Physiological Insulin Release Research Articles

Nanomedicine in the Treatment of Diabetes.

Nanomedicine could improve the treatment of diabetes by exploiting various therapeutic mechanisms through the use of suitable nanoformulations. For example, glucose-sensitive nanoparticles can release insulin in response to high glucose levels, mimicking the physiological release of insulin. Oral nanoformulations for insulin uptake via the gut represent a long-sought alternative to subcutaneous injections, which cause pain, discomfort, and possible local infection. Nanoparticles containing oligonucleotides can be used in gene therapy and cell therapy to stimulate insulin production in β-cells or β-like cells and modulate the responses of T1DM-associated immune cells. In contrast, viral vectors do not induce immunogenicity. Finally, in diabetic wound healing, local delivery of nanoformulations containing regenerative molecules can stimulate tissue repair and thus provide a valuable tool to treat this diabetic complication. Here, we describe these different approaches to diabetes treatment with nanoformulations and their potential for clinical application.

DPP4 Inhibitors Turnover is Important in Controlling Blood Glucose in Type 2 Diabetes

We should put into consideration that some humans are genetically more susceptible to develop type 2 diabetes than others. Of them, transcription factor 7-like 2 (TCF7L2) is the gene which is more accusative. Dipeptidyl peptidase 4 Inhibitors (DPP-4 inhibitors) are considered as a comparatively new class of anti hyperglycemic drugs, the first agent of this group was approved by FDA in 2006. This group known as gliptins work in a physiological manner, as we all know ,enteroendocrine l cells in the intestine produce glucagon-like peptide-1,a hormone acting on glp1 receptors on pancreatic beta cells, leading to physiological insulin release. Dpp 4 inhibitors are classified into 3 classes according to subsite interaction in the dpp4 enzyme. Materials and methods: 200 patients of type2 diabetes mellitus followed in a private clinic for 6 months in observational prospective study. Results: The results of our study show that turnover of dpp4 inhibitors in treatment of type 2 diabetes decrease hba1c and improve treatment outcomes. Conclusion: Dpp4 inhibitors turnover in diabetes mellitus treatment give a good control of type 2 diabetes better than using on drug for a long time.

Fast-acting insulin aspart - from insulin portraits to patient portraits

Postprandial hyperglycemia is an independent risk factor for cardiovascular disease (CVD). Bolus insulins aim to mimic the physiological action of endogenous insulin secreted in response to food intake to control peaks of postprandial glycemia (PPG). Ultrafast insulin aspart is insulin with a high rate of absorption into the bloodstream that is designed to mimic the physiological prandial release of insulin more accurately than currently available short-acting or ultra-short-acting insulin preparations. The high bioavailability of ultrafast insulin aspart was achieved through the addition of two excipients — nicotinamide and L-arginine. At the same time, L-arginine ensures the stability of the drug, and nicotinamide is responsible for the accelerated absorption of insulin after subcutaneous administration. The results of clinical studies showed that subcutaneous injection of ultra-fast-acting insulin aspart provided an earlier onset of action and a greater effect of lowering blood glucose levels compared with ultra-short-acting aspart. The use of ultrafast insulin aspart both with subcutaneous injections and with CSII provided better control of PPG compared to the analogue of ultra-short-acting aspart. Moreover, the use of ultra-fast-acting insulin aspart 20 minutes after the start of a meal was not inferior to the ultra-short-acting aspart administered before meals in terms of HbA1c control. This emphasizes the possibility of using ultra-fast insulin aspart both before and after meals, without impairing glycemic control.

Biofabrication of a vascularized islet organ for type 1 diabetes

Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin.

Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time-action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time-action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control.

Insulin.

Insulin.

