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Human Insulin (human + insulin)
Kinds of Human Insulin Selected AbstractsField Safety and Efficacy of Protamine Zinc Recombinant Human Insulin for Treatment of Diabetes Mellitus in CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2009R.W. Nelson Background: This study describes the efficacy of a new protamine zinc recombinant human insulin (PZIR) preparation for treating diabetic cats. Objective: To evaluate effects of PZIR on control of glycemia in cats with newly diagnosed or poorly controlled diabetes mellitus. Animals: One hundred and thirty-three diabetic cats 120 newly diagnosed and 13 previously treated. Methods: Prospective, uncontrolled clinical trial. Cats were treated with PZIR twice daily for 45 days. Control of glycemia was assessed on days 7, 14, 30, and 45 by evaluation of change in water consumption, frequency of urination, appetite, and body weight, serum fructosamine concentration, and blood glucose concentrations determined 1, 3, 5, 7, and 9 hours after administration of PZIR. Adjustments in dosage of PZIR were made as needed to control glycemia. Results: PZIR administration resulted in a significant decrease in 9-hour mean blood glucose (199 ± 114 versus 417 ± 83 mg/dL, X± SD, P < .001) and serum fructosamine (375 ± 117 versus 505 ± 96 ,mol/L, P < .001) concentration and a significant increase in mean body weight (5.9 ± 1.4 versus 5.4 ± 1.5 kg, P= .017) in 133 diabetic cats at day 45 compared with day 0, respectively. By day 45, polyuria and polydipsia had improved in 79% (105 of 133), 89% (118 of 133) had a good body condition, and 9-hour mean blood glucose concentration, serum fructosamine concentration, or both had improved in 84% (112 of 133) of the cats compared with day 0. Hypoglycemia (<80 mg/dL) was identified in 151 of 678, 9-hour serial blood glucose determinations and in 85 of 133 diabetic cats. Hypoglycemia causing clinical signs was confirmed in 2 diabetic cats. Conclusions and Clinical Relevance: PZIR is effective for controlling glycemia in diabetic cats and can be used as an initial treatment or as an alternative treatment in diabetic cats that do not respond to treatment with other insulin preparations. [source] Titelbild: Design and Folding of [GluA4(O,ThrB30)]Insulin ("Ester Insulin"): A Minimal Proinsulin Surrogate that Can Be Chemically Converted into Human Insulin (Angew. Chem.ANGEWANDTE CHEMIE, Issue 32 201032/2010) Die effiziente chemische Totalsynthese von Insulin war über 40,Jahre lang eine Herausforderung. In ihrer Zuschrift auf S.,5621,ff. zeigen Y. Sohma, S.,B.,H. Kent und Mitarbeiter, dass eine Ester-verknüpfte "Nulllängen"-Vorstufe genauso effizient faltet wie Volllängen-Proinsulin und leicht durch Verseifung in das vollständig aktive Insulin überführt werden kann. (Titelbild: D. Kent nach einem Entwurf von Y. Sohma.) [source] Design and Folding of [GluA4(O,ThrB30)]Insulin ("Ester Insulin"): A Minimal Proinsulin Surrogate that Can Be Chemically Converted into Human Insulin,ANGEWANDTE CHEMIE, Issue 32 2010Youhei Sohma Prof. Insulinfaltung: Ein esterverknüpftes Polypeptid-Proinsulinsurrogat faltet effizient unter Disulfidbindungsbildung und lässt sich zum nativen Insulin mit voller biologischer Aktivität verseifen. Diese Strategie vermeidet die mäßig erfolgreiche Kombination der individellen Insulin-A- und -B-Ketten und bietet einen einfachen und effektiven Ansatz zur chemischen Totalsynthese von Humaninsulin und dessen Analoga. [source] Prediction of the association state of insulin using spectral parametersJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2003Vladimir N. Uversky Abstract Human insulin exists in different association states, from monomer to hexamer, depending on the conditions. In the presence of zinc the "normal" state is a hexamer. The structural properties of 20 variants of human insulin were studied by near-UV circular dichroism, fluorescence spectroscopy, and small-angle X-ray scattering (SAXS). The mutants showed different degrees of association (monomer, dimers, tetramers, and hexamers) at neutral pH. A correlation was shown between the accessibility of tyrosines to acrylamide quenching and the degree of association of the insulin mutants. The near-UV CD spectra of the insulins were affected by protein association and by mutation-induced structural perturbations. However, the shape and intensity of difference CD spectra, obtained by subtraction of the spectra measured in 20% acetic acid (where all insulin species were monomeric) from the corresponding spectra measured at neutral pH, correlate well with the degree of insulin association. In fact, the near-UV CD difference spectra for monomeric, dimeric, tetrameric, and hexameric insulin are very distinctive, both in terms of intensity and shape. The results show that the spectral properties of the insulins reflect their state of association, and can be used to predict their oligomeric state. