Long-acting Insulin Preparations Research Articles

How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers.

The therapeutic effect of basal insulin analogs will be sustained at a rather low insulin level. When employing healthy volunteers to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of long-acting insulin preparations by euglycemic clamp techniques, endogenous insulin cannot be ignored and sufficient endogenous insulin inhibition is crucial for the PD and/or PK assessment. This study aimed to explore a way to sufficiently inhibit endogenous insulin secretion. Healthy Chinese male and female volunteers were enrolled. After a subcutaneous injection of insulin glargine (IGlar) (LY2963016 or Lantus) (0.5 IU/kg), they underwent a manual euglycemic clamp for up to 24 h where the target blood glucose (BG) was set as 0.28 mmol/L below the individual’s baseline. Blood samples were collected for analysis of PK/PD and C-peptide. The subjects fell into two groups according to the reduction extent of postdose C-peptide from baseline. After matching for the dosage proportion of Lantus, there were 52 subjects in group A (C-peptide reduction<50%) and 26 in group B (C-peptide reduction≥50%), respectively. No significant difference was detected in age, body mass index, the proportion of Latus treatment and female participants. A lower basal BG was observed in group B compared to group A (4.35 ± 0.26 vs. 4.59 ± 0.22 mmol/L, p < 0.05). The clamp studies were all conducted with high quality (where BG was consistently maintained around the target and exhibited a low variety). The binary logistic regression analysis indicated low basal BG as an independent factor for the success of sufficient endogenous insulin suppression. In conclusion, setting a lower sub-baseline target BG (e.g., 10% instead of 5% below baseline) might be an approach to help achieve sufficient endogenous insulin suppression in euglycemic clamps with higher basal BG levels (e.g., beyond 4.60 mmol/L).

A comparative study between topical short and long-acting insulin preparations in management of wounds in diabetic patients

Wounds of diabetic patients often require weeks of adequate and appropriate care for full recovery. The use of systemic insulin in diabetic patients was reported to enhance wound healing. Thus, the present study was conducted to evaluate the effect of topical insulin on diabetic wounds. Our objective was to compare the effectiveness of topical short and long acting insulin combined with standard wound dressings in healing of wounds in diabetic patients. Thirty adult patients of both sexes from the outpatient settings of the General and Plastic surgery wards at Minia University Hospital were included in the study. Patients were assigned into three groups; control, patients applying short acting insulin and those applying long-acting insulin. The wounds were compared for healing time, inflammation and pain at days 0, 14, and 21. The mean age of patients included in the study was 58.9±5.3 years. The unit healing time for diabetic control group was 25.1±22.9 which was significantly higher than the two other groups (10.02±5.4 and 5.1±2.4, respectively) with no significant difference between topical short and long-acting insulin applying groups. Upon scoring of wounds, the long acting score of the short acting insulin was significantly lower than the control group at day 14 (p=0.001) while both topical insulin groups showed significantly reduced scores at day 21 compared to the control group (p=0.001 and p=0.009 for short and long-acting insulin, respectively). Both topical insulin treatments resulted in an acceleration of the wound healing process with no significant difference between short and long-acting insulin.

Compound traditional Chinese medicine in treatment of diabetes

Diabetes is a chronic disorder of glucose metabolism characterized by elevated blood glucose levels. With the improvement in living standards and the changes in lifestyle,T2 DM incidence has a dramatic increase in the past decades,bringing a series of public health problems. In the research and development field of diabetic drugs,T1 DM drugs are mainly long-acting sustained-release insulin preparations,whereas T2 DM drugs mainly are based on single target. T2 DM drugs usually have a good anti-hyperglycemic effect,but with side effects for long-term administration. Therefore,the research and development of hypoglycemic drugs focus on formula drugs with multi-component,multi-target and multi-pathway effects. In the similar principle of action,traditional Chinese medicine formula has achieved a good efficacy in the treatment of diabetes,with mild anti-hyperglycemic effects and multiple-component synergistic effects in intervening the pathogenesis of diabetes,including additive effect,synergy effect and toxicity scattering effect. This article mainly reviews clinical trials and mechanisms of action of traditional Chinese medicine formula for the treatment of diabetes,so as to provide a reference to the rational and effective clinical application of traditional Chinese medicine formula in treating diabetes.