Engineering β-cell islets or islet-like structures for type 1 diabetes treatment

Type 1 diabetes mellitus is a disease characterized by the destruction of the β-cells in the pancreatic islets of Langerhans. The current primary treatment for type 1 diabetes is insulin injections administered multiple times throughout the day. However, this treatment cannot provide sustained physiological release of insulin and the insulin amount is not finely tuned to the glycemia condition. Pancreatic transplantation or islet transplantation would be the preferred treatment strategy but the lack of donor tissue and immunoincompatibility has been shown to be a roadblock to their widespread use. Bioengineering strategies are poised to combat these challenges. Islet encapsulation is expected to offer both immunoisolation and immunomodulation effects by: (1) physically protecting islets from the attacks of immunoglobulins, complements, and host immune cells, and (2) delivering immune regulatory and immunomodulatory factors locally to the islets to protect those islets from immune rejection. Semi-permeable coatings using biocompatible biomaterials can be used for immunoisolating islets away from the host immune systems. Immunoisolation technology also provides an opportunity to use other cell sources for cell therapy to treat type 1 diabetes. Recently, some studies reported that co-transplantation of islets with mesenchymal stem cells (MSCs) can control graft inflammation. MSCs have immunomodulatory property. They are able to secrete anti-inflammatory factors and repress the activity of various immune cells. Growth factors like interleukin 10 (IL-10) and leukemia inhibitory factor (LIF) also have immune regulatory properties. Therefore immunoisolation and immunomodulation technologies can be integrated and applied to β-cell encapsulation for the treatment of type 1 diabetes. Through engineering β-cell islets or islet-like microtissues, the viability and function of transplanted β-cells may be improved. In the meantime, the survival of transplanted β-cells can be further improved by promoting vascular network formation surrounding the transplanted islets or microtissues.

Insulin aspart for the treatment of Type 2 diabetes

SUMMARY Insulin aspart is a rapid-acting insulin analog and is approved for use in Type 1, Type 2 and gestational diabetes. Following the subcutaneous injection, it more closely mimics the physiological release of insulin in the human body with a faster onset and shorter duration of action. It also offers several advantages like flexibility in mealtime administration, better glycemic control in the form of superior control of postprandial glucose excursion and less nocturnal hypoglycemia as compared with regular human insulin. It is safe to use in patients with renal and hepatic impairment and is approved for use in pregnancy, in children above 2 years of age, in continuous subcutaneous infusion pumps and can be used intravenously in hospital settings.

Progressive glucose stimulation of islet beta cells reveals a transition from segregated to integrated modular functional connectivity patterns.

Collective beta cell activity in islets of Langerhans is critical for the supply of insulin within an organism. Even though individual beta cells are intrinsically heterogeneous, the presence of intercellular coupling mechanisms ensures coordinated activity and a well-regulated exocytosis of insulin. In order to get a detailed insight into the functional organization of the syncytium, we applied advanced analytical tools from the realm of complex network theory to uncover the functional connectivity pattern among cells composing the intact islet. The procedure is based on the determination of correlations between long temporal traces obtained from confocal functional multicellular calcium imaging of beta cells stimulated in a stepwise manner with a range of physiological glucose concentrations. Our results revealed that the extracted connectivity networks are sparse for low glucose concentrations, whereas for higher stimulatory levels they become more densely connected. Most importantly, for all ranges of glucose concentration beta cells within the islets form locally clustered functional sub-compartments, thereby indicating that their collective activity profiles exhibit a modular nature. Moreover, we show that the observed non-linear functional relationship between different network metrics and glucose concentration represents a well-balanced setup that parallels physiological insulin release.

Hypoglycemia with New Generation Basal Analog Insulins: A Descriptive Critical Review

Optimizing the treatment of people with diabetes relies on balancing the benefits of glycemic control with the risk of hypoglycemia. Although insulin is essential for treating patients with type 1 diabetes mellitus (T1DM), patient and physician concerns regarding an increased risk of hypoglycemia can lead to delays in initiating insulin treatment in patients with type 2 diabetes mellitus (T2DM). This clinical inertia contributes to reduced glycemic control and poorer outcomes for patients. Advances in insulin agents have reduced the risk of hypoglycemia. In particular, the introduction of insulin glargine, the first basal analog insulin with a 24-hour glucose-lowering profile with no pronounced peak, represented a significant step towards achieving this goal. To further improve patient management, a number of insulin formulations and molecules are in development and are designed to have pharmacokinetic/pharmacodynamic (PK/PD) profiles allowing closer mimicking of normal physiologic insulin release. Here we review these new agents, and discuss their hypoglycemic risk as reported in clinical trials. In addition, the difficulties in making comparative evaluations from studies with different patient populations and definitions of hypoglycemia are discussed. Solutions to improve future clinical trials are suggested. In general, the improved PK/PD profiles of new generation insulins appear to result in better clinical outcomes in terms of hypoglycemia. What is needed are head-to-head trials using standardized methods and criteria to allow clinicians to compare hypoglycemia rates between insulins, and help them to discuss appropriate choices of therapy with their patients.