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:847,858, 2003 [source] Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose controlDIABETES OBESITY & METABOLISM, Issue 2 2010J. S. Christiansen Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of ,low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin , human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin , analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal,bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA1c) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal,bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular. [source] The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 1 2010S. D. Luzio Aim: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Methods: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m2, haemoglobin A1c (HbA1c) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Results: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280,330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC0,6 h (910 ± 270 vs. 472 ± 245 pmol h/L; 950 ± 446 vs. 433 ± 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA1c, weight and triglycerides were observed. Conclusions: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations. [source] An exploratory study of the effect of using high-mix biphasic insulin aspart in people with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 7 2009U. Dashora Objective:, To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high-mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin. Research design and methods:, In a 60-day, open-label, crossover study, people with insulin-treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 ± 0.9 (s.d.) %] were randomized to BIAsp three times a day before meals, as BIAsp 70 (70% insulin aspart and 30% protamine-complexed insulin aspart) before breakfast and lunch and BIAsp 30 (30/70 free and protamine-complexed insulin aspart) before dinner, or to human premix insulin (BHI) 30/70 twice a day before meals. A 24-h in-patient plasma glucose profile was performed at the end of each 30-day treatment period. The total daily insulin dose of BIAsp regimen was 110% of BHI and the doses were not changed during the study. Results:, There was no difference between BIAsp and BHI in geometric weighted average serum glucose over 24 h [7.3 vs. 7.7 mmol/l, BIAsp/BHI ratio 0.95 (95% CI 0.88,1.02), not significant (NS)], but daytime geometric weighted average glucose concentration was significantly lower with the BIAsp regimen than with BHI [8.3 vs. 9.2 mmol/l, BIAsp/BHI ratio 0.90 (0.84,0.98), p = 0.014]. The mealtime serum glucose excursion was also lower with BIAsp than with BHI with statistically significant differences at lunchtime [difference ,4.9 (,7.0 to ,2.7) mmol/l, p = 0.000); the difference in glucose excursions above 7.0 mmol/l was also significant [,5.8 (,8.3 to ,3.2) mmol/l, p = 0.000). The proportion of participants experiencing confirmed hypoglycaemic episodes was similar between regimens (42 vs. 43%, NS). Conclusions:, An insulin regimen using high-mix BIAsp (BIAsp 70) before breakfast and lunch and BIAsp 30 before dinner can achieve lower blood glucose levels during the day through reduced mealtime glucose excursions in particular at lunchtime than a twice-daily premix regimen. [source] Insulin therapy in type 2 diabetes: what is the evidence?DIABETES OBESITY & METABOLISM, Issue 5 2009Mariëlle J. P. Van Avendonk Aim:, To systematically review the literature regarding insulin use in patients with type 2 diabetes mellitus Methods:, A Medline and Embase search was performed to identify randomized controlled trials (RCT) published in English between 1 January 2000 and 1 April 2008, involving insulin therapy in adults with type 2 diabetes mellitus. The RCTs must comprise at least glycaemic control (glycosylated haemoglobin (HbA1c), postprandial plasma glucose and /or fasting blood glucose (FBG)) and hypoglycaemic events as outcome measurements. Results:, The Pubmed search resulted in 943 hits; the Embase search gave 692 hits. A total of 116 RCTs were selected by title or abstract. Eventually 78 trials met the inclusion criteria. The studies were very diverse and of different quality. They comprised all possible insulin regimens with and without combination with oral medication. Continuing metformin and/or sulphonylurea after start of therapy with basal long-acting insulin results in better glycaemic control with less insulin requirements, less weight gain and less hypoglycaemic events. Long-acting insulin analogues in combination with oral medication are associated with similar glycaemic control but fewer hypoglycaemic episodes compared with NPH insulin. Most of the trials demonstrated better glycaemic control with premix insulin therapy than with a long-acting insulin once daily, but premix insulin causes more hypoglycaemic episodes. Analogue premix provides similar HbA1c, but lower postprandial glucose levels compared with human premix, without increase in hypoglycaemic events or weight gain. Drawing conclusions from the limited number of studies concerning basal,bolus regimen seems not possible. Some studies showed that rapid-acting insulin analogues frequently result in a better HbA1c or postprandial glucose without increase of hypoglycaemia than regular human insulin. Conclusion:, A once-daily basal insulin regimen added to oral medication is an ideal starting point. All next steps, from one to two