Insulin analogues in the management of diabetes

Insulin therapy has been strongly influenced by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), both of which support intensive antidiabetic therapy. Conventional insulin therapy can be limited, due to the difficulty in achieving tight glycemic control in people with diabetes, which is crucial to reducing the risk of long-term complications associated with diabetes. In recent years, three short-acting (insulin lispro, insulin aspart and insulin glulisine) and two long-acting (insulin glargine and insulin detemir) recombinant analogues of regular human insulin have been developed for the management of diabetes. Short-acting insulin analogues are an alternative to regular human insulin before meals. Compared with regular human insulin, these new short-acting insulin analogues show faster subcutaneous absorption, a 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, thereby synchronizing insulin administration and food absorption. The long-acting insulin analogue insulin glargine was developed to provide basal insulin levels for 24 h when administered once daily at bedtime. Compared with previous intermediate- or long-acting conventional insulin, insulin glargine shows a flat profile of plasma insulin levels with no prominent peak. The use of this long-acting insulin analogue appears to be associated with a reduced incidence of hypoglycemia, especially at night. Insulin detemir is another basal insulin that may reduce nocturnal hypoglycemia and variability in glycemic values. The availability of these new insulin analogues has the potential to significantly improve long-term control over blood glucose in diabetic patients.     

Application of polymeric nanoparticles and micelles in insulin oral delivery

Diabetes mellitus is an endocrine disease in which the pancreas does not produce sufficient insulin or the body cannot effectively use the insulin it produces. Insulin therapy has been the best choice for the clinical management of diabetes mellitus. The current insulin therapy is via subcutaneous injection, which often fails to mimic the glucose homeostasis that occurs in normal individuals. This provokes numerous attempts to develop a safe and effective noninvasive route for insulin delivery. Oral delivery is the most convenient administration route. However, insulin cannot be well absorbed orally because of its rapid enzymatic degradation in the gastrointestinal tract. Therefore, nanoparticulate carriers such as polymeric nanoparticles and micelles are employed for the oral delivery of insulin. These nanocarriers protect insulin from degradation and facilitate insulin uptake via a transcellular and/or paracellular pathway. This review article focuses on the application of nanoparticles and micelles in insulin oral delivery. The recent advances in this topic are also reviewed.     

Inhaled insulin for diabetes mellitus.

PURPOSE: Pharmacokinetic and safety data related to the use of inhaled insulin for the management of diabetes mellitus are discussed. The various pulmonary insulin delivery systems under development are also reviewed. SUMMARY: Several pharmaceutical companies are developing pulmonary insulin delivery systems. These products fall into two main groups: solution and drug powder formulations, which are delivered through different patented inhaler systems. Exubera, a rapid-acting insulin in powder form, has been studied extensively in patients with type 1 and type 2 diabetes mellitus. The AERx Insulin Diabetes Management System delivers a liquid form of human insulin. Preliminary data indicate that patients converting from insulin injections to this system showed higher compliance to therapy, demonstrated by improved glycemic control. Other pulmonary insulin delivery systems, including ProMaxx, AIR, Spiros, and Technosphere, are also under investigation. In humans, inhaled regular insulin is more rapidly absorbed than insulin from the subcutaneous injection site. The efficiency of inhaled insulin is lower than that of subcutaneous injection because pulmonary delivery of insulin involves some loss of drug within the inhaler or mouth during inhalation. A concern of many clinicians is the possibility of long-term effects from the intraalveolar deposition of insulin within the lung, since insulin is known to have growth-promoting properties. The long-term safety of these products has not been established. CONCLUSION: Several inhaled insulin products are under development. If these products receive marketing approval, the pulmonary delivery of insulin may offer patients with diabetes an alternative to repeated insulin injections.     

Clinical evaluation of inhaled insulin

Diabetes affects over 18.2 million individuals in the United States alone. Current therapy to treat type 1 diabetes relies on subcutaneous insulin administration either by injection or continuous infusion. In addition, patients with type 2 diabetes who fail lifestyle intervention and oral therapy require subcutaneous insulin. Optimal injection protocols to achieve tight metabolic control often prove burdensome to patients. Thus, development of pulmonary insulin delivery to supplement and/or replace subcutaneous insulin injections may be an effective alternative, allowing patients to achieve intensive diabetes management. This review will discuss the devices in development for the delivery of inhaled insulin. In addition, the efficacy of inhaled insulin in both type 1 and type 2 diabetic populations will be discussed. Finally, the available safety data with respect to the unique pulmonary effects of inhaled insulin will be covered.     

