New developments in the treatment and monitoring of type 1 diabetes mellitus

In recent years, insulin analogues are the benefits of the use in functional intensive insulin therapy for the treatment of diabetes. Shortacting insulin (lispro, aspart and glulisine) and long-acting insulin (glargine and detemir) have been developed for the management of diabetes. Short-acting insulin analogues are an alternative to regular human insulin before meals. These new short-acting insulin analogues show more rapid onset of activity and a shorter duration of action. As a result of these pharmacokinetic differences, an improved postprandial glycemic control is achieved, without increasing the risk of hypoglycemia. In addition, these insulin analogues can be administered immediately before a meal. The long-acting insulin analogues provide basal insulin levels for 24 h when administered once (glargine) or two (detemir) daily. Compared with previous intermediate- or long-acting conventional insulin, these insulins shows a flat profile of plasma insulin levels . The use of these long-acting insulin analogues appears to be associated with a reduced incidence of hypoglycemia, especially at night. The availability of these new insulin analogues has the potential to significantly improve long-term control over blood glucose in diabetic patients. In recent years more and more frequently the method of multiple daily injections (MDI) of insulin is being replaced by the method of continuous subcutaneous insulin infusion (CSII). It is the most physiological way to administer insulin. In recent years treatment with insulin pumps has been used more frequently in the pediatric patients and in the treatment of diabetes in pregnancy. Use of continuous glucose monitoring systems enables detection of glycemia fluctuations unrevealed by selfmonitoring of blood glucose, such as night hypoglycemias and early postprandial hyperglycemias. Real-time systems allow to reduce HbA1c levels and limit number of excursions. Non-invasive glucose measurement devices are introduced. Fully automated continuous glucose monitoring systems integrated with insulin pumps operating in closed-loop model, requiring no patient assistance, are still being researched. Commercially available systems operate in open-loop model, where the patient has to decide on administration and dose of insulin.     

The Use of Premixed Insulin Analogues in the Treatment of Patients with Type 2 Diabetes Mellitus: Advantages and Limitations

Background:Intensive, target-oriented therapy is the standard of care in the management of patients with type 2 diabetesmellitus (DM). Early and aggressive use of insulin that is as close as possible to the physiologic pattern of insulin secretion from healthy pancreatic β-cells is advocated to achieve glycemic goals and reduce complications of DM.Objective:The objective of this article was to review the characteristics, advantages, and drawbacks of premixedinsulin analogues and to evaluate their role in the treatment of patients with type 2 DM.Methods:A PubMed search of articles from 1990 to 2006 was undertaken using the search terms type 2 diabetes, basalbolus therapy, premixed insulins, biphasic insulins, and insulin analogues. Pertinent content from relevant articles was extracted and combined with the authors' knowledge, experience, and clinical expertise.Results:The advent of insulin analogues has streamlined the treatment of patients with DM. When to initiate insulin during the course of treatment is the subject of much debate. Insulin therapy targeting both fasting and postprandial hyperglycemia is important in achieving optimal blood glucose (BG) control in patients with type 2 DM. A practical and feasible option is the use of >1 injection of premixed insulin analogues. Premixed insulin preparations provide both basal and prandial coverage because of their biphasic pharmacokinetic properties. Clinical trials have shown that these agents improve glycemic control, are associated with an acceptably low rate of severe hypoglycemia, and have a high degree of patient acceptance. Limitations include the inability to adjust the long- and short-acting components separately, to use a flexible regimen of self-titration and premeal bolus-insulin calculations, and to adequately treat postlunch and earlymorning BG elevations.Conclusion:Clinicians should be aware of premixed insulin analogues' advantages and limitations so that these agentscan be used appropriately in the treatment of patients with type 2 DM.     

Genetically engineered insulin and its pharmaceutical analogues

Studies of replacement therapy of diabetes mellitus resulted not only in introduction of series of forms of insulin available at pharmaceutical market but also in new insulin analogues, which exhibit better control of blood glucose level. The present paper deals with basic tendencies in this field.     