or even more injections per day should be taken very carefully and in thorough deliberation with the patient, who has to comply with such a regimen for many years. [source] Long-acting insulin analogues vs.DIABETES OBESITY & METABOLISM, Issue 4 2009NPH human insulin in type 1 diabetes. Aim:, Basal insulin in type 1 diabetes can be provided using either NPH (Neutral Protamine Hagedorn) human insulin or long-acting insulin analogues, which are supposed to warrant a better metabolic control with reduced hypoglycaemic risk. Aim of this meta-analysis is the assessment of differences with respect to HbA1c (Glycated hemoglobin), incidence of hypoglycaemia, and weight gain, between NPH human insulin and each long-acting analogue. Methods:, Of 285 randomized controlled trials with a duration > 12 weeks comparing long-acting insulin analogues (detemir or glargine) with NPH insulin in type 1 diabetic patients identified through Medline search and searches on www.clinicaltrials.gov, 20 met eligibility criteria (enrolling 3693 and 2485 in the long-acting analogues and NPH group respectively). Data on HbA1c and body mass index at endpoint, and incidence of any, nocturnal and severe hypoglycaemia, were extracted and meta-analysed. Results:, Long-acting analogues had a small, but significant effect on HbA1c [-0.07 (,0.13; ,0.01)%; p = 0.026], in comparison with NPH human insulin. When analysing the effect of long-acting analogues on body weight, detemir was associated with a significantly smaller weight gain than human insulin [by 0.26 (0.06;0.47) kg/m2; p = 0.012]. Long-acting analogues were associated with a reduced risk for nocturnal and severe hypoglycaemia [OR (Odd Ratio, 95% Confidence Intervals) 0.69 (0.55; 0.86), and OR 0.73 (0.60; 0.89) respectively; all p < 0.01]. Conclusions:, The switch from NPH to long-acting analogues as basal insulin replacement in type 1 diabetic patients had a small effect on HbA1c, and also reduced the risk of nocturnal and severe hypoglycaemia. [source] Insulin analogues: an example of applied medical scienceDIABETES OBESITY & METABOLISM, Issue 1 2009B. Sheldon Insulin analogues were developed to try and achieve more physiological insulin replacement from injection in the subcutaneous site. Their pharmacokinetics and pharmacodynamics differ from human insulin when injected subcutaneously because of alterations in the amino acid sequence of the insulin molecule. The rapid-acting insulin analogues, lispro, aspart and glulisine, have a rapid onset of action and shorter duration of action because of changes to the B26,30 portion of insulin inhibiting formation of dimers and hexamers. They appear to improve postprandial glucose, incidence of hypoglycaemia and patient satisfaction and, when used in combination with basal insulin analogues, improve glycosylated haemoglobin in comparison to conventional insulin therapy. Additionally, they have been successfully used in children, pregnant women, in pump therapy and as part of premixed biphasic regimens. The two basal insulin analogues, glargine and detemir, developed by adjusting the isoelectric point and adding a fatty acid residue, respectively, have a protracted duration of action and a relatively smooth profile. Their pharmacokinetic and pharmacodynamic profiles have been assessed using euglycaemic clamp protocols. Both analogues have a longer duration of action, less of a peak of activity and a reduced variability with repeated injection. There is some evidence to suggest that detemir may have a slight hepatoselective effect. Clinical studies have shown a lower relative risk of hypoglycaemia and detemir appears to have a weight-sparing action. Insulin analogues represent a successful example of applied medical science. [source] Premixed insulin treatment for type 2 diabetes: analogue or human?DIABETES OBESITY & METABOLISM, Issue 5 2007Alan J. Garber The progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Premixed insulin formulations containing both basal and prandial insulin (so called biphasic insulin) are often prescribed because they are superior to long- or intermediate-acting insulin in obtaining good metabolic control. In addition, they are considered as an attractive alternative to classical basal-bolus therapy as fewer daily injections are required. Premixed insulin formulations include conventional (e.g. biphasic human insulin 70/30, or 30/70 in European countries, BHI 30) and newer premixed human analogues (e.g. biphasic insulin aspart 70/30, or 30/70 in Europe, BIAsp 30; insulin lispro mix 75/25,Mix 75/25, or Mix 25/75 in Europe). Like conventional premixed human insulin, premixed insulin analogues contain a fixed proportion of soluble, rapid-acting insulin analogue, with protaminated analogue comprising the remainder. Unlike conventional premixes, analogue premixes have more physiological pharmacokinetic and therapeutically more desirable pharmacodynamic profiles than premixed human insulin. Consequently, postprandial glycaemic control is better with premixed insulin analogues than with premixed human insulin. In nontreat-to-target registration trials, the lowering of haemoglobin A1c with premixed insulin analogues was not inferior to that