Fast-acting Analogues Research Articles

Optimal Prandial Timing of Insulin Bolus in Youths with Type 1 Diabetes: A Systematic Review.

The aim of this systematic review was to report the evidence on optimal prandial timing of insulin bolus in youths with type 1 diabetes. A systematic search was performed including studies published in the last 20 years (2002-2022). A PICOS framework was used in the selection process and evidence was assessed using the GRADE system. Up to one third of children and adolescents with type 1 diabetes injected rapid-acting insulin analogues after a meal. Moderate-high level quality studies showed that a pre-meal bolus compared with a bolus given at the start or after the meal was associated with a lower peak blood glucose after one to two hours, particularly after breakfast, as well as with reduced HbA1c, without any difference in the frequency of hypoglycemia. There were no differences related to the timing of bolus in total daily insulin and BMI, although these results were based on a single study. Data on individuals' treatment satisfaction were limited but did not show any effect of timing of bolus on quality of life. In addition, post-prandial administration of fast-acting analogues was superior to rapid-acting analogues on post-prandial glycemia. There was no evidence for any difference in outcomes related to the timing of insulin bolus across age groups in the two studies. In conclusion, prandial insulin injected before a meal, particularly at breakfast, provides better post-prandial glycemia and HbA1c without increasing the risk of hypoglycemia, and without affecting total daily insulin dose and BMI. For young children who often have variable eating behaviors, fast-acting analogues administered at mealtime or post-meal could provide an additional advantage.

Influence of Preservatives on Insulin in Postmortem Blood: Application to a Case of Insulin Aspart Suicide.

Insulin aspart (NovoRapid®, NovoMix®, Novolog® and Fiasp®) is a fast-acting analog of human insulin, indicated in the treatment of type I and II diabetes. It is administered before meals to mimic the physiological insulin secretion that follows a rise in blood glucose. Its misuse for the purposes of suicide and murder and in the context of factitious order has often been described. In forensic medicine, the identification of insulin in biological samples has always been complex. In this paper, we present a case of suicide of a 64-year-old man who died after the injection of insulin aspart. He was suffering from terminal lung cancer and left a letter explaining the reasons for his suicide. Four empty NovoRapid® pens were found near the body. Body examination was unremarkable, and the femoral blood was collected in two dry Vacutainer™ tubes (red cap) and two sodium fluoride (NaF) tubes (gray cap). A liquid chromatography coupled to high-resolution mass spectrometry method was used to identify and discriminate insulin aspart from human insulin after immunopurification in the blood samples and in the pens. Blood specimens tested positive for insulin aspart with the concentrations of 36 and 37 ng/mL in dry tubes and 58 and 71 ng/mL in tubes containing NaF when tested ∼3 weeks after the collection of the specimens. The contents of the pens also matched with insulin aspart. The stability of insulin in blood is a critical point in the interpretation of the concentrations due to their rapid decrease caused by the activity of proteases in blood. During a degradation study implemented to compare three preservatives and dry tubes, suitable insulin aspart stability was observed with disodium salt of ethylenediaminetetracetic acid and NaF. Given that NaF is standard in forensic toxicology for measuring blood alcohol concentrations, the authors suggest its use for blood collection when insulin intoxication is suspected.

BrazIliaN Type 1 & 2 DiabetEs Disease Registry (BINDER): longitudinal, real-world study of diabetes mellitus control in Brazil.