Frequency of return visits to the emergency department in patients discharged following hypoglycemia episodes

BackgroundIn-hospital observation is typically recommended for patients who present to the emergency department with symptomatic hypoglycemia who are taking oral diabetes medications or long acting insulin. Individuals considered to be at low risk of further hypoglycemic episodes by treating providers are however on occasion discharged to home when a low suspicion of recurrence and close observation is available. We describe the frequency of hypoglycemia recurrence requiring further emergency department evaluation who have been recently discharged from the emergency department and are taking oral diabetes medications or long-acting insulin.MethodsA retrospective chart review was performed over a 2-year period of time at a large community-based academic emergency department for patients with an ICD-9 diagnosis of hypoglycemia who were taking oral or injectable diabetes medications. Patients were included with symptomatic blood sugar readings less than 55 mg/dL measured by prehospital or hospital providers. For those discharged from the emergency department, medical records from the study hospital and nearby health care facilities, Emergency Medical Service reports, and county death records were reviewed to determine recurrence of symptoms requiring care.ResultsThere were 196 patients discharged over the study period with 10 (5.1%) patients returning to the emergency department within 48 h with recurrent hypoglycemia. Return visits occurred in 4 of 144 taking insulin alone; 2.8% (CI 1.1–6.9%), in 3 of 19 patients taking oral agents alone; 15.8% (CI 5.5–37.5%), and in 3 of 33 patients taking both insulin and oral medications; 9.1% (CI 3.1–23.6%). Frequency of hypoglycemia recurrence requiring repeat ED visits was more common in those taking oral agents compared to individuals taking insulin alone (p = 0.04). All 7 individuals with recurrent hypoglycemia who were taking insulin were taking long-acting insulin preparations. No discharged patients were identified on Emergency Medical Service refusal of care reports or county death records.ConclusionIndividuals discharged from the emergency department following hypoglycemic episodes who were taking oral diabetes medications are at a greater risk than individuals taking insulin alone of a return emergency department visit within 48 h for recurrent hypoglycemia.

Update on insulin treatment of dogs and cats with non-complicated diabetes mellitus

Diabetes mellitus is a common endocrine disease of dogs and cats. Treatment is mainly based on insulin administration and dietary modifications. The aim of this review is to provide updated information on insulin treatment of dogs and cats with non-complicated diabetes mellitus. During the last years, there has been significant progress in the management of this disease, thanks to the use of long-acting insulin preparations that do not cause pronounced fluctuations of blood glucose concentrations (insulin glargin and detemir) and because of the widespread use of home glucose monitoring by the owners of diabetic pets. Home glucose monitoring is based on capillary blood sampling from the ear pinnae or the foot pad and measurement of blood glucose concentration with a portable blood glucose meter. This can be done periodically (e.g. every week) to replace the traditional in-clinic blood glucose curve; in this case, blood glucose concentration is measured just before the morning insulin administration and then every 1-2 hours until the next dose (usually for 12 hours). Furthermore, especially for the cat, home glucose monitoring can be performed 3-5 times per day, on a daily basis, in order to safely adjust insulin dose and achieve tight control of hyperglycemia (i.e. blood glucose concentration between 50 and 200 mg dl-1 throughout the day). The combination of dietary management, of insulin glargine or detemir administration and of the tight control of hyperglycemia has substantially increased the proportion of cats that enter into temporal or permanent diabetic remission and can be further managed without insulin. Another important achievement is the use of continuous glucose monitoring systems to monitor interstitial fluid glucose concentrations. These devices can be used in the clinic and at home and they can measure glucose concentration every 5 minutes for up to 72 consecutive hours, thus facilitating optimal adjustment of insulin treatment.

Addition of Insulin to Parenteral Nutrition for Control of Hyperglycemia.