seen with premixed human insulin. Minor hypoglycaemia was similar for premixed analogue and premixed human insulins, while major hypoglycaemia appears to be rare with either formulation. The occurrence of adverse events, other than hypoglycaemia, was also similar between various premix insulins. The premixed insulin analogues, BIAsp 30 and Mix 75/25, like the fast-acting analogues from which they are derived, also allow flexible injection timing, relative to meal timing, thus improving adherence, compliance and quality of life compared with premixed human insulin. Overall, the evidence suggests that premixed insulin analogues are cost effective and have useful advantages over premixed human insulin for the treatment of type 2 diabetes. [source] Appraising the mitogenicity of insulin analogues relative to human insulin,response to: Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activity in cultured cancer cells.DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2010Diabetes Metab Res Rev 2009; 25(1): 4 Abstract Interest in mitogenic and potentially carcinogenic effects of insulin and insulin analogues has been renewed by several recent publications that have examined the relationship between cancer and insulin analogues. Actions mediated through the insulin-like growth factor-I receptor in a hyperinsulinaemic state have been implicated mechanistically. Both type 2 diabetes and endogenously elevated insulin-like growth factor-I have been epidemiologically linked to malignancies. Therefore, in vitro mitogenic effects and binding affinities of the various analogues have been analysed. A recent publication by Weinstein et al. studied the in vitro mitogenic and anti-apoptotic activities of insulin analogues, and their conclusion asserts that insulins glargine, detemir, and lispro displayed proliferative and anti-apoptotic effects in a number of malignant cell lines. However, their conclusions are not supported by the data which are not complete and lack clear statistical significance. This data should be interpreted cautiously in light of all other presently available scientific evidence. Prospective, randomized clinical trials will best address any direct relationship between insulin analogues and cancer. Until those studies are designed and completed, clinicians should consider the demonstrated strong benefit of glycaemic control in balance with any alleged risk. Copyright © 2010 John Wiley & Sons, Ltd. [source] Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 8 2007Derek Le Roith Abstract Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI). Searches of the PubMed database were performed using terms that included ,IR,' ,insulin-like growth factor-1,' ,IGF-1R,' ,type 2 diabetes mellitus,' and ,insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed. Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential. Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy. Copyright © 2007 John Wiley & Sons, Ltd. [source] Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectivenessDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2004Régis Pierre Radermecker Abstract Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open-label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast-acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well-educated diabetic patients. Copyright © 2004 John Wiley & Sons, Ltd. [source] Insulin analogues: have they changed insulin treatment and improved glycaemic control?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2002Sten Madsbad Abstract To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time,action profile most studies have not been able to show any improvement in overall glycaemic control with the fast-acting analogues. A reduced post-prandial increase in blood glucose has been found in all studies, whereas between 3 and 5,h after the meal and during the night an increased blood glucose level is the normal course. This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting in a long half-life with a residual activity of about 50% 24,h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly, the new fast,acting analogues have not achieved the expected commercial success, which emphasises the need for new strategies for basal insulin supplementation, exercise, diet and blood glucose monitoring. Copyright © 2002 John Wiley & Sons, Ltd. [source] Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetesDIABETIC MEDICINE, Issue 3 2006S. G. Ashwell Abstract Aims To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. Methods In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 ± 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. Results HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference ,0.5 (95% CI ,0.7, ,0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l,1 h,1, P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l,1 h,1, P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l,1 h,1, P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). Conclusions Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia. [source] A 75% insulin lispro/25% NPL mixture provides a longer duration of insulin activity compared with insulin lispro alone