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Sample records for insulin analogue basal-bolus

  1. Personalized intensification of insulin therapy in type 2 diabetes - does a basal-bolus regimen suit all patients?

    PubMed

    Giugliano, D; Sieradzki, J; Stefanski, A; Gentilella, R

    2016-08-01

    Many patients with type 2 diabetes mellitus (T2DM) require insulin therapy. If basal insulin fails to achieve glycemic control, insulin intensification is one possible treatment intensification strategy. We summarized clinical data from randomized clinical trials designed to compare the efficacy and safety of basal-bolus and premixed insulin intensification regimens. We defined a between-group difference of ≥0.3% in end-of-study glycated hemoglobin (HbA1c) as clinically meaningful. A PubMed database search supplemented by author-identified papers yielded 15 trials which met selection criteria: randomized design, patients with T2DM receiving basal-bolus (bolus injection ≤3 times/day) vs. premixed (≤3 injections/day) insulin regimens, primary/major endpoint(s) HbA1c- and/or hypoglycemia-related, and trial duration ≥12 weeks. Glycemic control improved with both basal-bolus and premixed insulin regimens with - in most cases - acceptable levels of weight gain and hypoglycemia. A clinically meaningful difference between regimens in glycemic control was recorded in only four comparisons, all of which favored basal-bolus therapy. The incidence of hypoglycemia was significantly different between regimens in only three comparisons, one of which favored premixed insulin and two basal-bolus therapy. Of the four trials that reported a significant difference between regimens in bodyweight change, two favored basal-bolus therapy and two favored premixed insulin. Thus, on a population level, neither basal-bolus therapy nor premixed insulin showed a consistent advantage in terms of glycemic control, hypoglycemic risk, or bodyweight gain. It is therefore recommended that clinicians should adopt an individualized approach to insulin intensification - taking into account the benefits and risks of each treatment approach and the attitude and preferences of each patient - in the knowledge that both basal-bolus and premixed regimens may be successful. PMID:27126277

  2. Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial

    PubMed Central

    Lundby-Christensen, Louise; Vaag, Allan; Tarnow, Lise; Almdal, Thomas P; Lund, Søren S; Wetterslev, Jørn; Gluud, Christian; Boesgaard, Trine W; Wiinberg, Niels; Perrild, Hans; Krarup, Thure; Snorgaard, Ole; Gade-Rasmussen, Birthe; Thorsteinsson, Birger; Røder, Michael; Mathiesen, Elisabeth R; Jensen, Tonny; Vestergaard, Henrik; Hedetoft, Christoffer; Breum, Leif; Duun, Elsebeth; Sneppen, Simone B; Pedersen, Oluf; Hemmingsen, Bianca; Carstensen, Bendix; Madsbad, Sten

    2016-01-01

    Objective To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. Design and setting Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design, conducted at 8 hospitals in Denmark. Participants and interventions Participants with type 2 diabetes (glycated haemoglobin (HbA1c)≥7.5% (≥58 mmol/mol), body mass index >25 kg/m2) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1–3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c≤7.0% (≤53 mmol/mol). Outcomes Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes. Results Carotid IMT change did not differ between groups (biphasic −0.009 mm (95% CI −0.022 to 0.004), aspart+detemir 0.000 mm (95% CI −0.013 to 0.013), detemir −0.012 mm (95% CI −0.025 to 0.000)). HbA1c was more reduced with biphasic (−1.0% (95% CI −1.2 to −0.8)) compared with the aspart+detemir (−0.4% (95% CI −0.6 to −0.3)) and detemir (−0.3% (95% CI −0.4 to −0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ. Conclusions Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and

  3. Cost comparison of insulin glargine with insulin detemir in a basal-bolus regime with mealtime insulin aspart in type 2 diabetes in Germany

    PubMed Central

    Pscherer, Stefan; Dietrich, Eva Susanne; Dippel, Franz-Werner; Neilson, Aileen Rae

    2010-01-01

    Objective: To compare the treatment costs of insulin glargine (IG; Lantus®) to detemir (ID; Levemir®), both combined with bolus insulin aspart (NovoRapid®) in type 2 diabetes (T2D) in Germany. Methods: Cost comparison was based on data of a 1-year randomised controlled trial [1]. IG was administered once daily and ID once (57% of patients) or twice daily (43%) according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG) and 0.82 U/kg (ID). Aspart doses were 0.32 U/kg (IG) and 0.36 U/kg (ID). Costs were calculated from the German statutory health insurance (SHI) perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results. Results: Annual basal and bolus insulin costs per patient were € 1,473 (IG) and € 1,940 (ID). The cost of lancets and blood glucose test strips were € 1,125 (IG) and € 1,286 (ID). Annual costs for needles were € 393 (IG) and € 449 (ID). The total annual cost per patient of administering IG was € 2,991 compared with € 3,675 for ID, translating into a 19% annual cost difference of € 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations. Conclusion: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of € 684/patient compared to ID. PMID:20725588

  4. Insulin requirement profiles in Japanese hospitalized subjects with type 2 diabetes treated with basal-bolus insulin therapy.

    PubMed

    Shimoda, Seiya; Okubo, Mina; Koga, Kotaro; Sekigami, Taiji; Kawashima, Junji; Kukidome, Daisuke; Igata, Motoyuki; Ishii, Norio; Shimakawa, Akiko; Matsumura, Takeshi; Motoshima, Hiroyuki; Furukawa, Noboru; Nishida, Kenro; Araki, Eiichi

    2015-01-01

    To assess the total daily inulin dose (TDD) and contribution of basal insulin to TDD and to identify the predictive factors for insulin requirement profiles in subjects with type 2 diabetes, we retrospectively examined insulin requirement profiles of 275 hospitalized subjects treated with basal-bolus insulin therapy (BBT) (mean age, 60.1 ± 12.9 years; HbA1c, 10.2 ± 4.5%). Target plasma glucose level was set between 80 and 129 mg/dL before breakfast and between 80 and 179 mg/dL at 2-hour after each meal without causing hypoglycemia. We also analyzed the relationship between the insulin requirement profiles (TDD and basal/total daily insulin ratio [B/TD ratio]) and insulin-associated clinical parameters. The mean TDD was 0.463 ± 0.190 unit/kg/day (range, 0.16-1.13 unit/kg/day). The mean B/TD ratio was 0.300 ± 0.099 (range, 0.091-0.667). A positive correlation of TDD with B/TD ratio was revealed by linear regression analysis (r=0.129, p=0.03). Stepwise multiple regression analysis identified post-breakfast glucose levels before titrating insulin as an independent determinant of the insulin requirement profile [Std β (standard regression coefficient) = 0.228, p<0.01 for TDD, Std β = -0.189, p<0.01 for B/TD ratio]. The TDD was <0.6 unit/kg/day and the B/TD ratio was <0.4 in the majority (70.2%) of subjects in the present study. These findings may have relevance in improving glycemic control and decreasing the risk of hypoglycemia and weight gain in subjects with type 2 diabetes treated with BBT. PMID:25392020

  5. Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

    PubMed

    Giugliano, Dario; Chiodini, Paolo; Maiorino, Maria Ida; Bellastella, Giuseppe; Esposito, Katherine

    2016-03-01

    The purpose of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the effect of intensified insulin regimens (basal-bolus versus premixed) on glycemic control in patients with type 2 diabetes. We conducted an electronic search until March 2015 on many electronic databases including online registries of ongoing trials. All RCTs comparing basal-bolus with premixed insulin regimens, with a duration of >12 weeks and with >30 patients per arm, were included. Investigators extracted data on study characteristics, outcome measures, and methodological quality. We found thirteen RCTs lasting 16-60 weeks and involving 5255 patients assessed for the primary endpoint (reduction of HbA1c from baseline). Meta-analysis of change in HbA1c level between basal-bolus and premixed insulin regimens resulted in a small and non-significant difference of 0.09% (95% CI -0.03 to 0.21), with substantial heterogeneity between studies (I(2) = 74.4%). There was no statistically significant difference in the event rate for overall hypoglycemia (0.16 episode/patient/year, 95%CI -2.07 to 2.3), weight change (-0.21 kg, -0.164 to 0.185), and daily insulin dose (-0.54 U/day, -2.7 to 1.6). The likelihood for reaching the HbA1c <7% was 8% higher (3-13%, I(2) = 68.8%) with the basal-bolus as compared with the premixed regimen. There is no clinically relevant difference in the efficacy of basal-bolus versus premixed insulin regimens for HbA1c decrease in type 2 diabetic patients. These findings may be helpful to adapt treatment to individual patient needs. PMID:26281001

  6. Biphasic Insulin Aspart 30/70: Pharmacokinetics and Pharmacodynamics Compared With Once-Daily Biphasic Human Insulin and Basal-Bolus Therapy

    PubMed Central

    Heise, Tim; Heinemann, Lutz; Hövelmann, Ulrike; Brauns, Bianca; Nosek, Leszek; Haahr, Hanne L.; Olsen, Klaus J.

    2009-01-01

    OBJECTIVE Pharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients. RESEARCH DESIGNS AND METHODS Study 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h. RESULTS Study 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg. CONCLUSIONS BIAsp had pharmacological advantages over BHI. BIAsp t.i.d. had a similar PD profile to basal-bolus therapy. PMID:19487640

  7. [Reflections of a clinician on the switch from human to analogue insulin treatment].

    PubMed

    Deák, László

    2012-10-01

    The development of insulin therapy has not been stopped since the manufacturing of human insulin, because better mimic of physiological insulin response made it necessary to modify the human insulin molecule in order to create rapidly absorbing insulin analogues and 24-hour acting basal insulin analogues. Clinical observations indicate that the complete switch from human basal-bolus therapy to insulin analogues means not only "unit-for-unit" switch but it represents a transfer to an insulin therapy with different basal/bolus ratio as a result of different pharmacokinetic and pharmacodynamic properties of insulin and the level of insulin resistance of the patient. With reference to a case-history, the author presents his experience on a switch from human insulin to insulin analogue. Furthermore, the author summarizes data obtained from a few cases reported in international literature which draw the attention to the fact that the basal/bolus ratio should be adjusted individually, which may be the key for the success in the therapy in these cases. PMID:23022882

  8. Twenty-four-hour simultaneous subcutaneous basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to examine the effect of continuous subcutaneous (sc) replacement of amylin and insulin for a 24-h period on glucose homeostasis in adolescents with type 1 diabetes. Thirteen adolescents with type 1 diabetes on insulin pump therapy participated in a randomized, controll...

  9. Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec.

    PubMed

    Robinson, Jennifer D; Neumiller, Joshua J; Campbell, R Keith

    2012-12-24

    The basal-bolus concept of delivering insulin to diabetic patients makes physiological sense, as it mimics normal insulin release in people without diabetes. In line with this concept, a major effort put forth by insulin manufacturers has been to develop the ideal exogenous basal insulin product. The perfect basal insulin product would be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 hours, be stable, not contribute to weight gain, have a low risk of allergic reactions and, very importantly, minimize the risk of hypoglycaemia. While the perfect insulin has not yet been discovered, advancements are still being made. Insulin degludec is an ultra-long-acting basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Insulin degludec achieves these pharmacokinetic properties by forming soluble multihexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue that is slowly released and absorbed into circulation. Insulin degludec has been associated with slightly less weight gain and fewer nocturnal hypoglycaemic episodes when compared with insulin glargine in some, but not all, clinical studies. This article briefly reviews current evidence for the use of insulin degludec in patients with type 1 or type 2 diabetes mellitus and discusses the potential impact of this new basal insulin on clinical practice. PMID:23145524

  10. Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096)

    PubMed Central

    Ratner, R; Wynne, A; Nakhle, S; Brusco, O; Vlajnic, A; Rendell, M

    2011-01-01

    Aim: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. Methods: This was a multicenter, randomized, open-label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) ≥7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent-to-treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA1c, fasting plasma glucose and weight from study baseline to endpoint (week 52). Results: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA1c: 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of −0.87 kg (p = 0.243). Conclusion: Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated. PMID:21812890

  11. [Rational use of insulin analogues in the treatment of type 1 diabetic children and adolescents: personal experience].

    PubMed

    Dorchy, H

    2006-09-01

    In the last decade, four fast- and long-acting insulin analogues have been created. Due to the pharmacokinetic characteristics of insulin analogues, they provide an insulin profile closer to normal physiology than can be achieved with human insulins. However, they do not necessarily improve glycated haemoglobin, but they allow better quality of life. In the two daily insulin injection regime, fast-acting analogues are very useful to rapidly correct hyperglycaemia, to allow sleeping in and eating something sweet. In the basal-bolus regime (> or =4 insulin injections), long-acting analogues reduce nocturnal hypoglycaemias and improve fasting blood glucose. In the two insulin regime (2 or > or =4 injections), rapid-acting human insulin must not be systematically replaced by a fast-acting analogue. On the other hand, insulin dose alteration must be triple: retrospective, according to numerous previous experiments, in order to enjoy more freedom for meals, sports, etc.; prospective according to programmed changes in meals and sports; with only a "touch" of compensatory adaptation according to actual glycaemia. PMID:16920339

  12. A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

    PubMed Central

    2012-01-01

    Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID:22727048

  13. [Insulin analogues: modifications in the structure, molecular and metabolic consequences].

    PubMed

    de Luis, D A; Romero, E

    2013-01-01

    Recombinant DNA technology has provided insulin analogues for the treatment of diabetes mellitus, with an efficacy and safety that has improved the treatment of this disease. We briefly review the principal characteristics of the insulin analogues currently available. Both rapid-acting (lispro, aspart and glulisine) and long acting (glargine and determir) insulin analogues are included in this review. We describe the pharmacology of each insulin analogue, their differences with the human insulin, the administration, indication, efficacy and safety. In addition we discussed the main controversies of the use of these insulin analogues. In particular, those related with the risk of cancer and retinopathy, and their use in pregnant women. PMID:23517895

  14. [Insulin therapy for type 1 diabetes mellitus: past and present].

    PubMed

    Pires, Antonio Carlos; Chacra, Antonio Roberto

    2008-03-01

    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. PMID:18438537

  15. Evidence-based clinical use of insulin premixtures.

    PubMed

    Tambascia, Marcos Antônio; Nery, Márcia; Gross, Jorge Luiz; Ermetice, Mariana Narbot; de Oliveira, Carolina Piras

    2013-01-01

    Brazil is expected to have 19.6 million patients with diabetes by the year 2030. A key concept in the treatment of type 2 diabetes mellitus (T2DM) is establishing individualized glycemic goals based on each patient's clinical characteristics, which impact the choice of antihyperglycemic therapy. Targets for glycemic control, including fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (A1C), are often not reached solely with antihyperglycemic therapy, and insulin therapy is often required. Basal insulin is considered an initial strategy; however, premixed insulins are convenient and are equally or more effective, especially for patients who require both basal and prandial control but desire a more simplified strategy involving fewer daily injections than a basal-bolus regimen. Most physicians are reluctant to transition patients to insulin treatment due to inappropriate assumptions and insufficient information. We conducted a nonsystematic review in PubMed and identified the most relevant and recently published articles that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. These studies suggest that premixed insulin analogues are equally or more effective in reducing A1C compared to basal insulin analogues alone in spite of the small increase in the risk of nonsevere hypoglycemic events and nonclinically significant weight gain. Premixed insulin analogues can be used in insulin-naïve patients, in patients already on basal insulin therapy, and those using basal-bolus therapy who are noncompliant with blood glucose self-monitoring and titration of multiple insulin doses. We additionally provide practical aspects related to titration for the specific premixed insulin analogue formulations commercially available in Brazil. PMID:24011173

  16. Current european regulatory perspectives on insulin analogues.

    PubMed

    Enzmann, Harald G; Weise, Martina

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  17. Review of insulin and its analogues in diabetes mellitus.

    PubMed

    Mane, Krishnappa; Chaluvaraju, Kc; Niranjan, Ms; Zaranappa, Tr; Manjuthej, Tr

    2012-03-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin's, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  18. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus.

    PubMed

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-11-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  19. The metabolic and mitogenic properties of basal insulin analogues

    PubMed Central

    2013-01-01

    Context Retrospective, observational studies have reported an association between diabetes treatment with insulin and a higher incidence of cancer. Objective Overview the literature for in vitro and in vivo studies of the metabolic and mitogenic properties of basal insulin analogues and assess the implications for clinical use. Methods Relevant studies were identified through PubMed and congress abstract database searches; data on metabolic and mitogenic signalling in relation to insulin treatment of diabetes are included in this review. Results The balance of evidence shows that although some analogues have demonstrated mitogenic potency in some in vitro studies in cancer cell lines, these findings do not translate to the in vivo setting in animals or to the clinical setting in humans. Conclusions The current consensus is that there is no clinical or in vivo evidence to indicate that any commercially available insulin analogue has carcinogenic effects. Large-scale, prospective clinical and observational studies will further establish any potential link. PMID:23373726

  20. Pharmacokinetic model for the absorption of subcutaneously injected soluble insulin and monomeric insulin analogues.

    PubMed

    Trajanoski, Z; Wach, P; Kotanko, P; Ott, A; Skraba, F

    1993-09-01

    A subcutaneous insulin absorption model is presented for parameter estimation from the time course of plasma insulin. Modifications of a published model were made for the absorption of soluble insulin and monomeric insulin analogues in the range of therapeutic concentrations and volumes. The modified diffusion-dissociation model with distributed parameters was approximated by a multiple-compartment model. Subcutaneous absorption of soluble insulin and monomeric insulin analogues with various volumes, concentrations, and injection depths was simulated. The model for soluble insulin exhibits volume, concentration, and injection depth dependent absorption, as experimentally observed. It was found that binding of soluble insulin in the subcutaneous tissue is negligible for U-40 and U-100 strengths. The absorption of identical doses (10 U) of soluble U-40 insulin was markedly faster (T-50% = 159.4 min) than the absorption of U-100 (T-50% = 196.2 min). According to the simulation results, the absorption rate of monomeric analogues is not dependent on concentration. No significant chances of the absorption rate could also be observed by varying volume and injection depth of the monomeric analogues. PMID:8218870

  1. Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue.

    PubMed

    Kanikkannan, N; Singh, J; Ramarao, P

    1999-05-01

    The present study was undertaken to explore the possibility of delivering bovine insulin in streptozocin (STZ)-induced diabetic rats by iontophoresis. Further, the effect of iontophoresis of monomeric human insulin analogue (r-DNA origin) on the plasma glucose level (PGL) of diabetic rats was studied. Iontophoresis of bovine insulin (10-200 IU/ml) was not effective in decreasing the PGL in untreated diabetic rats. Pretreatment of skin with oleic acid or menthol for 3 h followed by iontophoresis of bovine insulin also failed to produce a fall in PGL. Application of a depilatory cream for hair removal (24 h before the experiment), followed by iontophoresis of bovine insulin (10, 30 and 100 IU/ml) produced a concentration-dependent fall in PGL. Further, application of depilatory cream immediately before the experiment produced a substantial fall in PGL both by passive diffusion and iontophoresis. Depilatory cream might have drastically reduced the barrier function of skin such that conventional bovine insulin (dimer and hexamer) penetrates through the intact skin by iontophoresis and even by passive diffusion. Depilatory cream or the active components of depilatory cream may be useful as penetration enhancers for transdermal delivery of drugs especially macromolecules such as insulin. Iontophoresis of monomeric human insulin analogue (B9 Asp, B27 Glu) through intact skin (untreated) produced a significant fall in PGL in diabetic rats. Monomeric human insulin analogues which have low tendency to self aggregation may be promising candidates for the transdermal iontophoretic delivery of insulin. PMID:10210726

  2. Determinants of intensive insulin therapeutic regimens in patients with type 1 diabetes: data from a nationwide multicenter survey in Brazil

    PubMed Central

    2014-01-01

    Background To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D). Methods This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups. Results We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). The majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001). Conclusions Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits. PMID:24920963

  3. Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir.

    PubMed

    Kurtzhals, P

    2004-09-01

    The suboptimal nature of the absorption profiles of human insulin formulations following subcutaneous administration has prompted the development of insulin analogues better suited for therapeutic use in diabetes mellitus. A particular challenge has been to engineer long-acting agents that do not produce unduly variable responses from one injection to another. One recent approach that has met with success has been to acylate, the insulin molecule with a fatty acid, thereby enabling reversible albumin binding. The first clinically available agent of this type is insulin detemir. Pharmacological studies have established that this principle is effective in prolonging action, primarily by retarding absorption. The solubility of insulin detemir in the vial and after injection and an important buffering mechanism effected by plasma albumin binding explain a significant decrease in within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. Owing to the extremely high ratio of albumin-binding sites to insulin detemir molecules at therapeutic concentrations, no safety considerations have been identified pertaining to albumin binding. The insulin detemir molecule retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Thus, insulin detemir offers the promise of an improved tolerability:efficacy ratio in the clinical setting. PMID:15306834

  4. Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps

    PubMed Central

    Valla, Vasiliki

    2010-01-01

    Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Results. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial “closed-loop” systems mimicking the pancreatic activity have been also developed. Conclusions. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients. PMID:20589066

  5. A critical appraisal of the role of insulin analogues in the management of diabetes mellitus.

    PubMed

    Oiknine, Ralph; Bernbaum, Marla; Mooradian, Arshag D

    2005-01-01

    Insulin is one of the oldest and best studied treatments for diabetes mellitus. Despite many improvements in the management of diabetes, the nonphysiological time-action profiles of conventional insulins remain a significant obstacle. However, the advent of recombinant DNA technology made it possible to overcome these limitations in the time-action profiles of conventional insulins. Used as prandial (e.g. insulin lispro or insulin aspart) and basal (e.g. insulin glargine) insulin, the analogues simulate physiological insulin profiles more closely than the older conventional insulins. If rapid-acting insulin analogues are used in the hospital, healthcare providers will need a new mind-set. Any error in coordination between timing of rapid-acting insulin administration and meal ingestion may result in hypoglycaemia. However, guidelines regarding in-hospital use of insulin analogues are few. The safety profile of insulin analogues is still not completely established in long-term clinical studies. Several studies have shown conflicting results with respect to the tumourigenic potential of this new class of agents. The clinical implications of these findings are not clear. Although novel insulin analogues are promising 'designer drugs' in our armamentarium to overcome some of the limitations of conventional insulin therapy, cost may be a limiting factor for some patients. PMID:15669878

  6. Insulin requirements in patients with diabetes and declining kidney function: differences between insulin analogues and human insulin?

    PubMed Central

    Kulozik, Felix

    2013-01-01

    Objectives: In diabetic nephropathy the decline of renal function causes modifications of the insulin and carbohydrate metabolism resulting in changed insulin requirements. The aim of the present study was to identify potential differences in the requirements of human insulin and various insulin analogues in patients with type 1 diabetes mellitus and renal dysfunction. Methods: The insulin requirements of 346 patients with type 1 diabetes mellitus under everyday life circumstances were assessed in an observational study. Simultaneously, laboratory parameters were measured and the estimated glomerular filtration rate (eGFR) was calculated using the formula by Cockcroft–Gault. Medical history and concomitant medication were recorded. The insulin requirements of long- and short-acting insulin were tested for a relationship with the eGFR and laboratory parameters. Results: The dosage of long-acting human insulin did not show any relation to eGFR. In contrast, a strong positive relation between dosage and renal function was found for insulin glargine and insulin detemir. After classification according to renal function, the insulin dosage at eGFR less than 60 ml/min was 29.7% lower in glargine-treated and 27.3% lower in detemir-treated patients compared with eGFR greater than 90 ml/min. Considering the whole range of eGFR, short-acting human insulin did not show a relation with renal function. Only after classification according to renal function was a dose reduction found for human insulin at eGFR less than 60 ml/min. In contrast, requirements of insulin lispro were significantly related to eGFR over the whole range of eGFR. At eGFR less than 60 ml/min the insulin dosage was 32.6% lower than at eGFR greater than 90 ml/min. The requirements of insulin aspart did not show any association with the eGFR. Conclusions: Patients with type 1 diabetes mellitus show different insulin requirements according to the renal function depending on the applied insulin. This finding is

  7. [Clinical importance of basal insulin analogues and insulin Toujeo® 300 units/ml].