This study aimed at assessing the patterns of care and glycemic control of patients with diabetes (DM) in real life during a follow-up of 2 years in the public and private health sectors in Brazil. BINDER was an observational study of patients >18 years old, with type-1 (T1DM) and type-2 DM (T2DM), followed at 250 sites from 40 cities across the five regions of Brazil. The results for the 1,266 participants who were followed for 2 years are presented. Most patients were Caucasians (75%), male (56.7%) and from the private health sector (71%). Of the 1,266 patients who entered the analysis, 104 (8.2%) had T1DM and 1162 (91.8%) had T2DM. Patients followed in the private sector represented 48% of the patients with T1DM and 73% of those with T2DM. For T1DM, in addition to insulins (NPH in 24%, regular in 11%, long-acting analogues in 58%, fast-acting analogues in 53%, and others in 12%), the patients received biguanide (20%), SGLT2-I (4%), and GLP-1Ra (<1%). After 2 years, 13% of T1DM patients were using biguanide, 9% SGLT2-I, 1% GLP-1Ra, and 1% pioglitazone; the use of NPH and regular insulins decreased to 13% and 8%, respectively, while 72% were receiving long-acting insulin analogues, and 78% fast-acting insulin analogues. Treatment for T2DM consisted of biguanide (77%), sulfonylureas (33%), DPP4 inhibitors (24%), SGLT2-I (13%), GLP-1Ra (2.5%), and insulin (27%), with percentages not changing during follow-up. Regarding glucose control, mean HbA1c at baseline and after 2 years of follow-up was 8.2 (1.6)% and 7.5 (1.6)% for T1DM, and 8.4 (1.9)% and 7.2 (1.3)% for T2DM, respectively. After 2 years, HbA1c<7% was reached in 25% of T1DM and 55% of T2DM patients from private institutions and in 20.5% of T1DM and 47% of T2DM from public institutions. Most patients did not reach the HbA1c target in private or public health systems. At the 2-year follow-up, there were no significant improvements in HbA1c in either T1DM or T2DM, which suggests an important clinical inertia.

An autopsy case of fatal insulin preparation overdose

Insulin preparations, a group of drugs used to treat diabetes, are of great forensic interest because they are difficult to detect in blood while they are sometimes intentionally administered in large doses for suicide or murder. In this study, we validated a quantification method for insulin glargine and insulin lispro using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the blood sample from a case of suicidal overdose with insulin. Case: A woman in her 30s had a history of mental illness and diabetes. A day before her death, she informed her partner that she had self-administered large doses of insulin preparations and prescription drugs. Bovine insulin was used as the internal standard (IS). The blood sample (250 μL) was added to the diluent and IS solution, followed by 250 μL each of hexane and N,N-dimethylformamide, and the mixture was centrifuged (10000 g × 10 min). The supernatant was collected and 900 μL of 5% ammonium solution was added. The extract was analyzed using Nexera 30A, LCMS8060 (Shimadzu), L-column3 ODS C18 metal-free column (150 × 2.1 mm, 3 μm), ionization method: electrospray ionization+, multiple reaction monitoring conditions: insulin glargine [M + 6H]6+ 1011.5 > 1179.4, insulin lispro[M + 6H]6+ 968.9 > 217.0, bovine insulin (IS) [M + 6H]6+ 956.3 > 1120.9. The autopsy revealed no evidence of fatal injuries. Coronary artery stenosis was observed as a finding of endogenous disease, but there were no significant histopathological changes in the myocardium. Biochemical tests revealed the following: blood glucose level, 6 mg/dL; glucose in the vitreous region, 6 mg/dL; glycated hemoglobin (HbA1c), 11.2%; blood insulin level estimated using the chemiluminescent enzyme immunoassay method, 1.03 μU/mL (6.27 pmol/mL); and C-peptide concentration, 0.6 ng/mL (16.8 pmol/L). A drug screening test and simple quantification using LC-MS/MS detected many prescription drugs, but none of them were at intoxicating concentrations. The insulin analysis showed insulin glargine concentrations of 429 μU/mL in femoral blood and 1362 μU/mL in cardiac blood, and insulin lispro was detected in femoral and cardiac blood below the lower limit of quantification (<50 μU/mL). The cardiac/peripheral blood ratio, a measure of postmortem redistribution, was 3.2. Although the therapeutic ranges of insulin glargine and insulin lispro have not been defined, the femoral and cardiac blood concentrations of insulin lispro in this case was lower than the serum concentration (155 μU/mL) listed in the package insert. However, while the femoral and cardiac blood insulin glargine concentrations were considerably higher than the serum concentration (15 μU/mL) listed in the package insert. Considering that insulin is easily degraded in whole blood due to hemolysis, it is possible that insulin concentrations were even higher at the time of administration and death than those observed in autopsy specimens on the third postmortem day. However, since insulin lispro is a fast-acting analog of insulin (1–3 hours), it may have contributed to hypoglycemia but was not the direct cause of death, and hypoglycemia due to insulin glargine overdose was the most likely cause of death in this case. We quantified insulin lispro and insulin glargine in a case of suicide to determine insulin glargine's involvement in causing death. In future, it is necessary to examine postmortem degradation and redistribution of insulin and consider the appropriate concentration in postmortem samples of insulin poisoning.

Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques

This study concerns glulisine, a rapid-acting insulin analogue that plays a fundamental role in diabetes management. We have applied a combination of methods namely X-ray crystallography, and biophysical characterisation to provide a detailed insight into the structure and function of glulisine. X-ray data provided structural information to a resolution of 1.26 Å. Crystals belonged to the H3 space group with hexagonal (centred trigonal) cell dimensions a = b = 82.44 and c = 33.65 Å with two molecules in the asymmetric unit. A unique position of D21Glu, not present in other fast-acting analogues, pointing inwards rather than to the outside surface was observed. This reduces interactions with neighbouring molecules thereby increasing preference of the dimer form. Sedimentation velocity/equilibrium studies revealed a trinary system of dimers and hexamers/dihexamers in dynamic equilibrium. This new information may lead to better understanding of the pharmacokinetic and pharmacodynamic behaviour of glulisine which might aid in improving formulation regarding its fast-acting role and reducing side effects of this drug.

Exploration of temperature and shelf-life dependency of the therapeutically available Insulin Detemir

PurposeInsulin, in typical use, undergoes multiple changes in temperature; from refrigerator, to room temperature, to body temperature. Although long-term storage temperature has been well-studied, the short term changes to insulin are yet to be determined.Insulin detemir (IDet) is a clinically available, slow-acting, synthetic analogue characterised by the conjugation of a C14 fatty acid. The function of this modification is to cause the insulin to form multi-hexameric species, thus retarding the pharmacokinetic rate of action. In this investigation, the temperature dependence properties of this synthetic analogue is probed, as well as expiration. MethodsDynamic light scattering (DLS) and viscometry were employed to assess the effect of temperature upon IDet. Mass spectrometry was also used to probe the impact of shelf-life and the presence of certain excipients. ResultsIDet was compared with eight other insulins, including human recombinant, three fast-acting analogues and two other slow-acting analogues. Of all nine insulins, IDet was the only analogue to show temperature dependent behaviour, between 20 °C and 37 °C, when probed with non-invasive backscatter dynamic light scattering. Upon further investigation, IDet observed significant changes in size related to temperature, direction of temperature (heated/cooled) and expiration with cross-correlation observed amongst all 4 parameters. ConclusionsThese findings are critical to our understanding of the behaviour of this particular clinically relevant drug, as it will allow the development of future generations of peptide-based therapies with greater clinical efficacy.

Characterisation of insulin analogues therapeutically available to patients.

The structure and function of clinical dosage insulin and its analogues were assessed. This included ‘native insulins’ (human recombinant, bovine, porcine), ‘fast-acting analogues’ (aspart, glulisine, lispro) and ‘slow-acting analogues’ (glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation velocity and equilibrium experiments, were employed to yield distributions of both molar mass and sedimentation coefficient of all nine insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also used to explore the function of these analogues. On ultracentrifugation analysis, the insulins under investigation were found to be in numerous conformational states, however the majority of insulins were present in a primarily hexameric conformation. This was true for all native insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir was a multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was present as a dimer-hexamer-dihexamer system. However, size-exclusion chromatography showed that the two hexameric fast-acting analogues (aspart and lispro) dissociated into monomers and dimers due to the lack of zinc in the mobile phase. This comprehensive study is the first time all nine insulins have been characterised in this way, the first time that insulin detemir have been studied using analytical ultracentrifugation and the first time that insulins aspart and glulisine have been studied using sedimentation equilibrium. The structure and function of these clinically administered insulins is of critical importance and this research adds novel data to an otherwise complex functional physiological protein.

Highlights from the Diabetes UK Professional Conference 2017

Highlights from the Diabetes UK Professional Conference 2017

One center in Brussels has consistently had the lowest HbA1c values in the 4 studies (1994-2009) by the Hvidoere International Study Group on Childhood Diabetes: What are the "recipes"?