in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 11 2003P. Roach Abstract Aims To compare a new insulin formulation, high mix (HM) [75% lispro (LP) and 25% neutral protamine lispro (NPL)], to regular human insulin (HR) and LP with respect to glucose response and pharmacokinetics following a test meal in patients with Type 1 diabetes. Methods After fasting overnight, patients received an intravenous insulin infusion to standardize blood glucose (BG) to 7.5 mmol/l (135 mg/dl). In a randomised, three-way crossover study, HR was injected 30 min before, and LP or HM was injected immediately before the test meal on three separate occasions. For each patient, LP and HR were administered at identical doses; the HM dose was one and one third times that of HR and LP to maintain the same dose of short or rapid-acting insulin. The insulin infusion was stopped 15 min after the insulin injection. Free insulin and BG concentrations were measured frequently for 7 h following the test meal. Results HM and LP resulted in better glycaemic control than HR during the observation period. BG concentrations during the first 4,5 h did not differ between HM and LP. However, HM exhibited prolonged insulin activity relative to LP beyond 5 h, extending the duration of action by approximately 1 h, and resulting in lower overall BG concentrations when the 0,6- and 0,7-h intervals were considered. Conclusions Compared with LP, HM provided similar glycaemic control for up to 5 h and superior glycaemic control from 5 to 7 h following a standard test meal [source] Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trialDIABETIC MEDICINE, Issue 11 2000P. D. Home SUMMARY Aims To compare the efficacy of insulin aspart, a rapid-acting insulin analogue, with that of unmodified human insulin on long-term blood glucose control in Type 1 diabetes mellitus. Methods Prospective, multi-centre, randomized, open-labelled, parallel-group trial lasting 6 months in 88 centres in eight European countries and including 1070 adult subjects with Type 1 diabetes. Study patients were randomized 2:1 to insulin aspart or unmodified human insulin before main meals, with NPH-insulin as basal insulin. Main outcome measures were blood glucose control as assessed by HbA1c, eight-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia, and adverse events. Results After 6 months, insulin aspart was superior to human insulin with respect to HbA1c with a baseline-adjusted difference in HbA1c of 0.12 (95% confidence interval 0.03,0.22) %Hb, P < 0.02. Eight-point blood glucose profiles showed lower post-prandial glucose levels (mean baseline-adjusted ,0.6 to ,1.2 mmol/l, P < 0.01) after all main meals, but higher pre-prandial glucose levels before breakfast and dinner (0.7,0.8 mmol/l, P < 0.01) with insulin aspart. Satisfaction with treatment was significantly better in patients treated with insulin aspart (WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ) baseline-adjusted difference 2.3 (1.2,3.3) points, P < 0.001). The relative risk of experiencing a major hypoglycaemic episode with insulin aspart compared to human insulin was 0.83 (0.59,1.18, NS). Major night hypoglycaemic events requiring parenteral treatment were less with insulin aspart (1.3 vs. 3.4% of patients, P < 0.05), as were late post-prandial (4,6 h) events (1.8 vs. 5.0% of patients, P < 0.005). Conclusions These results show small but useful advantage for the rapid-acting insulin analogue insulin aspart as a tool to improve long-term blood glucose control, hypoglycaemia, and quality of life, in people with Type 1 diabetes mellitus. [source] New strategies in insulin treatment: analogues and noninvasive routes of administrationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2005Jørgen Rungby Abstract Recent years have seen the development of alternatives to human insulin for the treatment of diabetes. Both rapid-acting and long-acting analogues are available. Alternative routes of insulin administration are emerging. The present review briefly summarizes the present knowledge on insulin analogues and alternative administration routes. [source] Effect of insulin on rat ovarian leptin expression by immunohistochemical stainingJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 6 2003Naci Kemal Kuscu Abstract Aim:, Leptin and insulin may interact in regulating ovarian steroid synthesis. The objective of this study was to investigate immunohistochemical staining of leptin in normal rat ovarian tissues and in rats treated with insulin and insulin plus human chorinoic gonadotropin (hCG). Methods:, Paraffin blocks of rat ovarian tissues from a previous study, in which 18 adult, female Wistar rats with an average weight of 250 g were divided into three groups to receive either saline solution, human insulin (2 U/day) or human insulin (2 U/day) plus hCG (4 U/day) for 4 weeks, were used in this study to compare the effects on leptin staining. The results were analysed using a semiquantitative scoring system, such as mild, moderate and strong. Results:, No staining was observed in granulosa cells and theca interna cells of normal ovarian tissues. Theca externa cells had mild staining intensity (+), corpus luteum had moderate (+ +) and stroma