Ultra-fast acting insulin analogues.

Insulin analogues are a major improvement in diabetes pharmacotherapy. Rapid acting insulins have certain advantages over regular insulin, but there is a need to develop even faster acting insulin preparations, which mimic physiological insulin release in a better manner. This review discusses recent developments and patents in the field of Ultra- fast acting insulins. It classifies various approaches towards creation of an Ultra-fast acting insulin profile based upon the method used to achieve a faster onset of action. These include change in formulation of insulin, addition of excipients to insulin, and utilization of novel insulin sites or delivery methods. It examines the current state of evidence, and the developments in the field of newer insulin analogues & delivery methods.

Does the Timing of Insulin Pump Therapy Initiation After Type 1 Diabetes Onset Have an Impact on Glycemic Control?

Continuous subcutaneous insulin infusion (CSII) mimics physiologic insulin release better than multiple daily injection (MDI) therapy and allows for greater flexibility in food intake and physical activity. Given these benefits, it raises the question "Is it required to wait to offer CSII to patients with type 1 diabetes (T1D) only after MDI therapy has failed"? This study sought to determine if starting CSII in patients with T1D within 1 year of diagnosis results in better long-term glycemic control than starting it later. This retrospective observational study was conducted in a tertiary-care medical center. The charts of 488 patients with T1D (273 females) 2.6-39 years old (mean, 19.9 ± 7.7 years) who started CSII in 1998-2008 and used it for at least 1 year were reviewed for background, disease-related, and treatment-related variables. Study end points were glycosylated hemoglobin (HbA1c) level, rate of severe hypoglycemia, and diabetic ketoacidosis events during CSII use. Findings were compared between patients who started CSII within 1 year of diagnosis (Group 1, n=93) or later (Group 2, n=395). Compared with Group 2, Group 1 patients were characterized by a significantly younger age at CSII initiation (10.7±5.7 vs. 16.4±7.0 years, P<0.001), more frequent blood glucose monitoring (5.4 ± 1.8 vs. 3.9 ± 1.5 times per day, P<0.001), and shorter total duration of diabetes (4.3 ± 2.1 vs. 11.9 ± 6.4 years, P<0.001) and of CSII therapy (3.6 ± 2.1 vs. 4.7 ± 2.5 years, P<0.001). There were no significant between-group differences in patient gender or ethnicity, indications for initiating CSII, mean HbA1c level, attainment of target HbA1c, or rates of severe hypoglycemia or ketoacidosis events after CSII initiation. Starting pump therapy at an early disease stage has no added benefit for glycemic control over time than starting later. The timing of CSII initiation should be tailored to the individual patient by the diabetes care team.

Dual microfluidic perifusion networks for concurrent islet perifusion and optical imaging.

This study explores a new class of duplex microfluidic device which utilizes a dual perifusion network to simultaneously perform live-cell optical imaging of physiological activities and study insulin release kinetics on two islet populations. This device also incorporates on-chip staggered herringbone mixers (SHMs) to increase mixing efficiency and facilitate the generation of user-defined chemical gradients. Mouse islets are used to simultaneously measure dynamic insulin release, changes in mitochondrial potentials, and calcium influx in response to insulin secretagogues (glucose and tolbutamide), and show a high signal-to-noise ratio and spatiotemporal resolution of all measured parameters for both perifusion chambers. This system has many potential applications for studying β-cell physiology and pathophysiology, as well as for therapeutic drug screening. This dual perifusion device is not limited to islet studies and could easily be applied to other tissues and cells without major modifications.

Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence.