    PubMed

    Adamíková, Alena

    2015-11-01

    Type 2 diabetes mellitus is a heterogeneous disease that requires a personalized approach to treatment with goals tailored to capabilities and abilities of the patient, his other diseases so as to ensure good diabetes control without the risk of hypoglycemic events and the development or progression of late diabetic complications. Recommendations for treatment of diabetes is classified in second-line as a one of the possibilities of treatment of basal insulin immediately after the failure of therapy with metformin and diet. The new generation of basal insulin analogues provides its effect profile and features a completely new quality to the treatment of diabetes. Toujeo® 300 units/ml is a new long-acting basal insulin glargine concentration of 300 units/ ml with a low glycemic variability, which in studies has demonstrated consistent control of diabetes in a significant reduction in the risk of hypoglycemia especially at night compared with insulin glargin of concentration 100 units/ml. PMID:26652788

  8. Insulin analogues in pregnancy and specific congenital anomalies: a literature review.

    PubMed

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa; Morgan, Margery; de Jong-van den Berg, Lolkje T W; Wang, Hao

    2016-05-01

    Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26431249

  9. Capillary electrokinetic chromatography of insulin and related synthetic analogues.

    PubMed

    Ortner, K; Buchberger, W; Himmelsbach, M

    2009-04-01

    With the implementation of recombinant DNA technology in the pharmaceutical industry, some synthetic insulins have been developed in order to improve the therapy of diabetes. These analogues differ only slightly in the amino acid sequence, therefore displaying a great challenge for analytical chemistry. Within the work presented in this paper, capillary zone electrophoresis (CZE), micellar electrokinetic chromatography (MEKC) with sodium dodecylsulphate (SDS) as micelle-forming agent, and microemulsion electrokinetic chromatography (MEEKC) with microemulsions consisting of SDS, n-octane and 1-butanol were investigated for the separation of human insulin and five synthetic analogues. Best results were achieved with a solvent-modified MEKC system consisting of 100mM sodium dodecyl sulphate and 15% acetonitrile in 10mM borate buffer (pH 9.2). A similar system based on perfluorooctanoic acid as micelle-forming agent in ammonium acetate (pH 9.2) was successfully employed for the hyphenation with a quadrupole/time-of-flight mass spectrometer via a sheath-flow interface. In this case, detection limits at 10mg/L could be achieved. PMID:19027906

  10. Synthesis and Identification of FITC-Insulin Conjugates Produced Using Human Insulin and Insulin Analogues for Biomedical Applications.

    PubMed

    Jacob, Dolly; Joan Taylor, M; Tomlins, Paul; Sahota, Tarsem S

    2016-03-01

    Human insulin was fluorescently labelled with fluorescein isothiocyanate (FITC) and the conjugate species produced were identified using high performance liquid chromatography and electrospray mass spectroscopy. Mono-labelled FITC-insulin conjugate (A1 or B1) was successfully produced using human insulin at short reaction times (up to 5 h) however the product always contained some unlabelled native human insulin. As the reaction time was increased over 45 h, no unlabelled native human insulin was present and more di-labelled FITC-insulin conjugate (A1B1) was produced than mono-labelled conjugate with the appearance of tri-labelled conjugate (A1B1B29) after 20 h reaction time. The quantities switch from mono-labelled to di-labelled FITC-insulin conjugate between reaction times 9 and 20 h. In the presence of phenol or m-cresol, there appears to be a 10 % decrease in the amount of mono-labelled conjugate and an increase in di-labelled conjugate produced at lower reaction times. Clinically used insulin analogues present in commercially available preparations were successfully fluorescently labelled for future biomedical applications. PMID:26658795

  11. The Effects of Anti-insulin Antibodies and Cross-reactivity with Human Recombinant Insulin Analogues in the E170 Insulin Immunometric Assay

    PubMed Central

    Kim, Serim; Hur, Mina; Moon, Hee Won; Kim, Jin Q

    2011-01-01

    Background Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. Methods Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. Results In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). Conclusions IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for β cell function assessment in diabetic patients undergoing insulin therapy. PMID:21239867

  12. Short acting insulin analogues in intensive care unit patients

    PubMed Central

    Bilotta, Federico; Guerra, Carolina; Badenes, Rafael; Lolli, Simona; Rosa, Giovanni

    2014-01-01

    Blood glucose control in intensive care unit (ICU) patients, addressed to actively maintain blood glucose concentration within defined thresholds, is based on two major therapeutic interventions: to supply an adequate calories load and, when necessary, to continuously infuse insulin titrated to patients needs: intensive insulin therapy (IIT). Short acting insulin analogues (SAIA) have been synthesized to improve the chronic treatment of patients with diabetes but, because of the pharmacokinetic characteristics that include shorter on-set and off-set, they can be effectively used also in ICU patients and have the potential to be associated with a more limited risk of inducing episodes of iatrogenic hypoglycemia. Medical therapies carry an intrinsic risk for collateral effects; this can be more harmful in patients with unstable clinical conditions like ICU patients. To minimize these risks, the use of short acting drugs in ICU patients have gained a progressively larger room in ICU and now pharmaceutical companies and researchers design drugs dedicated to this subset of medical practice. In this article we report the rationale of using short acting drugs in ICU patients (i.e., sedation and treatment of arterial hypertension) and we also describe SAIA and their therapeutic use in ICU with the potential to minimize iatrogenic hypoglycemia related to IIT. The pharmacodynamic and pharmachokinetic characteristics of SAIA will be also discussed. PMID:24936244

  13. Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10

    PubMed Central

    Hansen, Bo F.; Glendorf, Tine; Hegelund, Anne C.; Lundby, Anders; Lützen, Anne; Slaaby, Rita; Stidsen, Carsten Enggaard

    2012-01-01

    Aims/Hypothesis There is controversy with respect to molecular characteristics of insulin analogues. We report a series of experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparison with human insulin, IGF-1, and the super-mitogenic insulin, X10. Methods We measured binding of ligands to membrane-bound and solubilised receptors, receptor activation and mitogenicity in a number of cell types. Results Detemir and glargine each displayed a balanced affinity for insulin receptor (IR) isoforms A and B. This was also true for X10, whereas IGF-1 had a higher affinity for IR-A than IR-B. X10 and glargine both exhibited a higher relative IGF-1R than IR binding affinity, whereas detemir displayed an IGF-1R:IR binding ratio of ≤1. Ligands with high relative IGF-1R affinity also had high affinity for IR/IGF-1R hybrid receptors. In general, the relative binding affinities of the analogues were reflected in their ability to phosphorylate the IR and IGF-1R. Detailed analysis revealed that X10, in contrast to the other ligands, seemed to evoke a preferential phosphorylation of juxtamembrane and kinase domain phosphorylation sites of the IR. Sustained phosphorylation was only observed from the IR after stimulation with X10, and after stimulation with IGF-1 from the IGF-1R. Both X10 and glargine showed an increased mitogenic potency compared to human insulin in cells expressing many IGF-1Rs, whereas only X10 showed increased mitogenicity in cells expressing many IRs. Conclusions Detailed analysis of receptor binding, activation and in vitro mitogenicity indicated no molecular safety concern with detemir. PMID:22590494

  14. Type 1 Ig-E mediated allergy to human insulin, insulin analogues and beta-lactam antibiotics*

    PubMed Central

    Andrade, Pedro; Barros, Luísa; Gonçalo, Margarida

    2012-01-01

    Insulin, a crucial therapeutic agent for diabetes mellitus, has been rarely associated with hypersensitivity events. We present a 69-year-old type-2 diabetic patient with urticariform lesions on the sites of subcutaneous injection of insulin. The patient denied any known allergies, except for an unspecific cutaneous reaction after intramuscular penicillin administration in childhood. Prick tests revealed positive reactions to all tested human insulins and insulin analogues. Serum IgE levels were above normal range and RAST tests were positive for human, bovine and porcine insulins, as well as beta-lactams. Type 1 IgE-mediated allergy to insulin analogues demands a prompt diagnosis and represents a significant therapeutic challenge in diabetic patients. PMID:23197216

  15. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

    PubMed

    Redwan, Elrashdy M; Linjawi, Moustafa H; Uversky, Vladimir N

    2016-01-01

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID:26983499

  16. Efficacy of insulin analogues in diabetic patients attending primary care centers

    PubMed Central

    Bardisi, Wedad M.; Khorsheed, Manal M.; Magliah, Faisal; Magliah, Ayman F.

    2015-01-01

    Objectives: To measure the efficacy of new insulin analogues compared with the conventional types of insulin, and to compare their effects on patient satisfaction regarding their weight changes and the frequency of hypoglycemic episodes. Methods: In this retrospective cohort observational study, data was collected from the medical records of 122 eligible diabetics on insulin therapy attending government primary care centers in Jeddah, Kingdom of Saudi Arabia from June 2013 to July 2014. The data collected considered the efficacy, safety, and patient satisfaction of the types of insulin therapy used for their treatment. Results: After 12 weeks, there was a reduction in mean glycosylated hemoglobin (HbA1c) of -0.88% for the analogue type versus -0.19% for the conventional type, and at 24 weeks, the mean drop in HbA1c was -2.02% for the analogue type versus -1.12% for the conventional type, but the differences were not statistically significant. More patients (87% versus 38%) on analogue compared with conventional insulin treatment were satisfied with therapy. Conclusion: In the primary health care setting, insulin analogues showed greater efficacy improvements than conventional insulin therapy within 6 months. However, conventional insulin therapy can still be used at primary care centers with limited resources, and when patients refuse to be converted. PMID:26108587

  17. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism

    PubMed Central

    Redwan, Elrashdy M.; Linjawi, Moustafa H.; Uversky, Vladimir N.

    2016-01-01

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID:26983499

  18. [Significance of insulin analogues in the treatment of people with type 2 diabetes].

    PubMed

    Gallwitz, B; Westrup, D; Schmeisl, G-W

    2014-10-01

    Assessment of the significance of the different insulins used in type 2 diabetes mellitus is of fundamental importance for routine treatment. Compared with human insulin, rapid acting insulin analogues have a faster uptake and a higher peak effect as well as a shorter duration of action. Long acting insulin analogues have a flatter action profile and a longer duration of action than NPH insulin. Consequently, insulin analogues generally allow an improved glycaemic control to be achieved. Moreover, differences relating to practical aspects are of importance (snacks and interval between injection and meals in the case of short acting insulin as well as mixing of suspensions and number of injections in the case of long acting insulins). The consequences for clinical practice are seen differently by countries as shown by a prescription rate of 50 % for insulin analogues in Germany compared with approximately 90 % in certain other European countries. One of the main reasons why questions remain is the lack of meaningful long-term studies on diabetes-related complications. PMID:25317651

  19. Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years

    PubMed Central

    2011-01-01

    In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog®), insulin aspart ( NovoRapid®), insulin glulisine (Apidra®), and the slow acting analogues insulin glargine (Lantus®), and insulin detemir (Levemir®) were gathered from the past 20 years (except for receptor binding studies). A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation). Whether or not these differences have clinical bearings (and among which patient populations) remains to be determined. PMID:21714872

  20. Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue

    PubMed Central

    Korn, Marcus; Schmidt, Ronald; Wendrich, Thomas M.; Tennagels, Norbert

    2014-01-01

    Context Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI). Objective To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA). Methods Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS. Results Blood glucose lowering was prolonged with D-GLA. D-GLA comprised ≥98% of insulin after D-GLA injection; M1 comprised 76–92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation. Conclusions Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity. PMID:25144413

  1. Quantitation of Insulin Analogues in Serum Using Immunoaffinity Extraction, Liquid Chromatography, and Tandem Mass Spectrometry.

    PubMed

    Van Der Gugten, J Grace; Wong, Sophia; Holmes, Daniel T

    2016-01-01

    Insulin analysis is used in combination with glucose, C-peptide, beta-hydroxybutyrate, and proinsulin determination for the investigation of adult hypoglycemia. The most common cause is the administration of too much insulin or insulin secretagogue to a diabetic patient or inadequate caloric intake after administration of either. Occasionally there is a question as to whether hypoglycemia has been caused by an exogenous insulin-whether by accident, intent, or even malicious intent. While traditionally this was confirmed by a low or undetectable C-peptide in a hypoglycemic specimen, this finding is not entirely specific and would also be expected in the context of impaired counter-regulatory response, fatty acid oxidation defects, and liver failure-though beta-hydroxybutyrate levels can lend diagnostic clarity. For this reason, insulin is often requested. However, popular automated chemiluminescent immunoassays for insulin have distinctly heterogeneous performance in detecting analogue synthetic insulins with cross-reactivities ranging from near 0 % to greater than 100 %. The ability to detect synthetic insulins is vendor-specific and varies between insulin products. Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) offers a means to circumvent these analytical issues and both quantify synthetic insulins and identify the specific type. We present an immunoaffinity extraction and LC-MS/MS method capable of independent identification and quantitation of native sequence insulins (endogenous, Insulin Regular, Insulin NPH), and analogues Glargine, Lispro, Detemir, and Aspart with an analytical sensitivity for endogenous insulin of between 1 and 2 μU/mL in patient serum samples. PMID:26602124

  2. The solution structure of a superpotent B-chain-shortened single-replacement insulin analogue.

    PubMed Central

    Kurapkat, G.; Siedentop, M.; Gattner, H. G.; Hagelstein, M.; Brandenburg, D.; Grötzinger, J.; Wollmer, A.

    1999-01-01

    This paper reports on an insulin analogue with 12.5-fold receptor affinity, the highest increase observed for a single replacement, and on its solution structure, determined by NMR spectroscopy. The analogue is [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. C-terminal truncation of the B-chain by four (or five) residues is known not to affect the functional properties of insulin, provided the new carboxylate charge is neutralized. As opposed to the dramatic increase in receptor affinity caused by the substitution of D-Ala for the wild-type residue TyrB26 in the truncated molecule, this very substitution reduces it to only 18% of that of the wild-type hormone when the B-chain is present in full length. The insulin molecule in solution is visualized as an ensemble of conformers interrelated by a dynamic equilibrium. The question is whether the "active" conformation of the hormone, sought after in innumerable structure/function studies, is or is not included in the accessible conformational space, so that it could be adopted also in the absence of the receptor. If there were any chance for the active conformation, or at least a predisposed state to be populated to a detectable extent, this chance should be best in the case of a superpotent analogue. This was the motivation for the determination of the three-dimensional structure of [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. However, neither the NMR data nor CD spectroscopic comparison of a number of related analogues provided a clue concerning structural features predisposing insulin to high receptor affinity. After the present study it seems more likely than before that insulin will adopt its active conformation only when exposed to the force field of the receptor surface. PMID:10091652

  3. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues.

    PubMed

    Lundby, Anders; Bolvig, Pernille; Hegelund, Anne Charlotte; Hansen, Bo F; Worm, Jesper; Lützen, Anne; Billestrup, Nils; Bonnesen, Christine; Oleksiewicz, Martin B

    2015-07-01

    There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC(50) values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. PMID:25413577

  4. Comparative Effectiveness and Safety of Premixed Insulin Analogues in Type 2 Diabetes

    PubMed Central

    Qayyum, Rehan; Bolen, Shari; Maruthur, Nisa; Feldman, Leonard; Wilson, Lisa M.; Marinopoulos, Spyridon S.; Ranasinghe, Padmini; Amer, Muhammed; Bass, Eric B.

    2009-01-01

    Background Evidence comparing premixed insulin analogues with other antidiabetic agents is urgently required to guide appropriate therapy. Purpose To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues as compared with other antidiabetic agents in adults with type 2 diabetes. Data Sources We searched MEDLINE®, EMBASE®, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008, and unpublished data from U.S. Food and Drug Administration, European Medicines Agency, and industry. Study Selection Studies with control arms that compared premixed insulin analogues to another antidiabetic medication in adults with type 2 diabetes Data Extraction Serial abstraction by 2 reviewers using standardized protocols Data Synthesis Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed analogues were similar to premixed human insulin in lowering fasting glucose, hemoglobin A1c, and the incidence of hypoglycemia but were more effective in lowering postprandial glucose (mean difference = -1.1 mmol/L; 95% CI = -1.4 to -0.7 mmol/L [-19.2 mg/dL; 95% CI=-25.9 to -12.5 mg/dL]). As compared to long-acting insulin analogues, premixed analogues were superior in lowering postprandial glucose (mean difference= -1.5 mmol/L; 95%CI = -1.9 to -1.2 mmol/L [-27.9 mg/dL; 95% CI=-34.3 to -21.5 mg/dL]) and hemoglobin A1c (mean difference=-0.39%; 95% CI=-0.50% to -0.28%) but inferior in lowering fasting glucose (mean difference=0.7 mmol/L; 95%CI = 0.3 to 1.0 mmol/L [12.0 mg/dL; 95% CI=6.0 to 18.1 mg/dL]) and had higher incidence of hypoglycemia. When compared to noninsulin antidiabetic agents, premixed analogues were more effective in lowering fasting glucose (mean difference= -1.1mmol/L; 95%CI = -1.7 to 0.6 mmol/L [-20.5 mg/dL; 95% CI=-29.9 to -11.2 mg/dL]), postprandial glucose (mean difference= -2.1 mmol/L; 95%CI

  5. Basal insulin analogues in the management of diabetes mellitus: What progress have we made?

    PubMed

    Owens, David R; Matfin, Glenn; Monnier, Louis

    2014-02-01

    Insulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time-action profile (peak activity 4-6 h after subcutaneous administration) confers an increased propensity for between-meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long-acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time-action profiles and reduced day-to-day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged-acting insulin which forms long subcutaneous multi-hexamers that delay absorption. Recent phase III trials in type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials. PMID:24026961

  6. [Management of type 1 diabetes (insulin, diet, sport): "Dorchy's recipes"].

    PubMed

    Dorchy, Harry

    2010-01-01

    The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or = 4, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Due to their pharmakokinetic characteristics, fast-acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c. Dietary recommendations issued over the last few years are the same for diabetic and non-diabetic individuals in order to avoid degenerative diseases. In the twice-daily free-mix regimen, the allocation of carbohydrates throughout the day is essential. There is no linear correlation between the metabolization of x grams of glucose by y units of insulin and carbohydrate counting is a piece of nonsense. Glycamic changes during exercise depend largely on blood insulin levels. In the young diabetic, during insulin deficiency, and therefore in a poor degree of metabolic control, i.e. hyperglycemic and ketotic, exercise accentuates hyperglycemia and ketosis, leading to extreme fatigue. If the insulin dosage is too high, the increase in muscular assimilation, combined with the shutdown of liver glucose production, may result in a severe hypoglycemia. During the recovery period, the repletion of muscular and hepatic glycogen stores may also provoke an hypoglycemia during hours after the cessation of muscular work. PMID:21812215

  7. Assessment of Patient-Led or Physician-Driven Continuous Glucose Monitoring in Patients With Poorly Controlled Type 1 Diabetes Using Basal-Bolus Insulin Regimens

    PubMed Central

    Riveline, Jean-Pierre; Schaepelynck, Pauline; Chaillous, Lucy; Renard, Eric; Sola-Gazagnes, Agnès; Penfornis, Alfred; Tubiana-Rufi, Nadia; Sulmont, Véronique; Catargi, Bogdan; Lukas, Céline; Radermecker, Régis P.; Thivolet, Charles; Moreau, François; Benhamou, Pierre-Yves; Guerci, Bruno; Leguerrier, Anne-Marie; Millot, Luc; Sachon, Claude; Charpentier, Guillaume; Hanaire, Hélène

    2012-01-01

    OBJECTIVE The benefits of real-time continuous glucose monitoring (CGM) have been demonstrated in patients with type 1 diabetes. Our aim was to compare the effect of two modes of use of CGM, patient led or physician driven, for 1 year in subjects with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes aged 8–60 years with HbA1c ≥8% were randomly assigned to three groups (1:1:1). Outcomes for glucose control were assessed at 1 year for two modes of CGM (group 1: patient led; group 2: physician driven) versus conventional self-monitoring of blood glucose (group 3: control). RESULTS A total of 257 subjects with type 1 diabetes underwent screening. Of these, 197 were randomized, with 178 patients completing the study (age: 36 ± 14 years; HbA1c: 8.9 ± 0.9%). HbA1c improved similarly in both CGM groups and was reduced compared with the control group (group 1 vs. group 3: −0.52%, P = 0.0006; group 2 vs. group 3: −0.47%, P = 0.0008; groups 1 + 2 vs. group 3: −0.50%, P < 0.0001). The incidence of hypoglycemia was similar in the three groups. Patient SF-36 questionnaire physical health score improved in both experimental CGM groups (P = 0.004). Sensor consumption was 34% lower in group 2 than in group 1 (median [Q1–Q3] consumption: group 1: 3.42/month [2.20–3.91] vs. group 2: 2.25/month [1.27–2.99], P = 0.001). CONCLUSIONS Both patient-led and physician-driven CGM provide similar long-term improvement in glucose control in patients with poorly controlled type 1 diabetes, but the physician-driven CGM mode used fewer sensors. PMID:22456864

  8. [Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment].

    PubMed

    Hamaguchi, Tomoya; Sadahiro, Katsuhiko; Satoh, Tomomi

    2015-03-01

    The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid-acting insulin analogs may offer a proper method to reach glycemic goals. PMID:25812371

  9. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

    SciTech Connect

    Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela; Watson, Christopher J.; Turkenburg, Johan P.; Jiráček, Jiří; Brzozowski, Andrzej M.

    2014-10-01

    [AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

  10. Efficacy and safety of insulin degludec in Japanese patients with type 1 and type 2 diabetes: 24-week results from the observational study in routine clinical practice.

    PubMed

    Kobuke, Kazuhiro; Yoneda, Masayasu; Nakanishi, Shuhei; Ohno, Haruya; Maeda, Shusaku; Egusa, Genshi

    2016-01-01

    This is first observational prospective study of insulin degludec in routine clinical practice that we evaluated the effect on glycemic control and risk of hypoglycemia in basal-bolus insulin therapy. We found that insulin degludec can maintain glycemic control at a lower insulin dose and frequency of hypoglycemia in type 1 diabetes, while it can improve glycemic control at equally insulin dose in type 2 diabetes. These results mean that insulin degludec is of use in routine clinical practice. PMID:26816606

  11. Intraperitoneal insulin therapy for a patient with type 1 diabetes with insulin injection site inflammation.

    PubMed

    Lee, Siang Ing; Narendran, Parth

    2014-01-01

    A 36-year-old man with type 1 diabetes developed skin inflammation at the site of subcutaneous insulin injection after 10 years of basal bolus subcutaneous insulin therapy. This inflammation led to poor insulin absorption, poorly controlled blood glucose and subsequently to ketoacidosis. The problem persisted despite a trial of continuous subcutaneous insulin infusion. The patient went on to be treated with continuous intraperitoneal insulin infusion. Three months after the procedure, he was achieving good glucose control and was able to resume his normal life, with the only complication being an episode of cellulitis surrounding the port site. PMID:25188930

  12. Intraperitoneal insulin therapy for a patient with type 1 diabetes with insulin injection site inflammation

    PubMed Central

    Lee, Siang Ing; Narendran, Parth

    2014-01-01

    A 36-year-old man with type 1 diabetes developed skin inflammation at the site of subcutaneous insulin injection after 10 years of basal bolus subcutaneous insulin therapy. This inflammation led to poor insulin absorption, poorly controlled blood glucose and subsequently to ketoacidosis. The problem persisted despite a trial of continuous subcutaneous insulin infusion. The patient went on to be treated with continuous intraperitoneal insulin infusion. Three months after the procedure, he was achieving good glucose control and was able to resume his normal life, with the only complication being an episode of cellulitis surrounding the port site. PMID:25188930

  13. Effect of Insulin Analogues on Insulin/IGF1 Hybrid Receptors: Increased Activation by Glargine but Not by Its Metabolites M1 and M2

    PubMed Central

    Pierre-Eugene, Cécile; Pagesy, Patrick; Nguyen, Tuyet Thu; Neuillé, Marion; Tschank, Georg; Tennagels, Norbert; Hampe, Cornelia; Issad, Tarik

    2012-01-01

    Background In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R), present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. Methodology To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET) assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP3) production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. Results Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. Conclusion Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in MCF-7 cells. PMID:22848683

  14. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.