Insulin analogues - state of the art

The use of insulin analogues is rapidly expanding. At present, there are two short-acting analogues available for practical use, insulin aspart and insulin lispro, and one long-acting analogue, insulin glargine. Another long-acting analogue, insulin detemir, is still under development. The time action profile of short-acting analogues is both much more rapid and shorter than that of human insulin; the prominent feature of the long-acting analogues is their peakfree and fairly constant action. Insulin analogues offer alternative options for the whole spectrum of insulin therapy in type 1 and type 2 diabetes patients. The perception by many patients is strikingly positive, in particular regarding the overall quality of life. In objective efficacy terms, however, the potential to improve the degree of metabolic control appears to be only minor, yet demonstrable, provided the analogues are used according to their specific time action profile. This ensured, analogues are instrumental in minimizing the side effects of insulin therapy, i.e. the risk of (nocturnal) hypoglycaemia or problems with body weight control. Although there are no indications of safety concerns with insulin analogues, the availability of long-term outcome data based upon observations in human patients would be very valuable.     

Taurine-diabetes interaction: from involvement to protection

Taurine is a sulfur amino acid (2-amino ethane sulfonic acid) and has been claimed for a number of beneficial actions ranging from anti-epilepsy to anti-hypertension. Taurine in diabetes has an age old story; taurine is involved in the development and protection of insulin apparatus. Taurine and insulin both have mutual stimulating actions with hypoglycemic properties. On the clinical front, taurine supplementation has an acceptable beneficial effect in platelet aggregation and, to name few more, in neuropathy, cardiomyopathy, and nephropathy to retinopathy. Recent studies have provided a role for taurine in fetal development and in blocking the transfer of diabetes from diabetic mother to offspring. A number of mechanisms for the actions of taurine have been advocated, from osmoregulation to anti-oxidation. Though sulfonylurea and recently introduced thiazolidinediones are effective, however they are not free from complications, thus there is a need to design new therapeutics. As taurine is also a sulfonyl derivative, it will be of great interest to develop taurine analogues as an alternative therapy. Considering the great involvement of taurine in diabetes, this review may provide a holistic view of taurine in diabetes and in its prevention in this century.     

联合应用甘精胰岛素和门冬胰岛素治疗儿童1型糖尿病疗效初步观察

目的:观察联合应用甘精胰岛素和门冬胰岛素治疗儿童1型糖尿病(type1diabetes mellitus,T1DM)的临床效果。方法:比较12例采用传统治疗方案(诺和灵30R,2/3量早餐前半小时皮下注射,1/3量晚餐前半小时皮下注射)的T1DM患儿,改用3+1治疗方案(3餐前0-15分钟诺和锐皮下注射,睡前来的时皮下注射)治疗后HbA1c水平、低血糖发生和胰岛素用量变化。结果:12例T1DM患儿改用3+1方案治疗时HbA1c基础值为9.51±0.71%,治疗后3个月时为9.12±0.82%,6个月时为8.61±0.87%、9个月时为8.71±0.68%、12个月时为8.65±0.79%。换用3+1方案治疗后第6、9、12个月时HbA1c值较基础值明显降低,差异有统计学意义(P<0.05)。每日胰岛素用量由1.1±0.8U/kg降至1.0±0.5U/kg,差异无统计学意义。传统方案治疗期间,6例次发生过严重低血糖,改用3+1治疗方案后,无1例发生严重低血糖。轻中度低血糖的发生次数由2.2±0.1次/周降至1.3±0.1次/周,差异有显著统计学意义(P<0.001)。结论:采用传统治疗方案治疗的T1DM患儿,改...     

Introduction of mutations to the insulin molecule: Positive and negative mutations

Introduction of mutations in the insulin molecule is one of the important approaches in drug development for treatment of diabetes mellitus. Generally, mutations are used to activate interactions between insulin and the insulin receptor. Such mutations can be considered as positive. Mutations that reduce the binding efficacy are negative. Neutral mutations also exist. This paper considers both natural mutations typical for various members of the insulin superfamily and artificial ones which are introduced to improve pharmacological characteristics of insulin. Data summarized here can be useful for subsequent developing of new effective insulin analogues for treatment of diabetes mellitus.     

