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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin lispro [Lys (B28), Pro (B29) human insulin] is a rapidly absorbed analog that has diminished tendency to self-associate. In four open-label, 1-year-long international randomized trials, we contrasted the immunogenicity of insulin lispro versus regular human insulin (RHI) in patients previously treated with insulin who had IDDM or NIDDM. Using a self-blank subtraction assay, we assessed sera for the presence of insulin-specific antibodies (ISA), insulin lispro-specific antibodies (LSA), and cross-reactive antibodies (CRA). Basal insulin needs were provided either with human ultralente (UL) or NPH insulins. After 2 to 4 weeks of therapy with RHI plus UL or RHI plus NPH, 50% of patients were randomly assigned to begin insulin lispro or continue on RHI. At baseline, few pretreated patients had LSA (0-4%) and approximately 10% had ISA, whereas 41-45% of patients with IDDM and 23-27% of patients with NIDDM had CRA (IDDM vs. NIDDM, P < 0.001). Within studies, no significant differences were noted over time in ISA, LSA, or CRA attributable to the type of short-acting insulin. When data were pooled, inconsistent changes were noted in ISA and LSA (LSA were greater in NIDDM vs. IDDM at baseline, P = 0.001, and ISA were greater in IDDM vs. NIDDM at 6 months, P = 0.007). Significant levels of CRA were more common in IDDM at all times (P < 0.001, P = 0.022, and P = 0.002 at baseline, 6 months, and 12 months, respectively). For patients receiving insulin lispro, no significant changes occurred in antibody status among IDDM and NIDDM patients throughout the study (became positive, remained positive, became negative, or remained negative). IDDM patients were more likely to develop or maintain CRA levels (P = 0.008 vs. NIDDM), whereas antibody levels were comparable among positive individuals. No evidence was noted that insulin lispro differs in immunogenicity from RHI in previously treated IDDM and NIDDM patients.
Diabetes 1996 Dec
PMID:Immunologic effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients previously treated with insulin. 892 61

We studied the effects of the new rapid acting human insulin analogue (Lys(B28), Pro(B29) insulin), insulin Lispro (Lispro) on metabolic control and insulin receptor binding in type II diabetes mellitus. We investigated 2 patients: Patient 1 was obese, clearly insulin-resistant, injected high doses of insulin (3-4 IU/kg body weight), and had insufficient diabetes control. Patient 2 was of normal body weight, injected normal insulin doses (0.7-0.8 IU/kg body weight), and had good diabetes control. Patient 1 showed a considerable improvement of insulin binding after receiving Lispro (26,700 vs. 5,600 receptors/monocyte; Kd 560 vs. 1,500 pM). Concommitantly, a decrease of serum glucose and insulin dose was observed, reflecting a higher insulin sensitivity during Lispro treatment. In patient 2 injected with Lispro the time course of serum glucose, serum insulin, and insulin binding after an oral meal was comparable to values obtained in healthy controls. We conclude that the quick and pulsatile pharmacokinetic profile of the insulin analogue Lispro may improve glycemia, insulin receptor binding, and insulin resistance in type II diabetes.
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PMID:Pharmacodynamics of insulin Lispro in 2 patients with type II diabetes mellitus. 893 33

To test whether the binding of insulin to an endogenous serum protein can be used to extend the time action of insulin, human insulin was acylated at the epsilon-amino group of Lys(B29) with palmitic acid to promote binding to serum albumin. Size-exclusion chromatography was used to demonstrate specific binding of the resulting analog, [N(epsilon)-palmitoyl Lys(B29)] human insulin, to serum albumin in vitro, and the time action and activity of the analog were determined in vivo using overnight-fasted, insulin-withdrawn diabetic dogs. In the diabetic animal model, the duration of action of [N(epsilon)-palmitoyl Lys(B29)] human insulin administered intravenously was nearly twice that of unmodified human insulin, and the plasma half-life was nearly sevenfold that of the unmodified protein. Administered subcutaneously, [N(epsilon)-palmitoyl Lys(B29)] human insulin had a longer duration of action; a flatter more basal plasma insulin profile; and a lower intersubject variability of response than the intermediate-acting insulin suspension Humulin L (Lilly, Indianapolis, IN). These studies support the concept that modification of insulin to promote binding to an existing serum protein can be used to extend the time action of human insulin. In addition, the time action, pattern, and decreased variability of response to [N(epsilon)-palmitoyl Lys(B29)] human insulin support the development and further testing of this soluble insulin analog as a basal insulin to increase the safety of intensive insulin therapy.
Diabetes 1997 Apr
PMID:Acylation of human insulin with palmitic acid extends the time action of human insulin in diabetic dogs. 907 4