    PubMed

    Záková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela; Watson, Christopher J; Turkenburg, Johan P; Jiráček, Jiří; Brzozowski, Andrzej M

    2014-10-01

    The structural characterization of the insulin-insulin receptor (IR) interaction still lacks the conformation of the crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms. PMID:25286859

  15. A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues.

    PubMed

    Baricevic, Ivona; Jones, David R; Roberts, Darren L; Lutzen, Anne; Lundby, Anders; Worm, Jesper; Hansen, Bo F; Renehan, Andrew G

    2015-09-01

    Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose-response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from <1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for insulin-like growth factor I (IGF-I) and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from five additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities. PMID:26026165

  16. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

    PubMed Central

    Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela; Watson, Christopher J.; Turkenburg, Johan P.; Jiráček, Jiří; Brzozowski, Andrzej M.

    2014-01-01

    The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms. PMID:25286859

  17. Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes

    SciTech Connect

    Serri, O.; Beauregard, H.; Brazeau, P.; Abribat, T.; Lambert, J.; Harris, A.; Vachon, L. Sandoz Canada Inc., Dorval, Quebec )

    1991-02-20

    To determine whether treatment with a somatostatin analogue can reduce kidney hyperfiltration and hypertrophy in insulin-dependent diabetes mellitus, the authors studied 11 patients with insulin-dependent diabetes mellitus and glomerular hyperfiltration. The patients were assigned randomly to receive continuous subcutaneous infusion of either octreotide, 300 {mu}g/24 h (five patients) or placebo (six patients) for 12 weeks. At baseline, mean glomerular filtration rate and mean total kidney volume were not significantly different in the two groups. However, after 12 weeks of treatment, the mean glomerular filtration rate was significantly lower in the octreotide group than in the placebo group. Furthermore, the mean total kidney volume was significantly lower after treatment in the octreotide group than in the placebo group. Glycemic control did not change significantly in either group. They conclude that subcutaneous infusion of octreotide for 12 weeks reduces increased glomerular filtration rate and kidney size in patients with insulin-dependent diabetes mellitus despite the fact that glycemic control remains unchanged.

  18. Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: A narrative review

    PubMed Central

    Elizarova, Svetlana; Galstyan, Gagik R; Wolffenbuttel, Bruce HR

    2014-01-01

    Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin-naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision-making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control. PMID:24127999

  19. Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: a narrative review.

    PubMed

    Elizarova, Svetlana; Galstyan, Gagik R; Wolffenbuttel, Bruce H R

    2014-03-01

    Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin-naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision-making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control. PMID:24127999

  20. Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

    PubMed

    Dowlat, H A; Kuhlmann, M K; Khatami, H; Ampudia-Blasco, F J

    2016-08-01

    Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included. PMID:27097592

  1. Synthesis and biological activities of d-chiro-inositol analogues with insulin-like actions.

    PubMed

    Rendle, P M; Kassibawi, F; Johnston, K A; Hart, J B; Cameron, S A; Falshaw, A; Painter, G F; Loomes, K M

    2016-10-21

    d-chiro-inositol (DCI, 1) evokes therapeutic actions in diabetes and insulin resistance but has sub-optimal pharmacokinetic profiles. To investigate what positions on the DCI cyclohexanol ring may be amenable to modification to improve pharmaceutical formulations, a series of analogues based on DCI were synthesised. These compounds were then evaluated for their ability to stimulate glucose transport using 3T3-L1 adipocytes as a model system. Positional analyses indicate that the hydroxyl group at position 1 is not essential for activity and can be modified without affecting glucose uptake. Removal of the hydroxyl at position 3 also had minimal effect on activity but this group is sensitive to modification. By comparison, the oxygen at position 2 is crucial to the potency of DCI, although this group can withstand modification without fundamentally affecting activity. These data reveal that positions 1 and 2 on the cyclohexanol ring of DCI offer further scope for modification to develop DCI analogues with desirable pharmacokinetic profiles for the potential treatment of metabolic disease. PMID:27410479

  2. Synthesis and properties of carbonylbis(methionyl)insulin, a proinsulin analogue which is convertible to insulin by cyanogen bromide cleavage.

    PubMed

    Busse, W D; Carpenter, F H

    1976-04-20

    The preparation and use of carbonylbis (L-methionine p-nitrophenyl ester) as a reversible cross-linking reagent for insulin are described. The reaction of 1 equiv of reagent with zinc insulin in dimethylformamide in the presence of triethylamine yields as one of the products NalphaA1, NepsilonB29-carbonylbis(methionyl)insulin, (CBM-insulin). The CBM-insulin was characterized by end group analysis and by the products formed on tryptic and chymotryptic cleavage. It possessed 91% of the immunological and 6.5% of the hormonal activity of insulin. Treatment of CBM-insulin with cyanogen bromide (CNBr) in 70% formic acid for 1 h resulted in nearly complete removal of the methionine bridge to yield insulin. A small amount of a side product was removed on DEAE-cellulose at pH 7.2 to give an overall recovery of insulin of 70-80%. Oxidative sulfitolyses of CBM-insulin gave the hexa(S-sulfonate) which was reduced with dithiothreitol to yield reduced CBM-insulin. The latter compound, containing 6 sulfhydryls, exhibited a pH-dependent circular dichroic spectrum. The form at pH 10 exhibited a spectrum typical of random coil which was converted to a form at pH 7.8 which was characterized by a negative extremum at 213 nm. The change in the spectrum at 213 nm with pH was characterized by an apparent pKa of 8.5. Studies on the reoxidation of reduced CBM-insulin were performed at pH values between 7.8 and 10 and at protein concentrations of 0.01-1 mg/ml. The best yields (ca. 85%) of the correctly paired disulfide bonds were obtained in reoxidations at pH 9.5-10 at protein concentration of 0.01-0.1 mg/ml. CBM-insulin, which had been isolated from reoxidation at high pH of the reduced CBM-insulin, was cleaved by CNBr to yield a fully active insulin in an overall yield of 60% from the reduced CBM-insulin. PMID:5108

  3. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

    NASA Astrophysics Data System (ADS)

    Lee, Hyun Chul; Kim, Su-Jin; Kim, Kyung-Sup; Shin, Hang-Cheol; Yoon, Ji-Won

    2000-11-01

    A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.

  4. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    PubMed

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes. PMID:25065475

  5. Efficacy and safety of biphasic insulin aspart and biphasic insulin lispro mix in patients with type 2 diabetes: A review of the literature.

    PubMed

    Kumar, Ajay

    2016-01-01

    Type 2 diabetes (T2D) represents an escalating burden worldwide, particularly in China and India. Compared with Caucasians, Asian people with diabetes have lower body mass index, increased visceral adiposity, and postprandial glucose (PPG)/insulin resistance. Since postprandial hyperglycemia contributes significantly to total glycemic burden and is associated with heightened cardiovascular risk, targeting PPG early in T2D is paramount. Premixed insulin regimens are widely used in Asia due to their convenience and effectiveness. Data from randomized controlled trials and observational studies comparing efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) with biphasic insulin lispro mix (LM 25/50) and versus other insulin therapies or oral antidiabetic drugs (OADs) in T2D demonstrated that BIAsp 30 and LM 25/50 were associated with similar or greater improvements in glycemic control versus comparator regimens, such as basal-bolus insulin, in insulin-naÏve, and prior insulin users. Studies directly comparing BIAsp 30 and LM 25 provided conflicting glycemic control results. Safety data generally showed increased hypoglycemia and weight gain with premixed insulins versus basal-bolus insulin or OADs. However, large observational trials documented improvements in glycated hemoglobin, PPG, and hypoglycemia with BIAsp 30 in multi-ethnic patient populations. In summary, this literature review demonstrates that premixed insulin regimens are an appropriate and effective treatment choice in T2D. PMID:27186543

  6. When to treat a diabetic patient using an external insulin pump. Expert consensus. Société francophone du diabète (ex ALFEDIAM) 2009.

    PubMed

    Lassmann-Vague, V; Clavel, S; Guerci, B; Hanaire, H; Leroy, R; Loeuille, G A; Mantovani, I; Pinget, M; Renard, E; Tubiana-Rufi, N

    2010-02-01

    For years, external insulin pumps have enjoyed proven efficacy as an intensive diabetes treatment to improve glycaemic control and reduce hypoglycaemia. Since the last ALFEDIAM guidelines in 1995, however, basal-bolus treatment using a combination of long- and short-acting insulin analogues have emerged and could challenge, at a lower cost, the efficacy of pumps using rapid-acting insulin analogues, considered the 'gold standard' of insulin treatment. Nevertheless, given its theoretical and practical advantages, some patients will derive more benefit from pump treatment. These cases have been carefully evaluated in the literature by a panel of experts appointed by ALFEDIAM to determine the indications for pump treatment. In patients with type 1 diabetes, persistent elevated HbA(1c) despite multiple daily injections (MDI), and repeated hypoglycaemia and high glycaemic variability, represent the most validated indications. In patients with type 2 diabetes, pump treatment may be indicated in cases of MDI failure to achieve HbA(1c) targets. Absolute contraindications are rare, and comprise severe psychiatric disorders, rapidly progressing ischaemic or proliferative retinopathy before laser treatment and exposure to high magnetic fields. Relative contraindications are mostly related to the patient's lack of compliance or inability to cope with the treatment, and need to be evaluated individually to clearly assess the benefit/risk ratio for the given patient. However, as these conditions are progressive, there should also be annual reassessment of the appropriateness of pump treatment. Specific education on pump treatment initially and throughout the follow-up, delivered by experienced medical and paramedical teams, are the best guarantees of treatment efficacy and safety. PMID:20074990

  7. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

    PubMed Central

    Barnett, A H

    2012-01-01

    In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

  8. Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues

    PubMed Central

    Jiráček, Jiří; Žáková, Lenka; Antolíková, Emília; Watson, Christopher J.; Turkenburg, Johan P.; Dodson, Guy G.; Brzozowski, Andrzej M.

    2010-01-01

    Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin’s induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200–500%) insulin analogues that are truncated at residue 26 of the B-chain (B26). They show a structural convergence in the form of a new β-turn at B24-B26. We propose that the key element in insulin’s transition, from an inactive to an active state, may be the formation of the β-turn at B24-B26 associated with a trans to cis isomerisation at the B25-B26 peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B25-B26 peptide bond or by the insertion of certain D-amino acids at B26. The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes. PMID:20133841

  9. Liposomes containing cholesterol analogues of botanical origin as drug delivery systems to enhance the oral absorption of insulin.

    PubMed

    Cui, Meng; Wu, Wei; Hovgaard, Lars; Lu, Yi; Chen, Dawei; Qi, Jianping

    2015-07-15

    In fear of animal-associated diseases, there is a trend in searching for non-animal derived substitutes for existing excipients in the pharmaceutical industries. This paper aimed to screen cholesterol analogues as membrane stabilizers of liposomes from botanical sterols, including β-sitosterol, stigmasterol, ergosterol and lanosterol. Liposomes containing four kinds of sterols were prepared and evaluated in vitro and in vivo as oral delivery system of insulin. Liposomes containing β-sitosterol (Si-Lip), stigmasterol (St-Lip) and lanosterol (La-Lip) was found not to protect insulin against degradation. Only 10% of the initial insulin in liposomes was preserved after a 30 min exposure to simulated gastric fluids. However, the protective ability of liposomes containing ergosterol (Er-Lip) was similar to that of liposomes containing sodium glycocholate (Sgc-Lip) and superior to that of liposomes containing cholesterol (Ch-Lip). In addition, the blood glucose level can decrease to about 50% of initial level after oral Er-Lip which was significantly superior to the in vivo performance of Si-Lip and Ch-Lip and similar to Sgc-Lip. Er-Lips of ergosterol/phospholipids ratios of 1:4 or 1:6 exerts more pronounced protective ability of insulin in simulated gastrointestinal fluids and hypoglycemic effects in rats than other formulations. Furthermore, Er-Lips exerted low toxicity to Caco-2 cells through a cell viability study. Meahwhile, insulin permeability was significantly increased across Caco-2 monolayers by encapsulating in Er-Lip. It was concluded that ergosterol could be used as a substitute for cholesterol and bile salt derivatives in liposomes to enhance oral bioavailability of insulin. PMID:25957702

  10. Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial

    PubMed Central

    Thalange, N; Bereket, A; Larsen, J; Hiort, L C; Peterkova, V

    2013-01-01

    Aims This 52-week, randomized, multinational, open-label, parallel-group, non-inferiority trial investigated the efficacy and safety of basal–bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 2–16 years with Type 1 diabetes mellitus. Methods Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks. Results After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA1c [mean difference insulin detemir–NPH: 1.30 mmol/mol, 95% CI –1.32 to 3.92 (0.12%, 95% CI –0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI –1.26 to 4.08 (0.13%, 95% CI –0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject-year of exposure of 24-h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60–0.97, P = 0.028 and 0.62, 95% CI 0.47–0.84, P = 0.002, respectively). Weight standard deviation (sd) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: –0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups. Conclusions Insulin detemir was non-inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 2–16 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin. PMID:23094597

  11. Long-acting insulin analogues (insulin glargine or determir) and continuous subcutaneous insulin infusion in the treatment of type 1 diabetes mellitus in the paediatric population.

    PubMed

    Barrio Castellanos, Raquel

    2005-12-01

    Despite many improvements in the treatment of type 1 diabetes mellitus (DM1), the non-physiological time-action profiles of conventional insulins remain a significant obstacle. In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular and NPH insulin. The rapid insulin analogs used as prandial and the long-acting insulin analogs used as basal simulate physiological insulin profiles more closely than the older conventional insulins. The efficacy of insulin analogs now available for multiple daily injection (MDI) and continuous subcutaneous insulin infusion (CSII) therapy in DM1 has been established in pediatric patients. Insulin pumps have improved since they were first introduced. CSII therapy may provide an effective alternative for selected pediatric patients with DM1. In most studies at pediatric age, CSII therapy resulted in a improvement in HbA1c, a decreased rate of hypoglycemia without an abnormal increase in BMI, and without adversely affecting psychosocial outcomes in children and adolescents with DM1. PMID:16398447

  12. Pragmatic use of insulin degludec/insulin aspart co-formulation: A multinational consensus statement.

    PubMed

    Kalra, Sanjay; Latif, Zafar A; Comlekci, Abdurrahman; Galvez, Guillermo Gonzalez; Malik, Rached; Pathan, Md Faruque; Kumar, Ajay

    2016-01-01

    Insulin degludec/insulin aspart (IDegAsp) is a modern coformulation of ultra-long-acting basal insulin degludec, with rapid-acting insulin aspart. IDegAsp provides effective, safe, well-tolerated glycemic control, with a low risk of hypoglycemia while allowing flexibility in meal patterns and timing of administration. This consensus statement describes a pragmatic framework to identify patients who may benefit from IDegAsp therapy. It highlights the utility of IDegAsp in type 2 diabetic patients who are insulin-naive, suboptimally controlled on basal or premixed insulin, or dissatisfied with basal-bolus regimens. It also describes potential IDegAsp usage in type 1 diabetic patients. PMID:27366723

  13. Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus—the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial

    PubMed Central

    Lundby-Christensen, Louise; Tarnow, Lise; Boesgaard, Trine W; S Lund, Søren; Wiinberg, Niels; Perrild, Hans; Krarup, Thure; Snorgaard, Ole; Gade-Rasmussen, Birthe; Thorsteinsson, Birger; Røder, Michael; Mathiesen, Elisabeth R; Jensen, Tonny; Vestergaard, Henrik; Hedetoft, Christoffer; Breum, Leif; Duun, Elsebeth; Sneppen, Simone B; Pedersen, Oluf; Hemmingsen, Bianca; Carstensen, Bendix; Madsbad, Sten; Gluud, Christian; Wetterslev, Jørn; Vaag, Allan; Almdal, Thomas P

    2016-01-01

    Objective To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. Design and setting Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design conducted at eight hospitals in Denmark. Participants and interventions 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥7.5% (≥58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤7.0% (≤53 mmol/mol). Outcomes The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. Results Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI −0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference −0.42% (95% CI −0.62% to −0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference −2.6 kg (95% CI −3.3 to −1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001). Conclusions Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power

  14. NA1, NA1, NA1-trimethylinsulin--an insulin analogue with a quaternary amino group at the A1 terminus.

    PubMed

    Drewes, S E; Magojo, H E; Gliemann, J

    1981-06-01

    By utilizing the differing reactivity of the amino groups in aqueous organic solvents, des-GlyA1-NB1,N epsilon B29-(Msc)2-insulin was prepared. Its reaction with the phenyl ester of N,N,N-trimethylglycine in the presence of N-hydroxysuccinimide afforded the crystalline NA1,NA1,NA1-trimethylinsulin analogue. In the fat cell assay this analogue has an activity of 49% and, in the mouse convulsion assay, it is 70%. PMID:7024089

  15. Determination of human insulin and its analogues in human blood using liquid chromatography coupled to ion mobility mass spectrometry (LC-IM-MS).

    PubMed

    Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2014-01-01

    The qualitative and quantitative determination of insulin from human blood samples is an emerging topic in doping controls as well as in other related disciplines (e.g. forensics). Beside the therapeutic use, insulin represents a prohibited, performance enhancing substance in sports drug testing. In both cases accurate, sensitive, specific, and unambiguous determination of the target peptide is of the utmost importance. The challenges concerning identifying insulins in blood by liquid chromatography coupled to ion mobility mass spectrometry (LC-IM-MS) are detecting the basal concentrations of approximately 0.2 ng/mL and covering the hyperinsulinaemic clamps at > 3 ng/mL simultaneously using up to 200 μL of plasma or serum. This is achieved by immunoaffinity purification of the insulins with magnetic beads and subsequent separation by micro-scale liquid chromatography coupled to ion mobility / high resolution mass spectrometry. The method includes human insulin as well as the synthetic or animal analogues insulin aspart, glulisine, glargine, detemir, lispro, bovine, and porcine insulin. The method validation shows reliable results considering specificity, limit of detection (0.2 ng/mL except for detemir: 0.8 ng/mL), limit of quantification (0.5 ng/mL for human insulin), precision (CV < 20%), linearity (r > 0.99), recovery, accuracy (>90%), robustness (plasma/serum), and ion suppression. For quantification of human insulin a labelled internal standard ([[(2) H10 ]-Leu(B6,B11,B15,B17) ] - human Insulin) is introduced. By means of the additional ion mobility separation of the different analogues, the chromatographic run time is shortened to 8 min without losing specificity. As proof-of-concept, the procedure was successfully applied to different blood specimens from diabetic patients receiving recombinant synthetic analogues. PMID:25219675

  16. Response of isolated ruminant mammary arteries to the long R3 analogue of insulin-like growth factor I.

    PubMed

    Gow, I F

    2000-05-01

    Isolated mammary arteries from ruminants were used in a conventional organ bath system. Acetylcholine relaxed bovine but not ovine mammary arteries; both types responded to sodium nitroprusside. Noradrenaline (NA) caused a dose-dependent increase in generated tension. An analogue of insulin-like growth factor I (long R3-IGF-I) caused a rightward shift in the NA response curve in bovine vessels with intact endothelium (P < 0.02), and also in sheep arteries (P < 0.01). In bovine vessels, this effect was abolished when the endothelium was removed. The effect of long R3-IGF-I in bovine vessels was abolished by N -nitro-L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide synthase, suggesting the effect of IGF-I on mammary arteries in vitro requires NO generation. PMID:10825414

  17. Inhibition of insulin- and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25-dihydroxyvitamin D3 and the vitamin D3 analogue EB1089.

    PubMed

    Vink-van Wijngaarden, T; Pols, H A; Buurman, C J; Birkenhäger, J C; van Leeuwen, J P

    1996-05-01

    1,25 Dihydroxyvitamin D3 (1,25-(OH)2D3) and a number of synthetic vitamin D3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The purpose of the present study was to investigate a possible interaction of 1,25-(OH)2D3 and the vitamin D3 analogue EB1089 with the insulin-IGF-I regulatory system. The oestrogen receptor-positive MCF-7 human breast cancer cells used in this study are able to grow autonomously and their growth is stimulated by insulin. In order to avoid interference of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, long R3 IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R3 IGF-I was completely inhibited by 1,25-(OH)2D3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)2D3 and EB1089. The analogue EB1089 was active at 50 times lower concentrations than 1,25-(OH)2D3. It was shown that growth inhibition was not achieved through downregulation of insulin and IGF-I binding after 48 h. Paradoxically, after prolonged treatment (8 days), an upregulation of insulin and IGF-I binding was observed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-induced C-FOS mRNA was inhibited by 1,25-(OH)2D3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)2D3. MAP kinase activation appeared not to be involved in growth stimulation by both insulin and IGF-I. Together, the present study demonstrates that vitamin D3 compounds can block the mitogenic activity of insulin and IGF-I, which may contribute to their tumour suppressive activity observed in vivo. PMID:9081364

  18. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus

    PubMed Central

    Pettitt, D. J.; Ospina, P.; Howard, C.; Zisser, H.; Jovanovic, L.

    2007-01-01

    Aim The efficacy and safety of insulin aspart (IAsp), a rapid-acting human insulin analogue, were compared with regular human insulin (HI) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus (GDM). Methods In a randomized, parallel-group, open-labelled trial, 27 women with GDM (age 30.7 ± 6.3 years, HbA1c < 7%) were randomized to receive IAsp (5 min before meal) or HI (30 min before meal). The trial period extended from diagnosis of GDM (18–28 weeks) to 6 weeks postpartum. Results Both treatment groups maintained good overall glycaemic control during the study (beginning and end of study HbA1c≤ 6%). During the meal test, mean glucose at week 6 (IAsp 4.2 ± 0.57 mmol/l, HI 4.8 ± 0.86 mmol/l) was slightly lower than at week 0 (IAsp 4.9 ± 0.59 mmol/l, HI 5.1 ± 0.36 mmol/l). However, change from baseline values for average glucose (IAsp –1.09 ± 0.54 mmol/l, HI –0.54 ± 0.74 mmol/l; P = 0.003) and C-peptide (IAsp –0.50 ± 0.67 nmol/l, HI –0.30 ± 0.70 nmol/l; P = 0.027) were significantly lower after IAsp treatment than HI treatment. No major hypoglycaemic events were reported during the study. Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups (end of study: IAsp 2.1 ± 5.4%, HI 6.4 ± 13.9%), whereas antibodies specific to IAsp or HI remained relatively low (< 1% binding). Conclusion IAsp was more effective than HI in decreasing postprandial glucose concentrations. Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM. Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM. Diabet. Med. 24, 1129–1135 (2007) PMID:17888133

  19. Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues.

    PubMed

    Green, Brian D; Gault, Victor A; Mooney, Mark H; Irwin, Nigel; Harriott, Patrick; Greer, Brett; Bailey, Cliff J; O'Harte, Finbarr P M; Flatt, Peter R

    2004-02-01

    The hormone glucagon-like peptide-1(7-36)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucose-dependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidyl-peptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the epsilon-amino group in the side chain of the Lys26 residue and to combine this modification with substitutions of the Ala8 residue, namely Val or amino-butyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal)26]GLP-1, [Abu8, Lys(pal)26]GLP-1 and [Val8 Lys(pal)26]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal beta-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 cells was similar, or in the case of [Val8,Lys(pal)26]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys(pal)26]GLP-1 did not demonstrate acute glucose-lowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability. PMID:15101559

  20. Conformational Analysis of the Host-Defense Peptides Pseudhymenochirin-1Pb and -2Pa and Design of Analogues with Insulin-Releasing Activities and Reduced Toxicities.