The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications (retinopathy, neuropathy, nephropathy, cardiovascular disease, etc.) by maintaining blood glucose concentrations close to normal level. Glycated hemoglobin levels (HbA1c) provide a good criterion of overall glycemic control. The Hvidoere Study Group (HSG) on Childhood Diabetes, founded in 1994, is an international group representing about twenty highly experienced pediatric centers from Europe, North America, Japan and Australia. Four international comparisons of metabolic control (1995, 1998, 2005, 2009) have been performed. The one center that has consistently had the lowest HbA1c values (approximate 7.3% or 56.3 mmol/mol) is my center in Brussels. This is more often obtained with a twice-daily free-mixed regimen with additional supplemental fast insulins ad hoc. The so-called "Dorchy's recipes" are summarized. The conclusion is that the number of daily insulin injections, 2 or ≥ 4, or the use of pumps, by itself does not necessarily give better results. Intensified therapy should not depend upon the number of insulin doses per day, by syringe, pen or pump but rather should be redefined as to intent-to-treat ascertainment (i.e., goals). When there are no mutually agreed upon goals for BG and/or HbA1c, when there is insufficient education and psychosocial support by the medical team or at home, there is likely to be poor outcomes, as shown by the HSG. One of our recipes is not to systematically replace rapid-acting human insulins by fast-acting analogues. Because the multicenter studies of the HSG, performed in developed countries without financial restriction, show that treatment of childhood diabetes is inadequate in general and that levels of HbA1c are very different, diabetes treatment teams should individually explore the reasons for failure, without any prejudice or bias. Any dogmatism must be avoided. Treatment cost vs results must also be taken into account.

Near-infrared–actuated devices for remotely controlled drug delivery

A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained on-state drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

Preparation of monomeric B27 Lys destripeptide insulin by intein mediated expression in Escherichia coli

The B27K-DTrI insulin (human insulin with B28–30 removed and B27 Thr replaced by Lys) was reported to have superior monomeric property with 80% insulin activity in vivo. It has potential use as a new fast-acting analog of insulin. We cloned the monomeric insulin B27 DTrI precursor (MIP) into the pTWIN1 vector, and prepared by intein mediated expression in Escherichia coli. After tryptic digestion, the MIP was converted to B27K-DTrI insulin. The product was purified by HPLC. The mass spectrometry showed that the molecular mass of purified B27K-DTrI was consistent with the theoretical value.

Nasal absorption of mixtures of fast-acting and long-acting insulins

Mixtures of fast-acting and long-acting insulins were administered nasally to anesthetized, hyperglycemic rats in the presence and absence of tetradecyl-β- d-maltoside (TDM). The fast-acting analogs, aspart insulin, lispro insulin and glulisine insulin, were all rapidly absorbed from the nose when applied individually with 0.125% TDM ( T max = 15 min). One long-acting insulin analog, glargine insulin, was also absorbed from the nose when applied individually in the presence of 0.125% TDM ( T max = 60 min). The other long-acting insulin analog, detemir insulin, was not soluble when formulated with 0.125% TDM. A series of mixtures (1:1) of the three rapid-acting insulins and long-acting glargine insulin were formulated with 0.125% TDM and applied nasally. The pharmacokinetic and pharmacodynamic profiles of the insulin mixtures reflected the additive contributions of both the rapid-acting and the long-acting insulins. These results support the possibility of formulating certain insulin mixtures in tandem to provide nasal insulin products that match the needs of patients with diabetes mellitus better than those currently available.

Nuevas insulinas. Actualización

Standard human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. In the last decade, due to advances in genetic engineering, structurally modified insulin molecules have been developed with the aim of changing their galenic properties to make regular soluble insulin faster and NPH insulin slower. Five insulin analog preparations have become commercially available: two long-acting analogs (insulin glargine and detemir) and three rapid or fast-acting analogs (insulin lispro, aspart and glulisine). This article highlights the specific properties of these new insulin analog preparations and focuses on their potential advantages and disadvantages when used in children with diabetes mellitus.

