Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.

The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this study was to propose a more informative, although less laborious, IVGTT design to be used for model-based assessment of SI and SG . The IVGTT design was optimized simultaneously for all design variables: glucose and insulin infusion doses, time of glucose dose and start of insulin infusion, insulin infusion duration, sampling times, and number of samples. Design efficiency was used to compare among different designs. The simultaneously optimized designs showed a profound higher efficiency than both standard rich (32 samples) and sparse (10 samples) designs. The optimized designs, after removing replicate sample times, were 1.9 and 7.1 times more efficient than the standard rich and sparse designs, respectively. After including practical aspects of the designs, for example, sufficient duration between samples and avoidance of prolonged hypoglycemia, we propose 2 practical designs with fewer sampling times and lower input of glucose and insulin than standard designs, constrained to prevent hypoglycemia. The optimized practical rich design is equally efficient in assessing SI and SG as the rich standard design, but with half the number of the samples, while the optimized practical sparse design has 1 less sample and requires 4.6 times fewer individuals for equal certainty when assessing SI and SG than the sparse standard design.

Injectable combination therapies for the management of diabetes: an Indian perspective.

Introduction: This review focuses on currently available injectable combination therapies (ICTs) for managing diabetes.Areas covered: References were identified through searches of PubMed, Medline, and Embase for articles published till July 2019 using terms 'insulin' [MeSH Terms] OR 'glucagon like peptide 1 analogue' [All Fields] OR 'combination therapy' [All Fields] 'combination insulin therapy' [All Fields] OR 'combination GLP1 analogue therapy' [All Fields] OR 'premixed insulin' [All Fields].Expert opinion: Currently, there are nine types of ICTs for diabetes available. ICTs are classified on the basis of whether they are combinations of conventional human insulin, human insulin analogs, insulin coformulations, and insulin glucagon-like peptide-1 receptor agonists (GLP-1RA) and have a subtle difference in pharmacokinetic and pharmacodynamic properties. ICTs have been consistently demonstrated to play a major role in improving glycemic control. In a different meta-analysis involving patients assessed for glycemic control as the primary endpoint, no significant difference was noted with regard to HbA1c reduction, hypoglycemia, weight change, and daily insulin dose in patients on basal-bolus regimen, as compared to ICTs. All international guidelines recommend ICTs for treatment intensification.ICTs provide more flexibility to the treating doctor in fine-tuning the insulin/GLP-1RA regimen and have the advantages of reducing daily needle-prick count and better long-term compliance.

Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles.

OBJECTIVE: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability. METHODS: Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats. RESULTS: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times. CONCLUSION: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.

Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment.

Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection (PNI) device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors (gas pressure, cylinder volume, and nozzle distance) were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs.

A model-based control protocol for transition from ICU to HDU: Robustness analysis.

The robustness of a model-based control protocol as a less intensive TGC protocol using insulin Glargine for provision of basal insulin is simulated in this study. To quantify the performance and robustness of the protocol to errors, namely physiological variability and sensor errors, an in-silico Monte Carlo analysis is performed. Actual patient data from Christchurch Hospital, New Zealand were used as virtual trial patients.

MATLAB-implemented estimation procedure for model-based assessment of hepatic insulin degradation from standard intravenous glucose tolerance test data.

Present study provides a novel MATLAB-based parameter estimation procedure for individual assessment of hepatic insulin degradation (HID) process from standard frequently-sampled intravenous glucose tolerance test (FSIGTT) data. Direct access to the source code, offered by MATLAB, enabled us to design an optimization procedure based on the alternating use of Gauss-Newton's and Levenberg-Marquardt's algorithms, which assures the full convergence of the process and the containment of computational time. Reliability was tested by direct comparison with the application, in eighteen non-diabetic subjects, of well-known kinetic analysis software package SAAM II, and by application on different data. Agreement between MATLAB and SAAM II was warranted by intraclass correlation coefficients ≥0.73; no significant differences between corresponding mean parameter estimates and prediction of HID rate; and consistent residual analysis. Moreover, MATLAB optimization procedure resulted in a significant 51% reduction of CV% for the worst-estimated parameter by SAAM II and in maintaining all model-parameter CV% <20%. In conclusion, our MATLAB-based procedure was suggested as a suitable tool for the individual assessment of HID process.