Insulin glargine: a new long-acting insulin product.

The pharmacodynamics, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of insulin glargine are reviewed. Current treatment regimens for patients with type 1 diabetes mellitus and some with type 2 are designed to provide a basal insulin level with intermittent preprandial insulin coverage. Insulin glargine precipitates after subcutaneous injection, slowing absorption. Insulin glargine is used as a basal insulin and exhibits a flat pharmacokinetic profile, with a duration of action of at least 24 hours. Hypoglycemia is the most commonly reported adverse effect, especially within the first four weeks after a switch to insulin glargine. Insulin glargine should not be mixed with any other insulin product and should be administered with a syringe that has not been used for other insulin products or other medications. Insulin glargine is administered once daily at bedtime. Patients previously receiving twice-daily isophane insulin (NPH) should receive an insulin glargine dosage 20% less than the total daily dose of NPH insulin. Clinical trials did not consistently show improvements in hemoglobin A1c levels when patients with type 1 diabetes mellitus were switched from NPH insulin once or twice daily to insulin glargine. Insulin glargine should be considered for patients who continue to have elevated morning blood glucose levels and problems with nocturnal hypoglycemia despite receiving NPH insulin at bedtime. In patients with type 2 diabetes mellitus, insulin glargine significantly improved glycemic control compared with once-daily NPH insulin, but not when it was compared with combined treatment with once- or twice-daily NPH insulin. Clinical trials assessing progression of retinopathy and nephropathy and comparing insulin glargine therapy with continuous subcutaneous insulin infusion therapy are needed to more clearly determine insulin glargine's role. Insulin glargine is a new long-acting formulation that can provide prolonged basal glucose control in patients with diabetes mellitus.     

Transdermal drug delivery systems in diabetes management: A review

Diabetes mellitus is a chronic disease in which there is an insufficient production of insulin by the pancreas, or the insulin produced is unable to be utilized effectively by the body. Diabetes affects more than 415 million people globally and is estimated to strike about 642 million people in 2040. The WHO reported that diabetes will become the seventh biggest cause of mortality in 2030. Insulin injection and oral hypoglycemic agents remain the primary treatments in diabetes management. These often present with poor patient compliance. However, over the last decade, transdermal systems in diabetes management have gained increasing attention and emerged as a potential hope in diabetes management owing to the advantages that they offer as compared to invasive injection and oral dosage forms. This review presents the recent advances and developments in transdermal research to achieve better diabetes management. Different technologies and approaches have been explored and applied to the transdermal systems to optimize diabetes management. Studies have shown that these transdermal systems demonstrate higher bioavailability compared to oral administration due to the avoidance of first-pass hepatic metabolism and a sustained drug release pattern. Besides that, transdermal systems have the advantage of reducing dosing frequency as drugs are released at a predetermined rate and control blood glucose level over a prolonged time, contributing to better patient compliance. In summary, the transdermal system is a field worth exploring due to its significant advantages over oral route in administration of antidiabetic drugs and biosensing of blood glucose level to ensure better clinical outcomes in diabetes management.     

Diabetes care: risk factors, prediction, prevention, and individualized treatment

Predictive medicine is a new philosophy in healthcare and an attractive subject for currently initiated research activities aimed at a potential application of innovative biotechnologies in the prediction of human pathologies, a development of well-timed prevention and individual therapy-planning. Diabetes care is one of the best examples of an absolute necessity for well-timed prediction, prevention and personalized treatment. Diabetes mellitus frequently results in diverse severe complications, such as retinopathy, nephropathy, silent ischemia, dementia, and cancer--the cascade of chronic complications appearing as "domino-effect". Promising approaches of differential plasma proteome, detection of circulating nucleic acids and gene expression profiling in circulating leukocytes are currently discussed for development of potent diagnostic, prognostic and therapeutic targets. Minimal invasive insulin administration approaches and/or improvement of pancreatic activity in own insulin production is the main goal of novel drug delivery systems highly desirable for advanced treatment of diabetic patients with both type 1 and type 2 of the disease. High potential of an application of novel gene therapy approaches in diabetes care is expected for such advanced technologies as gene repair by gene replacement therapies.     