had mild (+) staining intensity. Histological structure was impaired in the insulin group, luteinized cells had mild staining, there was no difference in other cell groups. Only theca externa cells of the developing follicles were stained in insulin plus hCG group, luteinized cells again had mild staining. Conclusions: Besides damaging the rat ovarian structure, insulin reduced staining intensity of leptin in luteinized cells. Insulin may stimulate ovarian steroid synthesis not only through its own receptors, but also by acting on the leptin expression of these cells. [source] Multivariate calibration of covalent aggregate fraction to the raman spectrum of regular human insulinJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2008Connie M. Gryniewicz Abstract Insulin aggregates were prepared by exposing samples of formulated regular human insulin to agitation at 60°C. Aliquots were drawn from the samples periodically over a time range spanning 192 h, and their aggregate compositions were determined with size exclusion chromatography. The complete data set was composed of 39 separate aliquots. The Raman spectra of three separate 10 µL volumes from each aliquot were measured using the drop-coat deposition Raman (DCDR) method. The spectra were calibrated to aggregate composition by partial least squares regression (PLS), resulting in linear calibration (R2,=,0.997) with a root mean squared error of calibration (RMSEC) of 1.3% and a root mean squared error of cross validation (RMSECV) of 5.1% in aggregate composition. Though the time required for aggregates to form under stressed conditions showed substantial sample-to-sample variation, the correlation between aggregate composition and Raman spectrum was remarkably consistent, indicating that Raman spectroscopy may be a viable screening method for aggregation of protein drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3727,3734, 2008 [source] Prediction of the association state of insulin using spectral parametersJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2003Vladimir N. Uversky Abstract Human insulin exists in different association states, from monomer to hexamer, depending on the conditions. In the presence of zinc the "normal" state is a hexamer. The structural properties of 20 variants of human insulin were studied by near-UV circular dichroism, fluorescence spectroscopy, and small-angle X-ray scattering (SAXS). The mutants showed different degrees of association (monomer, dimers, tetramers, and hexamers) at neutral pH. A correlation was shown between the accessibility of tyrosines to acrylamide quenching and the degree of association of the insulin mutants. The near-UV CD spectra of the insulins were affected by protein association and by mutation-induced structural perturbations. However, the shape and intensity of difference CD spectra, obtained by subtraction of the spectra measured in 20% acetic acid (where all insulin species were monomeric) from the corresponding spectra measured at neutral pH, correlate well with the degree of insulin association. In fact, the near-UV CD difference spectra for monomeric, dimeric, tetrameric, and hexameric insulin are very distinctive, both in terms of intensity and shape. The results show that the spectral properties of the insulins reflect their state of association, and can be used to predict their oligomeric state. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:847,858, 2003 [source] Field Safety and Efficacy of Protamine Zinc Recombinant Human Insulin for Treatment of Diabetes Mellitus in CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2009R.W. Nelson Background: This study describes the efficacy of a new protamine zinc recombinant human insulin (PZIR) preparation for treating diabetic cats. Objective: To evaluate effects of PZIR on control of glycemia in cats with newly diagnosed or poorly controlled diabetes mellitus. Animals: One hundred and thirty-three diabetic cats 120 newly diagnosed and 13 previously treated. Methods: Prospective, uncontrolled clinical trial. Cats were treated with PZIR twice daily for 45 days. Control of glycemia was assessed on days 7, 14, 30, and 45 by evaluation of change in water consumption, frequency of urination, appetite, and body weight, serum fructosamine concentration, and blood glucose concentrations determined 1, 3, 5, 7, and 9 hours after administration of PZIR. Adjustments in dosage of PZIR were made as needed to control glycemia. Results: PZIR administration resulted in a significant decrease in 9-hour mean blood glucose (199 ± 114 versus 417 ± 83 mg/dL, X± SD, P < .001) and serum fructosamine (375 ± 117 versus 505 ± 96 ,mol/L, P < .001) concentration and a significant increase in mean body weight (5.9 ± 1.4 versus 5.4 ± 1.5 kg, P= .017) in 133 diabetic cats at day 45 compared with day 0, respectively. By day 45, polyuria and polydipsia had improved in 79% (105 of 133), 89% (118 of 133) had a good body condition, and 9-hour mean blood glucose concentration, serum fructosamine concentration, or both had improved in 84% (112 of 133) of the cats compared with day 0. Hypoglycemia (<80 mg/dL) was identified in 151 of 678, 9-hour serial blood glucose determinations