Administration of parenteral nutrition (PN) may result in hyperglycemia in patients with preexisting diabetes or disease-related insulin resistance, and it can be associated with increased rates of complications. Treatment requires insulin therapy. Insulin can be administered subcutaneously, intravenously via a variable rate sliding scale, or by adding it directly to the PN. The last method is a potentially attractive technique for a number of reasons-it could deliver the insulin intravenously at a steady rate alongside carbohydrates, and in malnourished patients with little subcutaneous tissue, it may prevent the need for frequent insulin injections. Despite such potential advantages, the addition of insulin to PN remains controversial, largely with respect to the bioavailability of insulin in PN and resultant concerns of the risk of hypoglycemia. There is a paucity of long-term quality controlled studies to address this question. The available literature suggests that, at least in the short term, insulin addition to PN can achieve reasonable glycemic control with low rates of hypoglycemia, and the technique compares favorably with the use of long-acting insulin preparations. This literature review finds a wide range of values reported for insulin availability via PN, ranging from 44% to 95% depending on the type of PN container material used and the presence of added vitamins and trace elements. Few studies looking at glycemic control among patients receiving home PN were found, and larger prospective trials are needed to assess the efficacy and safety of this technique in this patient group.

Tratamiento de la diabetes mellitus (III). Insulinoterapia

IntroductionAfter the discovery of insulin, new insulin preparations have been developed that, together with technological improvements in glucose monitoring and in the knowledge of the physiological secretion of insulin, have allowed to design insulinisation guidelines according to the patients’ needs. Insulin preparationsRapid-acting insulin or prandials are administered before meals to avoid postprandial hyperglycaemia, intermediate-acting insulins combine basal and prandial components, and the analogous long-acting insulin preparations intend to mimick endogenous basal insulinemia. DM1There is an absolute insulin deficiency, therefore the treatment goal is to mimic, as closely as possible, physiological insulin secretion, by means of basal-bolus regimens, combining analogous long-acting and prandial insulin, or by means of continuous subcutaneous insulin infusion. DM2It is characterised by insulin resistance; its natural progression produces a gradual loss of the pancreatic beta-cell function, thus most patients end up requiring insulin treatment. It is introduced in a sequential manner and combined with other drugs and therapeutic measures.

Reversible Insulin Hexamer Assembly Promoted by Ethyl Violet: pH-Controlled Uptake and Release.

Therapeutically improved long-acting insulin preparations require in-depth understanding of the hexamer assembly, structural selectivity, and its stability in solution. This Letter demonstrates, for the first time, an efficient method for the hexamerization of human insulin by a structure-specific triphenylmethane (TPM) dye, Ethyl Violet (EV), particularly, in the absence of Zn2+. Upon detailed spectroscopic evaluation and comparison with other TPM homologues, we establish that the diethylamino phenyl arms of EV are specific and effective in clipping the three dimer helices in a hexameric assembly. We establish that at physiological pH 7.4 and in the presence of the EV, insulin exists predominantly in its hexameric form, a condition appropriate for storage and preparation of long-acting insulin formulations. On the other hand, the disassembly of the hexamer into the monomeric form is accomplished at pH 5, highlighting its potential as a delivery vehicle for such custom-modified dyes/drugs.

Safety and effectiveness of long-acting versus intermediate-acting insulin for patients with type 1 diabetes: protocol for a systematic review and individual patient data network meta-analysis

IntroductionThe choice of a basal insulin regimen to manage type 1 diabetes mellitus (T1DM) may have different risks of adverse events and effectiveness, due to the difference in the effectiveness...

Safety, effectiveness, and cost of long-acting versus intermediate-acting insulin for type 1 diabetes: Protocol for a systematic review and network meta-analysis