A growing body of medical research has demonstrated that intensive control of serum glucose levels can minimize the development of diabetes-related complications. Success with insulin management ultimately depends on how closely a given regimen can mimic normal physiologic insulin release patterns. The new insulin analogs, including the rapid-acting analogs (aspart, lispro, glulisine), the long-acting basal analogs (glargine, detemir), and the premixed insulin analog formulations (75% neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been formulated to allow for a closer replication of a normal insulin profile. The rapid-acting analogs can be administered at mealtimes and produce a rapid and short-lived insulin spike to address postprandial glucose elevations, while the long-acting analogs come close to the ideal of a smooth, relatively flat, 24-hour basal insulin supply, with less variability in action compared to NPH insulin. Despite these clear pharmacologic advantages, measurable clinical benefits in a complex disease such as diabetes can be hard to measure. To date, reviews of insulin analog studies have not found a dramatic overall improvement in glycosylated hemoglobin (HbA1c) outcomes compared to traditional human insulins, although all-analog basal-bolus regimens were associated with significantly lower HbA1c than all-human-insulin basal bolus regimens in some studies. Beyond HbA1c comparisons, however, insulin analogs have been shown in many instances to be associated with lower risks of hypoglycemia, lower levels of postprandial glucose excursions, better patient adherence, greater quality of life, and higher satisfaction with treatment. The long-acting basal analog insulin detemir has the additional advantage of producing less weight gain, which has been considered until now an almost inevitable consequence of insulin replacement.

A evolução da insulinoterapia no diabetes melito tipo 1

The discovery of insulin can be considered the milestone of diabetes mellitus history and a great achievement for its treatment. The first insulin available was the regular. Afterwards, Hagedorn added the protamine to the insulin, thus, creating the NPH insulin. In the 1950s an insulin free of protamine was synthesized: the lente insulin. With the advent of molecular biology, synthetic human insulin was synthesized using recombinant DNA technology. Most recently several types of insulin analogues were available, providing the patients with better metabolic control. Type 1 diabetes mellitus treatment includes plain substitution and individualization for short-acting plus long-acting insulin according to the physician's assistance, besides regular practice of physical activities and diet orientations. In type 1 diabetes mellitus the insulin of low variability is the best choice since basal/bolus insulin therapy or continuous subcutaneous insulin infusion pump can mimetize the physiological release of insulin by beta cells.

Coverage of Postprandial Blood Glucose Excursions With Inhaled Technosphere Insulin in Comparison to Subcutaneously Injected Regular Human Insulin in Subjects With Type 2 Diabetes

Technosphere Insulin (TI) is a formulation of regular human insulin (RHI) that provides efficient pulmonary administration (1) and demonstrates unique pharmacokinetic and pharmacodynamic properties compared with subcutaneous RHI, rapid-acting insulin analogs, and other inhaled insulins (2). Administration of TI results in a time to maximum insulin concentration of ∼15 min, with almost complete absorption within 3 h (3,4). With an onset of action comparable to intravenous insulin, TI represents the first formulation that approaches the physiological early insulin release. In this study, we evaluated the efficacy and safety of TI compared with subcutaneous RHI in covering prandial insulin needs. We measured blood glucose excursions after a meal challenge after individual titration of either insulin formulation during a 7-day treatment period in subjects with type 2 diabetes. This prospective, open-label, randomized, two-period, cross-over study was conducted at one center (Profil Institute for Metabolic Research, Neuss, Germany). The study included a screening visit, 24-h in-house exposure to TI to establish initial dosing, two 7-day ambulant periods of daily mealtime TI or subcutaneous RHI separated by a 2- to 7-day washout, and a final visit. In-house meal challenges, using a standardized mixed meal with 496 kcal, were conducted at the end of each ambulant period. During treatment periods, each subject inhaled TI via a MedTone Model C Inhaler (MannKind Corporation, Valencia, CA) …

The role of rapid-acting insulin analogues and inhaled insulin in type 2 diabetes mellitus