    PubMed

    Manzo, Giorgia; Scorciapino, Mariano Andrea; Srinivasan, Dinesh; Attoub, Samir; Mangoni, Maria Luisa; Rinaldi, Andrea C; Casu, Mariano; Flatt, Peter R; Conlon, J Michael

    2015-12-24

    Pseudhymenochirin-1Pb (Ps-1Pb; IKIPSFFRNILKKVGKEAVSLIAGALKQS) and pseudhymenochirin-2Pa (Ps-2Pa; GIFPIFAKLLGKVIKVASSLISKGRTE) are amphibian peptides with broad spectrum antimicrobial activities and cytotoxicity against mammalian cells. In the membrane-mimetic solvent 50% (v/v) trifluoroethanol-H2O, both peptides adopt a well-defined α-helical conformation that extends over almost all the sequence and incorporates a flexible bend. Both peptides significantly (p < 0.05) stimulate the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥ 0.1 nM but produce loss of integrity of the plasma membrane at concentrations ≥ 1 μM. Increasing cationicity by the substitution Glu(17) → l-Lys in Ps-1Pb and Glu(27) → l-Lys in Ps-2Pa generates analogues with increased cytotoxicity and reduced insulin-releasing potency. In contrast, the analogues [R8r]Ps-1Pb and [K8k,K19k]Ps-2Pa, incorporating d-amino acid residues to destabilize the α-helical domains, retain potent insulin-releasing activity but are nontoxic to BRIN-BD11 cells at concentrations of 3 μM. [R8r]Ps-1Pb produces a significant increase in insulin release rate at 0.3 nM and [K8k,K19k]Ps-2Pa at 0.01 nM. Both analogues show low hemolytic activity (IC50 > 100 μM) but retain broad-spectrum antimicrobial activity and remain cytotoxic to a range of human tumor cell lines, albeit with lower potency than the naturally occurring peptides. These analogues show potential for development into agents for type 2 diabetes therapy. PMID:26606380

  1. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  2. Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists?

    PubMed

    Darmon, P; Raccah, D

    2015-12-01

    Type 2 diabetes is an evolutive disease with a progressive defect of beta-cell insulin secretion. This characteristic points to a need for treatment that takes into account such a natural history. When oral antidiabetic drugs fail to achieve the patient's target HbA1c level, basal insulin treatment is usually initiated and titrated in association with oral drugs to manage fasting hyperglycaemia. Over a period of time, it is enough to simply achieve the HbA1c target. However, when even a good fasting blood glucose level is no longer sufficient to control overall glycaemia, then prandial treatment must be combined with the titrated basal insulin to deal with the postprandial hyperglycaemia responsible for the elevation of HbA1c. Of the different therapeutic options now available for this, rapid-acting insulins and GLP-1 receptor agonists (RAs) can be used. Rapid-acting insulins can be added either at each meal, achieving full insulin supplementation with a basal-bolus regimen, or at the main meal only as a "basal-plus" regimen. Compared with the full basal-bolus, the basal-plus strategy is associated with fewer injections, yet provides similar efficacy in terms of HbA1c improvement, but with less weight gain and lower hypoglycaemic risk. As for GLP-1 RAs, numerous studies, and especially those using short-acting GLP-1 RAs, have demonstrated more pronounced effects on postprandial hyperglycaemia, good complementary effects with basal insulin, and significant improvement of HbA1c with no weight gain and a low risk of hypoglycaemia. Similarly, direct and indirect comparisons of the use of rapid-acting insulins and GLP-1 RAs to intensify basal insulin have shown comparable efficacy in terms of HbA1c control, but with less weight gain and fewer hypoglycaemic episodes with GLP-1 RAs. PMID:26774016

  3. The nuts and bolts of subcutaneous insulin therapy in non-critical care hospital settings.

    PubMed

    Juneja, Rattan; Foster, Shonda A; Whiteman, Douglas; Fahrbach, Jessie L

    2010-01-01

    In non-critical care settings, patients with hyperglycemia experience increased morbidity and mortality. Despite an increased recognition of the importance of treating inpatient hyperglycemia, many patients are still not adequately controlled. Insulin offers flexibility to address varying glucose levels and therefore is the preferred therapy to achieve recommended targets and manage hyperglycemia. Traditional sliding-scale insulin regimens often ineffectively control blood glucose levels as they are unable to mimic physiologic insulin secretion. Basal-bolus insulin regimens are recognized as a more effective way to correct hyperglycemia in non-critical care settings and a systematic glycemic control program is necessary to address hyperglycemia while minimizing hypoglycemia. Critical components of these programs include addressing barriers to glycemic control, understanding varying needs of different types of patients, and developing standardized subcutaneous insulin orders to achieve target glucose levels. This article provides strategies for using insulin in non-critical care settings to facilitate glycemic control. PMID:20107299

  4. A randomized controlled trial of liraglutide versus insulin detemir plus sitagliptin: Effective switch from intensive insulin therapy to the once-daily injection in patients with well-controlled type 2 diabetes.

    PubMed

    Inoue, Yuichiro; Nakamura, Akinobu; Kondo, Yoshinobu; Hamano, Kumiko; Satoh, Shinobu; Terauchi, Yasuo

    2015-07-01

    This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c ] ≤ 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% ± 0.9% versus 0.3% ± 0.8% in the liraglutide versus detemir groups, respectively (P = .46). The "overall" satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 ± 7.4 to 29.9 ± 5.3 (P < .001) and from 26.4 ± 6.1 to 28.3 ± 6.4 (P = .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control. PMID:25677642

  5. Comparison of thrice daily biphasic human insulin (30/70) versus basal detemir & bolus aspart in patients with poorly controlled type 2 diabetes mellitus – A pilot study

    PubMed Central

    Shanmugasundar, G.; Bhansali, Anil; Walia, Rama; Dutta, Pinaki; Upreti, Vimal

    2012-01-01

    Background & objectives: Conventionally, biphasic human insulin (30/70, BHI) is used twice daily for the management of patients with diabetes. However, this regimen is suboptimal to control post-lunch and/or pre-dinner hyperglycaemia in some patients. This study was undertaken to compare the efficacy and safety of thrice-daily biphasic human insulin (30/70, BHI) versus basal detemir and bolus aspart (BB) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Methods: In this open labelled randomized pilot study, 50 patients with uncontrolled T2DM on twice-daily BHI and insulin sensitizers were randomized either to BHI thrice-daily or BB regimen. HbA1c, six point plasma glucose profile, increment in insulin dose, weight gain, hypoglycaemic episodes and cost were compared between the two treatment groups at the end of 12 wk. Results: Mean HbAlc (±SD) decreased from 9.0±0.9 per cent at randomization to 7.9±0.8 per cent in BHI (P<0.001) and from 9.4±1.3 to 8.2±1.0 per cent in BB regimen (P<0.001) after 12 wk of treatment. The mean (±SEM) weight gain in patients in the BHI regimen was 1.5±0.33 kg compared to 1.4±0.34 kg in the BB regimen. Insulin dose increment at 12 wk was significantly more in the BB regimen 0.46±0.32 U/kg/day compared to 0.15±0.21 U/kg/day in the BHI regimen (P<0.001). The incidence of major as well as minor hypoglycaemic episodes was not different in both the regimen. The BB regimen was more expensive than the BHI regimen (P<0.001). Interpretation & conclusions: The thrice daily biphasic human insulin regimen is non-inferior to the basal bolus insulin analogue regimen in terms efficacy and safety in patients with poorly controlled T2DM. However, these data require further substantiation in large long term prospective studies. PMID:22382187

  6. Effect of a β-Hydroxyphosphonate Analogue of ʟ-Carnitine on Insulin-Sensitive and Insulin-Resistant 3T3-L1 Adipocytes.

    PubMed

    Avalos-Soriano, Anaguiven; De la Cruz-Cordero, Ricardo; López-Martínez, Francisco Josue; Rosado, Jorge L; Duarte-Vázquez, Miguel Ángel; Garcia-Gasca, Teresa

    2015-01-01

    This study investigated the effect of a β-x200B;hydroxyphosphonate analog of ʟ-carnitine (L-CA) (CAS number: 1220955-x200B;20-3, Component: 1221068-91-2, C12H29NO4PI), (3-Hexanaminium, 1-(dimethoxyphosphinyl)-2-hydroxy-N,N,N,5-x200B;tetramethy-iodide (1:1), (2R, 3S)) on parameters related with type-2 diabetes in an in vitro model. Nontoxic concentrations of L-CA were assayed and compared to commercial ʟ-carnitine effects. L-CA did not affect adipogenesis in normal cells, but an increment of TG accumulation was observed on insulin-resistant adipocytes (80%) when compared with resistant control. L-CA also stimulated glucose analog 2-NBDG uptakes on insulin-resistant adipocytes in a similar way as insulin when compared to insulin-resistant cells. Our results show that the L-CA promoted insulin-like responses on insulin-resistant adipocytes without appreciable pro-adipogenic effect in sensitive adipocytes. PMID:26160659

  7. Total Chemical Synthesis of a Heterodimeric Interchain Bis-Lactam-Linked Peptide: Application to an Analogue of Human Insulin-Like Peptide 3

    PubMed Central

    Karas, John; Shabanpoor, Fazel; Hossain, Mohammed Akhter; Wade, John D.; Scanlon, Denis B.

    2013-01-01

    Nonreducible cystine isosteres represent important peptide design elements in that they can maintain a near-native tertiary conformation of the peptide while simultaneously extending the in vitro and in vivo half-life of the biomolecule. Examples of these cystine mimics include dicarba, diselenide, thioether, triazole, and lactam bridges. Each has unique physicochemical properties that impact upon the resulting peptide conformation. Each also requires specific conditions for its formation via chemical peptide synthesis protocols. While the preparation of peptides containing two lactam bonds within a peptide is technically possible and reported by others, to date there has been no report of the chemical synthesis of a heterodimeric peptide linked by two lactam bonds. To examine the feasibility of such an assembly, judicious use of a complementary combination of amine and acid protecting groups together with nonfragment-based, total stepwise solid phase peptide synthesis led to the successful preparation of an analogue of the model peptide, insulin-like peptide 3 (INSL3), in which both of the interchain disulfide bonds were replaced with a lactam bond. An analogue containing a single disulfide-substituted interchain lactam bond was also prepared. Both INSL3 analogues retained significant cognate RXFP2 receptor binding affinity. PMID:24288548

  8. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  9. Insulin Analogs Versus Human Insulin in the Treatment of Patients With Diabetic Ketoacidosis

    PubMed Central

    Umpierrez, Guillermo E.; Jones, Sidney; Smiley, Dawn; Mulligan, Patrick; Keyler, Trevor; Temponi, Angel; Semakula, Crispin; Umpierrez, Denise; Peng, Limin; Cerón, Miguel; Robalino, Gonzalo

    2009-01-01

    OBJECTIVE To compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS In a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34). RESULTS There were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose <70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03). CONCLUSIONS Regular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA. PMID:19366972

  10. Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice.

    PubMed

    O'Harte, F P M; Ng, M T; Lynch, A M; Conlon, J M; Flatt, P R

    2016-08-15

    The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 β-cells (p < 0.001) and reduced acute glycaemic responses following intraperitoneal glucose (25 nmol/kg) in healthy NIH Swiss mice (p < 0.05-p<0.001). The in vitro insulinotropic actions of [S2a]dogfish glucagon, [S2a]dogfish glucagon-exendin-4(31-39) and [S2a]dogfish glucagon-Lys(30)-γ-glutamyl-PAL, were blocked (p < 0.05-p<0.001) by the specific GLP-1 and glucagon receptor antagonists, exendin-4(9-39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated cAMP production in GLP-1 and glucagon (p < 0.05-p<0.001) but not GIP-receptor transfected cells. They improved acute glycaemic and insulinotropic responses in high-fat fed diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p < 0.05-p<0.001), but not GLP-1R-KO mice, confirming action on GLP-1 but not GIP receptors. Overall, dogfish glucagon analogues have potential for diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors. PMID:27179756

  11. Characteristics of binding of insulin-like growth factor (IGF)-I and IGF-II analogues to the type 1 IGF receptor determined by BIAcore analysis.

    PubMed

    Forbes, Briony E; Hartfield, Perry J; McNeil, Kerrie A; Surinya, Kathy H; Milner, Steven J; Cosgrove, Leah J; Wallace, John C

    2002-02-01

    Insulin-like growth factor (IGF) binding to the type 1 IGF receptor (IGF1R) elicits mitogenic effects, promotion of differentiation and protection from apoptosis. This study has systematically measured IGF1R binding affinities of IGF-I, IGF-II and 14 IGF analogues to a recombinant high-affinity form of the IGF1R using BIAcore technology. The analogues assessed could be divided into two groups: (a) those designed to investigate binding of IGF-binding protein, which exhibited IGF1R-binding affinities similar to those of IGF-I or IGF-II; (b) those generated to probe IGF1R interactions with greatly reduced IGF1R-binding affinities. The relative binding affinities of IGF-I analogues and IGF-I for the IGF1R determined by BIAcore analysis agreed closely with existing data from receptor-binding assays using cells or tissue membranes, demonstrating that BIAcore technology is a powerful tool for measuring affinities of IGFs for IGF1R. In parallel studies, IGF1R-binding affinities were related to ability to protect against serum withdrawal-induced apoptosis in three different assays including Hoechst 33258 staining, cell survival, and DNA fragmentation assays using the rat pheochromocytoma cell line, PC12. In this model system, IGF-I and IGF-II at low nanomolar concentrations are able to prevent apoptosis completely. We conclude that ability to protect against apoptosis is directly related to ability to bind the IGF1R. PMID:11846798

  12. Effects of insulin-like growth factor-I and its analogues on bovine hydrogen peroxide release by neutrophils and blastogenesis by mononuclear cells.

    PubMed

    Zhao, X; McBride, B W; Trouten-Radford, L M; Burton, J H

    1993-11-01

    The biological potencies of recombinant human insulin-like growth factor-I (IGF-I) and two of its analogues were examined for hydrogen peroxide release by neutrophils and blastogenesis by mononuclear cells. The binding affinities of these peptides for bovine serum IGF-binding proteins (IGFBPs) and IGF-I receptors on bovine neutrophils and mononuclear cells were also investigated. Relative to control treatment containing no IGF-I, preincubation of neutrophils with 12.5 micrograms/l of IGF-I, des(1-3)IGF-I (an analogue of human IGF-I lacking the N-terminal tripeptide Gly-Pro-Glu) and long R3 IGF-I (an analogue of human IGF-I with arginine replacing glutamate at position 3 of human IGF-I and the N-terminal extension Met-Phe-Pro-Ala-Met-Pro-Leu-Ser-Ser-Leu-Phe-Val-Asn) increased the release of H2O2 by 65%, 64% and 32% respectively. However, the difference in stimulating the release of H2O2 between long R3 IGF-I and other two (IGF-I and des(1-3)IGF-I) was reduced at a dosage of 100 micrograms/l. In the absence or presence of 2.5% fetal calf serum (FCS), 100 micrograms/l of IGF-I, des(1-3)IGF-I but not long R3 IGF-I significantly stimulated thymidine incorporation into mononuclear cells. In addition, des(1-3)IGF-I was more potent than IGF-I in stimulating thymidine incorporation into mononuclear cells in the presence of 2.5% FCS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7508487

  13. Effect of IGFBP-3 on IGF- and IGF-analogue-induced insulin-like growth factor-I receptor (IGFIR) signalling.

    PubMed

    Devi, G R; Graham, D L; Oh, Y; Rosenfeld, R G

    2001-08-01

    Insulin-like growth factor binding protein-3 (IGFBP-3) binds IGF-I and IGF-II with high affinity, at least an order of magnitude higher than the affiniy of the IGFs for the IGFIR. It has been hypothesized that IGFBP-3 inhibits IGF binding to the IGFIR via a mechanism independent of its ability to sequester IGFs. In the present study, we examined the effects of IGFBP-3 and its proteolytic fragments on the initial events of the IGFIR signalling pathway. IGFBP-3 inhibited IGF-I-, IGF-II-, Des(1-3)IGF-I- and Long(R3)IGF-I-induced IGFIR phosphorylation in a dose-dependent manner at similar concentration range but not QAYL-induced IGFIR-P. The((1-97))IGFBP-3 fragment was able to inhibit only IGF-I-induced IGFIR-P. The((1-97))IGFBP-3 fragment but not intact IGFBP-3 inhibited insulin-induced IGFIR-P. Monolayer cross-linking with [(125)I]IGFBP-3 indicated that there is no direct interaction of IGFBP-3 with the IGFIR. This study demonstrates that the effect on the initial step of IGFIR signalling by IGFBP-3 is largely due to its ability to sequester IGF and the IGF analogues in the extracellular milieu and not the result of any interaction of IGFBP-3 with the IGFIR or a mechanism independent of its ability to bind IGFs. PMID:11735239

  14. Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing.

    PubMed

    Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl; Zhao, Yuguang; Papakyriakou, Athanasios; Kokkala, Paraskevi; Georgiadis, Dimitris; Stratikos, Efstratios

    2015-09-15

    Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepares antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes. PMID:26259583

  15. Effects of APP 5-mer peptide analogue P165 on the synaptic proteins and insulin signal transduction proteins

    PubMed Central

    Feng, Bo; Hu, Peng; Lu, Shu-Jun; Wang, Rong; Du, Yi-Feng

    2014-01-01

    Diabetic encephalopathy (DE) is one of risk factors for Alzheimer’s disease (AD). Our previous findings indicated that DE animals had impairment of learning and memory and degeneration of hippocampal neurons, which could be improved by neurotrophic peptide. APP 17-mer peptide is a synthesized peptide sequenced from soluble amyloid precursor protein. APP 17-mer peptide has neural protective effect, but is susceptible to enzyme degradation. Soluble APP 5-mer peptide is the active form of APP 17-mer peptide, and composed of arginine, glutamic acid, arginine, methionine and serine. P165, an APP 5-mer peptide analog reconstructed by our lab, is resistant to enzyme degradation, and can be orally used to protect neurons. In the present study, high glucose and Aβ25-35 were used to cause injury to human neuroblastoma cell line SH-SY5Y in vitro, and streptozotocin was used to induce diabetes in mice in vivo. The changes in synaptic proteins and proteins of insulin signal transduction which closely correlate with learning and memory were detected in these cells and the brain of mice. Results showed that P165 could up-regulate the expression of α-synuclein and insulin receptor (IR), down-regulate the expression of insulin receptor substrate-1 (IRS-1), PSD-95, Shank1 and MAPK expression. All these findings suggest that nicorandil might be a potential drug used for the treatment of AD. PMID:24753747

  16. Impact of telephonic interviews on persistence and daily adherence to insulin treatment in insulin-naïve type 2 diabetes patients: dropout study

    PubMed Central

    Yavuz, Dilek Gogas; Bilen, Habip; Sancak, Seda; Garip, Tayfun; Hekimsoy, Zeliha; Sahin, Ibrahim; Yilmaz, Murat; Aydin, Hasan; Atmaca, Aysegul; Sert, Murat; Karakaya, Pinar; Arpaci, Dilek; Oguz, Aytekin; Guvener, Nilgun

    2016-01-01

    Objective The objective of this study is to evaluate the impact of sequential telephonic interviews on treatment persistence and daily adherence to insulin injections among insulin-naïve type 2 diabetes patients initiated on different insulin regimens in a 3-month period. Methods A total of 1,456 insulin-naïve patients with type 2 diabetes (mean [standard deviation, SD] age: 56.0 [12.0] years, 49.1% were females) initiated on insulin therapy and consecutively randomized to sequential (n=733) and single (n=723) telephonic interview groups were included. Data on insulin treatment and self-reported blood glucose values were obtained via telephone interview. Logistic regression analysis was performed for factors predicting increased likelihood of persistence and skipping an injection. Results Overall, 76.8% patients (83.2% in sequential vs 70.3% in single interview group, (P<0.001) remained on insulin treatment at the third month. Significantly higher rate for skipping doses was noted in basal bolus than in other regimens (27.0% vs 15.0% for premixed and 15.8% basal insulin, respectively, P<0.0001). Logistic regression analysis revealed sequential telephonic interview (odds ratio [OR], 1.531; 95% confidence interval [CI], 1.093–2.143; P=0.013), higher hemoglobin A1c levels (OR, 1.090; 95% CI, 0.999–1.189; P=0.049), and less negative appraisal of insulin therapy as significant predictors of higher persistence. Basal bolus regimen (OR, 1.583; 95% CI, 1.011–2.479; P=0.045) and higher hemoglobin A1c levels (OR, 1.114; 95% CI, 1.028–1.207; P=0.008) were the significant predictors of increased likelihood of skipping an injection. Conclusion Our findings revealed positive influence of sequential telephonic interview, although including no intervention in treatment, on achieving better treatment persistence in type 2 diabetes patients initiating insulin. PMID:27274207

  17. Several insulin-like growth factor-I analogues and complexes of insulin-like growth factors-I and -II with insulin-like growth factor-binding protein-3 fail to mimic the effect of growth hormone upon lactation in the rat.

    PubMed

    Flint, D J; Tonner, E; Beattie, J; Gardner, M

    1994-02-01

    Lactation was suppressed in rats using a combined treatment of bromocriptine (to reduce prolactin concentrations) and a specific antiserum to rat GH administered twice daily for 2 days. When milk production had ceased, as determined by litter weight loss and the absence of milk in the stomachs of pups, attempts were made to reinitiate lactation using prolactin, GH, insulin-like growth factor-I (IGF-I) precomplexed to recombinant human IGF-binding protein-3 (hIGFBP-3) or IGF-I plus IGF-II precomplexed to hIGFBP-3. Despite the fact that all treatments except prolactin led to increases in serum IGFs and IGFBP-3, only prolactin and GH provoked the reinitiation of milk production as determined by increased litter weight gain, milk in the stomach of pups and a significant increase in the weight of the mammary glands. Since the mammary gland has been shown to produce IGFBPs which may inhibit IGF action we also tested three IGF-I analogues, R3-IGF-I, Long-IGF-I and Long-R3-IGF-I. R3-IGF-I has a single amino acid substitution (Glu to Arg) at position 3 whereas Long-IGF-I has a 13 amino acid N-terminal extension. These modifications dramatically reduce the ability of these analogues to bind to IGFBPs although they remain active at the IGF-I receptor. Such IGF analogues would therefore be expected to be active irrespective of the production of inhibitory IGFBPs. However, none was effective in reinitiating lactation, even at doses which have been shown to be biologically effective in terms of nitrogen retention.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7513341

  18. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  19. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

    PubMed Central

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-01-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  20. Insulin formulations--a review.

    PubMed

    Gualandi-Signorini, A M; Giorgi, G

    2001-01-01

    Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being

  1. Insulin glargine maintains equivalent glycemic control and better lipometabolic control than NPH insulin in type 1 diabetes patients who missed a meal.

    PubMed

    Rosak, C; Jung, R; Hofmann, U

    2008-08-01

    Our goal was to investigate blood glucose and lipometabolism control in type 1 diabetes patients who missed breakfast and the accompanying insulin injection of NPH insulin (NPH) or insulin glargine (glargine) as part of a basal-bolus regimen. This was a multi-center, open-label, controlled study in adults (> or =18 years) with HbA (1c)< or =11.5% on insulin therapy with NPH as basal insulin. Patients were randomized to receive prandial insulin plus either bedtime glargine (n=28) or NPH (n=32). Insulin was titrated to target fasting blood glucose levels 80-130 mg/dl at 06:00-07:00. Patients had no intake of insulin or food between 22:00 and 12:00 the next day. The change in blood glucose levels (07:00-11:00) was similar (27.5 mg/dl vs. 35.4 mg/dl), but the mean blood glucose level was higher with glargine vs. NPH at 22:00 (158.2 mg/dl vs. 130.2 mg/dl). During the period without insulin or food intake, blood glucose decreased with glargine (-25.8 mg/dl) and increased with NPH (+9.1 mg/dl; p=0.0284). Nonesterified fatty acid (07:00 and 09:00-12:00) and beta-hydroxybutyrate (07:00 and 10:00-12:00) levels were lower with glargine vs. NPH (both p<0.05). For patients who miss a morning meal, glargine is associated with maintained glycemic and lipometabolic control compared with NPH insulin. PMID:18493882

  2. When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

    PubMed

    Cohen, Ohad; Filetti, Sebastiano; Castañeda, Javier; Maranghi, Marianna; Glandt, Mariela

    2016-08-01

    Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events. PMID:27440831

  3. Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

    PubMed

    Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

    2015-09-01

    Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. PMID:25865149

  4. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

    Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience. PMID:27582150

  5. [Medication of the month. Insulin glargine (Lantus)].