BackgroundType 1 diabetes mellitus (T1DM) causes progressive destruction of pancreatic beta cells leading to absolute insulin deficiency. Treatment of T1DM requires insulin, and some evidence suggests that longer acting insulin analogues might have a higher effectiveness and greater safety profile compared to intermediate-acting insulin. Our objective is to evaluate the comparative effectiveness, safety, and cost of long-acting insulin versus intermediate-acting insulin through a systematic review and network meta-analysis.Design/methodsStudies examining long-acting versus intermediate-acting insulin or placebo preparations for adult T1DM patients will be included. The primary outcome is glycosylated hemoglobin (A1C), and secondary outcomes include emergency department and physician visits, hospital admissions, weight gain, quality of life, microvascular complications (e.g., retinopathy), macrovascular complications (e.g., cardiovascular disease), all-cause mortality, incident cancers, and cost. We will include experimental [randomized clinical trials (RCTs), quasi-RCTs, non-RCTs], quasi-experimental (controlled before-after, interrupted time series), observational (cohort), and cost studies, of any duration of follow-up, conducted during all time periods, and disseminated in any language.We will conduct comprehensive searches of electronic databases from inception onwards, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. We will also search for difficult to locate and unpublished literature by searching dissertation databases, public health organization websites, and trial registries. After a calibration exercise using our eligibility criteria and data abstraction forms, two reviewers will screen all citations, full-text articles, and abstract data in duplicate. Conflicts will be resolved by team discussion. Using a similar process, the Cochrane Effective Practice and Organization of Care Risk of Bias tool will be used to appraise the risk of bias of experimental and quasi-experimental studies, while the Newcastle Ottawa Scale will be used to assess the methodological quality of cohort studies. If feasible and appropriate, we will conduct a random effects meta-analysis, as well as a network meta-analysis.DiscussionOur systematic review will be of utility to healthcare providers, policy-makers, T1DM patients and family members regarding treatment options of long-acting versus intermediate-acting insulin preparations.Trial registrationPROSPERO registry number: CRD42013003610

Effects of Add-On Treatment with Sitagliptin on Narrowing the Range of Glucose Fluctuations in Japanese Type 2 Diabetes Patients Receiving Insulin Therapy

In an earlier continuous glucose monitoring (CGM)-based study, we reported that sitagliptin not only reduced 24-h mean glucose levels but also suppressed postprandial glucose increases, thus reducing the range of glycemic fluctuations in type 2 diabetes patients. In this study, we investigated whether sitagliptin might provide similar benefits in type 2 diabetes patients receiving insulin therapy by using CGM. The study included a total of 13 type 2 diabetes patients in whom stable glycemic control had been achieved after admission for glycemic control. Insulin regimens used included long-acting insulin preparations once daily in four patients and biphasic insulin preparations twice daily in nine, with the daily insulin dose being 19.0±12.7 U. During the CGM-based study, the patients were given insulin therapy alone on Days 1 and 2 and were given sitagliptin 50 mg/day as add-on treatment on Days 3-6, with their daily insulin doses maintained. The add-on treatment with sitagliptin led to significant decreases in 24-h mean glucose levels and SDs of 288 glucose levels measured by CGM for 24 h, as well as in the indices for magnitude of glucose variability and proportion of time in hyperglycemia, compared with insulin therapy alone (P<0.01), whereas there was no significant change seen in regard to the proportion of time in hypoglycemia with or without add-on treatment with sitagliptin. This CGM-based study clearly demonstrated that insulin therapy alone, whether with long-acting or biphasic insulin preparations, does not provide adequate glycemic control in type 2 diabetes patients. In contrast, add-on sitagliptin was shown to narrow the range of 24-h glucose fluctuations in these patients, suggesting that add-on treatment with sitagliptin is effective for postprandial glucose control in type 2 diabetes patients receiving insulin therapy.

Characterization of Protamine Uptake by Opossum Kidney Epithelial Cells

Protamine, a mixture of polypeptides that is rich in arginine, has been used clinically as an antidote to heparin overdoses and a complexing agent in a long-acting insulin preparation. When protamine is administered intravenously, its abundant accumulation in the kidneys has been reported. However, the renal uptake mechanism for protamine is not clear. In this study, we examined the transport mechanism for protamine in opossum kidney (OK) cells, a suitable in vitro model for renal proximal tubular epithelial cells. Flow cytometric analysis revealed that the association of fluorescein isothiocyanate (FITC)-labeled protamine from salmon (FITC-protamine) by OK cells was inhibited by unlabeled protamine in a concentration-dependent manner. The association of FITC-protamine was temperature- and energy-dependent. Confocal microscopy analysis showed that the fluorescence was localized in the cytoplasm and nucleus of OK cells. In addition, FITC-protamine association was inhibited by cationic drugs such as polycationic gentamicin and polymixin B, but it was increased by a basic amino acid, arginine. Inhibitors for clathrin- and caveolin-dependent endocytosis showed inhibitory effects on FITC-protamine association. Pretreatment with heparinase III partially but significantly decreased the association of FITC-protamine. These results suggest that protamine may be taken up by OK cells via receptor-mediated endocytosis, which may result in its localization in the cytoplasm and nucleus of the cells.