Analysis of the injection force of solostar® compared with other disposable insulin pen devices at constant volume flow rates.

Insulin pen devices have greatly enhanced the portability and accessibility to insulin therapy for millions of people with diabetes. Comparison research data should be reviewed thoroughly. In this issue of Journal of Diabetes Science and Technology, the study presented by Thomas van der Burg is balanced in number of samples tested, same tensile meter, and identical units per second delivery rate into an open beaker. Mean plateau force of SoloSTAR® and KwikPen™ were significantly lower. KwikPen and SoloSTAR utilized 5-mm length 31-gauge (G) needles vs 6-mm 31G needles for FlexPen® and Next Generation FlexPen®, perhaps skewing results in favor of shorter needles instead of device design. Individual understanding of correct insulin use, appropriate self-monitoring of blood glucose, vision and dexterity capability, and affordability of therapy must be considered first. SoloSTAR holds one unique market advantage, delivery of up to 80 units of insulin per injection.

Comparison of interval and Monte Carlo simulation for the prediction of postprandial glucose under uncertainty in type 1 diabetes mellitus.

In this paper, the problem of tackling uncertainty in the prediction of postprandial blood glucose is analyzed. Two simulation approaches, Monte Carlo and interval models, are studied and compared. Interval simulation is carried out using modal interval analysis. Simulation of a glucoregulatory model with uncertainty in insulin sensitivities, glucose absorption and food intake is carried out using both methods. Interval simulation is superior in predicting all severe and mild hyper- and hypoglycemia episodes. Furthermore, much less computational time is required for interval simulation than for Monte Carlo simulation.

Extreme insulin resistance: indications and approaches to the use of U-500 insulin in type 2 diabetes mellitus.

The use of U-500 insulin in the management of highly insulin resistant diabetic patients is growing. There are a number of reports that have noted the effects of U-500 insulin using multiple daily injections or continuous subcutaneous insulin infusion on hemoglobin A(1c), weight, and total daily insulin dosage. The effect of U-500 insulin use on glycemic control, changes in body weight, total daily insulin dosage, incidence of hypoglycemia, and effect on lipid levels and blood pressure as well as patient satisfaction and quality of life will be reviewed. In addition, this article will delineate algorithms of U-500 use, compare multiple daily injections or continuous subcutaneous insulin infusion, and discuss U-500 insulin pharmacokinetics.

Inhaled insulin: a model for pulmonary systemic absorption?

The European Union recently approved a form of insulin intended to be inhaled. This innovative presentation has the potential to partially or completely replace the injections and thus facilitate starting insulin therapy which is considered with apprehension and often differed. On this occasion, we reviewed the issues raised by this pulmonary route for systemic absorption (anatomical and cytological limits, cellular mechanisms, relevant physical parameters, facilitating chemical cofactors, role of tobacco smoking and of common respiratory diseases). The pharmacokinetics of inhaled and injectable insulins are comparable, apart from an appreciably faster absorption of the former, and both show the same intra-individual variability. The total bioavailability is definitely lower with the inhaled route but is notably increased in smokers. These characteristics can vary according to the inhalation system used. A frequent induced cough, the increase in circulating anti-insulin antibodies, and a potentially higher cost are not really determining obstacles. The indications will have to be clearly specified and the long-term innocuousness of repeated inhalation of such a mitogen, especially in children and former smokers, remains to be fully proven.

Specification and verification of pharmacokinetic models.