and in 85 of 133 diabetic cats. Hypoglycemia causing clinical signs was confirmed in 2 diabetic cats. Conclusions and Clinical Relevance: PZIR is effective for controlling glycemia in diabetic cats and can be used as an initial treatment or as an alternative treatment in diabetic cats that do not respond to treatment with other insulin preparations. [source] Mass spectrometric determination of insulins and their degradation products in sports drug testingMASS SPECTROMETRY REVIEWS, Issue 1 2008Mario Thevis Abstract Insulins' anabolic and anti-catabolic properties have supposedly led to its misuse in sport. Hence, doping control assays were developed to allow the unequivocal identification of synthetic insulin analogs and metabolic products derived from human insulin and its artificial counterparts in urine and plasma specimens. Analyses were based on immunoaffinity purification and subsequent characterization of target analytes by top-down sequencing-based approaches, which were conducted with hybrid tandem mass spectrometers that consisted of either quadrupole-linear ion trap or linear ion trap-orbitrap analyzers. Diagnostic product ions and analytical strategies are presented and discussed in light of the need to unambiguously identify misused drugs in urine and plasma specimens for doping control. © 2007 Wiley Periodicals, Inc., Mass Spec Rev 27:35,50, 2008 [source] Same-patient allergy to ampicillin and human insulinALLERGY, Issue 7 2009C. Caruso No abstract is available for this article. [source] Biphasic insulin aspart vs. human insulin in adolescents with type 1 diabetes on multiple daily insulin injectionsPEDIATRIC DIABETES, Issue 1 2006Henrik Mortensen Abstract:, The aim was to compare clinical efficacy and safety of two treatment regimens: biphasic insulin aspart (BIAsp) injected at all three meals plus neutral protamine Hagedorn (NPH) insulin at bedtime vs. a human insulin regimen, premixed human insulin at breakfast and soluble insulin at lunch and dinner and NPH at bedtime. A total of 167 adolescents (80 males and 87 females) with type 1 diabetes was included in the trial (multinational, randomized, open-label, and parallel group). Each subject received either of two treatment regimens for a 4-month period. BIAsp was injected immediately before main meals, human insulin products 30 min before meals, and NPH at night. Glycemic control was monitored by eight-point evaluations (after 6 and 16 wks) and hemoglobin A1c (HbA1c) (after 2, 6, and 16 wks). Safety evaluations included adverse events and incidence of hypoglycemic episodes. HbA1c (mean ± SD) after 4 months on BIAsp (9.39 ± 0.14) was not significantly different from that with human insulin (9.30 ± 0.15). The average postprandial glucose increment in the BIAsp group was about half the increment in the human insulin group; the difference not statistically significant. The body mass index (BMI) increased in both groups, but significantly (p = 0.005) less in the BIAsp group. However, in males on BIAsp, the BMI decreased compared with those on human insulin (p = 0.007). No significant group differences were found for the rate of hypoglycemic episodes. We concluded that the BIAsp regimen was associated with similar glycemic control and similar incidence of hypoglycemic episodes as human insulin. However, the BIAsp regimen caused a significantly smaller increase in BMI, particularly in males, compared with the human insulin regimen. [source] Insulins in equine urine: qualitative analysis by immunoaffinity purification and liquid chromatography/tandem mass spectrometry for doping control purposes in horse-racingRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 3 2008Tiia Kuuranne Insulin is a peptide hormone consisting of two peptide chains (A- and B-chain) that are cross-linked by two disulfide bonds. To obtain improved pharmacokinetic onset of action profiles of insulin treatment in diabetic patients, recombinant long-, intermediate-, and rapid-acting insulin analogs are produced, in which the C-terminal end of the B-chain plays an especially important role. A review of the veterinary literature reveals the low prevalence of equine type I diabetes mellitus, which indicates that the therapeutic use of insulin in racing horses is unlikely. Although there is no unequivocal evidence of an overall performance-enhancing effect of insulin, in human sports the misuse of insulin preparations is reported among elite athletes. The desired effects of insulin include the increase of muscular glycogen prior to sports event or during the recovery phase, in addition to a chalonic action, which increases the muscle size by inhibiting protein breakdown. In the present study urinary insulin was detected in equine samples and differences between equine insulin, human insulin, as well as rapidly acting recombinant insulin variants were examined. The method was based on sample purification by solid-phase extraction (SPE) and immunoaffinity chromatography (IAC), and subsequent analysis by microbore liquid chromatography (LC) and tandem mass spectrometry (MS/MS) using top-down sequencing for the determination of various insulins. Product ion scan experiments of intact proteins and