FGF1:一种治疗糖尿病的新型潜在药物

糖尿病是一种常见的内分泌代谢性疾病,它及其并发症的治疗是现代医学仍未解决的难题。常见的药物治疗有诸多不良反应,譬如胰岛素的长期使用会产生胰岛素耐受性。近年研究发现,酸性成纤维细胞因子（Fibroblast growth factor 1,FGF1或aFGF）及其衍生物能够使2型糖尿病小鼠的血糖快速恢复至正常水平,并且具有胰岛素增敏效果,规避了胰岛素治疗产生耐受性的问题。因此,人们对FGF1及其衍生物在开发新型T2DM疗法方面给予诸多期待。该综述系统介绍了FGF1的结构与功能、降糖功效的机制及新发现,对FGF1的2种注射方式和FGF家族在降糖作用方面进行了比较,并对FGF1在治疗糖尿病方面的研究进程进行展望,旨在为调节血糖、解决胰岛素耐受性问题提供一种新的思路和方法。     

Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis

Background

Although insulin analogues are commonly prescribed for the management of diabetes mellitus, there is uncertainty regarding their optimal use. We conducted meta-analyses to compare the outcomes of insulin analogues with conventional insulins in the treatment of type 1, type 2 and gestational diabetes.

Methods

We updated 2 earlier systematic reviews of the efficacy and safety of rapid-and long-acting insulin analogues. We searched electronic databases, conference proceedings and “grey literature” up to April 2007 to identify randomized controlled trials that compared insulin analogues with conventional insulins. Study populations of interest were people with type 1 and type 2 diabetes (adult and pediatric) and women with gestational diabetes.

Results

We included 68 randomized controlled trials in the analysis of rapid-acting insulin analogues and 49 in the analysis of long-acting insulin analogues. Most of the studies were of short to medium duration and of low quality. In terms of hemoglobin A_1c, we found minimal differences between rapid-acting insulin analogues and regular human insulin in adults with type 1 diabetes (weighted mean difference for insulin lispro: –0.09%, 95% confidence interval [CI] –0.16% to –0.02%; for insulin aspart: –0.13%, 95% CI –0.20% to –0.07%). We observed similar outcomes among patients with type 2 diabetes (weighted mean difference for insulin lispro: –0.03%, 95% CI –0.12% to –0.06%; for insulin aspart: –0.09%, 95% CI –0.21% to 0.04%). Differences between long-acting insulin analogues and neutral protamine Hagedorn insulin in terms of hemoglobin A_1c were marginal among adults with type 1 diabetes (weighted mean difference for insulin glargine: –0.11%, 95% CI –0.21% to –0.02%; for insulin detemir: –0.06%, 95% CI –0.13% to 0.02%) and among adults with type 2 diabetes (weighted mean difference for insulin glargine: –0.05%, 95% CI –0.13% to 0.04%; for insulin detemir: 0.13%, 95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. There were insufficient data to determine whether insulin analogues are better than conventional insulins in reducing long-term diabetes-related complications or death.

Interpretation

Rapid-and long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycemic control or reduced hypoglycemia. Long-term, high-quality studies are needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.Diabetes mellitus is associated with serious long-term complications and premature death.¹ Data from the Health Canada National Diabetes Surveillance System indicate that, in 2004/05, diabetes was diagnosed in about 5.5% (1.8 million) of Canadians aged 20 years and older.² Because the disease goes undetected in many cases, the true prevalence may approach 1.9 million.³Tight glycemic control, to maintain a hemoglobin A_1c concentration of 7.0% or less, is recommended for all patients with diabetes to reduce the risk of long-term complications such as cardiovascular-related death, retinopathy and nephropathy.⁴ Insulin is indicated for all patients with type 1 diabetes and for patients with type 2 diabetes if adequate glycemic control cannot be achieved through exercise, diet or oral antidiabetic therapy.⁴Conventional insulins include regular human insulin and intermediate-acting neutral protamine Hagedorn insulin. However, these agents do not replicate the pattern of basal and postprandial endogenous secretion of insulin. Insulin analogues are modified human insulins developed to address this limitation.⁵ The rapid-acting insulin analogues insulin lispro, insulin aspart and insulin glulisine are marketed in Canada as bolus insulins; the long-acting agents insulin glargine and insulin detemir are marketed as basal insulins.⁶Systematic reviews of the insulin analogues have been published previously.^7–10 However, through our comprehensive search of the literature, we did not identify any reviews of long-acting insulin analogues in the management of type 1 diabetes or gestational diabetes. In this article, we provide an up-to-date, comprehensive systematic review and meta-analysis of outcomes associated with the use of rapid-and long-acting insulin analogues in type 1 and type 2 diabetes (adult and pediatric patients) and gestational diabetes. Detailed methods and complete results are reported elsewhere.^11,12     

糖尿病基因治疗的新进展

目前,糖尿病的基因治疗主要分为替代基因治疗、免疫基因治疗和调节基因治疗三部分.近年来,随着人们对糖尿病本质的深层次揭示和现代分子生物学手段的发展,糖尿病基因治疗的内容不断增加.如：对K细胞的新认识,发现了胰腺十二指肠同源异形盒基因1(PDX-1)的新价值及单链胰岛素类似物基因的构建成功等.另外,还利用各种方法来提高转染效率,增加安全性.如使用腺病毒(HD)载体,应用电穿孔法(electroporation)等.     