sBackground: The availability of rapid-acting insulin analogues and inhaled insulin gives clinicians additional treatmentoptions in the management of patients with diabetes mellitus (DM). Combining rapid-acting insulin analogues with basal insulin can more closely mimic physiologic insulin release to maximize glycemic control. Objective: The objective of this article was to discuss the role of rapid-acting insulin analogues and inhaled insulin inthe treatment of patients with type 2 DM. Methods: Materials for this article were obtained through an online search of MEDLINE/PubMed and Google(1996-2006) using the search terms bolus insulin, postprandial, rapid-acting insulin analogues, titration, hypoglycemia, glycemic control, inhaled insulin, and insulins lispro, aspart, and glulisine. Results: Glycosylated hemoglobin (A1C) levels and number of all hypoglycemic episodes were similar in patients withtype 2 DM taking either mealtime rapid-acting insulin analogues or regular human insulin (RHI). Rapid-acting insulins have been successfully used in basal-bolus regimens with a variety of long- and intermediate-acting insulins, as well as with oral hypoglycemic agents. Injectable rapid-acting insulin analogues markedly decreased postprandial glucose (PPG) levels compared with RHI. Better reduction in PPG levels may be key to achieving target A1C levels in some patients, but long-term outcome studies are needed to assess whether lowering PPG levels decreases cardiovascular risk in patients with type 2 DM. Inhaled insulin may be an option for patients who cannot inject insulin, but route of administration and dosing issues limit its use in many patients. The effect of inhaled insulin on PPG is unclear at this time. Conclusions: Although rapid-acting insulin analogues are effective in the management of patients with type 2 DM, the limited numbers of studies have yet to demonstrate that these agents have any significant long-term advantage compared with RHI. In addition, they cost more than RHI. Further studies are needed to compare the efficacy of the rapid-acting insulin analogues, to compare the different dosing regimens used with mealtime insulin administration, and to ascertain if the decrease in PPG levels seen with the use of rapid-acting insulin analogues translates into improved glycemic control and perhaps even a reduction in cardiovascular risk in patients with type 2 DM. (Insulin. 2007;2:61-67) Copyright 2007 Excerpta Medica, Inc.

Review: Insulin glulisine — the potential for improved glycaemic control

Tight glycaemic control is essential to reduce the risk of developing the micro- and macrovascular complications of diabetes. Plasma levels of glycosylated haemoglobin (HbA 1C) are a marker for long-term glycaemia; controlling these levels within tight limits forms the cornerstone of long-term diabetes management. As a result of evidence from key clinical trials in type 1 and type 2 diabetes, HbA1C targets ranging from &lt; 6.5 to &lt; 7.5% have been set by various authorities. To achieve these targets, insulin regimens need to reflect normal physiological insulin release. Several rapid- and long-acting insulin analogues have been developed to mimic aspects of insulin secretion. Insulin glulisine is a genetically engineered insulin which has a rapid onset and short lived action, allowing it to closely mimic prandial release of insulin. In addition to the structural change in the insulin molecule, the absence of excess zinc and the addition of polysorbate 20 as a surfactant facilitates its disassociation in the subcutaneous tissue and inhibits its aggregation when used in subcutaneous insulin delivery systems due to improved physical stability.

Insulin glargine and its place in the treatment of Types 1 and 2 diabetes mellitus

Insulin treatment in Type 1 and Type 2 diabetes has come a long way since its discovery by Banting and Best in 1922. Early insulin therapy was life-saving, but was associated with practical problems and had side effects such as lipoatrophy. Initial modifications of insulin structure produced several classes of insulins with varying pharmacokinetics, but did not sufficiently mimic physiological insulin release. Novel long- and short-acting insulin analogues, the so-called ‘designer insulins’, developed through genetic engineering in the 1990s, paved the way for more physiological insulin therapy, which was theoretically less problematic in terms of hypoglycaemia and patient satisfaction. Insulin glargine (glargine) was the first DNA-recombinant long-acting insulin analogue. The replacement of asparagine with glycine and the addition of two arginine molecules in the molecular structure results in modified pharmacokinetics. Consequently, glargine has a longer, often 24-h profile, which is described as ‘peakless’ compared with other insulins such as neutral protamine Hagedorn insulin (NPH) and insulin ultralente. Since its launch, the use of glargine in Type 1 and Type 2 diabetes has been extensively reviewed to determine its place in the current insulin market. A potential advantage of glargine seems to be a lower risk of hypoglycaemia, particularly at night. The UK National Institute of Clinical Excellence has recommended that glargine is a treatment option for people with Type 1 diabetes. In Type 2 diabetes, it has been advised that glargine only be considered for: those who require assistance to administer insulin injections; those whose lifestyle is restricted significantly by recurrent symptomatic hypoglycaemic episodes; or those who would otherwise need twice-daily basal insulin injections in combination with oral glucose-lowering drugs.