B-chains enabled the differentiation between endogenously produced equine insulin, its DesB30 metabolite, human insulin and recombinant insulin analogs, and the assay allowed the assignment of individual product ions, especially those originating from modified C-termini of B-chains. Copyright © 2008 John Wiley & Sons, Ltd. [source] Safety and efficacy of adeno-associated viral vector-mediated insulin gene transfer via portal vein to the livers of streptozotocin-induced diabetic Sprague-Dawley ratsTHE JOURNAL OF GENE MEDICINE, Issue 5 2005Young Mi Park Abstract Background Previous studies demonstrating the efficacy of insulin gene therapy have mostly involved use of adenoviral vectors or naked DNA to deliver the insulin gene. However, this procedure may not guarantee long-term insulin production. To improve the performance, we prepared recombinant adeno-associated viral vectors (rAAV) harboring the gene encoding a furin-modified human insulin under the cytomegalovirus (CMV) promoter [rAAV-hPPI(F12)]. Methods Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats were used as a diabetic animal model. The levels of blood glucose, insulin, and HbA1c were measured to test the effect. An intraperitoneal glucose tolerance test was performed to test the capability of blood glucose disposal. Immunohistochemical staining and Northern blot analyses were performed to survey the expression pattern of the therapeutic insulin gene. Results STZ-induced diabetic Sprague-Dawley rats infused via the portal vein with rAAV-hPPI(F12) produced human insulin and after a 6-h fast were normoglycemic for over 90 days post-treatment, whereas diabetic rats treated with recombinant adenoviral vector harboring the hPPI(F12) gene [rAV-hPPI(F12)] were normoglycemic only for days 3 to 13 post-treatment. Insulin mRNA was detected mainly in the liver of the rAAV-hPPI(F12)-treated diabetic rats. The glucose tolerance capability of the rAAV-hPPI(F12)-treated diabetic rats was comparable to that of non-diabetic rats, even without injection of recombinant insulin. Furthermore, blood HbA1c concentrations in rAAV-hPPI(F12)-treated diabetic rats were reduced to almost the normal level. Importantly, studies of rAV or rAAV vector-dependent side effects on the targeted liver strongly suggested that only rAAV treatment caused no side effects. Conclusions These results demonstrate that our rAAV-mediated in vivo insulin gene therapy provides safer maintenance of the insulin gene expression required for long-term and thus more effective blood glycemic control. Copyright © 2005 John Wiley & Sons, Ltd. [source] A neutron crystallographic analysis of T6 porcine insulin at 2.1,Å resolutionACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2009Wakari Iwai Neutron diffraction data for T6 porcine insulin were collected to 2.1,Å resolution from a single crystal partly deuterated by exchange of mother liquor. A maximum-likelihood structure refinement was undertaken using the neutron data and the structure was refined to a residual of 0.179. The hydrogen-bonding network of the central core of the hexamer was observed and the charge balance between positively charged Zn ions and their surrounding structure was interpreted by considering the protonation and/or deprotonation states and interactions of HisB10, water and GluB13. The observed double conformation of GluB13 was essential to interpreting the charge balance and could be compared with the structure of a dried crystal of T6 human insulin at 100,K. Differences in the dynamic behaviour of the water molecules coordinating the upper and lower Zn ions were observed and interpreted. The hydrogen bonds in the insulin molecules, as well as those involving HisB10 and GluB13, are discussed. The hydrogen/deuterium (H/D) exchange ratios of the amide H atoms of T6 porcine insulin in crystals were obtained and showed that regions highly protected from H/D exchange are concentrated in the centre of a helical region of the B chains. From the viewpoint of soaking time versus H/D-exchange ratios, the amide H atoms can be classified into three categories. [source] X-ray investigation of gene-engineered human insulin crystallized from a solution containing polysialic acidACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010V. I. Timofeev Attempts to crystallize the noncovalent complex of recombinant human insulin with polysialic acid were carried out under normal and microgravity conditions. Both crystal types belonged to the same space group, I213, with unit-cell parameters a = b = c = 77.365,Å, , = , = , = 90.00°. The reported space group and unit-cell parameters are almost identical to those of cubic insulin reported in the PDB. The results of X-ray studies confirmed that the crystals obtained were cubic insulin crystals and that they contained no polysialic acid or its fragments. Electron-density maps were calculated using X-ray diffraction sets from earth-grown and microgravity-grown crystals and the three-dimensional structure of the insulin molecule was determined and refined. The conformation and secondary-structural elements of the insulin molecule in different crystal forms were compared. [source] | |||||||||||||||||||||||||||||||