Selection for and initiation of continuous subcutaneous insulin infusion. Proceedings from a workshop

Continuous subcutaneous insulin infusion (CSII) has been used in the paediatric age group for more than 20 years. The technique is not yet widely used in most countries but there has recently been increasing interest in pump therapy for young children and adolescents. In 1999, 7.5% of Swedish children and adolescents with diabetes used pumps, now the figure is approaching 12%. The indication for starting pump therapy has usually been a medical problem, but today quality of life issues are becoming increasingly important. One technique sometimes used is to start CSII by wearing the pump only at night. Daily insulin requirements are usually decreased compared with injection therapy. Studies have shown that it is possible to lower HbA1c when using an insulin pump and that the risk of severe hypoglycaemia can be lowered. The use of CSII has also been successful in preventing recurrent admission for diabetic ketoacidosis. While starting pump therapy does take an extra effort from both the diabetes team and the family, routine visits are generally no more time-consuming than for patients on multiple injection therapy. CSII can be initiated during admission to hospital but most pumps are started on an outpatient basis. Our department has the patients on the day care ward for 3-4 days of 'pump school'. Parents wear a saline pump for practice. The total daily insulin dose is usually lowered 15-20% compared with multiple injections; on average 40-50% (sometimes up to 60%) of the daily dose is given as basal rate. We start all pumps on rapid-acting analogues and use 40 IU/ml if the basal rate is <0.3 IU/h. In conclusion, the use of CSII in children and adolescents is well accepted and can be managed safely.     

Cost-effectiveness of insulin analogues for diabetes mellitus

Background

Insulin analogues may be associated with fewer episodes of hypoglycemia than conventional insulins. However, they are costly alternatives. We compared the cost-effectiveness of insulin analogues and conventional insulins used to treat type 1 and type 2 diabetes mellitus in adults.

Methods

We conducted a cost-effectiveness evaluation of insulin analogues versus conventional insulins using the Center for Outcomes Research Diabetes Model. We compared rapid-acting analogues (insulin aspart and insulin lispro) with regular human insulin, and long-acting analogues (insulin glargine and insulin detemir) with neutral protamine Hagedorn insulin. We derived clinical information for the comparisons from meta-analyses of randomized controlled trials. We obtained cost and utility estimates from published sources. We performed sensitivity analyses to test the robustness of our results.

Results

For type 1 diabetes, insulin aspart was more effective and less costly than regular human insulin. Insulin lispro was associated with an incremental cost of Can$28 996 per quality-adjusted life-year. The incremental cost per quality-adjusted life-year was Can$87 932 for insulin glargine and Can$387 729 for insulin detemir, compared with neutral protamine Hagedorn insulin. For type 2 diabetes, insulin aspart was associated with an incremental cost of Can$22 488 per quality-adjusted life-year compared with regular human insulin. For insulin lispro, the incremental cost was Can$130 865. Compared with neutral protamine Hagedorn insulin, insulin detemir was less effective and more costly. Insulin glargine was associated with an incremental cost of Can$642 994 per quality-adjusted life-year. The model was sensitive to changes in the effect size of hemoglobin A_1c and to decrements applied to utility scores when fear of hypoglycemia was included as a factor.

Interpretation

The cost-effectiveness of insulin analogues depends on the type of insulin analogue and whether the patient receiving the treatment has type 1 or type 2 diabetes. With the exception of rapid-acting insulin analogues in type 1 diabetes, routine use of insulin analogues, especially long-acting analogues in type 2 diabetes, is unlikely to represent an efficient use of finite health care resources.Insulin agents available for the treatment of diabetes mellitus include conventional insulins and insulin analogues. Insulin analogues were developed to mimic more closely the separate bolus and basal components of insulin secretion.¹ Rapid-acting (bolus or mealtime) and long-acting (basal or background) analogue formulations are available. This new class of drugs has been promoted as providing more flexible treatment schedules and a reduced risk of hypoglycemia relative to conventional insulins.¹The cost of insulin analogues exceeds that of conventional insulins.^2,3 More than US$7.3 billion was spent globally on the purchase of insulin products in 2005 — an increase of 19% over the previous year.⁴ It has been suggested that the increased expenditure was due to both the increasing prevalence of diabetes and the increased use of insulin analogues.⁵We performed an analysis of the cost-effectiveness of insulin analogues compared with conventional insulins in the management of type 1 or type 2 diabetes in adults.     

Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus

The modern goals of insulin replacement in Type 1 and Type 2 diabetes mellitus (T1, T2DM) are A1C <6.5% long-term, and prevention of hypoglycaemia (blood glucose, BG <70 mg/dl). In addition to appropriate education and motivation of diabetic subjects, the use of rapid- and long-acting insulin analogues, is critical to achieve these goals. The benefits of rapid-acting analogues (lispro, aspart and glulisine have similar pharmacodynamic effects) compared with non-modified human regular insulin, are: (a) lower 1- and 2-h post-prandial blood glucose; (b) lower risk of late post-prandial hypoglycaemia (and therefore lower BG variability); (c) better quality of life (greater flexibility in timing and dosing of insulin). In T1DM, rapid-acting analogues improve A1C only by the extent to which replacement of basal insulin is optimized at the same time, either by multiple daily NPH administrations, or continuous subcutaneous insulin infusion (CSII), or use of the long-acting insulin analogues glargine or detemir. In T2DM, rapid-acting analogues reduce post-prandial hyperglycaemia more than human regular insulin, but systematic studies are needed to examine the effects on A1C. The benefits of long-acting insulin analogues glargine and detemir vs. NPH, are: (1) lower fasting BG combined with lower risk of hypoglycaemia in the interprandial state (night); (2) lower variability of BG. Glargine and detemir differ in terms of potency and duration of action. Detemir should be given twice daily in the large majority of people with T1DM, and in a large percentage of subjects with T2DM as well, usually at doses greater vs those of the once daily glargine. However, when used appropriately for individual pharmacokinetics and pharmacodynamics, glargine and detemir result into similar effects on BG, risk of hypoglycaemia and A1C. Rapid- and long-acting insulin analogues should always be combined in the treatment of T1 and T2DM.     

Experience with insulin analogues in children

Current data on rapid and long-acting insulin analogues in the paediatric age group is limited. While several studies indicate a benefit in reducing hypoglycaemia, particularly at night, with rapid or long-acting insulin analogue treatment, the effect on long-term glycaemic control remains controversial. The continuous glucose monitoring system offers a new option for tailoring treatment with insulin analogues to achieve optimal glycaemia. In 29 adolescents with diabetes this approach confirmed the non-inferiority of postprandial rapid-acting analogue administration compared to preprandial regular insulin, but revealed significant mealtime differences, with increased analogue requirement at breakfast and dinner. Although rapid- and long-acting insulin analogues may offer potential benefits for problems frequently encountered in paediatric diabetology, their value for the individual child still has to be tested in long-term observations in daily clinical practice.     

内脂素与2型糖尿病关系的研究进展

内脂素是新近被发现的主要由内脏脂肪合成的一种脂肪细胞因子,它具有类胰岛素样作用,能降低血糖和促进脂肪组织的分化与合成。内脂素还可以调节血管平滑肌的成熟和影响胰岛细胞的胰岛素的分泌,亦具有调节炎症反应和免疫功能的作用。随着研究的发展,人们对内脂素的结构特性、分布、表达调控及其生物学功能有了更加深入的认识。2型糖尿病是以胰岛素抵抗和糖代谢紊乱为特征的代谢性疾病,研究发现内脂素与2型糖尿病密切相关,其中与肥胖、胰岛素抵抗及胰岛素分泌方面的关系尤为显著,深入研究内脂素的生理和病理生理作用将会有力地促进对2型糖尿病的进一步认识、治疗与预防。     