The primary objectives of this study were to assess the efficacy and safety of Lys(B28), Pro(B29) in the treatment of patients with diabetes mellitus and to compare Lys(B28), Pro(B29) to currently available regular insulin with respect to quality of life. This study was designed as an open-label, non-comparative one. The number of patients enrolled in the trial was 39. At Visit 1 (week 0), blood samples for fasting, 1- and 2-hour postprandial blood glucose, and HbA1c were taken. At Visit 2 (week 6) and Visit 3 (week 12), fasting, 1- and 2-hour postprandial blood glucose, and HbA1c levels were measured again. There was no significant change in HbA1c, fasting blood glucose and 1- and 2-hour postprandial blood glucose levels. The 1- and 2-hour postprandial blood glucose excursions decreased significantly from Visit 1 to Visit 3. There were no serious adverse events during the study. Half of the patients had less hypoglycemia with LysPro insulin, while 25% had an increase in episodes. Thirty percent of patients were more satisfied with LysPro insulin than with the short-acting insulin that they had previously used. In conclusion, LysPro therapy can be regarded as safe, since there were no unexpected adverse events and no changes in the usual physical parameters.
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PMID:Safety and efficacy of [Lys(B28), Pro(B29)]-human insulin in patients with diabetes mellitus. 943 6

The short-acting insulin analogue lispro ([LYS(B28), PRO(B29)] is absorbed from the subcutis more rapidly than soluble insulin (S). To compare the clinical effectiveness of lispro vs S, 11 Type 1 patients using continuous subcutaneous insulin infusion (CSII) therapy (6 F, 5 M, age 30 +/- 2.5 years, diabetes duration 14 +/- 1.0 years, BMI 24.0 +/- 0.8 kg m(-2), HbA1c 6.5 +/- 0.2%) were studied in an open, randomized, crossover study for 6 months (3 months lispro and 3 months S or vice versa). During lispro treatment mean fasting and 2 h postprandial blood glucose were lower compared to the S phase (fasting 6.5 +/- 0.4 vs 7.5 +/- 0.4 mmol l(-1) (NS), postprandial 6.8 +/- 0.3 vs 8.3 +/- 0.3 mmol l(-1), p = 0.03). In patients treated first with lispro HbA1c levels improved from 6.3 +/- 0.2% to 5.7 +/- 0.3%; On reversion to S HbA1c increased to 6.2 +/- 0.2%. In the group treated first with S, HbA1c fell (6.7 +/- 0.4% vs 6.5 +/- 0.3%) and then improved further to 6.3 +/- 0.3% with lispro. None of these changes were significant. There was no significant difference with respect to hypoglycaemic or other adverse events. It can be concluded that lispro in CSII therapy is safe and may improve postprandial glucose excursions.
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PMID:Human insulin analogue [LYS(B28), PRO(B29)]: the ideal pump insulin? 954 26

Insulin is a short-lived species in the circulatory system. After binding to its receptor sites and transmission of its biological signals, bound insulin undergoes receptor-mediated endocytosis and consequent degradation. An inactive insulin derivative that is not recognized by the receptor has a longer circulation life, but obviously is biologically impotent. (Fmoc)2 insulin is an insulin derivative purified through high-performance liquid chromatography in which two 9-fluorenylmethoxycarbonyl (Fmoc) moieties are covalently linked to the (alpha-amino group of phenylalanine B1 and the epsilon-amino group of lysine B29. It has 1-2% of the biological potency and receptor binding capacity of the native hormone. After incubation, (Fmoc)2 insulin undergoes a time-dependent spontaneous conversion to fully active insulin in aqueous solution at 37 degrees C and a pH range of 7-8.5. At pH 7.4, the conversion proceeds slowly (t1/2 = 12 +/- 1 days) and biological activity is generated gradually. A single subcutaneous administration of (Fmoc)2 insulin to streptozocin-treated diabetic rats normalized their blood glucose levels and maintained the animals in an anabolic state over 2-3 days. A broad shallow peak of immunoreactive insulin was found to persist in circulation over this period. To confirm further that the long-acting effect of (Fmoc)2 insulin proceeds via slow release in the blood circulation itself, we administered native insulin, NPH insulin, or the (Fmoc)2 derivative intraperitoneally. The rats recovered from hypoglycemia at t1/2 = 8.0 +/- 0.3 and 10 +/- 0.4 h after administration of native and NPH insulin, respectively. In contrast, (Fmoc)2 insulin was active for a significantly longer time, with an extended onset of t1/2 = 26 +/- 1h, and a glucose-lowering effect even 40 h after administration. (Fmoc)2 insulin was also found to be more resistant to proteolysis. Finally, we found that (Fmoc)2 insulin does not induce antigenic effects. In summary, we present here a new concept for prolonging the half-life of insulin in the circulatory system, in which receptor-mediated endocytosis and degradation is delayed and accompanied by a time-dependent generation of basal insulin.
Diabetes 1999 Jul
PMID:New concept for long-acting insulin: spontaneous conversion of an inactive modified insulin to the active hormone in circulation: 9-fluorenylmethoxycarbonyl derivative of insulin. 1038 50