New insulin analogues and routes of delivery: pharmacodynamic and clinical considerations

Analogues of human insulin have been developed to more closely replicate the physiology of meal-related and basal insulin secretion. Three rapid-acting analogues and two basal analogues are available for clinical use. Insulin aspart and insulin lispro have nearly identical pharmacokinetic and pharmacodynamic profiles and provide better postprandial glucose control and less hypoglycaemia (primarily nocturnal and severe hypoglycaemia in type 1 diabetes mellitus) than regular insulin. Insulin glulisine is a new rapid-acting analogue and has characteristics nearly identical to those of its predecessors. Insulin glargine was the first basal analogue approved for clinical use and has shown better fasting glucose control and less risk of hypoglycaemia than conventional human neutral protamine Hagedorn (NPH) insulin. More recent studies have indicated that insulin glargine may not be truly 'peakless' at higher doses and that the adjustment of dose timing and frequency may have favourable effects on the risk of hypoglycaemia and the duration of the effect. Insulin detemir is a new basal insulin analogue with superiority to NPH insulin similar to that demonstrated by insulin glargine, though its duration of action appears to be shorter. The intraindividual variability in the response to a given dose is lower for insulin detemir than for both NPH insulin and insulin glargine. The clinical significance of this finding is not clear, though it may contribute to the lower rate of hypoglycaemia seen with insulin detemir. A number of 'alternative routes' of insulin administration have been studied, the most promising of which has been the pulmonary route. The time-action profile of inhaled insulins is generally characterized by a rapid onset of action similar to those of rapid-acting analogues and a slightly protracted duration of action similar to that of regular insulin. Inhaled insulin is similar to regular insulin with respect to efficacy and safety, though small reversible changes in pulmonary function have been noted. For technical and practical reasons, other alternative routes have generally not met with clinical success.     

Insulin detemir: a long-acting insulin product.

PURPOSE: The pharmacology, pharmacokinetics, efficacy and tolerability, safety, drug interactions, dosage and administration, cost, and place in therapy of insulin detemir are reviewed. SUMMARY: Insulin detemir is a long-acting, neutral, and soluble insulin analogue with a lower within-subject variability of fasting plasma glucose levels than isophane insulin human (NPH insulin) and insulin glargine. The lower within-subject variability of insulin detemir may decrease hypoglycemic events, especially nocturnal events, and may contribute to a decreased incidence of weight gain. In vivo, insulin detemir is 98-99% bound to albumin-one of the mechanisms contributing to its long duration of action. Several open-labeled, randomized, multicenter trials have been conducted comparing the safety and efficacy of insulin detemir to NPH insulin in patients with type 1 or type 2 diabetes mellitus. In most trials, patients were randomized to receive insulin on three different dosing schedules: basal insulin twice daily before breakfast and at bedtime, basal insulin at 12-hour intervals, or basal insulin before breakfast and dinner. Mealtime insulin was given as part of the basal-bolus therapy. Glycosylated hemoglobin values were similar in patients receiving insulin detemir or NPH insulin. Insulin detemir appears to be well tolerated. The most common adverse effects reported during clinical trials were hypoglycemia, headache, dizziness, and injection-site reactions. CONCLUSION: Insulin detemir given once or twice daily as part of basal-bolus insulin therapy is at least as effective as NPH insulin in maintaining overall glycemic control in adult patients with type 1 or type 2 diabetes mellitus.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Insulin analogues and other developments in insulin therapy for diabetes

Diabetes mellitus is a common chronic disorder, which is increasing in prevalence on a global scale. Insulin replacement therapy is required for all people with Type 1 diabetes and for many with Type 2 diabetes, to correct the metabolic abnormalities of these disorders. However, the pharmacokinetics and glucodynamics of available insulins have numerous limitations. Problems include delayed absorption from subcutaneous absorption sites (soluble [regular] insulin), and wide variability of absorption characteristics (insulin isophane suspension [NPH] and insulin lente) that is influenced by the adequacy of resuspension, and by a variable and insufficient duration of action, which usually requires intermediate-acting insulins to be administered twice-daily. All insulin preparations are associated with the common side effect of hypoglycaemia, and encourage weight gain.     