Gene therapy for diabetes mellitus

There are diverse strategies for gene therapy of diabetes mellitus. Prevention of beta-cell autoimmunity is a specific gene therapy for prevention of type 1 (insulin-dependent) diabetes in a preclinical stage, whereas improvement in insulin sensitivity of peripheral tissues is a specific gene therapy for type 2 (non-insulin-dependent) diabetes. Suppression of beta-cell apoptosis, recovery from insulin deficiency, and relief of diabetic complications are common therapeutic approaches to both types of diabetes. Several approaches to insulin replacement by gene therapy are currently employed: 1) stimulation of beta-cell growth, 2) induction of beta-cell differentiation and regeneration, 3) genetic engineering of non-beta cells to produce insulin, and 4) transplantation of engineered islets or beta cells. In type 1 diabetes, the therapeutic effect of beta-cell proliferation and regeneration is limited as long as the autoimmune destruction of beta cells continues. Therefore, the utilization of engineered non-beta cells free from autoimmunity and islet transplantation with immunological barriers are considered potential therapies for type 1 diabetes. Proliferation of the patients' own beta cells and differentiation of the patients' own non-beta cells to beta cells are desirable strategies for gene therapy of type 2 diabetes because immunological problems can be circumvented. At present, however, these strategies are technically difficult, and transplantation of engineered beta cells or islets with immunological barriers is also a potential gene therapy for type 2 diabetes.     

Biotechnological and administration innovations in insulin therapy

The importance of the intensive control of blood glucose in patients with diabetes has been well documented in several large scale studies. Attempts to attain strict glucose control when managing diabetes have traditionally utilized daily subcutaneous injections of human insulin. This strategy has offered improvements in glycaemic control but is unable to replicate fully the normal diurnal plasma profile of endogenous human insulin. Advances in protein engineering techniques have, however, resulted in the formulation of a number of insulin analogues that offer more desirable properties of absorption from the subcutaneous depot and hence improved insulin profiles in patients with diabetes. Concurrent to the development of insulin analogues, devices to deliver insulin either subcutaneously or by other routes have also advanced. These novel delivery strategies are also likely to contribute to improved glycaemic control for patients with diabetes in the future.     

A case of insulin resistant diabetes with possible antibodies to insulin receptors.

A case of a 19-year-old, non-obese female with insulin resistant diabetes mellitus and polycystic ovary syndrome was reported. The maximal insulin requirement attained 360 units per day, but a satisfactory control of diabetes did not follow. The patient's serum contained not only anti-insulin antibodies, but also possible anti-insulin receptor antibodies which were demonstrated by the 125I-insulin binding test using insulin receptors derived from human placental plasma membrane. The insulin resistance in this case was assumed to be caused primarily by possible blocking antibodies to insulin receptors and partly by anti-insulin antibodies because of the following observations. First, high serum free insulin (165 microunits/ml) without hypoglycemia indicates the presence of insulin resistance due to other factors than antiinsulin antibodies. Second, the titer of 125I-insulin binding capacity of serum was not unusually higher than those seen in chronically insulin-treated diabetics. Third, immunologically heterospecies insulin (fish insulin) was also ineffective. The clinical features such as absence of ketoacidosis and association with polycystic ovary syndrome resemble those of an unique diabetic syndrome reported previously though acanthosis nigricans and endogenous hyperinsulinemia were not found in this case. Her insulin resistance remitted spontaneously and over the next 18 months' observation, her diabetes remained regulated without insulin therapy.     

Review on the in vitro interaction of insulin glargine with the insulin/insulin-like growth factor system: potential implications for metabolic and mitogenic activities

Insulin analogues provide clinically important benefits for people with diabetes, including more predictable action profiles and lower risk of hypoglycemia compared with human insulin. However, it has been suggested that certain insulin analogues may lead to greater activation of insulin-like growth factor-1 (IGF-1) signaling, with risk for adverse mitogenic effects. This article aims to critically review studies on the mitogenic effects of the insulin analogue insulin glargine (glargine) and its metabolites. A review of in vitro studies suggests that glargine may stimulate mitogenic activity in some cell lines at supraphysiological concentrations (nanomolar/micromolar concentrations). Mitogenicity appeared to be related to the expression of the IGF-1 receptor, being present in cells expressing high levels of the receptor and absent in cells with limited or no IGF-1 receptor expression. In animal studies, glargine did not promote tumor growth, despite administration at supraphysiological concentrations (nanomolar/micromolar), which are unlikely to be observed in clinical practice because the doses needed to produce these concentrations are liable to lead to hypoglycemia. Furthermore, glargine in vivo is rapidly transformed into its metabolites, the metabolic and mitogenic characteristics of which have been shown to be broadly equal to those of human insulin. Thus, the suggestion of increased relative mitogenic potency of insulin glargine seen in some cell lines does not appear to carry over to the in vivo situation in animals and humans.