Crystallographic studies of insulin-protamine complexes, such as neutral protamine Hagedorn (NPH) insulin, have been hampered by high crystal solvent content, small crystal dimensions, and extensive disorder in the protamine molecules. We report herein in situ tapping mode atomic force microscopy (TMAFM) studies of crystalline neutral protamine Lys(B28)Pro(B29) (NPL), a complex of Lys(B28)Pro(B29) insulin, in which the C-terminal prolyl and lysyl residues of human insulin are inverted, and protamine that is used as an intermediate time-action therapy for treating insulin-dependent diabetes. Tapping mode AFM performed at 6 degrees C on bipyramidally tipped tetragonal rod-shaped NPL crystals revealed large micron-sized islands separated by 44-A tall steps. Lattice images obtained by in situ TMAFM phase and height imaging on these islands were consistent with the arrangement of individual insulin-protamine complexes on the P4(1)2(1)2 (110) crystal plane of NPH, based on a low-resolution x-ray diffraction structure of NPH, arguing that the NPH and NPL insulins are isostructural. Superposition of the height and phase images indicated that tip-sample adhesion was larger in the interstices between NPL complexes in the (110) crystal plane than over the individual complexes. These results demonstrate the utility of low-temperature TMAFM height and phase imaging for the structural characterization of biomolecular complexes.
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PMID:Structural studies of a crystalline insulin analog complex with protamine by atomic force microscopy. 1062 Mar 10

Since the 1980s, recombinant human insulin for the treatment of diabetes mellitus has been produced using either the yeast Saccharomyces cerevisiae or the prokaryote Escherichia coli. Here, development of the insulin secretory expression system in S. cerevisiae and its subsequent optimisation is described. Expression of proinsulin in S. cerevisiae does not result in efficient secretion of proinsulin or insulin. However, expression of a cDNA encoding a proinsulin-like molecule with deletion of threonine(B30) as a fusion protein with the S. cerevisiae alpha-factor prepro-peptide (leader), followed either by replacement of the human proinsulin C-peptide with a small C-peptide (e.g. AAK), or by direct fusion of lysine(B29) to glycine(A1), results in the efficient secretion of folded single-chain proinsulin-like molecules to the culture supernatant. The secreted single-chain insulin precursor can then be purified and subsequently converted to human insulin by tryptic transpeptidation in organic aqueous medium in the presence of a threonine ester. The leader confers secretory competence to the insulin precursor, and constructed (synthetic) leaders have been developed for efficient secretory expression of the insulin precursor in the yeasts S. cerevisiae and Pichia pastories. The Kex2 endoprotease, specific for dibasic sites, cleaves the leader-insulin precursor fusion protein in the late secretory pathway and the folded insulin precursor is secreted to the culture supernatant. However, the Kex2 endoprotease processing of the pro-peptide-insulin precursor fusion protein is incomplete and a significant part of the pro-peptide-insulin precursor fusion protein is secreted to the culture supernatant in a hyperglycosylated form. A spacer peptide localised between the leader and the insulin precursor has been developed to optimise Kex2 endoprotease processing and insulin precursor fermentation yield.
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PMID:Yeast secretory expression of insulin precursors. 1103 May 62

