Insulin aspart development

A few patients treated with insulin aspart developed antibodies, which cross-reacted with antibodies against human insulin and fell after 3 months (19). In... 

A number of combination insulin products are available commercially. NPH is available in combinations of 70/30 and 50/50 with regular insulin. Two short-acting insulin analog mixtures are also available. Humalog Mix 75/25 contains 75% insulin lispro protamine suspension and 25% insulin lispro. Novolog Mix 70/30 contains 70% insulin aspart protamine suspension and 30% insulin aspart. The lispro and aspart insulin protamine suspensions were developed specifically for these mixture products and will not be commercially available separately. 

A 45-year-old man with type 2 diabetes treated with glibenclamide and metformin received combined chemotherapy for non-Hodgkin s lymphoma and was given premixed insulin. He developed local wheal-and-flare reactions immediately after the injections. Skin prick tests were positive for various types of insulin but weakly positive for lispro and negative for insulin aspart. He tolerated aspart insulin without any allergic reactions. 

To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. Disposable insulin pens are also available for selected formulations. These include regular insulin, insulin lispro, insulin aspart, NPH insulin, and premixed 70%/30% and 50%/50% NPH/regular, 75% NPL/25% lispro, 50% NPL/50% lispro, and 70% NPA/30% aspart insulin. They have been well accepted by patients because they eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling. 

By the end of the 1980s, to accommodate postprandial hyperglycemia, monomeric insulin formulations, insulin lispro (the Lys-Pro analog) and insulin aspart (the Asp-Pro analog) had been developed for clinical use [19, 20] (Figure 6.3-1). 

A 6-year-old girl who had had type 1 diabetes for 18 months developed a noduie on her left arm. She regularly injected insulin aspart and insulin NPH into botii arms. After 4 months the lesion measured 1.5 x 1.0 cm and there was a lymph node in the left axilla. Biopsy showed atypical blasts. Bone marrow examination suggested a precursor B-cell lymphoblastic lymphoma. 

A 73 year old Japanese woman, weight 33.5 kg, took nateglinide 270 mg/day and pioglitazone 15 mg/day for 6 months (105). Her HbAic concentration was 8.6% and fasting glucose 11.4 mmol/1. Metformin 250 mg bd was added and 3 weeks later she developed jaundice and fatigue. A few months before her liver function tests had been normal. Aspartate transaminase activity was 689 IU/1, alanine transaminase 772 IU/1, alkaline phosphatase 639 IU/1, and bilirubin 6.5 mg/dl. All oral therapy was withdrawn and insulin started. Her liver function improved over the next few weeks. 

A new development is the binding of two 9-fluorenyl-methoxy-carbonyl moieties to two amino acids in the structure of aspart insulin, phenylalanine and lysine (3). This compound has no biological activity but gradually releases its groups and keeps diabetic animals in a good metabolic state over 2-3 days. Experiments in humans have not yet been reported. 

Recent development of insulin analogues has altered the rates of absorption. Insulin with aspartate and glutamate substituted at positions B9 and B27 respectively crystallizes poorly and has been termed "monomeric insulin (Vora et al., 1988). This insulin is absorbed more rapidly from subcutaneous depots and thus may be useful in meeting postprandial demands. In contrast, other insulin analogues tend to crystallize at the site of injection and are absorbed more slowly (Markussen et al., 1988). Insulins with enhanced biological potency have been produced by substitution of aspartate for histidine at position BIO and by modification of the C-terminal residues of the B-chain (Schwartz et al., 1989). 

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