    PubMed

    Scheen, A J

    2004-02-01

    Insulin glargine (Lantus) is a human insulin analogue produced by recombinant DNA technology and recently launched by Aventis. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue (pH > 7,4) from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant over 24 hours as compared to conventional human insulins, especially NPH. This allows once-daily injection as basal insulin therapy, at any moment of the clock time (but if possible at the same time from day to day). Reproducibility of plasma insulin levels is also improved with insulin glargine as compared to human NPH insulin. Insulin glargine administration should be combined to rapid insulin injections, before each meal in order to control postprandial hyperglycaemia, or with oral antidiabetic agents in type 2 diabetes. The pharmacokinetic properties of insulin glargine allow an easier titration of basal insulin dose, which should facilitate adequate blood glucose control while decreasing the risk of hypoglycaemia, especially during night time. Insulin glargine use is safe with no increased antigenicity, immunogenicity or mitogenicity reactions as compared to human insulin. Optimal use of this new insulin analogue should be integrated in a global management of the diabetic patient as well as in a new culture of insulin therapy. PMID:15112902

  6. Effects of insulin-like growth factor-I and its analogue, long-R3-IGF-I, on intestinal absorption of 3-O-methyl-D-glucose are less pronounced than gut mucosal growth responses.

    PubMed

    Garnaut, Sonja M; Howarth, Gordon S; Read, Leanna C

    2002-03-01

    The relationship between insulin-like growth factor-I (IGF-I) peptide-induced increases in bowel mass and functional improvement is unclear. We utilised three independent methods to investigate the effects of IGF-I peptides on intestinal absorption of the glucose analogue, 3-O-methyl-D-glucose (3MG) in rats. Rats received vehicle, IGF-I or the more potent analogue, long-R3-IGF-I via subcutaneously implanted mini-pump, for 7 days, at which time intestinal absorption was assessed by: (1) plasma 3MG appearance following oral gavage, (2) single-pass- or (3) recirculating-perfusion of a jejunal segment. 3MG (320 or 800 mg) was gavaged on day 7 to rats treated with vehicle, IGR-I or long-R3-IGF-I. With the lower 3MG dose, only long-R3-IGF-I increased (40%) the initial rate of 3MG appearance in plasma. IGF-I had no significant effect, whilst at the higher 3MG dose neither peptide was effective. Utilising perfusion techniques, long-R3-IGF-I, but not IGF-I, significantly increased 3MG uptake per cm of jejunum by up to 69%, although significance was lost when expressed as a function of tissue weight. Long-R3-IGF-I, but not native IGF-I, enhanced 3MG absorption from the intestinal lumen, presumably reflecting an increased mucosal mass rather than an up-regulation of specific epithelial glucose transporters. PMID:11999215

  7. Insulin-like growth factor-I (IGF-I) analogue, LR(3)IGF-I, ameliorates the loss of body weight but not of skeletal muscle during food restriction.

    PubMed

    Tomas, F M

    2001-04-01

    Insulin-like growth factor-I (IGF-I) is known to have anabolic effects in freely fed rats. We have investigated the ability of infused LR(3)IGF-I, an analogue of IGF-I, to attenuate the loss of lean tissue due to food restriction in young (5 weeks) and adult (12 weeks) rats. Groups of rats received food at 100%, 78%, 56% or 33% of ad libitum levels. Within each nutrition group the rats were continuously infused with LR(3)IGF-I at (98 nmol/day)/kg body weight or vehicle for 7 days. At each level of food intake, rats infused with LR(3)IGF-I maintained higher body weight (around 3-8%;P< 0.001) and nitrogen retention (P< 0.001) than those infused with vehicle alone but muscle protein was not conserved. LR(3)IGF-I infusion increased fat loss only in young rats (P< 0.05) despite a reduction in plasma insulin levels in both age groups (P< 0.01). Muscle protein turnover rates were unaffected by LR(3)IGF-I in young rats. In adult rats LR(3)IGF-I exacerbated the effects of food restriction through increased rates of protein breakdown, reduced RNA content and reduced rates of protein synthesis (P< 0.05) despite their larger fat reserves. Although young and adult rats show differing metabolic responses, we conclude that infusion of LR(3)IGF-I to either group during short-term food restriction does not ameliorate the loss of lean tissue by allowing more efficient utilization and/or partitioning of nutrients. PMID:11472075

  8. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

    Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context. PMID:26092979

  9. Similar risk of exercise-related hypoglycaemia for insulin degludec to that for insulin glargine in patients with type 1 diabetes: a randomized cross-over trial.

    PubMed

    Heise, T; Bain, S C; Bracken, R M; Zijlstra, E; Nosek, L; Stender-Petersen, K; Rabøl, R; Rowe, E; Haahr, H L

    2016-02-01

    We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open-label, two-period, crossover trial. After individual titration and a steady-state period, patients performed 30 min of moderate-intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter-regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) -0.15, 0.42; p = 0.34], as was mean BG (ETD -0.16 mmol/l; 95% CI -0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post-exercise mean BG, counter-regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal-bolus regimen, the risk of hypoglycaemia induced by moderate-intensity exercise was low with IDeg and similar to that with IGlar. PMID:26450456

  10. Insulin degludec aspart: One-year real world experience

    PubMed Central

    Kalra, Sanjay; Baruah, Manash P.

    2016-01-01

    Background: This retrospective analysis describes the use of insulin degludec aspart (IDegAsp) in India. Material and Methods: All subjects who had received IDegAsp for 52 weeks at two endocrine centers were included in this study. Results: Forty-eight subjects (40 men), with mean age of 54.33 ± 9.63 years and mean duration of diabetes of 6.33 ± 2.96 years, started IDegAsp as insulin of initiation (16), as an intensification regime (4), as de-escalation from basal-bolus therapy (16), or as switch from premixed insulin (12). The dose of IDegAsp fell from 43.17 ± 21.18 U/day or 0.56 ± 0.23 U/kg to 37.75 ± 17.13U/day (0.51 ± 0.12 U/kg) at 24 weeks and 41.41 ± 15.33 U/day (0.56 ± 0.17 U/kg) at 52 weeks. Hemoglobin A1c (HbA1c), which was 9.52 ± 1.27% at the start of therapy, fell to 7.51 ± 0.46% at 26 weeks and to 7.48 ± 0.40% at 52 weeks. Fasting plasma glucose fell from 154.08 ± 33.30 mg% to 108.58 ± 22.26 mg% at 26 weeks and 102.17 ± 12.79 mg% at 52 weeks. Of the 48 subjects, 39 (81.25%) achieved a target of HbA1c <7.0% at both 26 and 52 weeks. No episode of hypoglycemia was reported in the 4 weeks preceding the analysis. Conclusion: This communication highlights the efficacy, safety, and tolerability, while providing insight into the usage patterns of IDegAsp. PMID:27186556

  11. How to achieve a predictable basal insulin?

    PubMed

    Kurtzhals, P

    2005-09-01

    The development of insulin analogues over the last two decades have aimed at optimising the pharmacokinetic profile of subcutaneously injected insulin for therapeutic use in diabetes mellitus. Rapid acting analogues were successfully engineered and marketed in the late 1990's. In engineering long-acting analogues it has been a particular challenge to obtain action profiles that would be predictable from day to day in the same person. The most recent approach has been to acylate the insulin molecule with a fatty acid which provides the insulin molecule with a specific affinity for albumin. The first clinically available agent of this type is insulin detemir. Pharmacological studies have shown that reversible albumin binding will protract absorption following subcutaneous injection but still allow the insulin molecule to be recognised by the insulin receptor following dissociation from the carrier protein. Moreover, the molecular features of insulin detemir are attractive in that the molecule can be formulated as a neutral aqueous solution and does not precipitate after injection. Together with an important buffering mechanism effected by plasma albumin binding, this explains a highly significant reduction of within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. No safety considerations have been identified in using albumin as an insulin carrier to protract and buffer insulin action. In assessing the clinical attractiveness of insulin analogues, it is furthermore critically important to consider how the molecular modifications impact efficacy and safety. A number of pharmacological studies have shown that insulin detemir overall retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Taken together, insulin detemir provides an attractive novel approach for

  12. Plerocercoid growth factor (PGF), a human growth hormone (hGH) analogue produced by the tapeworm Spirometra mansonoides, has direct insulin-like action in adipose tissue of normal rats in vitro

    SciTech Connect

    Salem, M.A.M.; Phares, C.K.

    1986-03-01

    The metabolic actions of GH can be divided into acute (insulin-like) and chronic (lipolytic/anti-insulin). The insulin-like actions of GH are most readily elicited in GH-deficient animals as GH induces resistance to its own insulin-like action. Like GH, PGF stimulates growth and cross-reacts with anti-hGH antibodies. Independent experiments were conducted comparing the direct actions of PGF to insulin or hGH in vitro. Insulin-like effects were determined by the ability of PGF, insulin or hGH to stimulate (U-/sup 14/C)glucose metabolism in epidydimal fat pads from normal rats and by inhibition of epinephrine-stimulated lipolysis. Direct stimulation of lipolysis was used as anti-insulin activity. To determine if PGF competes for insulin or GH receptors, adipocytes (3 x 10/sup 5/ cells/ml) were incubated with either (/sup 125/I)insulin or (/sup 125/I)hGH +/- PGF, +/- insulin or +/- hGH. PGF stimulated glucose oxidation and /sup 14/C-incorporation into lipids. Insulin, hGH and PGF inhibited lipolysis (33%, 29% and 34%, respectively). Adipose tissue was very sensitive to the lipolytic effect of hGH but PGF was neither lipolytic nor did it confer refractoriness to its insulin-like action. PGF bound to GH but not to insulin receptors. Therefore, PGF had direct insulin-like effects but did not stimulate lipolysis in tissue from normal rats in vitro.

  13. A Comparison of the Effects of the GLP-1 Analogue Liraglutide and Insulin Glargine on Endothelial Function and Metabolic Parameters: A Randomized, Controlled Trial Sapporo Athero-Incretin Study 2 (SAIS2)

    PubMed Central

    Nomoto, Hiroshi; Miyoshi, Hideaki; Furumoto, Tomoo; Oba, Koji; Tsutsui, Hiroyuki; Miyoshi, Arina; Kondo, Takuma; Tsuchida, Kenichi; Atsumi, Tatsuya; Manda, Naoki; Kurihara, Yoshio; Aoki, Shin

    2015-01-01

    Objectives GLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy. Materials and Methods In this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8%) with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force Monitor), and serum metabolic markers were assessed before and after the treatment period. Results A greater reduction (worsening) in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%). The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis. Trial Registration UMIN Clinical Trials Registry System as trial ID UMIN000005331. PMID:26284918

  14. Insulin therapy: going the "smarter" way.

    PubMed

    Kalra, Sanjay; Joshi, Ameya; Parmar, Girish

    2014-01-01

    Insulin pharmacology has evolved from nonhuman source based extraction of insulin, to use of recombinant technologies for human insulin production, to tailor made synthetic insulin analogues. The delivery techniques of insulin have also improved, from injections to pumps, and to pumps with sensors. However, to achieve the final goal of a closed loop insulin delivery is far from achieved. One of the researches in this direction includes synthetic smart insulins. These are systems with chemical sensors for glucose, linked to reactions that trigger glucose mediated insulin delivery. Interest in this field is high and recent publications and patents show promise. The current review tries to summarize the basic concept of smart insulin as well as cater the recent developments and patents in this direction. PMID:24975640

  15. Combining insulins for optimal blood glucose control in type I and 2 diabetes: focus on insulin glulisine.

    PubMed

    Ulrich, Heather; Snyder, Benjamin; Garg, Satish K

    2007-01-01

    Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM)-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs) reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI). Insulin glulisine (Apidra) is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs). The safety and tolerability profile of insulin glulisine is also comparable to that of insulin lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII). In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial

  16. [B17-D-leucine]insulin and [B17-norleucine]insulin: synthesis and biological properties.

    PubMed

    Knorr, R; Danho, W; Büllesbach, E E; Gattner, H G; Zahn, H; King, G L; Kahn, C R

    1983-11-01

    The chemical synthesis of two porcine insulin analogues is described. Leucine in position B17 of the native molecule was substituted by its D-enantiomer and by L-norleucine, respectively. Both B-chain derivatives were synthesized by fragment condensation and purified as di-S-sulphonates by gel filtration followed by ion exchange chromatography on SP-Sephadex at pH3. Combination with native sulphhydryl A-chain yielded [DLeuB17]insulin and [NleB17]insulin. Both insulin analogues were isolated by gel filtration followed by ion exchange chromatography on CM-cellulose at pH 4.0. Biological activities of the analogues were determined relative to native pork insulin: 1) glucose oxidation in rat epididymal adipocytes was 6% for [DLeuB17]insulin and 16% for [NleB17]insulin, 2) receptor-binding affinity tested with cultured human fibroblasts and with rat adipocytes was 3% for [DLeuB17]insulin and 26% for [NleB17]insulin, and 3) thymidine incorporation into DNA of human fibroblasts was 35% for [DLeuB17]insulin and 100% for [NleB17]insulin. PMID:6363268

  17. New insulin preparations: A primer for the clinician.

    PubMed

    Meneghini, Luigi

    2016-05-01

    The importance of glycemic control in preventing the chronic and devastating complications of diabetes is well established. Insulin administration is an important therapeutic option for managing diabetes, particularly for patients with profound insulin deficiency. Many insulin formulations are on the market, including short-acting insulin analogues, inhaled insulin, concentrated insulin, and basal insulin. Each category has a unique onset, peak, and duration of action. This article reviews the differing pharmacokinetic and pharmacodynamic properties and safety and efficacy data, and discusses the implications for clinical practice. PMID:27176680

  18. Identification of Host Insulin Binding Sites on Schistosoma japonicum Insulin Receptors

    PubMed Central

    Stephenson, Rachel J.; Toth, Istvan; Liang, Jiening; Mangat, Amanjot; McManus, Donald P.; You, Hong

    2016-01-01

    Schistosoma japonicum insulin receptors (SjIRs) have been identified as encouraging vaccine candidates. Interrupting or blocking the binding between host insulin and the schistosome insulin receptors (IRs) may result in reduced glucose uptake leading to starvation and stunting of worms with a reduction in egg output. To further understand how schistosomes are able to exploit host insulin for development and growth, and whether these parasites and their mammalian hosts compete for the same insulin source, we identified insulin binding sites on the SjIRs. Based on sequence analysis and the predicted antigenic structure of the primary sequences of the SjIRs, we designed nine and eleven peptide analogues from SjIR-1 and SjIR-2, respectively. Using the Octet RED system, we identified analogues derived from SjIR-1 (10) and SjIR-2 (20, 21 and 22) with insulin-binding sequences specific for S. japonicum. Nevertheless, the human insulin receptor (HIR) may compete with the SjIRs in binding human insulin in other positions which are important for HIR binding to insulin. However, no binding occurred between insulin and parasite analogues derived from SjIR-1 (2, 7 and 8) and SjIR-2 (14, 16 and 18) at the same locations as HIR sequences which have been shown to have strong insulin binding affinities. Importantly, we found two analogues (1 and 3), derived from SjIR-1, and two analogues (13 and 15) derived from SjIR-2, were responsible for the major insulin binding affinity in S. japonicum. These peptide analogues were shown to have more than 10 times (in KD value) stronger binding capacity for human insulin compared with peptides derived from the HIR in the same sequence positions. Paradoxically, analogues 1, 3, 13 and 15 do not appear to contain major antigenic determinants which resulted in poor antibody responses to native S. japonicum protein. This argues against their future development as peptide-vaccine candidates. PMID:27441998

  19. Insulin degludec. Uncertainty over cardiovascular harms.

    PubMed

    2014-06-01

    Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms

  20. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Qatar cohort of the A1chieve study

    PubMed Central

    Daghash, Mohamed Hasan; Raja, Jabbar Mubarak; Milad, Mohamed

    2013-01-01

    Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Qatar. Results: A total of 91 patients were enrolled in the study. Two insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 88), insulin detemir (n = 2), and other insulin combinations (n = 1). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.9%) and insulin users (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naïve: −1.8%, insulin users: −1.3%). Major hypoglycaemia did not occur in the study patients. SADRs were reported in 1.4% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID:24404484

  1. Oral Insulin

    PubMed Central

    2010-01-01

    Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

  2. Cell factories for insulin production.

    PubMed

    Baeshen, Nabih A; Baeshen, Mohammed N; Sheikh, Abdullah; Bora, Roop S; Ahmed, Mohamed Morsi M; Ramadan, Hassan A I; Saini, Kulvinder Singh; Redwan, Elrashdy M

    2014-01-01

    The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host organism with efficient machinery for posttranslational modifications and protein refolding. Recombinant human insulin has been produced predominantly using E. coli and Saccharomyces cerevisiae for therapeutic use in human. We would focus in this review, on various approaches that can be exploited to increase the production of a biologically active insulin and its analogues in E. coli and yeast. Transgenic plants are also very attractive expression system, which can be exploited to produce insulin in large quantities for therapeutic use in human. Plant-based expression system hold tremendous potential for high-capacity production of insulin in very cost-effective manner. Very high level of expression of biologically active proinsulin in seeds or leaves with long-term stability, offers a low-cost technology for both injectable as well as oral delivery of proinsulin. PMID:25270715

  3. Examination of a Viral Infection Mimetic Model in Human iPS Cell-Derived Insulin-Producing Cells and the Anti-Apoptotic Effect of GLP-1 Analogue

    PubMed Central

    Baden, Megu Yamaguchi; Fukui, Kenji; Hosokawa, Yoshiya; Iwahashi, Hiromi; Imagawa, Akihisa; Shimomura, Iichiro

    2015-01-01

    Aims Viral infection is associated with pancreatic beta cell destruction in fulminant type 1 diabetes mellitus. The aim of this study was to investigate the acceleration and protective mechanisms of beta cell destruction by establishing a model of viral infection in pancreatic beta cells. Methods Polyinosinic:polycytidylic acid was transfected into MIN6 cells and insulin-producing cells differentiated from human induced pluripotent stem cells via small molecule applications. Gene expression was analyzed by real-time PCR, and apoptosis was evaluated by caspase-3 activity and TUNEL staining. The anti-apoptotic effect of Exendin-4 was also evaluated. Results Polyinosinic:polycytidylic acid transfection led to elevated expression of the genes encoding IFNα, IFNβ, CXCL10, Fas, viral receptors, and IFN-inducible antiviral effectors in MIN6 cells. Exendin-4 treatment suppressed the elevated gene expression levels and reduced polyinosinic:polycytidylic acid-induced apoptosis both in MIN6 cells and in insulin-producing cells from human induced pluripotent stem cells. Glucagon-like peptide-1 receptor, protein kinase A, and phosphatidylinositol-3 kinase inhibitors counteracted the anti-apoptotic effect of Exendin-4. Conclusions Polyinosinic:polycytidylic acid transfection can mimic viral infection, and Exendin-4 exerted an anti-apoptotic effect both in MIN6 and insulin-producing cells from human induced pluripotent stem cells. PMID:26659307

  4. Effect of combined application insulin and insulin detemir on continous glucose monitor in children with type 1 diabetes mellitus

    PubMed Central

    Chen, Xiao-Yun; Dong, Qing; Li, Gui-Mei

    2015-01-01

    Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action, which could strengthen the effects of insulin. This study aims to explore the effects of insulin combined with insulin detemir on the continous glucose in children with type 1 diabetes mellitus. In this study, 150 patients with type 1 diabetes enrolled were included and randomly divided into 3 groups: insulin group (group A), insulin detemir group (group B) and insulin combined with insulin detemir group (group C). Each subject underwent 72 h of continuous glucose monitoring (CGM). MAGE, HbA1c and Noctumal Hypoglycemia levels were examined by using the ELISA kits. The body weight changes were also detected in this study. The results indicated that the information including age, body weight, disease duration and glucose level and HbA1c percentage on the start time point among three groups indicated no statistical differences. Insulin combined with insulin detemir decrease MAGE and HbA1c level in Group C compared to Group A and Group A (P < 0.05). Insulin combined with insulin detemir decreas noctumal hypoglycemia levels and body weight changes (P < 0.05). In conclusion, this study confirmed efficacy of insulin detemir by demonstrating non-inferiority of insulin detemir compared with insulin with respect to HbA1c, with an improved safety profile including significantly fewer hypoglycaemic episodes and less undesirable weight gain in children. PMID:26064343

  5. Influence of Unweighting on Insulin Signal Transduction in Muscle

    NASA Technical Reports Server (NTRS)

    Tischler, Marc E.

    2002-01-01

    Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

  6. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

    Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI. PMID:24876530

  7. Biosimilar insulins.

    PubMed

    Heinemann, Lutz

    2012-08-01

    Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets. PMID:22583127

  8. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the West India cohort of the A1chieve study

    PubMed Central

    Jain, Sunil M.; Jindal, Sushil; Malve, Harshad; Shetty, Raman; Bhoraskar, Anil

    2013-01-01

    Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from West India. Results: A total of 4192 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2846), insulin detemir (n = 596), insulin aspart (n = 517), basal insulin plus insulin aspart (n = 140) and other insulin combinations (n = 83). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.8%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: −1.6%, insulin users: −1.7%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID:24404488

  9. Insulin during pregnancy, labour and delivery.

    PubMed

    de Valk, Harold W; Visser, Gerard H A

    2011-02-01

    Optimal glycaemic control is of the utmost importance to achieve the best possible outcome of a pregnancy complicated by diabetes. This holds for pregnancies in women with preconceptional type 1 or type 2 diabetes as well as for pregnancies complicated by gestational diabetes. Glycaemic control is conventionally expressed in the HbA1c value but the HbA1c value does not completely capture the complexity of glycaemic control. The daily glucose profile measured by the patients themselves through measurements performed in capillary blood obtained by finger stick provides valuable information needed to adjust insulin therapy. Hypoglycaemia is the major threat to the pregnant woman or the woman with tight glycaemic control in the run-up to pregnancy. Repetitive hypoglycaemia can lead to hypoglycaemia unawareness, which is reversible with prevention of hypoglycaemia. A delicate balance should be struck between preventing hyperglycaemia and hypoglycaemia. Insulin requirements are not uniform across the day: it is low during the night with a more or less pronounced rise at dawn, followed by a gradual decrease during the remainder of the day. A basal amount of insulin is needed to regulate the endogenous glucose production, short-acting insulin shots are needed to handle exogenous glucose loads. Insulin therapy means two choices: the type of insulin used and the method of insulin administration. Regarding the type of insulin, the choice is between human and analogue insulins. The analogue short-acting insulin aspart has been shown to be safe during pregnancy in a randomised trial and has received registration for this indication; the short-acting analogue insulin lispro has been shown to be safe in observational studies. No such information is available on the long-acting insulin analogues detemir and glargine and both are prescribed off-label with human long-acting insulin as obvious alternatives. Randomised trials have not been able to show superiority of continuous

  10. Pursuit of a perfect insulin.

    PubMed

    Zaykov, Alexander N; Mayer, John P; DiMarchi, Richard D

    2016-06-01

    Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. PMID:26988411

  11. Randomized Controlled Trial of Insulin Supplementation for Correction of Bedtime Hyperglycemia in Hospitalized Patients With Type 2 Diabetes

    PubMed Central

    Vellanki, Priyathama; Bean, Rachel; Oyedokun, Festus A.; Pasquel, Francisco J.; Smiley, Dawn; Farrokhi, Farnoosh; Newton, Christopher; Peng, Limin

    2015-01-01

    OBJECTIVE Clinical guidelines recommend point-of-care glucose testing and the use of supplemental doses of rapid-acting insulin before meals and at bedtime for correction of hyperglycemia. The efficacy and safety of this recommendation, however, have not been tested in the hospital setting. RESEARCH DESIGN AND METHODS In this open-label, randomized controlled trial, 206 general medicine and surgery patients with type 2 diabetes treated with a basal-bolus regimen were randomized to receive either supplemental insulin (n = 106) at bedtime for blood glucose (BG) >7.8 mmol/L or no supplemental insulin (n = 100) except for BG >19.4 mmol/L. Point-of-care testing was performed before meals, at bedtime, and at 3:00 a.m. The primary outcome was the difference in fasting BG. In addition to the intention-to-treat analysis, an as-treated analysis was performed where the primary outcome was analyzed for only the bedtime BG levels between 7.8 and 19.4 mmol/L. RESULTS There were no differences in mean fasting BG for the intention-to-treat (8.8 ± 2.4 vs. 8.6 ± 2.2 mmol/L, P = 0.76) and as-treated (8.9 ± 2.4 vs. 8.8 ± 2.4 mmol/L, P = 0.92) analyses. Only 66% of patients in the supplement and 8% in the no supplement groups received bedtime supplemental insulin. Hypoglycemia (BG <3.9 mmol/L) did not differ between groups for either the intention-to-treat (30% vs. 26%, P = 0.50) or the as-treated (4% vs. 8%, P = 0.37) analysis. CONCLUSIONS The use of insulin supplements for correction of bedtime hyperglycemia was not associated with an improvement in glycemic control. We conclude that routine use of bedtime insulin supplementation is not indicated for management of inpatients with type 2 diabetes. PMID:25665812

  12. Incorporating a Generic Model of Subcutaneous Insulin Absorption into the AIDA v4 Diabetes Simulator 3. Early Plasma Insulin Determinations

    PubMed Central

    Lehmann, Eldon D.; Tarín, Cristina; Bondia, Jorge; Teufel, Edgar; Deutsch, Tibor

    2009-01-01

    Introduction AIDA is an interactive educational diabetes simulator that has been available without charge via the Internet for over 12 years. Recent articles have described the incorporation of a novel generic model of insulin absorption into AIDA as a way of enhancing its capabilities. The basic model components to be integrated have been overviewed, with the aim being to provide simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 IU (the current upper limit within the latest release of AIDA [v4.3a]). Some preliminary calculated insulin absorption results have also recently been described. Methods This article presents the first simulated plasma insulin profiles from the integration of the generic subcutaneous insulin absorption model, and the currently implemented model in AIDA for insulin disposition. Insulin absorption has been described by the physiologically based model of Tarín and colleagues. A single compartment modeling approach has been used to specify how absorbed insulin is distributed in, and eliminated from, the human body. To enable a numerical solution of the absorption model, a spherical subcutaneous depot for the injected insulin dose has been assumed and spatially discretized into shell compartments with homogeneous concentrations, having as its center the injection site. The number of these compartments will depend on the dose and type of insulin. Insulin inflow arises as the sum of contributions to the different shells. For this report the first bench testing of plasma insulin determinations has been done. Results Simulated plasma insulin profiles are provided for currently available insulin preparations, including a rapidly acting insulin analogue (e.g., lispro/Humalog or aspart/Novolog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (e.g., glargine/Lantus), as

  13. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  14. Modern insulins, old paradigms and pragmatism: choosing wisely when deciding how to treat type 1 diabetes.

