Per Balschmidt

Ten Years of Experience with Biphasic Insulin Aspart 30: From Drug Development to the Latest Clinical Findings

Biphasic insulin aspart 30 (BIAsp 30) includes 30% soluble rapid-acting insulin aspart (IAsp) along with an intermediate-acting 70% protaminated IAsp that provides coverage of prandial and basal insulin in a single injection. As BIAsp 30 has been available internationally for 10 years, this review provides a comprehensive overview of the discovery of BIAsp 30, its pharmacokinetic and pharmacodynamic profile, safety and efficacy outcomes from the clinical trial programme, ‘real-life’ clinical insights provided by observational study data, and cost effectiveness and quality-of-life information. These studies have demonstrated that BIAsp 30 once or twice daily is an appropriate option for insulin initiation. BIAsp 30 also provides a switch option in patients on biphasic human insulin (BHI). Switching from BHI to BIAsp 30 is associated with improved postprandial glucose (PPG) and reduced nocturnal and major hypoglycaemia, although daytime hypoglycaemia is higher with BIAsp 30. Intensification of BIAsp 30 can be achieved by increasing the number of daily doses up to three times daily with meals. Therefore, BIAsp 30 provides an intensification option for individuals who are not achieving control with basal insulin and would prefer the simplicity of a single biphasic insulin instead of progressing to a basal-bolus approach. BIAsp 30 has a simple dose-titration algorithm, which enables patients to effectively self-titrate their insulin dose. Cost-effectiveness analyses have demonstrated that BIAsp 30 is cost effective or dominant compared with BHI 30 or insulin glargine in a number of healthcare settings. In conclusion, BIAsp 30 offers a simple and flexible option for insulin initiation and intensification that provides coverage of both fasting and prandial glucose.

Expression of insulin in yeast: the importance of molecular adaptation for secretion and conversion.

The globular, two...chain and 51 amino acid residue peptide-hormone insulin is produced and secreted by the ~-cellsof the pancreatic islets of Langerhans. Insulin is synthesized as preproinsnlin (110 amino acids). The pre-peptide (signal peptide) is removed upon entrance into the endoplasmic reticulum. Proinsulin folds in the endoplasmic reticulum, is transported to the Goigi apparatus and subsequently processed into the mature insulin molecule that is stored in well-defined storage vesicles (Figure 5.1) (Steiner etaI., 1967, 1986; Dodsonand Steiner, 1998). Proinsulin and insulin have self-assembling properties that play an important role in processing and storage in the J3-cells secretory pathway and both associate to dimers and in the presence of zinc these further assemble into hexamers (Dodson and Steiner, 1998). In the late Golgi apparatus proinsulin is targeted to acidifying secretory granules and conversion ofproinsulin to insulin occurs by removal of the C-peptide by cleavage at dibasic processing sites by the endoproteases PC3 (or PCl) and pe2 (mammalian

Proton nuclear magnetic resonance study of the B9(Asp) mutant of human insulin: Sequential assignment and secondary structure

The sequence-specific 1H nuclear magnetic resonance (n.m.r.) assignment of 49 of the 51 amino acid residues of human B9(Asp) insulin in water at low pH is reported. Spin systems were identified using a series of two-dimensional n.m.r. techniques. For the majority of the amino acid residues with unique spin systems, particularly Ala, Thr, Val, Leu, Ile and Lys, the complete spin systems were identified. Sequence-specific assignments were obtained from sequential nuclear Overhauser enhancement (NOE) connectivities. The results indicate that the solution structure of the mutant closely resembles the crystal structure of native insulin. Thus, the NOE data reveal three helical domains all consistent with the secondary structure of the native human 2Zn insulin in the crystal phase. Numerous slowly exchanging amide protons support these structural elements, and indicate a relatively stable structure of the protein. A corresponding resemblance of the tertiary structures in the two phases is also suggested by slowly exchanging amide protons, and by the extreme chemical shift values observed for the beta-protons of B15(Leu) that agree with a close contact between this residue and the aromatic rings of B24(Phe) and B26(Tyr), as found in the crystal structure of the 2Zn insulin. Finally, there are clear indications that the B9(Asp) insulin mutant exists primarily as a dimer under the given conditions.