Insulin Analog Preparations and Their Use in Children and Adolescents with Type 1 Diabetes Mellitus

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Inhaled insulin using AERx® insulin Diabetes Management System (AERx® iDMS)

Diabetes is a chronic, debilitating disease that afflicts millions of people worldwide and poor glycemic control in this disease leads to numerous microvascular and macrovascular complications. There is growing evidence that tight glycemic control prevents the development, and delays the progression, of microvascular complications and possibly macrovascular disease in patients with diabetes. All patients with Type 1 diabetes and many patients with Type 2 diabetes require intensive insulin therapy to achieve optimal glucose control. Although subcutaneous insulin therapy is the mainstay of insulin therapy, there are patients who fear needles and often refuse to start insulin therapy despite suboptimal glucose control. In these patients, inhaled insulin represents a non-invasive, painless method to administer intensive insulin treatment. The Novo Nordisk AS AERx® iDMS (insulin Diabetes Management System) for inhaled insulin is a novel device that administers an aerosol of liquid insulin into the deep lung with dose adjustments as precise as one subcutaneous unit. Initial pharmacokinetic and pharmacodynamic studies demonstrate that the device delivers liquid insulin in a clear dose–response manner and with a rapid onset of action similar to the fast-acting analog insulins. At present, large, long-term Phase III studies are in progress to document not only the efficacy, but also the safety and feasibility of this device in the treatment of patients with diabetes.

Comparison of dinner with bedtime administration of insulin glargine in type 1 diabetic patients treated with basal-bolus regimen

Objective To establish the equivalence in efficacy (HbA 1c) of insulin glargine injected at dinner versus bedtime in a large number of patients with type 1 diabetes using a fast-acting analogue (FAA) or regular human insulin (RHI) as prandial insulin in an insulin glargine-bolus regimen. Research design and methods In a 26-week trial, 1178 patients with type 1 diabetes and treated with different basal-bolus regimens were randomized to receive insulin glargine once daily at dinner ( n = 589) or at bedtime ( n = 589) while continuing their previous prandial insulin (FAA: 75%; RHI: 25% of patients). The primary objective was to demonstrate equivalence in terms of HbA 1c levels at endpoint. Results Baseline characteristics were similar in the two groups. At endpoint, HbA 1c (mean ± standard deviation [S.D.]) had decreased by 0.25 ± 0.66% to 7.77 ± 0.96% in the dinnertime group ( P < 0.0001), and by 0.24 ± 0.76% to 7.83 ± 1.07% in the bedtime group ( P < 0.0001). The HbA 1c difference between dinner and bedtime was –0.022% (two-sided 90% confidence interval [CI] –0.09; 0.05), demonstrating statistical equivalence of HbA 1c at endpoint between the two groups. Equivalence was also demonstrated within prandial groups: HbA 1c difference between dinner and bedtime was –0.03% (two-sided 90% CI: –0.11; 0.06) for FAAs and –0.04% (two-sided 90% CI: –0.19; 0.11) for RHIs. The incidence of severe hypoglycaemia did not differ between the treatment groups. Conclusion These data confirm that insulin glargine in combination with either FAA or RHI is equally effective and safe, whether it is administered at dinner or bedtime.

Insulin Glulisine Complementing Basal Insulins: A Review of Structure and Activity

The advancement in protein engineering offers targeted development of insulin analogs that display either faster absorption kinetics or longer time-action profiles compared with human insulin and, therefore, more closely mimic endogenous insulin secretion. Insulin glulisine (3(B)Lys29(B) Glu-human insulin) is a new fast-acting analog that provides absorption and onset of action more rapidly with a shorter duration of action compared with regular human insulin, and thus better resembles physiologic mealtime insulin requirements. Insulin glulisine has been designed to exhibit intrinsic stability while maintaining rapid deployment of insulin monomers. Pharmacokinetic and pharmacodynamic profiling of insulin glulisine in healthy subjects and patients with type 1 and type 2 diabetes not only confirms the rapid absorption and fast action of insulin glulisine compared with human insulin, but also provides evidence that the unique drug formulation may offer additional benefits. Insulin glulisine complements insulin glargine (21(A)-Gly30(Ba)-L-Arg-30(Bb)-L-Arg-human insulin), the first long-acting basal insulin analog that displays a smoothed time-action profile with a 24-h duration of action. Together these analogs offer patients a more physiologic approach to insulin replacement.