    PubMed

    Schaan, Beatriz D; Scheffel, Rafael Selbach

    2015-01-01

    There is a clinical imperative to improve metabolic control in the treatment of patients with type 1 diabetes, but in doing so, hypoglycemia should be avoided at all costs. Insulin analogues and the assumption they would better mimic the pharmacokinetic profile of endogenous insulin secretion emerged as a magic bullet in the treatment of patients with type 1 diabetes. However, although insulin analogues have pharmaceutical properties, such as pharmacodynamic stability, reproducibility of action, and a more physiological timing of action, which could possibly facilitate insulin use, the results obtained in clinical practice have not been as good as expected. Like all clinical decisions, the decision regarding which insulin would be better for the patient should be, if possible, evidence based. Here, we briefly discuss evidence for the use of insulin analogues and the different views with respect to the available evidence that lead to different interpretations and decisions regarding the use of this new technology. PMID:25964802

  15. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2011-02-01

    The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is

  16. [Evidence based therapy with insulin in diabetic patients].

    PubMed

    Jermendy, György

    2005-02-20

    A fast development in therapy with insulin was observed after its discovery. Besides the widely used human regular insulin preparations, nowadays ultrashort and long-acting insulin analogues are also available for the patients. At present, the results of large clinical trials enable an evidence based diabetes care. It is well documented, that near-normoglycemia should be achieved by intensive conservative insulin treatment or pump therapy in type 1 diabetic patients. The beneficial effects of the good metabolic control could also be observed years later concerning late specific complications of diabetes. Similarly, as good as possible metabolic control should be aimed with antidiabetic treatment including insulin, if necessary, in type 2 diabetic patients. It is documented that the risk of cardiovascular complications is not increased in type 2 diabetic patients treated with insulin. Hypoglycemia and weight gain are the most important side effects of the insulin treatment. Recently, evidence based recommendations for treatment with ultrashort (insulin lispro, insulin aspart) and long-acting insulin analogues (glargine) can also be determined. PMID:15803885

  17. Insulin Test

    MedlinePlus

    ... people with type 2 diabetes , polycystic ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A ... resistance), especially in obese individuals and those with PCOS . This test involves an IV-infusion of insulin, ...

  18. Insulin therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia after evening exercise in type 1 diabetes: a randomized controlled trial

    PubMed Central

    Campbell, Matthew D; Walker, Mark; Bracken, Richard M; Turner, Daniel; Stevenson, Emma J; Gonzalez, Javier T; Shaw, James A; West, Daniel J

    2015-01-01

    Introduction Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus insulin dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. Methods Ten male participants (glycated hemoglobin: 52.4±2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal insulin dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ∼08:00 h for a fasted blood sample, before returning in the evening. On arrival (∼17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting insulin dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting insulin dose, before returning home. At ∼23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (∼08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, β-hydroxybutyrate, interleukin 6, and tumor necrosis factor α. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. Results Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24

  19. Metabolism of human insulin after subcutaneous administration: A possible means to uncover insulin misuse.

    PubMed

    Thomas, Andreas; Brinkkötter, Paul; Schänzer, Wilhelm; Thevis, Mario

    2015-10-15

    The misuse of insulin for performance enhancement in sport or as toxic agent has frequently been reported in the past. In contrast to synthetic insulin analogues, the administration of recombinant human insulin is hardly recognized by mass spectrometry. The present study was designed to uncover the misuse of recombinant human insulin for doping control purposes as well as for forensic applications. It is hypothesized that an altered metabolite profile of circulating insulin prevails after subcutaneous administration due to exposure of insulin to epidermal proteases. In vitro experiments with skin tissue lysates (S9 fraction and microsomes), different biological fluids (urine, serum, plasma) and recombinant human insulin were performed and the deriving metabolites were characterized by liquid chromatography coupled to high resolution mass spectrometry (HRMS). Afterwards, authentic blood samples of patients suffering from diabetes mellitus and a control group of healthy humans were analysed. Therefore, a method using protein precipitation, ultrafiltration and antibody-coated magnetic beads for purification with subsequent separation by nano-scale liquid chromatography coupled a Q Exactive mass spectrometer was applied. Several metabolites of insulin with C-terminally truncated sequences of the B-chain (and A-chain in minor extent) were identified within this study. Here, the DesB30 human insulin represents the major metabolite in all experiments. This metabolite is frequently found in urine samples due to degradation processes and, thus, disqualifies this matrix for the intended purposes. In contrast, blood samples do commonly not contain DesB30 insulin, which was corroborated by data obtained from the control group. In post-administration blood samples, minute but distinct amounts (approx. 50 pg mL(-1)) of DesB30 insulin were found and suggest the use of this analyte as potential marker for subcutaneous human insulin administration, supporting the attempts to

  20. Possible involvement of the A/sup 20/-A/sup 21/ peptide bond in the expression of the biological activity of insulin. 1. (21-Desasparagine,20-cysteinamide-A)insulin and (21-desasparagine,20-cysteine isopropylamide-A)insulin

    SciTech Connect

    Chu, Y.C.; Wang, R.Y.; Burke, G.T.; Chanley, J.D.; Katsoyannis, P.G.

    1987-11-03

    The C-terminal region of the A chain of insulin has been shown to play a significant role in the expression of the biological activity of the hormone. To further delineate the contribution of this segment, we have synthesized (21-desasparagine,20-cysteinamide-A)insulin and (21-desasparagine,20-cysteine isopropylamide-A)insulin, in which the C-terminal amino acid residue of the A chain of insulin, asparagine, has been removed and the resulting free carboxyl group of the A/sup 20/ cysteine residue has been converted to an amide and an isopropylamide, respectively. Both insulin analogues display biological activity, 14-15% for the unsubstituted amide analogue and 20-22% for the isopropylamide analogue, both relative to bovine insulin. In contrast, a (21-desasparagine-A)insulin analogue has been reported to display less than 4% of the activity of the natural hormone. The implications of these findings are discussed, and we conclude that the A/sup 20/-A/sup 21/ amide bond plays a significant role in the expression of the biological activity of insulin.

  1. Diabetes and Insulin

    MedlinePlus

    ... years, but may eventually need insulin to maintain glucose control. What are the different types of insulin? Different ... glulisine • Short-acting: regular human insulin Basal insulin. Controls blood glucose levels between meals and throughout the night. This ...

  2. Analysis of alternatives for insulinizing patients to achieve glycemic control and avoid accompanying risks of hypoglycemia

    PubMed Central

    GAO, JIALIN; XIONG, QIANYIN; MIAO, JUN; ZHANG, YAO; XIA, LIBING; LU, MEIQIN; ZHANG, BINHUA; CHEN, YUEPING; ZHANG, ANSU; YU, CUI; WANG, LI-ZHUO

    2015-01-01

    The aims of the present study were to explore the efficacy of glycemic control and the risks of hypoglycemia with different methods of insulin therapy, and to provide reference data for the clinical treatment of diabetes. In this retrospective study, hospitalized patients diagnosed with type 2 diabetes between March and December 2014, in the Department of Endocrinology in the First Affiliated Hospital of Wannan Medical College, were divided into three groups, including an intensive insulin analogue therapy group, a premixed insulin analogue treatment group and a premixed human insulin therapy group. The efficacy of glycemic control and the incidence of hypoglycemia were determined in each of the insulin treatment groups. Compared with the other treatment groups, the intensive insulin analogue therapy group was associated with superior blood glucose control, shorter time to reach standard insulin regimen, shorter hospitalization time, fewer fluctuations in blood glucose levels and lower insulin dosage on discharge from hospital. However, this treatment was also associated with a high risk of hypoglycemia. In conclusion, when combined with the effective prevention of hypoglycemia and appropriate nursing care (especially in hospital care), intensive insulin analogue therapy may provide the greatest benefit to patients. PMID:26137223

  3. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2010-02-01

    foresee that with most new ways of insulin delivery the bioavailability/biopotency will be lower than with subcutaneous (SC) insulin administration. This in turn requires that more insulin has to be applied to induce the same metabolic (blood glucose lowering) effect in patients with diabetes. If the costs of insulin are of relevance for the price (this clearly depends on the source of insulin the individual company has to use) the price of the product will be higher relative to standard SC insulin therapy. The question is, clearly, what are the advantages of the new product? In times when SC insulin administration was painful and cumbersome it was clear that the ease of swallowing an insulin tablet was a good argument for many patients. With the invention of thin insulin needles that make the SC injection practically pain free in most cases, this argument of being 'convenient' becomes of limited relevance. However, for many patients (especially the public) the avoidance of 'injection' is an argument. The question is, how much is the patient (society) willing to pay for such a psychological 'advantage'? Most probably additional clear-cut clinical advantages must be demonstrable to convince the payers to reimburse a new product, especially when the price is higher than that of SC insulin. If, for example, postprandial glycaemic excursions are considerably better controlled because the pharmacodynamic (PD) effects are better than with SC injection of rapid-acting insulin analogues (this might be possible with inhaled Technosphere insulin), this would be a clinically relevant argument. Without such advantages, new products will have no market success. Most probably it will not be until one of the various ARIA developments (e.g. nasal insulin) makes it into a financially attractive product (sufficient return on investment) that more money will flow again in this area of research. The search for relevant articles about new ways to deliver insulin did not reveal very many

  4. [Childhood and adolescent diabetes in Japan].

    PubMed

    Amemiya, Shin

    2015-12-01

    The glycemic control in Japanese children and adolescents with type 1 diabetes has been improved with emphasis on increase in target level of HbA1c<7.5% and decrease in risk level ≥ 9%. It may be due to increase the basal-bolus insulin therapy in almost all patients across ages, especially pubertal ages, following the use of rapid acting insulin analogues and long-acting analogues. Regarding to type 2 diabetes, little improvement has been observed because of the lack of enough skill to guide. The interruption of therapy or visiting medical resources may be a big burden. Monogenic diabetes has been more frequently found from previously diagnosed type 1B diabetes and type 2 diabetes. MODY genes can be noticed in children from urine-screening program, with the history of low-birth weight, even not having family history of diabetes and so on. PMID:26666147

  5. Non-equivalent Role of Inter- and Intramolecular Hydrogen Bonds in the Insulin Dimer Interface*

    PubMed Central

    Antolíková, Emília; Žáková, Lenka; Turkenburg, Johan P.; Watson, Christopher J.; Hančlová, Ivona; Šanda, Miloslav; Cooper, Alan; Kraus, Tomáš; Brzozowski, A. Marek; Jiráček, Jiří

    2011-01-01

    Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with selective N-methylations of peptide bond amides at positions B24, B25, or B26 to delineate their structural and functional contribution to the dimer interface. All N-methylated analogues showed impaired binding affinities to IR, which suggests a direct IR-interacting role for the respective amide hydrogens. The dimerization capabilities of analogues were investigated by isothermal microcalorimetry. Selective N-methylations of B24, B25, or B26 amides resulted in reduced dimerization abilities compared with native insulin (Kd = 8.8 μm). Interestingly, although the N-methylation in [NMeTyrB26]-insulin or [NMePheB24]-insulin resulted in Kd values of 142 and 587 μm, respectively, the [NMePheB25]-insulin did not form dimers even at high concentrations. This effect may be attributed to the loss of intramolecular hydrogen bonding between NHB25 and COA19, which connects the B-chain β-strand to the core of the molecule. The release of the B-chain β-strand from this hydrogen bond lock may result in its higher mobility, thereby shifting solution equilibrium toward the monomeric state of the hormone. The study was complemented by analyses of two novel analogue crystal structures. All examined analogues crystallized only in the most stable R6 form of insulin oligomers (even if the dimer interface was totally disrupted), confirming the role of R6-specific intra/intermolecular interactions for hexamer stability. PMID:21880708

  6. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics.

    PubMed

    Pozzilli, Paolo; Battelino, Tadej; Danne, Thomas; Hovorka, Roman; Jarosz-Chobot, Przemyslawa; Renard, Eric

    2016-01-01

    The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients

  7. Technosphere insulin: an inhaled prandial insulin product.

    PubMed

    Neumiller, Joshua J; Campbell, R Keith

    2010-06-01

    Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous injection have been investigated since the discovery of insulin in the 1920s. Most companies researching and developing pulmonary administration systems for the use of insulin announced the termination of product development following the failure of the first US FDA-approved inhaled insulin product, Exubera. One company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation has developed a powder formulation of insulin that allows for a high percentage of the administered insulin to be absorbed via the lung. Their product, AFREZZA (Technosphere insulin), is currently under review by the FDA for use in patients with diabetes. Technosphere insulin appears to overcome some of the barriers that contributed to the market withdrawal of Exubera by the manufacturer. Studies with Technosphere insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in terms of improved glycemic control without contributing to increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin products. Additionally, Technosphere insulin has demonstrated a favorable safety and tolerability profile in clinical studies to date. PMID:20462282

  8. Insulin therapy in type 2 diabetes.

    PubMed

    Mudaliar, S; Edelman, S V

    2001-12-01

    concentration is normalized. If combination therapy is not successful, a split-mixed regimen of intermediate- and rapid-acting insulin equally divided between the prebreakfast and pre-dinner periods is advised for oese patients, and more intensive regimens are advised for thin patients. Insulin therapy is invariably associated with weight gain and hypoglycemia. The use of metformin or glitazones in combination with insulin has been demonstrated to have insulin-sparing properties. Also, metformin use may ameliorate weight gain. The use of continuous subcutaneous insulin infusion pumps can be particularly beneficial in treating patients with type 2 diabetes mellitus who do not respond satisfactorily to more conventional treatment strategies. Intraperitoneal insulin delivery systems hold considerable promise in type 2 diabetes because of their more physiologic delivery of insulin and their ability to inhibit hepatic glucose production selectively, with less peripheral insulinemia than with subcutaneous insulin injections. Newer insulin analogues such as the rapidly acting Lispro insulin and the peakless, long-acting glargine insulin are increasingly being used because of their unique physiologic pharmacokinetics. New developments such as inhaled and buccal insulin preparations will also make it easier for many patients to initiate and maintain a proper insulin regimen. Finally, a new generation of gut peptides such as amylin and GLP-1 will add a new dimension to glycemic control through modification of nutrient delivery and other mechanisms; however, the ultimate goal in the management of type 2 diabetes is the primary prevention of the disease. The Diabetes Prevention Program (DPP) sponsored by the National Institutes of Health has currently randomly assigned more than 3000 persons with impaired glucose tolerance and at high risk of developing diabetes into three treatment arms: metformin arm, an intensive lifestyle-modification arm, and a placebo arm. The study will conclude in

  9. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  10. Projections for insulin treatment for diabetics.

    PubMed

    Cao, Ying; Lam, Laura

    2002-06-01

    The evolution of insulin treatment of diabetes has dramatically changed the natural course of this disease. Modern recombinant DNA technology has brought about many new insulin analogues with improved pharmacokinetics, resulting in better glycemic control. In addition, improved insulin delivery systems, such as insulin pumps and pens, have been introduced to provide convenience and to enhance patient compliance. Efforts are currently being devoted to developing noninvasive insulin formulations, such as oral and pulmonary insulin. A number of products are at different stages of clinical trials. Meanwhile, the quest for a permanent cure for diabetes continues. The frontier of diabetes research has gone through a period of substantial expansion, with the emergence of new areas that include gene therapy, islet cell transplantation and diabetic vaccine. Technological breakthroughs, such as recombinant DNA, nanotechnology, microarray-aided genomics and proteomics, will provide more profound insights into the pathogenesis, and the immunological and biological basis of diabetes. Our growing knowledge in these areas will ultimately contribute to the discovery of preventive methods against or a cure for this disease. PMID:12532178

  11. Giving an insulin injection

    MedlinePlus

    ... One Type of Insulin Wash your hands with soap and water. Dry them well. Check the insulin ... syringe before injecting it. Wash your hands with soap and water. Dry them well. Check the insulin ...

  12. Insulin Human Inhalation

    MedlinePlus

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  13. Insulin Lispro Injection

    MedlinePlus

    ... is a short-acting, man-made version of human insulin. Insulin lispro works by replacing the insulin ... niacin (Niacor, Niaspan, in Advicor); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) ...

  14. [Factors limiting glycaemic control in insulin-treated type 2 diabetes].

    PubMed

    Ferencz, Viktória; Domján, Beatrix; Gerő, László; Tänczer, Tímea; Tabák, Gy Ádám

    2015-09-01

    Insulin therapy is the most effective treatment of diabetes. It is proven to prevent microvascular disease and likely to decrease the risk of cardiovascular complications. However, these benefits are associated with a 2-3 times increased risk of hypoglycaemia and a faster weight gain compared to other antidiabetic medications. In addition, one study found elevated all-cause mortality among patients on intensive therapy (requiring more frequent insulinisation). Insulin has growth factor properties that may translate to increased mitogenicity. These factors could prevent the medical team or the patient from initiation or intensification of insulin therapy. The authors describe evidence on long-term remission related to transient intensified insulin therapy at diabetes diagnosis. The currently recommended method of insulin initiation is once daily basal insulin treatment that offers different schedules for intensification. The authors review the pharmacokinetics of analogue insulins that translate to similar efficacy to human insulins with a 20-30% lower risk of hypoglycaemia. PMID:26320598

  15. Clinical utility of insulin and insulin analogs

    PubMed Central

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  16. Concentrated insulins: the new basal insulins

    PubMed Central

    Lamos, Elizabeth M; Younk, Lisa M; Davis, Stephen N

    2016-01-01

    Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration. PMID:27022271

  17. Structural Analogues of Selfotel.

    PubMed

    Dziuganowska, Zofia A; Ślepokura, Katarzyna; Volle, Jean-Noël; Virieux, David; Pirat, Jean-Luc; Kafarski, Paweł

    2016-06-17

    A small library of phosphonopiperidylcarboxylic acids, analogues of NMDA antagonist selfotel (CGS 19755), was synthesized. First, the series of aromatic esters was obtained via a palladium-catalyzed cross-coupling reaction (Hirao coupling) of dialkyl phosphites with bromopyridinecarboxylates, followed by their hydrolysis. Then, hydrogenation of the resulting phosphonopyridylcarboxylic acids over PtO2 yielded the desired phosphonopiperidylcarboxylic acids. NMR studies indicated that the hydrogenation reaction proceeds predominantly by cis addition. Several compounds were obtained as monocrystal structures. Preliminary biological studies performed on cultures of neurons suggest that the obtained compounds possess promising activity toward NMDA receptors. PMID:27187758

  18. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  19. Insulin regulation of Na/K pump activity in rat hepatoma cells

    SciTech Connect

    Gelehrter, T.D.; Shreve, P.D.; Dilworth, V.M.

    1984-05-01

    Insulin rapidly increases Na/K pump activity in HTC rat hepatoma cells in tissue culture, as measured by the ouabain-sensitive influx of the potassium analogue 86Rb+. Increased influx is observed within minutes and is maximal (70% above control) within 1-2 h. The effect appears to be mediated by the insulin receptors, as: the concentration dependence on insulin is identical to that for insulin induction of tyrosine aminotransferase and stimulation of 2-aminoisobutyric acid transport, proinsulin is 6% as potent as insulin, and the effect is blocked by anti-receptor antibodies. The early stimulation of potassium influx is not blocked by cycloheximide and is not associated with an increased number of pump sites as measured by /sup 3/H-ouabain binding. The insulin effect is blocked by amiloride, which blocks sodium influx, and is mimicked by the sodium ionophore monensin, which increases sodium influx and intracellular accumulation. Insulin also rapidly increases the initial rate of /sup 22/Na+ influx, suggesting that insulin may enhance Na/K pump activity, in part, by increasing intracellular sodium concentration. Incubation of HTC cells with insulin for 24 h causes complete unresponsiveness to the insulin induction of transaminase and stimulation of amino acid transport, a phenomenon mediated by postbinding mechanisms. In contrast, similar incubation with insulin does not cause unresponsiveness to the insulin stimulation of Na/K pump activity. Therefore, the site of regulation of responsiveness to insulin must be distal to, or separate from, those events causing stimulation of ion fluxes.

  20. Agonism and Antagonism at the Insulin Receptor

    PubMed Central

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia; Pedersen, Thomas Åskov; Vestergaard, Kirsten; Schäffer, Lauge; Blagoev, Blagoy; Oleksiewicz, Martin B.; Kiselyov, Vladislav V.; De Meyts, Pierre

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B’29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1–10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints (3H-thymidine incorporation), and not on metabolic endpoints (14C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity (3H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B’29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed. PMID:23300584

  1. Phosphonate analogues of aminoacyl adenylates.

    PubMed Central

    Southgate, C C; Dixon, H B

    1978-01-01

    Phosphonomethyl analogues of glycyl phosphate and valyl phosphate, i.e. NH2-CHR-CO-CH2-PO(OH)2, were synthesized and esterified with adenosine to give analogues of aminoacyl adenylates. The interaction of these adenylate analogues with valyl-tRNA synthetase from Escherichia coli was studied by fluorescence titration. The analogue of valyl phosphate has an affinity for the enzyme comparable with that of valine, but that of valyl adenylate is bound much less tightly than either valyl adenylate or corresponding derivative of valinol. The affinity of the analogue of glycyl adenylate was too low to be measured. We conclude that this enzyme interacts specifically with both the side chain and the anhydride linkage of the adenylate intermediate. PMID:743207

  2. Insulin pumps.

    PubMed

    Pickup, J

    2011-02-01

    The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing

  3. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. PMID:27460418

  4. Rational steering of insulin binding specificity by intra-chain chemical crosslinking

    NASA Astrophysics Data System (ADS)

    Viková, Jitka; Collinsová, Michaela; Kletvíková, Emília; Buděšínský, Miloš; Kaplan, Vojtěch; Žáková, Lenka; Veverka, Václav; Hexnerová, Rozálie; Aviñó, Roberto J. Tarazona; Straková, Jana; Selicharová, Irena; Vaněk, Václav; Wright, Daniel W.; Watson, Christopher J.; Turkenburg, Johan P.; Brzozowski, Andrzej M.; Jiráček, Jiří

    2016-01-01

    Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone’s B-chain C-terminus for its IR-B specificity.