A model checking technique to specify and verify temporal properties of drug disposition changes is proposed. In pharmacokinetics and pharmaceutics, drug kinetics is often modeled as single or multiple compartment models. In this paper, a probabilistic temporal logic, called iLTL, is introduced to specify many interesting properties of drug kinetics. Given a specification, a computerized technique, called model checking [1], is used to check whether all drug disposition changes of a compartment model comply with the specification.

Biphasic insulin aspart in the treatment of type 2 diabetes mellitus.

BACKGROUND: Initiating and implementing insulin treatment in type 2 diabetic subjects is a major challenge in diabetes clinical practice. Although simple regimens, such as the combination of a once-daily basal insulin + oral agents, are widely used, they often are not able to achieve an adequate glycemic control, especially in the postprandial period. Biphasic insulin analogues are a valid tool to start and to improve insulin treatment in type 2 diabetes. Biphasic insulin aspart (BIAsp) is available in three different mixtures (30, 50 and 70% of rapid-acting insulin, respectively), which allows insulin treatment to be individualized. OBJECTIVE/METHODS: To review recent published papers concerning pharmacological properties and clinical use of BIAsp in type 2 diabetes. RESULTS/CONCLUSION: BIAsp seems to have some advantages over biphasic human insulins, especially for its practical pre- or post-meal administration and lesser hypoglycemic risk. Against basal insulins once daily, BIAsp twice daily seems to perform better in achieving the glucose targets and, even when compared with the more complex basal-bolus regimens, a BIAsp-based treatment using the different available mixtures is at least non-inferior. Side effects are no more frequent than with other insulins; more hypoglycemic episodes of low severity have been sometimes reported, but only in comparison with basal insulin.

Time-action profile and patient assessment of inhaled insulin via the Exubera device in comparison with subcutaneously injected insulin aspart via the FlexPen device.

BACKGROUND: The goal of our investigation was to compare the pharmacokinetics/pharmacodynamics properties of and patient preference for insulin aspart applied with the FlexPen (Novo Nordisk, Bagsvaerd, Denmark) (IAFP) with pulmonary human insulin applied with the Exubera (Pfizer, New York, NY) device (HIEX). METHODS: Twelve patients with diabetes (six with type 1 and six with type 2; eight men, four women; age, 54.5 +/- 11.0 years; duration of diabetes, 16.5 +/- 10.6 years; hemoglobin A1c, 7.5 +/- 0.7%; body mass index, 29.5 +/- 7.2 kg/m(2); mean +/- SD) participated in an open-label, randomized, euglycemic clamp study. The patients received 11 units of IAFP or a dose-equivalent of (3 + 1 mg) insulin from HIEX in a randomized sequence on two different study days. Insulin plasma levels and the required glucose infusion rate (GIR) were monitored for a time period of 6 h. In addition, the patients' individual ratings from 1 (excellent) to 5 (poor) regarding several different handling items were assessed using a questionnaire. RESULTS: No significant difference in the pharmacokinetics/pharmacodynamics parameters could be observed between IAFP and HIEX within the first 120 min. In the second part of the clamp procedure, plasma insulin levels (area under the curve versus time [AUC]) and the GIR was significantly higher after HIEX compared with IAFP (insulin AUC(120-360), 66,232 +/- 4,521 vs. 48,852 +/- 2,999 pmol/L, P < 0.05; GIR AUC(120-360), 8,928 +/- 1,334 vs. 6,805 +/- 1,655 mg/kg/min). A superior patient judgment was obtained for the FlexPen with regard to trust in insulin delivery (2.3 +/- 1.1 vs. 2.8 +/- 1.0), trust in correct insulin dosing (1.8 +/- 1.1 vs. 2.6 +/- 0.9), size (2.3 +/- 1.1 vs. 3.6 +/- 0.9), and appearance of the device (2.4 +/- 1.0 vs. 3.8 +/- 0.9) (P < 0.05, respectively). CONCLUSIONS: Insulin treatment with HIEX was found to have pharmacokinetics/pharmacodynamics properties comparable to IAFP. Both insulin administration technologies were overall evaluated positive, but most patients preferred IAFP.