The effects of increasing doses of 2 preparations of long-acting insulin on short-term plasma profiles of glucose and insulin in lactating dairy cows

Two experiments were conducted to investigate effects of administering increasing doses of 2 different preparations of long-acting insulin on the 24-h profiles of plasma glucose and insulin concentrations in mid lactation dairy cows. The 2 separately analyzed experiments investigated the effects administering either Humulin N (H), a neutral protamine Hagedorn insulin, or insulin glargine (Lantus, L), an insulin analog, at doses of 0 (control), 0.1, 0.2, and 0.4IU/kg of body weight in a randomized complete block design. Sixteen cows (237±11 d in milk for H; 213±10 d in milk for L; mean ± SD) were used for each insulin preparation, resulting in n=4 for each dose within insulin preparation. Cows were fitted with a single jugular catheter on the day before the study. On the day of the study, cows were given treatments by subcutaneous injection of either sterile water or the designated insulin type and dose. Blood samples were taken hourly from the jugular catheter. Subcutaneous injection of both H and L resulted in linear decreases in plasma glucose concentrations, increased area under the curve, and decreased nadir for plasma glucose following administration of the insulin preparations. Plasma insulin concentration linearly increased with increasing dose of H. Though elevated concentrations of insulin were measurable in cows treated with H, they were not measurable in cows treated with L. Attempts to measure overall insulin concentrations and metabolites of L by a commercially available ELISA and a commercially available RIA kit were not successful and did not retrieve values that we felt truly represented the amount of insulin activity exhibited during this treatment. Both long-acting insulin preparations elicited insulin-like activity in lactating dairy cows, as evidenced by reduced plasma glucose concentrations. Given these results, the potential exists to use both H and L to study the effects of insulin in mid lactation dairy cows without the confounding effect of severe hypoglycemia (<20mg/dL) or concurrent provision of glucose during treatment.

Blood Glucose Profiles in Diabetic Rodents Using Different Insulin Preparations

The aim of the present study was to evaluate several long-acting insulin preparations for their ability to normalize the blood glucose profile of rats and mice with streptozocin-induced diabetes mellitus. The single injection of a long-acting zinc insulin (CAS 8049-62-5) suspension or insulin glargine (CAS 160337-95-1) in both species induced a steep to moderate fall in blood glucose concentration. Blood glucose was then normalized for 2-3 h, until 3 h after insulin injection blood glucose concentration tended towards levels before insulin application. In contrast, implants produced with a mixture of human insulin and palmitic acid micro-crystals normalized blood glucose profile over 24 h in both species at least 30 days after implantation. Therefore, these implants with a sustained release of insulin are suitable to control the blood glucose in diabetic rats and mice.

Practical Aspects and Considerations When Switching Between Continuous Subcutaneous Insulin Infusion and Multiple Daily Injections

Insulin pump therapy is considered the gold standard for insulin management in patients requiring full physiologic insulin replacement. Compared to traditional delivery of short- and long-acting insulin preparations by multiple daily insulin injections, delivery of insulin via continuous subcutaneous infusion brings with it several advantages, which in the past have translated into better glycemic control and treatment satisfaction. Delivery of insulin via pump reduces the number needle insertions (from four or five per day to once every 2-3 days), allows for greater flexibility of insulin delivery with regard to both the basal and prandial component, facilitates portability of the insulin preparation, and allows for more accurate dosing. Continuous subcutaneous insulin infusion does have some drawbacks, including a greater risk of inadvertent insulin non-delivery, greater costs of therapy, and the need to be "tethered" with some systems that might be considered "burdensome" or even undesirable to some patients. For the most part patients who initiate insulin pump therapy are satisfied and continue using the technology, but there might be instances that arise that require the re-introduction of insulin delivery by pen or syringe. This article will review some of the reasons and strategies for switching from one mode of delivery to the other.

Diabète de type 2 sous schèma « basal-bolus »: les conséquences d’un jeûne diffèrent-elles selon le type d’insuline basale au coucher ?

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.