  5. Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia

    PubMed Central

    Jensen, Vivi Flou Hjorth; Mølck, Anne-Marie; Heydenreich, Annette; Jensen, Karin Juul; Bertelsen, Line Olrik; Alifrangis, Lene; Andersen, Lene; Søeborg, Henrik; Chapman, Melissa; Lykkesfeldt, Jens; Bøgh, Ingrid Brück

    2015-01-01

    New insulin analogues with a longer duration of action and a flatter pharmacodynamic profile are developed to improve convenience and safety for diabetic patients. During the nonclinical development of such analogues, safety studies must be conducted in nondiabetic rats, which consequently are rendered chronically hypoglycemic. A rat comparator model using human insulin would be valuable, as it would enable differentiation between effects related to either persistent insulin-induced hypoglycemia (IIH) or a new analogue per se. Such a model could alleviate the need for an in-study-comparator and thereby reduce the number of animals used during development. Thus, the aims of the present study were i) to develop a preclinical animal model of persistent hypoglycemia in rats using human insulin infusion for four weeks and ii) to investigate histopathological changes in sciatic nerves and quadriceps femoris muscle tissue, as little is known about the response to persistent hypoglycemia in these tissues. Histopathologic changes in insulin-infused animals included axonal degeneration and myofibre degeneration. To our knowledge, this is the first study to show that persistent IIH provokes peripheral nerve and skeletal myofiber degeneration within the same animals. This suggests that the model can serve as a nonclinical comparator model during development of long-acting insulin analogues. PMID:26989298

  6. Rational steering of insulin binding specificity by intra-chain chemical crosslinking.

    PubMed

    Viková, Jitka; Collinsová, Michaela; Kletvíková, Emília; Buděšínský, Miloš; Kaplan, Vojtěch; Žáková, Lenka; Veverka, Václav; Hexnerová, Rozálie; Tarazona Aviñó, Roberto J; Straková, Jana; Selicharová, Irena; Vaněk, Václav; Wright, Daniel W; Watson, Christopher J; Turkenburg, Johan P; Brzozowski, Andrzej M; Jiráček, Jiří

    2016-01-01

    Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone's B-chain C-terminus for its IR-B specificity. PMID:26792393

  7. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes?

    PubMed

    Home, P D

    2015-11-01

    Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of 'normal' physiological insulin secretion, thereby controlling basal and meal-time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3-10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet β cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day-to-day changes in insulin sensitivity. Physiologically, meal-time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal-time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day-to-day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer-to-average physiological meal-time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile. PMID:26041603

  8. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  9. Murder by insulin: suspected, purported and proven-a review.

    PubMed

    Marks, Vincent

    2009-04-01

    Murder by insulin-whether attempted, suspected or proven-is rare. Only 66 cases worldwide could be found for this review. A conviction was secured in 31 cases and additional weapon was employed in 11. Differentiation of attempted homicide from Munchausen syndrome by proxy in the young and from 'mercy killing' in the elderly was not attempted. Most perpetrators were close relatives and most victims were alive when discovered and responded to treatment. Hypoglycaemia is the first clue to homicidal insulin use in living subjects and requires the demonstration of a plasma insulin concentration of generally more than 1000 pmol/L and undetectable plasma C-peptide concentration to establish the diagnosis. Serum glucose measurements are valueless in victims found dead. The presence near the body of insulin vials, syringes or needles, loose talk by the suspected perpetrator or their ready access to insulin may be the only clue. The demonstration of insulin in tissue around an injection site by immunohistopathology or by measuring it in an extract clinches the diagnosis. Immunoassays suitable for clinical use to detect and measure insulin and C-peptide are subject to random errors and cannot be relied upon unless special precautions including separation by gel filtration or HPLC are undertaken prior to analysis. They do not detect or measure accurately a new generation of synthetic insulin analogues. Mass spectrometry will be required to do this and to validate clinical immunoassays, upon which convictions have always had to rely in the past. PMID:20355194

  10. Human insulin genome sequence map, biochemical structure of insulin for recombinant DNA insulin.

    PubMed

    Chakraborty, Chiranjib; Mungantiwar, Ashish A

    2003-08-01

    Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli. PMID:12769691

  11. Down-regulation of cyclin G2 by insulin, IGF-I (insulin-like growth factor 1) and X10 (AspB10 insulin): role in mitogenesis.

    PubMed

    Svendsen, Angela M; Winge, Sofia B; Zimmermann, Maike; Lindvig, Anne B; Warzecha, Caroline B; Sajid, Waseem; Horne, Mary C; De Meyts, Pierre

    2014-01-01

    The mechanisms whereby insulin analogues may cause enhanced mitogenicity through activation of either the IR (insulin receptor) or the IGF-IR (insulin-like growth factor 1 receptor) are incompletely understood. We demonstrate that in L6 myoblasts expressing only IGF-IRs as well as in the same cells overexpressing the IR, IGF-I (insulin-like growth factor 1), insulin and X10 (AspB10 insulin) down-regulate the mRNA expression level of the cell cycle inhibitor cyclin G2, as measured by qRT-PCR (quantitative reverse transcription-PCR), and induce cell growth measured by [6-(3)H]thymidine incorporation into DNA. Western blotting showed a marked down-regulation of cyclin G2 at the protein level in both cell lines. Overexpression of cyclin G2 in the two cell lines diminished the mitogenic effect of all three ligands. The use of specific inhibitors indicated that both the MAPK (mitogen-activated protein kinase) and the PI3K (phosphoinositide 3-kinase) pathways mediate the down-regulation of Ccng2. The down-regulation of CCNG2 by the three ligands was also observed in other cell lines: MCF-7, HMEC, Saos-2, R(-)/IR and INS-1. These results indicate that regulation of cyclin G2 is a key mechanism whereby insulin, insulin analogues and IGF-I stimulate cell proliferation. PMID:24059861

  12. Insulin glargine: an updated review of its use in the management of diabetes mellitus.

    PubMed

    Dunn, Christopher J; Plosker, Greg L; Keating, Gillian M; McKeage, Kate; Scott, Lesley J

    2003-01-01

    Insulin glargine is a human insulin analogue prepared by recombinant DNA technology. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant in relation to conventional human insulins, with no pronounced peak over 24 hours. This allows once-daily administration as basal therapy. Early randomised trials with insulin glargine generally showed greater reductions in fasting blood or plasma glucose levels and a reduced frequency of nocturnal hypoglycaemia relative to neutral protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus. In addition to this basal therapy, patients continued to use the regular mealtime insulin regimen to which they were accustomed. More recent data with insulin glargine have included evidence of improved glycaemic control, with improvements in satisfaction with treatment over NPH insulin. Furthermore, the time of day at which insulin glargine is injected has no clinically relevant effect on glycaemic control in these patients. There are also data from small, nonblind studies to suggest comparable glycaemic control with insulin glargine and continuous subcutaneous insulin infusion. Results from comparative studies and meta-analyses in individuals with type 2 diabetes show lower incidences of nocturnal hypoglycaemia with insulin glargine than with NPH insulin, with two studies showing a significantly greater improvement in glycosylated haemoglobin levels with insulin glargine than with NPH. Insulin glargine is well tolerated, and is not associated with greater immunogenicity or increases in bodyweight than NPH insulin. Long-term data show maintenance of glycaemic control with insulin glargine

  13. Insulin pump (image)

    MedlinePlus

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  14. Inflammation and Insulin Resistance

    PubMed Central

    de Luca, Carl; Olefsky, Jerrold M.

    2008-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMID:18053812

  15. High-mix insulins

    PubMed Central

    Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

    2015-01-01

    Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

  16. Giving an insulin injection

    MedlinePlus

    ... room temperature for a month. Gather your supplies: insulin, needles, syringes, alcohol wipes, and a container for used needles ... the plunger to get the right dose of insulin into the syringe. Check the syringe for air bubbles. If there ...

  17. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

    IN BRIEF Six million people with diabetes use insulin either alone or in combination with an oral medication. Many barriers exist that lead to poor adherence with insulin. However, there is an underwhelming amount of data on interventions to address these barriers and improve insulin adherence. Until pharmacological advancements create easier, more acceptable insulin regimens, it is imperative to involve patients in shared decision-making. PMID:27574371

  18. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

    Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy. PMID:27582152

  19. [Insulinization in type 2 diabetes mellitus. Intensification options].

    PubMed

    Fuente, Graciela V; Sinay, Isaac; Costa Gil, José E; Puchulu, Félix; Dieuzeide, Guillermo; Rodríguez, Martín; Faingold, María C; Litwak, León E

    2016-01-01

    Diabetes mellitus is associated with vascular complications and high rates of morbidity and mortality. Timely insulin therapy, intensified when necessary, represent appropriate measures to prevent or delay the onset of complications. However, the incidence of hypoglycemia and difficulties in treatment adherence represent barriers to achieve therapeutic success. Premixes analogs and, specially, combinations of insulin analogues are associated with pharmacokinetic and pharmacodynamic advantages, that translate into clinical benefits such as improved metabolic control, decreased hypoglycemic events and, for their simplicity, potentially greater adherence. PMID:27295707

  20. Forum for Injection Techniques, India: The First Indian Recommendations for Best Practice in Insulin Injection Technique

    PubMed Central

    Kalra, Sanjay; Balhara, Yatan Pal Singh; Baruah, Manash P.; Chadha, Manoj; Chandalia, Hemraj B.; Chowdhury, Subhankar; Kumar, K. M. Prasanna; Modi, Sonal; Pitale, Shailesh; Shukla, Rishi; Sahay, Rakesh; Sundaram, Annamalai; Unnikrishnan, Ambika G.; Wangnoo, Subhash K.

    2012-01-01

    Advances in the treatment of diabetes have led to an increase in the number of injectable therapies, such as human insulin, insulin analogues, and glucagon-like peptide-1 analogues. The efficacy of injection therapy in diabetes depends on correct injection technique, among many other factors. Good injection technique is vital in achieving glycemic control and thus preventing complications of diabetes. From the patients’ and health-care providers’ perspective, it is essential to have guidelines to understand injections and injection techniques. The abridged version of the First Indian Insulin Injection technique guidelines developed by the Forum for Injection Technique (FIT) India presented here acknowledge good insulin injection techniques and provide evidence-based recommendations to assist diabetes care providers in improving their clinical practice. PMID:23226630

  1. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin degludec works by replacing the insulin that is normally produced ... insulin label to make sure you received the right type of insulin from the pharmacy.Insulin degludec ...

  2. Comparison of a Multiple Daily Insulin Injection Regimen (Glargine or Detemir Once Daily Plus Prandial Insulin Aspart) and Continuous Subcutaneous Insulin Infusion (Aspart) in Short-Term Intensive Insulin Therapy for Poorly Controlled Type 2 Diabetes Patients

    PubMed Central

    Lv, Wen-shan; Li, Li; Wen, Jun-ping; Pan, Rong-fang; Sun, Rui-xia; Wang, Jing; Xian, Yu-xin; Cao, Cai-xia; Gao, Yan-yan

    2013-01-01

    Aims. To examine the potential differences between multiple daily injection (MDI) regimens based on new long-acting insulin analogues (glargine or detemir) plus prandial insulin aspart and continuous subcutaneous insulin aspart infusion (CSII) in patients with poorly controlled type 2 diabetes. Methods. Patients (n = 119) with poorly controlled type 2 diabetes of a duration exceeding five years were randomly assigned into three groups: Group A treated with CSII using insulin aspart; Group B treated with glargine-based MDI and Group C treated with detemir-based MDI. Results. Good glycemic control was achieved by patients in Group A in a significantly shorter duration than patients in Groups B and C. Total daily insulin, basal insulin dose and dose per kg body weight in Group A were significantly less than those in Groups B and C. Daily blood glucose fluctuation in Group A was significantly less than that in Groups B and C. There were no differences between Groups B and C. Conclusions. Aspart-based CSII may achieve good blood glucose control with less insulin doses over a shorter period compared with glargine or detemir-based MDI. No differences between glargine- and detemir-based MDI were detected in poorly controlled subjects with type 2 diabetes. PMID:23737776

  3. Oral Insulin Reloaded

    PubMed Central

    Heinemann, Lutz; Plum-Mörschel, Leona

    2014-01-01

    Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion’s share of research efforts is still allocated to the preclinical stages. PMID:24876606

  4. Incorporating a Generic Model of Subcutaneous Insulin Absorption into the AIDA v4 Diabetes Simulator: 1. A Prospective Collaborative Development Plan

    PubMed Central

    Lehmann, Eldon D.; Tarín, Cristina; Bondia, Jorge; Teufel, Edgar; Deutsch, Tibor

    2007-01-01

    Introduction AIDA v4 is an interactive educational diabetes simulator that has been made available, for over a decade, without charge via the Internet. The software is currently freely accessible at http://www.2aida.org. This report sets out a collaborative development plan to enhance the program with a new model of subcutaneous insulin absorption, which permits the simulation of rapidly acting and very long-acting insulin analogues, as well as insulin injection doses larger than 40 units. Methods A novel, generic, physiological subcutaneous insulin absorption model is overviewed and a methodology is proposed by which this can be substituted in place of the previously adopted insulin absorption model utilized within AIDA v4.3a. Apart from this substitution it is proposed to retain the existing model of the glucoregulatory system currently used in AIDA v4.3a. Results Initial simulation results based on bench testing of this approach using MATLAB are presented for the exogenous insulin flow profile (Iex) following subcutaneous injections of a rapidly acting insulin analogue, a short-acting (regular) insulin preparation, intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue. Discussion It is proposed to implement this collaborative development plan—first by bench testing the approach in MATLAB and then by integrating the generic subcutaneous insulin absorption Iex model into the AIDA simulator in Pascal. The aim is to provide enhanced functionality and educational simulations of regimens utilizing novel insulin analogues, as well as injections larger than 40 units of insulin. PMID:19885100

  5. Phosphonomethyl analogues of hexose phosphates.

    PubMed

    Webster, D; Jondorf, W R; Dixon, H B

    1976-05-01

    The analogue of fructose 1,6-bisphosphate in which the phosphate group, -O-PO3H2, on C-6 is replaced by the phosphonomethyl group, -CH2-PO3H2, was made enzymically from the corresponding analogue of 3-phosphoglycerate. It was a substrate for aldolase, which was used to form it, but not for fructose 1,6-bisphosphatase. It was hydrolysed chemically to yield the corresponding analogue of fructose 6-phosphate [i.e. 6-deoxy-6-(phosphonomethyl)-D-fructose, or, more strictly, 6,7-dideoxy-7-phosphono-D-arabino-2-heptulose]. This proved to be a substrate for the sequential actions of glucose 6-phosphate isomerase, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Thus seven out of the nine enzymes of the glycolytic and pentose phosphate pathways so far tested catalyse the reactions of the phosphonomethyl isosteres of their substrates. PMID:7247

  6. Flexibility in insulin prescription

    PubMed Central

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  7. Flexibility in insulin prescription.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  8. Insulin structure and function.

    PubMed

    Mayer, John P; Zhang, Faming; DiMarchi, Richard D

    2007-01-01

    Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported. PMID:17410596

  9. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test ... Normally, there are no antibodies against insulin in your blood. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or ...

  10. Alternative Devices for Taking Insulin

    MedlinePlus

    ... pumps contain enough insulin for several days. An infusion set carries insulin from the pump to the ... tube or needle inserted under the skin. Disposable infusion sets are used with insulin pumps to deliver ...

  11. Possible involvement of the A/sup 20/-A/sup 21/ peptide bond in the expression of the biological activity of insulin. 2. (21-Asparagine diethylamide-A)insulin

    SciTech Connect

    Chu, Y.C.; Burke, G.T.; Chanley, J.D.; Katsoyannis, P.G.

    1987-11-03

    The authors have synthesized (21-asparagine diethylamide-A)insulin, which differs from the parent molecule in that the free carboxyl group of the C-terminal amino acid residue, asparagine, of the A chain moiety has been converted to a diethylamide group. The analogue displays equivalent potency in receptor binding and biological activity, 48% and 56%, respectively, relative to bovine insulin. In contrast, they have reported previously that (21-asparaginamide-A)insulin exhibits a divergence in these properties, ca. 60% in receptor binding and ca. 13% in biological activity. The disparity in the biological behavior of these analogues is discussed, and we ascribe the modulation of biological activity independent of receptor binding activity observed between these analogues to the difference in the negativity of the carbonyl oxygen of the A chain moiety C-terminal amino acid residue.

  12. Binding and degradation of /sup 125/I-insulin by renal glomeruli and tubules isolated from rats

    SciTech Connect

    Meezan, E.; Freychet, P.

    1982-04-01

    Isolated rat renal glomeruli and tubules were shown to exhibit specific binding of /sup 125/I-insulin and enzymatic degradation of the hormone. Binding to both renal fractions reached a plateau by 1 h at 22/sup 0/C and increased linearly with increasing protein concentrations. Binding was inhibited in both preparations by insulin and its analogues in the order of relative potency: insulin > despentapeptide insulin > proinsulin, but insulin was ten times more potent in inhibiting /sup 125/I-insulin binding to glomeruli than that to tubules, indicating a different affinity of receptors for the hormone in the two renal fractions (about 17 versus 210 ..mu..g unlabelled insulin/1 inhibiting 50% of the /sup 125/I-insulin binding to glomeruli and tubules, respectively). Bound /sup 125/I-insulin dissociated at a faster rate from tubules than from glomeruli; this release was accelerated by unlabelled insulin in both renal fractions, but to a greater extent in glomeruli than in tubules. Two-thirds of the total bound material released from glomeruli was found to be intact insulin as measured by trichloroacetic acid precipitation, whereas only one-third of the material released from tubules was intact. No direct relationship between binding and degradation of /sup 125/I-insulin in these renal fractions could be demonstrated, however, because of the release of proteolytic enzymes into the incubation medium resulting in almost all degradation being extracellular. Although differing in their affinity for /sup 125/I-insulin the high affinity glomerular insulin receptor and the lower affinity tubular insulin receptor have characteristics similar to those of insulin receptors in insulin responsive tissues.

  13. Possible involvement of the A/sup 20/-A/sup 21/ peptide bond in the expression of the biological activity of insulin. 3. (21-Desasparagine,20-cysteine ethylamide-A)insulin and (21-desasparagine,20-cysteine 2,2,2-trifluoroethylamide-A)insulin

    SciTech Connect

    Chu, Y.C.; Wang, R.Y.; Burke, G.T.; Chanley, J.D.; Katsoyannis, P.G.

    1987-11-03

    The authors have synthesized (21-desasparagine,20-cysteine ethylamide-A)insulin and (21-desasparagine,20-cysteine,2,2,2,-trifluoroethylamide-A)insulin, which differ from natural insulin in that the C-terminal amino residue of the A chain, asparagine, has been removed and the resulting free carboxyl group of the A/sup 20/ cysteine residue has been converted to an ethylamide and a trifluoroethylamide group, respectively. (21-Desasparagine,20-cysteine ethylamide-A)insulin displayed equivalent potency in receptor binding and biological activity, ca. 12% and ca. 14%, respectively, relative to bovine insulin. In contrast, (21-desasparagine,20-cysteine 2,2,2-trifluoroethylamide-A)insulin displayed a divergence in these properties, ca. 13% in receptor binding and ca. 6% in biological activity. This disparity is ascribed to a difference in the electronic state of the A/sup 20/-A/sup 21/ amide bond in these two analogues. A model is proposed to account for the observation of divergence between receptor binding and biological activity in a number of synthetic insulin analogues and naturally occurring insulins. In this model, changes in the electronic state and/or the orientation of the A/sup 20/-A/sup 21/ amide bond can modulate biological activity independently of receptor binding affinity. The A/sup 20/-A/sup 21/ amide bond is thus considered as an important element in the message region of insulin.

  14. Protein Crystal Bovine Insulin

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The comparison of protein crystal, Bovine Insulin space-grown (left) and earth-grown (right). Facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  15. Devices for insulin administration.

    PubMed

    Selam, J L; Charles, M A

    1990-09-01

    There is a significant need for revised, safe, and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices, e.g., jet injectors, insulin pens, and access ports, cannot be considered as a major breakthrough in the quest for improved control, although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients, e.g., those with recurrent severe hypoglycemia, but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications, e.g., surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally, programmable implantable insulin pumps, used as an open-loop delivery system, are the most promising alternative to intensive subcutaneous insulin strategies in the short term, although clear evidence of improved safety and efficacy remains to be documented. PMID:2226111

  16. Insulin use: preventable errors.

    PubMed

    2014-01-01

    Insulin is vital for patients with type 1 diabetes and useful for certain patients with type 2 diabetes. The serious consequences of insulin-related medication errors are overdose, resulting in severe hypoglycaemia, causing seizures, coma and even death; or underdose, resulting in hyperglycaemia and sometimes ketoacidosis. Errors associated with the preparation and administration of insulin are often reported, both outside and inside the hospital setting. These errors are preventable. By analysing reports from organisations devoted to medication error prevention and from poison control centres, as well as a few studies and detailed case reports of medication errors, various types of error associated with insulin use have been identified, especially in the hospital setting. Generally, patients know more about the practicalities of their insulin treatment than healthcare professionals with intermittent involvement. Medication errors involving insulin can occur at each step of the medication-use process: prescribing, data entry, preparation, dispensing and administration. When prescribing insulin, wrong-dose errors have been caused by the use of abbreviations, especially "U" instead of the word "units" (often resulting in a 10-fold overdose because the "U" is read as a zero), or by failing to write the drug's name correctly or in full. In electronic prescribing, the sheer number of insulin products is a source of confusion and, ultimately, wrong-dose errors, and often overdose. Prescribing, dispensing or administration software is rarely compatible with insulin prescriptions in which the dose is adjusted on the basis of the patient's subsequent capillary blood glucose readings, and can therefore generate errors. When preparing and dispensing insulin, a tuberculin syringe is sometimes used instead of an insulin syringe, leading to overdose. Other errors arise from confusion created by similar packaging, between different insulin products or between insulin and other

  17. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  18. Is it dietary insulin?

    PubMed

    Vaarala, Outi

    2006-10-01

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets. PMID:17130578

  19. Muscarinic interactions of bisindolylmaleimide analogues.

    PubMed

    Lazareno, S; Popham, A; Birdsall, N J

    1998-11-01

    We have used radioligand binding studies to determine the affinities of seven bisindolylmaleimide analogues, six of which are selective inhibitors of protein kinase C, at human muscarinic M1-M4 receptors. The compounds were most potent at M1 receptors, and Ro-31-8220 was the most potent analogue, with a Kd of 0.6 microM at M1 receptors. The weakest compounds, bisindolylmaleimide IV and bisindolylmaleimide V, had Kd values of 100 microM. If it is necessary to use protein kinase C inhibitors at concentrations of 10 microM or more in studies involving muscarinic receptors then bisindolylmaleimide IV may be the most appropriate inhibitor to use. PMID:9851596

  20. Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease

    PubMed Central

    Jin, Lihua; Wang, Rui; Zhu, Yanlin; Zheng, Weili; Han, Yaping; Guo, Fusheng; Ye, Frank Bin; Li, Yong

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling. PMID:26620317

  1. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  2. Phosphonate analogue substrates for enolase.