La Suppléance Insulinique : nouvelles insulines, nouveaux procédés d'administration

The demonstrated role of the tight control of hyperglycaemia for the prevention of long-term diabetic complications has reoriented the goals of insulin supply toward the search for restoration of the effects of physiological insulin secretion rather than the simple survival of insulin deficient patients and the reduction in the number of daily insulin injections to be performed. Normal blood glucose control requires the availability of a fast-acting insulin therapy at meal time in order to reduce hyperglycaemic excursions and a basal insulin therapy able to stabilize blood glucose between meals. Reduction of induced hypoglycaemic risk represents the secondary objective beside the main goal of avoiding hyperglycaemia. Fast-acting analogues, by a faster dissociation of their hexameric conformation after their injection or infusion in subcutaneous tissue, reduce post-meal hyperglycaemia, while their shortened duration of action versus regular insulin minimizes late post-absorptive risk of hypoglycaemia. Long-acting analogues, by their precipitation in subcutaneous tissue or their slowly reversible binding to albumin, provide a benefit on blood glucose stability versus NPH or zinc insulins. Continuous insulin therapy using pumps offers both a better blood glucose stability than multiple daily injections and a broader flexibility in life mode. Using the peritoneal route by implantable pumps is a mean to improve blood glucose stability in poorly controlled patients in spite of optimized subcutaneous insulin therapy. The development of glucose sensors provides reinforced information on blood glucose, versus self-monitoring by capillary blood measurements, that contributes to a better adaptation of insulin therapy. First trials of connections between blood glucose data and insulin delivery open a perspective toward glucose-modulated insulin therapy, at least in periods outside meals, leading to first models of semi-automated artificial endocrine pancreas. The alternative of a cellular insulin supply by pancreas or islet transplantation looked promising during recent years, but lack of transplants and adverse events related to immune suppression limit their use to very specific cases where benefit/risk ratio is positive.

Premixed insulin treatment for type 2 diabetes: analogue or human?

The progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Premixed insulin formulations containing both basal and prandial insulin (so called biphasic insulin) are often prescribed because they are superior to long- or intermediate-acting insulin in obtaining good metabolic control. In addition, they are considered as an attractive alternative to classical basal-bolus therapy as fewer daily injections are required. Premixed insulin formulations include conventional (e.g. biphasic human insulin 70/30, or 30/70 in European countries, BHI 30) and newer premixed human analogues (e.g. biphasic insulin aspart 70/30, or 30/70 in Europe, BIAsp 30; insulin lispro mix 75/25-Mix 75/25, or Mix 25/75 in Europe). Like conventional premixed human insulin, premixed insulin analogues contain a fixed proportion of soluble, rapid-acting insulin analogue, with protaminated analogue comprising the remainder. Unlike conventional premixes, analogue premixes have more physiological pharmacokinetic and therapeutically more desirable pharmacodynamic profiles than premixed human insulin. Consequently, postprandial glycaemic control is better with premixed insulin analogues than with premixed human insulin. In nontreat-to-target registration trials, the lowering of haemoglobin A(1c) with premixed insulin analogues was not inferior to that seen with premixed human insulin. Minor hypoglycaemia was similar for premixed analogue and premixed human insulins, while major hypoglycaemia appears to be rare with either formulation. The occurrence of adverse events, other than hypoglycaemia, was also similar between various premix insulins. The premixed insulin analogues, BIAsp 30 and Mix 75/25, like the fast-acting analogues from which they are derived, also allow flexible injection timing, relative to meal timing, thus improving adherence, compliance and quality of life compared with premixed human insulin. Overall, the evidence suggests that premixed insulin analogues are cost effective and have useful advantages over premixed human insulin for the treatment of type 2 diabetes.

Utilisation rationnelle des nouveaux analogues de l'insuline dans le traitement du diabète de type 1 chez les enfants et adolescents : expérience personnelle

In the last decade, four fast- and long-acting insulin analogues have been created. Due to the pharmacokinetic characteristics of insulin analogues, they provide an insulin profile closer to normal physiology than can be achieved with human insulins. However, they do not necessarily improve glycated haemoglobin, but they allow better quality of life. In the two daily insulin injection regime, fast-acting analogues are very useful to rapidly correct hyperglycaemia, to allow sleeping in and eating something sweet. In the basal-bolus regime (≥ 4 insulin injections), long-acting analogues reduce nocturnal hypoglycaemias and improve fasting blood glucose. In the two insulin regime (2 or ≥ 4 injections), rapid-acting human insulin must not be systematically replaced by a fast-acting analogue. On the other hand, insulin dose alteration must be triple: • retrospective, according to numerous previous experiments, in order to enjoy more freedom for meals, sports, etc.; • prospective according to programmed changes in meals and sports; • with only a “touch” of compensatory adaptation according to actual glycaemia.