Minimal model assessment of hepatic insulin extraction during an oral test from standard insulin kinetic parameters.

In this article, a first aim was to develop a minimal modeling approach to noninvasively assess hepatic insulin extraction in 204 healthy subjects studied with a standard meal by coupling the already available meal C-peptide minimal model with a new insulin model. The ingredients of this model are posthepatic IDR, which in turn is described in terms of pancreatic ISR and hepatic insulin extraction HE, and a linear monocompartmental model of insulin kinetics. Even if ISR is provided by the C-peptide minimal model, the simultaneous assessment of HE and insulin kinetics is critical, since compensations may arise between parameters describing these two processes. Therefore, as a second aim of this study, a method was developed to predict standard values of insulin kinetic parameters in an individual on the basis of the individual's anthropometric characteristics. The statistical analysis, based on linear regression of insulin kinetic parameters estimated from IM-IVGTT data performed on the same subjects, demonstrated that insulin kinetic parameters can be accurately predicted from age and body surface area. Once kinetic parameters of the new insulin model were fixed to these values, HE profile and indexes during a meal were reliably estimated in each individual, indicating a significant suppression during the meal since the overall index of HE, equal to 60 +/- 1% in the basal state, is reduced to 40 +/- 1% during a meal. However, standard parameters provide an approximation of the individual one; thus, the third aim was to define the impact on estimated indexes of using standard instead of individually estimated values. Our results showed that the 25% uncertainty affecting as an average insulin kinetic parameters of an individual, when they are predicted from age and body surface area, translates into a similar relative uncertainty in the individual's hepatic insulin extraction indexes.

Overnight closed-loop insulin delivery with model predictive control: assessment of hypoglycemia and hyperglycemia risk using simulation studies.

BACKGROUND: Hypoglycemia and hyperglycemia during closed-loop insulin delivery based on subcutaneous (SC) glucose sensing may arise due to (1) overdosing and underdosing of insulin by control algorithm and (2) difference between plasma glucose (PG) and sensor glucose, which may be transient (kinetics origin and sensor artifacts) or persistent (calibration error [CE]). Using in silico testing, we assessed hypoglycemia and hyperglycemia incidence during over-night closed loop. Additionally, a comparison was made against incidence observed experimentally during open-loop single-night in-clinic studies in young people with type 1 diabetes mellitus (T1DM) treated by continuous SC insulin infusion. METHODS: Simulation environment comprising 18 virtual subjects with T1DM was used to simulate overnight closed-loop study with a model predictive control (MPC) algorithm. A 15 h experiment started at 17:00 and ended at 08:00 the next day. Closed loop commenced at 21:00 and continued for 11 h. At 18:00, protocol included meal (50 g carbohydrates) accompanied by prandial insulin. The MPC algorithm advised on insulin infusion every 15 min. Sensor glucose was obtained by combining model-calculated noise-free interstitial glucose with experimentally derived transient and persistent sensor artifacts associated with FreeStyle Navigator (FSN). Transient artifacts were obtained from FSN sensor pairs worn by 58 subjects with T1DM over 194 nighttime periods. Persistent difference due to FSN CE was quantified from 585 FSN sensor insertions, yielding 1421 calibration sessions from 248 subjects with diabetes. RESULTS: Episodes of severe (PG < or = 36 mg/dl) and significant (PG < or = 45 mg/dl) hypoglycemia and significant hyperglycemia (PG > or = 300 mg/dl) were extracted from 18,000 simulated closed-loop nights. Severe hypoglycemia was not observed when FSN CE was less than 45%. Hypoglycemia and hyperglycemia incidence during open loop was assessed from 21 overnight studies in 17 young subjects with T1DM (8 males; 13.5 +/- 3.6 years of age; body mass index 21.0 +/- 4.0 kg/m2; duration diabetes 6.4 +/- 4.1 years; hemoglobin A1c 8.5% +/- 1.8%; mean +/- standard deviation) participating in the Artificial Pancreas Project at Cambridge. Severe and significant hypoglycemia during simulated closed loop occurred 0.75 and 17.11 times per 100 person years compared to 1739 and 3479 times per 100 person years during experimental open loop, respectively. Significant hyperglycemia during closed loop and open loop occurred 75 and 15,654 times per 100 person years, respectively. CONCLUSIONS: The incidence of severe and significant hypoglycemia reduced 2300- and 200-fold, respectively, during stimulated overnight closed loop with MPC compared to that observed during open-loop overnight clinical studies in young subjects with T1DM. Hyperglycemia was 200 times less likely. Overnight closed loop with the FSN and the MPC algorithm is expected to reduce substantially the risk of hypoglycemia and hyperglycemia.