Increased insulin dose requirement of long-acting insulin analogues in obese patients with type 2 diabetes

To the Editor: Obesity, type 2 diabetes, insulin resistance and hyperinsulinaemia are associated with an increased risk of some types of cancer, and recent epidemiological data have refuelled discussions on the safety of insulin therapy [1]. The data published in the last issue of Diabetologia raise concern but do not provide evidence that any of the specific insulin preparations cause harm; there are too many confounders for which adjustment remains imperfect. Whether the potential risks of insulin preparations with increased affinity to type 1 IGF receptors are acceptable remains a matter of debate. We wish to point out that (apart from the intrinsic properties of an insulin preparation) higher levels of continuous insulin exposure resulting from the choice of insulin preparation should also be considered as a potential drawback. A similar (unit-based) glucose-lowering efficacy of NPH insulin and the long-acting analogues has been suggested, but it remains unclear whether this is also true for obese patients with type 2 diabetes. In our recently published prospective study comparing the effect of NPH insulin, insulin detemir (NN304) [B29Lys(e-tetradecanoyl),desB30 human insulin] and insulin glargine (A21Gly,B31Arg,B32Arg human insulin) injected at bedtime in patients with type 2 diabetes [2], each patient was sequentially treated with all three longacting insulin preparations. Comparable predefined glucose targets were achieved at midnight (00:00 hours) and in the morning (at 07:00 hours) with all three insulin preparations tested; none of them could totally prevent the rise of glucose between 05:00 and 08:00 hours. As mentioned (but not shown) in our communication, a trend for increased analogue (compared with NPH) insulin dose requirements (especially in obese patients on high total doses) to reach glucose targets was observed. The difference was significant in patients with a BMI of >30 kg/m, as shown in Table 1. In patients with type 2 diabetes, it has previously been reported that a higher dose of insulin analogues relative to NPH insulin is required to achieve similar glucose control, e.g. in the Treat-to-Target Trial, in which doses of insulin glargine were higher than those of NPH [3]. An increased insulin dose requirement compared with NPH insulin in patients with type 2 diabetes has also been reported for insulin detemir [4, 5]. Whereas such differences have not been found in all studies (e.g. in the LANMET study [6]), to the best of our knowledge, the opposite, i.e. a lower insulin dose requirement of the long-acting analogues compared with NPH insulin in patients with type 2 diabetes, has not been reported. Good glycaemic control and prevention of cardiovascular disease remain major goals when treating patients with type 2 diabetes. Lifestyle changes are difficult to achieve, C. Schmid Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland

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

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. 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/m(2), 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). 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). 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.

The role of insulin detemir in overweight type 2 diabetes management

The recent evidence-based shift towards an algorithm of early initiation and aggressive titration of insulin therapy in the management of type 2 diabetes requires the use of an effective insulin formulation that is both safe and acceptable to patients and physicians alike. The advent of the long-acting insulin analogues, insulin detemir and glargine, in the last decade has revolutionized insulin therapy in type 2 diabetes. Their unique pharmacokinetic and pharmacodynamic properties have offered tangible advantage over the conventional intermediate and long-acting insulin preparations in terms of improving glucose control as well as reducing risk of hypoglycemia and weight gain. This review focuses on the pharmacodynamic properties of the long-acting insulin analogue detemir, the outcome of studies on its relative efficacy and safety as well as its proposed place in the management of type 2 diabetes.

The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back

Glucose clamp studies assessing the time-action profile of long-acting insulin analogues have reported conflicting results. In an attempt to reconcile the data, we organised an expert meeting of four leading European clamp groups, during which consensus was reached on some but not all points discussed. In this paper, which reflects our personal views only, we aim to provide guidance for readers and reviewers on the interpretation of this type of clamp study and to clarify its inherent limitations.Glucose clamp studies are either performed manually or using an automated procedure, but differences in clamp methodology hardly seem a satisfactory explanation for the conflicting results. (Un)conscious investigator-related bias, especially during manual studies, cannot be ruled out, despite attempts at blinding the study insulin during the clamp.The duration of action of study insulins is influenced by many factors, such as glucose and insulin levels prior to injection, endogenous insulin secretion, insulin dose, definitions used for onset and end of action, and insulin sensitivity (which is influenced by the necessity of fasting during the clamp). These factors limit the translation of clamp study results into daily practice.Because of the inherent limitations of the glucose clamp technique and the lack of reproducibility of the outcomes, its results should be regarded as no more than an indication of the clinical action profile of long-acting insulin preparations.