A defect in transcapillary transport of insulin in skeletal muscle and adipose tissue has been proposed to play a role in the insulin resistance that leads to type 2 diabetes, yet the mechanism of insulin transfer across the capillary endothelium from plasma to interstitium continues to be debated. This study examined in vivo the interstitial appearance of insulin in hindlimb using the fatty acid acylated insulin analog Lys(B29)-tetradecanoyl des-(B30) human insulin, or NN304, as a marker for insulin transport. If the insulin transport were a saturable process, then "swamping" the capillary endothelial insulin receptors with native insulin would suppress the subsequent appearance in interstitial fluid of the insulin analog NN304. This analog binds to insulin receptors with an affinity of about 50% of native insulin. Experimental conditions established a physiologic NN304 dose in the absence or presence of pharmacologic and saturating concentrations of regular human insulin. Euglycemic clamps were performed in dogs under inhalant anesthesia with deep hindlimb lymphatic sampling, representative of skeletal muscle interstitial fluid (ISF). In group 1 (n = 8), NN304 alone was infused (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 2 (n = 6), starting at time 0, human insulin was infused at a pharmacologic dose (60 pmol center dot min(-1) center dot kg(-1)) with the addition of NN304 infusion (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 3 (n = 4), the human insulin infusion was increased to a saturating dose (120 pmol center dot min(-1) center dot kg(-1)). Pharmacologic insulin infusion (group 2) established steady-state human insulin concentrations of 6,300 plus minus 510 pmol/l in plasma and 5,300 plus minus 540 pmol/l in ISF. Saturating insulin infusion (group 3) achieved steady-state human insulin concentrations of 22,000 plus minus 1,800 pmol/l in plasma and 19,000 plus minus 1,500 pmol/l in ISF. Total (bound and unbound) NN304 plasma concentrations rose from a steady state of 1,900 plus minus 110 (group 1) to 2,400 plus minus 200 pmol/l (group 2) and 3,100 plus minus 580 pmol/l (group 3), consistent with a competition-driven decline in NN304 clearance from plasma as the human insulin level increased (P < 0.05 by ANOVA). Steady-state interstitial NN304 concentrations also rose with increasing human insulin levels but did not achieve significance in comparison with analog alone (162 plus minus 15 vs. 196 plus minus 22 and 241 plus minus 53 pmol/l for group 1 versus groups 2 and 3, respectively; P = 0.20), yet the steady-state plasma:ISF ratio for NN304 remained essentially unchanged in the absence and presence of elevated human insulin levels (12.6 plus minus 1.2 vs. 12.4 plus minus 0.5 and 13.1 plus minus 1.5 for group 1 versus groups 2 and 3, respectively; P = 0.93). Last, NN304 rate of appearance in interstitial fluid (i.e., half-time to steady state) was similar between groups; mean half-time of 92 plus minus 4 min (NS between groups). In conclusion, appearance of the insulin analog NN304 in skeletal muscle interstitial fluid was constant whether in the absence or presence of human insulin concentrations sufficient to saturate the endothelial insulin receptors. These findings support the hypothesis, provided that the mechanism of insulin and NN304 transcapillary transport is similar, that transcapillary transport of insulin in skeletal muscle occurs primarily via a nonsaturable process such as passive diffusion via a paracellular or transcellular route.
Diabetes 2002 Mar
PMID:Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion. 1187 53

NN304 [Lys(B29)-tetradecanoyl des(B30) human insulin] is a potentially therapeutic insulin analog designed to exhibit protracted glucose-lowering action. In dogs with infusion rates similar to insulin itself, NN304 exhibits similar glucose uptake (R(d)) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the approximately 2% unbound NN304 concentration. NN304 (or human insulin) (n = 6 each) was infused at 10.2 pmol center dot min(-1) center dot kg(-1) under euglycemic clamp conditions in anesthetized dogs. NN304 appearance in lymph, representing interstitial fluid (ISF), was slow compared with insulin (t(1/2) = 70 +/- 7 vs. 14 +/- 1 min, P < 0.001). R(d) was highly correlated with the ISF concentration for insulin and NN304 (r = 0.86 and 0.93, respectively), suggesting that slow transendothelial transport (TET) is responsible for sluggish NN304 action. Insulin and NN304 concentration data were fit to a two-compartment (plasma and ISF) model. NN304 plasma elimination and TET were reduced to 10 and 7% of insulin, respectively. Thus, there was reduction of NN304 transport, but not to the degree expected. In ISF, there was no reduction in NN304 elimination. Thus, this acylated insulin analog demonstrates blunted kinetics in plasma, and full efficacy in the compartment of action, ISF.
Diabetes 2002 Mar
PMID:Albumin binding of acylated insulin (NN304) does not deter action to stimulate glucose uptake. 1187 77


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