Deleterious outcomes after abrupt transition from insulin glargine to insulin detemir in patients with type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVE: Iowa Care (Iowa Medicaid), USA, switched insulin glargine to insulin detemir in subjects with diabetes mellitus without the approval of healthcare providers. This study set out to examine the impact of transition on parameters of diabetes management in type 1 diabetes. METHODS: This was a retrospective review of the records of subjects with type 1 diabetes up to August 2007 in whom transition occurred. Subjects completing 6 months of insulin detemir therapy were included. Twenty-four subjects switching from insulin glargine to insuline detemir (group 1) fulfilled the duration with insulin detemir. Glycaemic control (glycosylated haemoglobin [HbA1c]), bodyweight, daily insulin dose (units), total and insulin glargine or insulin detemir and rapid-acting insulin aspart and hypoglycaemic events during the last 4 weeks, pre-switch and again at 6 months post-switch were assessed. Records of 21 age-matched subjects and continuing insulin glargine for 6 months (group 2) were examined. Subjects switched from insulin glargine to insulin detemir in the same daily dose. The daily doses of insulin detemir and aspart in group 1 were adjusted by telephone weekly based on blood glucose monitoring until stabilization occurred. Subjects were followed up in the outpatient clinic every 3 months. RESULTS: Subjects in group 1 changed to insulin detemir twice a day because of a significant rise in hypoglycaemia with the daily dose used once a day. Glycaemic control remained stable on continuing insulin glargine; HbA1c 7.6+/-0.3 to 7.8+/-0.3%, while it worsened on switching to insulin detemir; HbA1c 7.9+/-0.6 to 8.8+/-0.8 despite a higher daily dose; insulin detemir 46+/-9 U/day versus pre-switch insulin glargine 36+/-8 U/day and group 2 insulin glargine 35+/-6 U/day; and greater total insulin dose: 80+/-12 U/day versus 68+/-10 pre-switch and group 2 insulin glargine 62+/-10 U/day (p<0.05 for all comparisons). Bodyweight and hypoglycaemic events were not significantly different pre- and post-switch. CONCLUSION: Switching to insulin detemir from glargine is likely to result in lapse of glycaemic control despite a higher daily insulin dose, increased number of injections and need for frequent evaluations.

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.

Developments in polymeric devices for oral insulin delivery.

BACKGROUND: Development of improved oral insulin administration is necessary for the treatment of diabetes mellitus, to overcome the problem of daily subcutaneous injections. The vast amount of literature data on oral insulin delivery prompted us to cover this area in a review. OBJECTIVE: Insulin delivery using polymeric devices is discussed, with an ultimate aim of addressing the technological development in this area. METHODS: The development of oral delivery devices for insulin using hydrogels and micro/nanoparticles is discussed with reference to polymers. These efforts must be directed to increase the residence time of insulin near the intestinal absorptive cells. RESULTS/CONCLUSION: The published results on oral insulin delivery devices, particularly on inter-polymer complexes of the grafted copolymers, are discussed in greater depth. The use of absorption enhancers like cyclodextrins, bile salts and surfactants is covered. The state-of-the-art technology and challenges in this area are discussed, with typical examples.