combination with oral agents, in patients with Type 2 diabetes mellitus (DM). Methods Two‐hundred‐and‐four patients with Type 2 DM, in whom oral treatment alone was inadequate, were randomized to insulin glargine with 30 µg/ml zinc [insulin glargine (30)], or insulin glargine with 80 µg/ml zinc [insulin glargine (80)] or NPH insulin subcutaneously once daily. Insulin was titrated to aim for fasting blood glucose (FBG) values between 4 and 7 mmol/l. All participants received oral therapy during the 3‐week titration phase and 1‐week maintenance phase of the trial. Results No differences between treatment groups were observed in adjusted mean fasting plasma glucose; significant decreases of 3.4 mmol/l, 3.5 mmol/l and 3.1 mmol/l were observed within the insulin glargine (30), insulin glargine (80) and NPH insulin groups, respectively (P < 0.0001 in each case). No differences between groups, but significant changes within groups, were observed in self‐monitored FBG, mean FBG, blood glucose profile, stability of FBG, nocturnal blood glucose, fasting serum C‐peptide, non‐esterified fatty acids, haemoglobin A_1c, fructosamine and fasting serum insulin. A significantly greater proportion of NPH insulin patients experienced symptomatic nocturnal hypoglycaemia (19.1 NPH group vs. 7.3% glargine groups; P = 0.0123). Both insulins were well tolerated; one patient in each group experienced an injection site reaction. Conclusions Insulin glargine is as safe and effective as NPH insulin given once daily and in this study caused fewer episodes of nocturnal hypoglycaemia. Diabet. Med. 20, 545–551 (2003)     

Omitting breakfast and lunch after injection of different long-acting insulin preparations at bedtime: a prospective study in patients with type 2 diabetes

Aims/hypothesis  The aim of this prospective trial was to compare the effect of different long-acting insulin preparations injected at bedtime on glucose concentrations in patients with type 2 diabetes omitting breakfast and lunch the next day. Methods  Twenty patients (ten women) with type 2 diabetes who were on an intensified insulin therapy participated. Mean (±SD) age was 63 ± 10 years, diabetes duration 18 ± 9 years, BMI 32.5 ± 5 kg/m², and HbA_1c 7.3 ± 0.7%. Patients received neutral protamine Hagedorn (NPH) insulin, insulin detemir or insulin glargine for at least 2 months; doses were adjusted to achieve morning blood glucose levels of <7 mmol/l. At the end of the respective treatment period, the long-acting insulin was injected at bedtime (at 22:45 hours) as usual but patients refrained from breakfast and lunch the next day; glucose was measured by a continuous glucose monitoring system (CGMS). Results   Comparable glucose target ranges were reached at midnight (5.8 to 6.1 mmol/l) and at 07:00 hours (6.7 to 6.9 mmol/l) with all three insulin preparations, using mean doses of 29 ± 10 U (NPH insulin), 33 ± 13 U (insulin detemir), and 32 ± 12 U (insulin glargine). Glucose levels between midnight and 07:00 hours were not significantly different for the three insulin preparations. Symptomatic hypoglycaemia did not occur from 08:00 to 16:00 hours; glucose concentrations during this time were slightly lower with NPH insulin than with insulin detemir (p = 0.012) and insulin glargine (p = 0.049). Conclusions/interpretation  Following bedtime injection of NPH insulin or of the analogues insulin detemir or insulin glargine, fasting glucose <7 mmol/l was achieved in the morning, without subsequent hypoglycaemia when participants continued to fast during the day.     

Effect of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with Type 1 (insulin-dependent) diabetes mellitus

Summary These studies were undertaken to assess the influence of storage temperature of insulin vials on pharmacokinetics and pharmacodynamics of a mixture of lente insulin (Monotard HM) and regular insulin (Actrapid HM) injected subcutaneously. Seven subjects with Type 1 (insulin-dependent) diabetes mellitus were studied twice after overnight normalization of plasma glucose. A mixture of lente insulin (0.22 U/kg) and regular insulin (0.11 U/kg) was prepared from insulin vials kept either refrigerated (4 °C) or at room temperature (18 °C) and injected subcutaneoulsy (abdomen). Euglycaemia was maintained for the following 16 h by glucose infusion at variable rate. With refrigerated insulin, the plasma free insulin peak was greater (53±5 versus 45±6 mU/l) and occurred earlier (2.5±0.2 versus 6±0.3 h), and the glucose infusion rate showed a greater (16.5±1.2 versus 14.5±0.9 mol·kg^–1·min^–1) and earlier peak (3.2±0.2 versus 6±0.4 h) as compared to that occurring with the non-refrigerated insulin (p<0.05). However, 6 h after insulin injection, both plasma free insulin and glucose infusion rate were 30% lower with the mixture of refrigerated as compared to that of non-refrigerated insulin (p<0.05). In contrast, when NPH-insulin (Protaphane HM) was mixed with regular insulin and injected in 4 out of the 7 diabetic patients, the storage temperature of insulin vials had no effect on the pharmacokinetics and pharmacodynamics of the mixture. Thus, the storage temperature of insulin vials profoundly influences the effects of the mixture lente/regular insulin, but does not affect the pharmacokinetics and pharmacodynamics of the mixture NPH/regular insulin.     

Comparison of two commonly used insulin injection techniques

In ten patients with insulin-dependent diabetes we compared postprandial blood glucose levels and plasma free insulin concentrations after the administration of insulin mixtures with two commonly used injection techniques. The morning dose of insulin was administered once using a 13 mm needle, inserted perpendicularly, and once with a 20 mm needle, inserted deep subcutaneously just above the muscle fascia at an angle dependent on the skinfold thickness. Plasma free insulin concentrations and postprandial blood glucose levels were virtually identical for either technique. We conclude, therefore, that the simpler perpendicular method is the technique of choice, saving the diabetics much unnecessary anxiety over a daily procedure.