    PubMed

    Anderson, V E; Cleland, W W

    1990-11-20

    Phosphonate analogues in which the bridge between C-2 and phosphorus is a CH2 group are slow substrates for yeast enolase. The pH variation of the kinetic parameters for the methylene analogue of 2-phosphoglycerate suggests that the substrate binds as a dianion and that Mg2+ can bind subsequently only if a metal ligand and the catalytic base are unprotonated. Primary deuterium isotope effects of 4-8 on V/KMg, but ones of only 1.15-1.32 on V for dehydration, show that proton removal to give the carbanion intermediate largely limits V/KMg and that a slow step follows which largely limits V (presumably carbanion breakdown). Since there is a D2O solvent isotope effect on V for the reverse reaction of 5, but not an appreciable one on the forward reaction, it appears that the slow rates with phosphonate analogues result from the fact that the carbanion intermediate is more stable than that formed from the normal substrates, and its reaction in both directions limits V. Increased stability as a result of replacement of oxygen by carbon at C-2 of the carbanion is the expected chemical behavior. PMID:2271661

  3. Policy issues in space analogues

    NASA Astrophysics Data System (ADS)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  4. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites

    SciTech Connect

    Duckworth, W.C.; Garcia, J.V.; Liepnieks, J.J.; Hamel, F.G.; Hermodson, M.A.; Frank, B.H.; Rosner, M.R. )

    1989-03-21

    Insulin degradation is an integral part of the cellular action of insulin. Recent evidence suggests that the enzyme insulin protease is involved in the degradation of insulin in mammalian tissues. Drosophila, which has insulin-like hormones and insulin receptor homologues, also expresses an insulin degrading enzyme with properties that are very similar to those of mammalian insulin protease. In the present study, the insulin cleavage products generated by the Drosophila insulin degrading enzyme were identified and compared with the products generated by the mammalian insulin protease. Both purified enzymes were incubated with porcine insulin specifically labeled with {sup 125}I on either the A19 or B26 position, and the degradation products were analyzed by HPLC before and after sulfitolysis. Isolation and sequencing of the cleavage products indicated that both enzymes cleave the A chain of intact insulin at identical sites between residues A13 and A14 and A14 and A15. These results demonstrate that all the insulin cleavage sites generated by the Drosopohila insulin degrading enzyme are shared in common with the mammalian insulin protease. These data support the hypothesis that there is evolutionary conservation of the insulin degrading enzyme and further suggest that this enzyme plays an important role in cellular function.

  5. Tagging insulin in microgravity

    NASA Technical Reports Server (NTRS)

    Dobeck, Michael; Nelson, Ronald S.

    1992-01-01

    Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

  6. [Alleged suicide by insulin].

    PubMed

    Birngruber, Christoph G; Krüll, Ralf; Dettmeyer, Reinhard; Verhoff, Marcel A

    2015-01-01

    A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin-dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self-treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID:26419091

  7. Technosphere inhaled insulin (Afrezza).

    PubMed

    Rendell, M

    2014-12-01

    Technosphere® insulin uses a unique carrier -fumaryl diketopiperazine (FDKP)- which adsorbs insulin to form microparticles to permit delivery to the alveoli by inhalation. Toxicity studies have been entirely negative. The pulmonary absorption of insulin is very rapid, and the disappearance time is shorter than for subcutaneously delivered rapid-acting insulins. As a result, after inhalation, there is a rapid drop in glucose levels which subsequently return to normal in a shorter time than after subcutaneous insulin administration. Consequently, there is a lower incidence of hypoglycemic reactions. Pulmonary function studies have shown a small, reversible decrease in FEV1, and pulmonary imaging studies have shown no adverse effect. The inhalation of Technosphere insulin can produce a cough in up to 27% of patients. The cough has resulted in discontinuance in as many as 9% of users. Technosphere insulin has been approved for use in type 1 and type 2 diabetes. Long-term studies of pulmonary safety and surveillance for malignancy will be performed in the future. Studies to assess the optimal time dosing regimen are needed. PMID:25588086

  8. Insulin glulisine: insulin receptor signaling characteristics in vivo.

    PubMed

    Hennige, Anita M; Lehmann, Rainer; Weigert, Cora; Moeschel, Klaus; Schäuble, Myriam; Metzinger, Elisabeth; Lammers, Reiner; Häring, Hans-Ulrich

    2005-02-01

    In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment. PMID:15677493

  9. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  10. Insulin Delivery System

    NASA Technical Reports Server (NTRS)

    1988-01-01

    When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

  11. Insulin Resistance and Prediabetes

    MedlinePlus

    ... sleep apnea; and cigarette smoking. [ Top ] Does sleep matter? Yes. Studies show that untreated sleep problems, especially ... a severe form of insulin resistance may have dark patches of skin, usually on the back of ...

  12. Insulin Human Inhalation

    MedlinePlus

    ... inhalation comes as a powder to inhale by mouth using a special inhaler. It is usually used ... to your doctor.Before you use your insulin oral inhaler the first time, read the written instructions ...

  13. Insulin Lispro Injection

    MedlinePlus

    ... a solution (liquid) and a suspension (liquid with particles that will settle on standing) to inject subcutaneously ( ... if it is colored, cloudy, or contains solid particles. If you are using insulin lispro suspension, the ...

  14. Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality*

    PubMed Central

    Žáková, Lenka; Kletvíková, Emília; Veverka, Václav; Lepšík, Martin; Watson, Christopher J.; Turkenburg, Johan P.; Jiráček, Jiří; Brzozowski, Andrzej M.

    2013-01-01

    Despite the recent first structural insight into the insulin-insulin receptor complex, the role of the C terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant PheB24, one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to d-amino acids but not to l-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, also determining the structures of [d-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24]-insulin molecule is remarkably rigid due to a tight accommodation of the l-His side chain in the B24 binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [d-HisB24]-insulin is more flexible, and the reverse chirality of the B24Cα atom swayed the d-HisB24 side chain into the solvent. Furthermore, the pocket vacated by PheB24 is filled by PheB25, which mimics the PheB24 side and main chains. The B25→B24 downshift results in a subsequent downshift of TyrB26 into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic l-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C terminus of the B-chain upon insulin activation. PMID:23447530

  15. Insulin allergy treated with human insulin (recombinant DNA).

    PubMed

    De Leeuw, I; Delvigne, C; Bekaert, J

    1982-01-01

    Two insulin-dependent diabetic subjects treated with pork and beef insulin during a period of 6 mo developed severe local reactions. Both patients had an important allergic history (asthma, urticaria, drug reactions, rhinitis). Skin-testing revealed type I allergy to beef and pork insulin. Specific IgE-insulin binding was demonstrated with both insulins. After negative skin testing with NPH Lilly human insulin (recombinant DNA), treatment was started with this compound and remained successful during a period of 6-9 mo. In one patient a local reaction occurred when regular human insulin (recombinant DNA) was added to NPH in order to obtain better control. Skin testing with regular human insulin was positive, but not with NPH human insulin alone. The mechanism of this phenomenon remains unsolved. PMID:6765530

  16. Moving toward the ideal insulin for insulin pumps.

    PubMed

    Cengiz, Eda; Bode, Bruce; Van Name, Michelle; Tamborlane, William V

    2016-01-01

    Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes. PMID:26560137

  17. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  18. Ecstasy analogues found in cacti.

    PubMed

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs." PMID:18720674

  19. Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production.

    PubMed

    Tran, Thi Thu Trang; Postal, Bárbara Graziela; Demignot, Sylvie; Ribeiro, Agnès; Osinski, Céline; Pais de Barros, Jean-Paul; Blachnio-Zabielska, Agnieszka; Leturque, Armelle; Rousset, Monique; Ferré, Pascal; Hajduch, Eric; Carrière, Véronique

    2016-07-29

    The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. PMID:27255710

  20. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome.

    PubMed

    Casesnoves, A; Mauri, M; Dominguez, J R; Alfayate, R; Picó, A M

    1998-11-01

    The autoimmune insulin syndrome (AIS) is a rare, benign syndrome characterized by hyperinsulinaemia and hypoglycaemia associated with the presence of autoantibodies to insulin in patients who have not been treated with insulin. We report here the case of a 52-year-old patient with recurrent attacks of severe postprandial hypoglycaemia and we also present the effect of anti-insulin antibodies on insulin immunoassays. The patient was submitted to the following diagnostic tests: 5-h oral glucose tolerance test (OGTT), a prolonged 72-h fast and an insulin tolerance test (ITT). Serum glucose, total and free insulin, C-peptide, proinsulin, insulin antibodies and other autoantibodies were measured. Insulin concentrations were measured by two methods: a double antibody radioimmunoassay (RIA) and an immunoradiometric assay (IRMA). Insulin concentration measured by RIA was extremely high in the OGTT and 72-h fast. In contrast, insulin concentrations measured by IRMA were between 120 and 888 pmol/L in the OGTT and between 37 and 133 pmol/L during the 72-h fast. Fasting free-insulin concentrations measured by RIA were between 2224 and 2669 pmol/L, whereas free-insulin concentrations measured by IRMA ranged between 93 and 237 pmol/L. Total insulin concentrations measured by RIA and IRMA were 57,615 and 94,021 pmol/L, respectively. The C-peptide concentrations were moderately high in the three tests. Serum insulin antibody concentrations were extremely high (62-71%), compared with less than 3% in normal serum samples. In conclusion, the high insulin concentrations measured by RIA were caused by insulin autoantibodies. However, insulin concentrations measured by IRMA were not influenced by them. We conclude that IRMA is the more accurate method for measuring insulin concentrations in such cases. PMID:9838991

  1. Retention and degradation of 125I-insulin by perfused livers from diabetic rats.

    PubMed Central

    Terris, S; Steiner, D F

    1976-01-01

    The retention of degradation of insulin by isolated perfused liver have been examined. Noncyclically perfused livers from streptozotocin-diabetic rats retained 25% and degraded 10% of 125I-insulin administered as a 1-min pulse. On gel filtration (Sephadex G50F), the degradation products released into the vascular effluent eluted in the salt peak. During the 45-min interval after the end of the 125I-insulin infusion, 0.19% of the total dose was excreted in the bile. 60-90% of this material consisted of iodinated, low-molecular-weight degradation products. Inclusion of native insulin with the 125I-insulin in the pulse depressed both the retention and degradation of iodinated material; however, this reflected increased retention and degradation of the total insulin dose (125I-insulin plus native hormone). The log of the total amounts of insulin retained and degraded were linearly related to the log of the total amount of insulin infused at concentrations between 12.7 nM and 2.84 muM. Increasing the amount of native insulin in the infused pulse also depressed the total amount of iodinated material found in the bile and led to the appearance in the bile of intermediate-sized degradation products that did not simultaneously appear in the vascular effluent. Addition of high concentrations of glucagon to the infused 125I-insulin had no effect on the retention or degradation of the labeled hormone, or on the apparent size and amount of iodinated degradation products found in the vascular effluent or in the bile. Preinfusion of concanavalin A inhibited both 125I-insulin retention and degradation. A greater depression by concanavalin A of degradation than binding was also observed with isolated hepatocytes. In contrast to 125I-insulin, the retention and degradation of two iodinated insulin analogues of relative low biological potency, proinsulin and desalanyl-desasparaginyl insulin, were small. The amount of radioactivity appearing in the bile after infusion of these

  2. Retention and degradation of 125I-insulin by perfused livers from diabetic rats.

    PubMed

    Terris, S; Steiner, D F

    1976-04-01

    The retention of degradation of insulin by isolated perfused liver have been examined. Noncyclically perfused livers from streptozotocin-diabetic rats retained 25% and degraded 10% of 125I-insulin administered as a 1-min pulse. On gel filtration (Sephadex G50F), the degradation products released into the vascular effluent eluted in the salt peak. During the 45-min interval after the end of the 125I-insulin infusion, 0.19% of the total dose was excreted in the bile. 60-90% of this material consisted of iodinated, low-molecular-weight degradation products. Inclusion of native insulin with the 125I-insulin in the pulse depressed both the retention and degradation of iodinated material; however, this reflected increased retention and degradation of the total insulin dose (125I-insulin plus native hormone). The log of the total amounts of insulin retained and degraded were linearly related to the log of the total amount of insulin infused at concentrations between 12.7 nM and 2.84 muM. Increasing the amount of native insulin in the infused pulse also depressed the total amount of iodinated material found in the bile and led to the appearance in the bile of intermediate-sized degradation products that did not simultaneously appear in the vascular effluent. Addition of high concentrations of glucagon to the infused 125I-insulin had no effect on the retention or degradation of the labeled hormone, or on the apparent size and amount of iodinated degradation products found in the vascular effluent or in the bile. Preinfusion of concanavalin A inhibited both 125I-insulin retention and degradation. A greater depression by concanavalin A of degradation than binding was also observed with isolated hepatocytes. In contrast to 125I-insulin, the retention and degradation of two iodinated insulin analogues of relative low biological potency, proinsulin and desalanyl-desasparaginyl insulin, were small. The amount of radioactivity appearing in the bile after infusion of these

  3. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  4. Depression and Insulin Resistance

    PubMed Central

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  5. Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein

    PubMed Central

    Hossain, Mohammad Uzzal; Khan, Md. Arif; Rakib-Uz-Zaman, S. M.; Ali, Mohammad Tuhin; Islam, Md. Saidul; Keya, Chaman Ara; Salimullah, Md.

    2016-01-01

    Diabetes mellitus (DM) is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR) agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre) were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients. PMID:27034931

  6. Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein.

    PubMed

    Hossain, Mohammad Uzzal; Khan, Md Arif; Rakib-Uz-Zaman, S M; Ali, Mohammad Tuhin; Islam, Md Saidul; Keya, Chaman Ara; Salimullah, Md

    2016-01-01

    Diabetes mellitus (DM) is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR) agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre) were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients. PMID:27034931

  7. [What glycemic control can be achieved in diabetic children and adolescents to avoid complications? Personal experience].

    PubMed

    Dorchy, H

    2006-01-01

    The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or =4 or pumps, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycaemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Dietary recommendations issued over the last few years are the same for diabetic and nondiabetic individuals in order to avoid degenerative diseases. In the twice-daily injection regimen, the allocation of carbohydrates throughout the day is essential. Due to their pharmakokinetic characteristics, fast-acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c. In the two daily insulin injection regimen, fast-acting analogues are very useful to rapidly correct hyperglycaemia, to allow sleeping in and eating something sweet. In the basal-bolus regimen, long-acting analogues reduce nocturnal hypoglycaemias and improve fasting blood glucose. Clinical studies, conducted since the 1970s by our team, have demonstrated that screening for subclinical retinopathy (fluorescein angiography), neuropathy (conduction velocities), nephropathy (microalbuminuria), should be started at puberty and at least 3 years after the diagnosis of diabetes. The goal is to detect early abnormalities responsible for subclinical disorders that can be reversed by improved metabolic control, thus preventing the occurrence of irreversible potentially incapacitating lesions. This motivates

  8. Prkar1a in the regulation of insulin secretion.

    PubMed

    Hussain, M A; Stratakis, C; Kirschner, L

    2012-09-01

    The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with significant consequences on individual quality of life as well as economic burden on states' healthcare costs. While origins of the pathogenesis of T2DM are poorly understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is considered a hallmark of T2DM. Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase burst of insulin, which is followed by a second, more sustained phase of insulin output. First phase insulin secretion is diminished early in T2DM as well is in subjects who are at risk of developing T2DM. An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1) or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments second-phase glucose stimulated insulin secretion. This effect of incretin action occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important consideration is that incretin hormones augment GSIS only above a certain glucose threshold, which is slightly above the normal glucose range. This ensures that incretin hormones stimulate GSIS only when glucose levels are high, while they are ineffective when insulin levels are below a certain threshold. Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells, stimulates 2 -distinct intracellular signaling pathways: a) the cAMP-protein kinase A branch and b) the cAMP-EPAC2 (EPAC=exchange protein activated by cAMP) branch. While the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA branch is necessary for the former branch to be active. However, how these 2 branches interplay and converge and how their effects on insulin secretion and insulin vesicle exocytosis are coordinated is poorly understood.Thus, at the outset of our studies we have a poorly understood intracellular interplay of cAMP-dependent signaling

  9. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID:26233724

  10. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  11. Insulin Aspart (rDNA Origin) Injection

    MedlinePlus

    ... unless it is used in an external insulin pump. In patients with type 2 diabetes, insulin aspart ... also can be used with an external insulin pump. Before using insulin aspart in a pump system, ...

  12. Insulin Detemir (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin detemir works by replacing the insulin that is normally produced ... using an insulin pen, always remove the needle right after you inject your dose. Dispose of needles ...

  13. Development of insulin delivery systems.

    PubMed

    Siddiqui, N I; Siddiqui, Ni; Rahman, S; Nessa, A

    2008-01-01

    Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems. PMID:18285745

  14. Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations

    PubMed Central

    Luippold, Gerd; Bedenik, Jessica; Voigt, Anke; Grempler, Rolf

    2016-01-01

    The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats. Single dosing of the long-acting insulin analogue glargine was able to dose-dependently reduce blood glucose over 4 h towards normoglycemia in STZ-treated rats. However, this effect was not sustained until 8 h post injection. A more sustained glucose-lowering effect was achieved using insulin-releasing implants. In STZ-rats, 1 insulin implant moderately lowered blood glucose levels 10 days after implantation, while 2 implants induced normoglycemia over the whole day. According to the glucose-lowering effect 1 as well as 2 insulin implants significantly reduced HbA1c measured after 26 days of implantation. In line with the improved glucose homeostasis due to the implants, urinary glucose excretion was also blunted in STZ-treated rats with 2 implants. Since diabetic nephropathy is one of the complications of longterm diabetes, renal function was characterized in the STZ-rat model. Increases in creatinine clearance and urinary albumin excretion resemble early signs of diabetic nephropathy. These functional abnormalities of the kidney could clearly be corrected with insulin-releasing implants 27 days after implantation. The data show that diabetic STZ-rats respond to exogenous insulin with regard to glucose levels as well as kidney parameters and a suitable dose of insulin implants for glucose control was established. This animal model together with the insulin dosing regimen is suitable to address diabetes-induced early diabetic nephropathy and also to study combination therapies with insulin for the treatment of type 1 diabetes. PMID:27253523

  15. Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations.

    PubMed

    Luippold, Gerd; Bedenik, Jessica; Voigt, Anke; Grempler, Rolf

    2016-01-01

    The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats. Single dosing of the long-acting insulin analogue glargine was able to dose-dependently reduce blood glucose over 4 h towards normoglycemia in STZ-treated rats. However, this effect was not sustained until 8 h post injection. A more sustained glucose-lowering effect was achieved using insulin-releasing implants. In STZ-rats, 1 insulin implant moderately lowered blood glucose levels 10 days after implantation, while 2 implants induced normoglycemia over the whole day. According to the glucose-lowering effect 1 as well as 2 insulin implants significantly reduced HbA1c measured after 26 days of implantation. In line with the improved glucose homeostasis due to the implants, urinary glucose excretion was also blunted in STZ-treated rats with 2 implants. Since diabetic nephropathy is one of the complications of longterm diabetes, renal function was characterized in the STZ-rat model. Increases in creatinine clearance and urinary albumin excretion resemble early signs of diabetic nephropathy. These functional abnormalities of the kidney could clearly be corrected with insulin-releasing implants 27 days after implantation. The data show that diabetic STZ-rats respond to exogenous insulin with regard to glucose levels as well as kidney parameters and a suitable dose of insulin implants for glucose control was established. This animal model together with the insulin dosing regimen is suitable to address diabetes-induced early diabetic nephropathy and also to study combination therapies with insulin for the treatment of type 1 diabetes. PMID:27253523

  16. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  17. Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama.

    PubMed

    Wan, Zhu-li; Huang, Kun; Xu, Bin; Hu, Shi-Quan; Wang, Shuhua; Chu, Ying-Chi; Katsoyannis, Panayotis G; Weiss, Michael A

    2005-04-01

    Naturally occurring mutations in insulin associated with diabetes mellitus identify critical determinants of its biological activity. Here, we describe the crystal structure of insulin Wakayama, a clinical variant in which a conserved valine in the A chain (residue A3) is substituted by leucine. The substitution occurs within a crevice adjoining the classical receptor-binding surface and impairs receptor binding by 500-fold, an unusually severe decrement among mutant insulins. To resolve whether such decreased activity is directly or indirectly mediated by the variant side chain, we have determined the crystal structure of Leu(A3)-insulin and investigated the photo-cross-linking properties of an A3 analogue containing p-azidophenylalanine. The structure, characterized in a novel crystal form as an R(6) zinc hexamer at 2.3 A resolution, is essentially identical to that of the wild-type R(6) hexamer. The variant side chain remains buried in a nativelike crevice with small adjustments in surrounding side chains. The corresponding photoactivatable analogue, although of low affinity, exhibits efficient cross-linking to the insulin receptor. The site of photo-cross-linking lies within a 14 kDa C-terminal domain of the alpha-subunit. This domain, unrelated in sequence to the major insulin-binding region in the N-terminal L1 beta-helix, is also contacted by photoactivatable probes at positions A8 and B25. Packing of Val(A3) at this interface may require a conformational change in the B chain to expose the A3-related crevice. The structure of insulin Wakayama thus evokes the reasoning of Sherlock Holmes in "the curious incident of the dog in the night": the apparent absence of structural perturbations (like the dog that did not bark) provides a critical clue to the function of a hidden receptor-binding surface. PMID:15794638

  18. Insulin and carbohydrate dysregulation.

    PubMed

    Gelato, Marie C

    2003-04-01

    Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed. PMID:12652377

  19. Acetoacetylation of insulin

    PubMed Central

    Lindsay, D. G.; Shall, S.

    1969-01-01

    Insulin was treated with diketen at pH6·9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The ∈-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed. ImagesFig. 10. PMID:5353531

  20. Ovarian tumors secreting insulin.

    PubMed

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  1. Alternative Devices for Taking Insulin

    MedlinePlus

    ... continuous glucose monitoring (CGM) system an insulin delivery system a computer program that adjusts insulin delivery based on changes in glucose levels CGM systems approved by the U.S. Food and Drug Administration ( ...

  2. Insulin C-peptide test

    MedlinePlus

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  3. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  4. An analogue study of intrusions.

    PubMed

    Laposa, Judith M; Alden, Lynn E

    2006-07-01

    According to cognitive theorists, intrusive trauma memories have their origin in how information during the event is processed. Two studies investigated functional cognitive strategies during medical crises that might protect against intrusions. In Study 1, interviews with health-care professionals were used to identify cognitive strategies judged to be effective in controlling emotions and dealing with medical crises. Study 2 systematically manipulated the use of those strategies in a trauma analogue film paradigm. Experimental participants reported fewer intrusions, and less fear and avoidance of film-related stimuli during the subsequent week than controls. The manipulation did not affect anxiety during the film or memory disorganization. Implications for cognitive theories of intrusion development are discussed. PMID:16125135

  5. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  6. Laboratory study of cometary analogues

    NASA Astrophysics Data System (ADS)

    Colangeli, L.; Brucato, J.; Mennella, V.; Palumbo, P.

    In situ exploration (e.g., GIOTTO mission) and astronomical observations (e.g., ISO) of comets have provided fundamental information about the structure, chemistry and physical properties of materials present in such primordial bodies of the Solar System. Moreover, it is known that cosmic materials evolve, depending on the efficiency of active processes (e.g., thermal annealing, UV irradiation, ion bombardment, gassolid interactions) in different space environments. Thus, the properties of cometary constituents must be considered in a wider perspective, including cosmic dust formation around cold stars and evolution in the interstellar medium until the formation of proto-planetary nebulae. In this scenario, laboratory experiments provide important hints to clarify the status of cometary compounds. The laboratory work is aimed at both reproducing material properties and at simulating their evolution based on the most effective mechanisms active in space. Several techniques are used to synthesise "analogues" of cometary compounds with controlled chemical and physical characteristics. The study of optical properties, complemented by other analytical techniques, is applied to investigate the products of synthesis in the experiments. The monitoring of the effects produced by processing methods, similar to those active in space, provides information both on the reactivity of materials and on the efficiency of treatments. Such an approach is able to provide quantitative information on chemical and structural modifications produced on organic and refractory materials. The comparison of laboratory results with data coming from space observations and in situ measurements provides a powerful tool to understand the real nature of comets and to place constraints on formation and evolution pathways. The laboratory experiments on analogues gain even more relevance as a sort of training in the future perspective of analysing cometary samples returned to Earth by space missions (e

  7. New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.

    PubMed

    Roy, Pierre-Philippe; D'Souza, Kenneth; Cuperlovic-Culf, Miroslava; Kienesberger, Petra C; Touaibia, Mohamed

    2016-08-01

    Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities. PMID:27155760

  8. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

    Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical–experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration. PMID:20144297

  9. Cinnamon, glucose and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  10. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037