Insulin analogues and other developments in insulin therapy for diabetes

Diabetes mellitus is a common chronic disorder, which is increasing in prevalence on a global scale. Insulin replacement therapy is required for all people with Type 1 diabetes and for many with Type 2 diabetes, to correct the metabolic abnormalities of these disorders. However, the pharmacokinetics and glucodynamics of available insulins have numerous limitations. Problems include delayed absorption from subcutaneous absorption sites (soluble [regular] insulin), and wide variability of absorption characteristics (insulin isophane suspension [NPH] and insulin lente) that is influenced by the adequacy of resuspension, and by a variable and insufficient duration of action, which usually requires intermediate-acting insulins to be administered twice-daily. All insulin preparations are associated with the common side effect of hypoglycaemia, and encourage weight gain.     

Can Insulin Therapy Delay or Prevent Insulin-Dependent Diabetes Mellitus?

Although the precise events preceding insulin-dependent diabetes mellitus (IDDM, type 1 diabetes) have not yet been elucidated, it is known that IDDM results from a slow, progressive, immune process directed against pancreatic islet β cells. Disrupting this autoimmune process has been the focus of research aimed at preventing or slowing the disease progression. Technologic advances in predicting the onset and likelihood of developing IDDM have made it possible to study the effects of early immune intervention. The National Institutes of Health recently launched a large-scale, multicenter trial to evaluate the effectiveness of insulin as preventive therapy. Although many different immunosuppressive and immunomodulating agents have been investigated, the use of insulin as a prophylactic agent is a fairly recent concept. Several methods have been used to halt the autoimmune destruction of the pancreas, with animal and human studies serving as the basis for insulin in preventing IDDM.     

Diabetic retinopathy: a clinical study with special reference to fluorescein angiography

The present study was conducted on 25 patients with Diabetes Mellitus (DM) having positive indication of diabetic retinopathy on ophthalmoscopic examination. The patients were examined clinically, ophthalmoscopically and with Fluorescein Angiography (FA). It was found that the maximum number of patients with retinopathy were in their 5th and 6th decade and that retinopathy was more common in Non Insulin dependent diabetics (NIDDM) than Insulin dependent Diabetics (IDDM). It was also seen that retinopathy takes longer time to develop in IDDM patients (16.37 years vs 11.7 years). Proliferative diabetic retinopathy was more common with patients having poor glycemic control and in IDDM patients. FA was very helpful in detecting microaneurysms and for exact localization of neovascularization, and other microangiopathic lesions as well as for permanent record.     

Management of type-1 and type-2 diabetes by insulin injections in diabetology clinics - a scientific research review

Better control of the diabetic metabolic state will prevent the diabetes complications. However in current clinical practice, it is sometimes difficult to achieve this goal. Additionally, physicians find themselves in an equivocal position to initiate insulin therapy, its selection, combining with Oral agents and further management. The current article was written to focus on diabetes pathogenesis at molecular level, its classification and management by insulin injections. Knowledge of basic biochemistry, pharmacology with kinetics of Insulin is essential for diabetes management. Nonetheless, it should be a priority to search for evidence based clinical methodologies for selecting the patients for initiating, modifying or combining the insulin therapy. Type-1 diabetic patients are best controlled on basal bolus insulin regimens. However in type-2 diabetes, metformin with lifestyle modifications should be the first line therapy, thereafter combined with oral hypoglycemic agents or shifting to insulin gradually if diabetes remains uncontrolled. Metformin is recommended to be prescribed with insulin as compared to oral hypoglycemic agents which should be discontinued while starting insulin. Monitoring the insulin therapy on regular visits to diabetologist and diabetes multidisciplinary team remains the integral part of diabetes management. The review also outlines relevant and recent insulin analogue patents for the management of Diabetes.     

三种长效基础胰岛素类似物的研究进展

糖尿病是一种威胁全世界的慢性病,其发病率高,影响人们的生活和工作。随着DNA重组技术的发展,长效基础型胰岛素类似物为糖尿病患者带来了希望,其中甘精胰岛素（IGla）、地特胰岛素（IDet）以及德谷胰岛素（IDeg）是临床上常用的3种基础型胰岛素,通过改变结构获得了缓慢的吸收和分布,以及相对较长的作用时间,更符合人体分泌胰岛素的生理模式。对这3种胰岛素制剂在分子结构以及长效作用机制、安全性评价和药效作用方面的研究进展进行总结。     

The insulin receptor concept and its relation to the treatment of diabetes

The initial step in insulin action is binding to specific receptors. Two covalent receptor modifications possibly involved in producing pharmacodynamic effects as a result of insulin receptor binding are autophosphorylation and disulphide insulin binding. Insulin receptor numbers are 'down regulated' by insulin, but this effect may be minimised by pulsatile insulin secretion. Insulin receptor affinity is modulated rapidly by fasting, exercise and dietary composition. In non-insulin-dependent diabetes coupling of receptor binding to bioeffects is impaired. Binding is also reduced in those subjects with hyperinsulinaemia and non-insulin-dependent diabetes. Insulin-dependent diabetics have reduced insulin sensitivity, which is only partially reversed by conventional insulin therapy. 'Post-binding defects' in some diabetics could be related to defective covalent receptor modifications resulting from genetic receptor defects. High carbohydrate diets improve diabetes control through effects on the binding and coupling defects. In addition to stimulating insulin secretion, oral hypoglycaemics stimulate post-binding insulin action in vivo and in vitro. Insulin therapy in diabetes also tends to reverse post-binding defects. Pulsatile insulin delivery is more effective in lowering blood sugar than continuous administration, and produces less 'down regulation' of receptors. Combined insulin and sulphonylurea drugs reduce insulin requirements only in insulin-dependent diabetics with some endogenous insulin secretion, whereas metformin reduces insulin requirement in C-peptide negative insulin-dependent diabetes mellitus.     

Advances in insulin sensitizers

Insulin resistance is the major cause in Non Insulin Dependent Diabetes Mellitus (NIDDM). In this review insulin production from beta-cells and action of insulin is briefly described. Any intervention either in the production or action of insulin has been the leading cause of NIDDM. Therapeutic intervention to deal with the defective action of insulin at various receptor or target tissues has been outlined. Structure-activity relationship of a large number of thiazolidinediones, oxazolidinediones, isoxazolidinediones, biguanides, tetrazole derivatives, pyrazoles and pyrazolones, oxathiadiazole oxide, hydroxyurea and carboxylic acid derivatives have been described. The probable mechanism of action of these novel compounds through Peroxisome Proliferator-Activated Receptors that ameliorate the insulin resistance, has been described. Finally the clinical candidates at various stages of clinical evaluation have been compiled.     

Reassessment of external insulin infusion pumps.

OBJECTIVE: To discuss the potential role of continuous subcutaneous insulin infusion (CSII) therapy in patients with insulin-dependent diabetes mellitus (IDDM). DATA SOURCES: Published studies describing intensive insulin therapy are reviewed and evaluated. DATA SYNTHESIS: CSII delivers insulin at a preset basal rate and at bolus doses, when needed, throughout the day. Although this technology allows for greater lifestyle flexibility, the risks of hypoglycemia and ketoacidosis are also increased if the pump malfunctions. Studies have shown that CSII therapy may offer some advantages over conventional insulin therapy; however, the full impact of these benefits has yet to be determined. The National Institutes of Health has recommended seven commercially available insulin pumps for patient use. Cost ranges between $2000 and $3500; the average lifespan is about five years. CONCLUSIONS: CSII may be a viable alternative to multiple daily injections for maintaining glycemic control in patients with IDDM who require intensive insulin therapy.     

Intranasal insulin. Clinical pharmacokinetics.

Insulin administered nasally has considerable potential for the treatment of both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes. For patients with NIDDM it is possible to prevent preprandial hyperglycaemia and postprandial hypoglycaemia by employing a suitable and properly timed intranasal insulin dose. The low bioavailability of simple formulations of insulin can be greatly improved by using absorption enhancers or novel delivery systems such as bioadhesive microspheres. The need for nontoxic and nonirritant systems is stressed.