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The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Sites of molecular alterations of insulin are identified in Figure 5.1 by a dotted circle around the specific amino acids (five such sites of change), which will be elucidated further below. The peptide sequence of insulin has been altered to create seven different new molecules with varied onsets and/or durations of activity in their glucose mechanism of action (e.g., aspart form, degludec, detemir, glargine, glulisine, glycine, lispro molecules). Insulin aspart has the B28 amino acid changed from proline to asparagine and has a rapid onset of action. The degludec form and the detemir form of insulin have the B30 threonine amino acid replaced with a carbon fatty acid chain (C-16 and C-14, respectively), imparting a long duration of action. The insulin glulisine molecule replaces two amino acids, B3 asparagine to lysine and B29 lysine to glutamine, causing a more rapid onset and shorter duration for its glucose actions. The insulin glargine form has one amino acid change at A21 from asparagine to glycine and two added arginine species to the carboxyl end of the B-chain, imparting a long action to the molecule. Insulin lispro molecule also possesses two amino acid changes, B28 proline to lysine and B29 lysine to proline, resulting in sustained activity.
Continuous Insulin Infusion Therapy and Nutrition
Published in Jeffrey I. Mechanick, Elise M. Brett, Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Andrew Jay Drexler, Carolyn Robertson
Insulin pump therapy has been shown to result in improvement of hemoglobin A1C (A1C) levels with reduced frequency of severe hypoglycemia in individuals with type-1 diabetes mellitus (T1DM) [1], often with a reduction in total daily insulin dose [2]. There are many reasons for a particular patient to utilize CSII, including increased flexibility of lifestyle, avoidance of injections, ease of meal dosing, and the potential for improved control. The strongest indication for CSII is in the patient with a major manifestation of the “dawn phenomenon.” The dawn phenomenon is a rise in plasma glucose or insulin requirements in the early morning hours before rising in the absence of antecedent hypoglycemia [3]. For these patients, the only alternative is to awaken in the middle of the night and take an insulin injection. In one recent study, the use of insulin aspart in the pump resulted in lower glycemic exposure—as determined by a continuous glucose monitoring system (CGMS)—as compared with multiple daily injections (MDI) therapy using aspart and glargine, without increased risk of hypoglycemia [4]. This was attributed to the ability to control the dawn phenomenon with adjustment of nighttime basal rates and the flexibility in mealtime dosing.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Patients suffer from many diseases as a result of deficiency in the endogenous proteins. Protein hormones such as insulin and human growth hormone belong to this category of endogenous proteins. Insulin deficiency causes type I diabetes. Hence, Insulin is given exogenously to the patients suffering from diabetes. Insulin is the first human recombinant protein therapeutic that is also known as Humulin®. It was prepared by Eh Lilly at Genentech and was approved by the US FDA in 1982 (Goeddel et al., 1979). Humulin® was used to replace the natural insulin which is absent in diabetic patients. With advancements in proteins engineering, several of insulin analogs have been designed that are classified into two categories, namely (1) fast-acting analog formulations for bolus injection before meals, and (2) basal analog formulations intended for once-a-day injections (Berenson et al., 2011). Insulin lispro, insulin aspart, and insulin glulisine are the fast-acting insulin analogs that are safe and effective in multi-injection regimens. Insulin lispro was engineered in which the C-terminal lysine and proline residues of insulin B-chain were swapped. This mutation completely knocked out the insulin hexamer formation without affecting its receptor binding efficiency, thus allowing the presence of higher concentration of insulin monomers in postprandial injections. Insulin lispro was first approved in the United States in 1996 (Thrasher et al., 2015b). Insulin aspart is the fast-acting insulin analog that gets absorbed quickly in the blood. It starts its action in several minutes and hence can be taken by the patients just before the meal (Muchmore, 2018). Insulin glulisine, marketed as Apidra, is a rapidly acting insulin analogue in which the amino acid aspargine at third position in the B-chain was swapped with lysine and the lysine residue at 29th position in B-chain was replaced by glutamic acid. Its receptor binding properties are same as the human insulin but it appears faster in the blood. Insulin glulisine also follows flexible administration, that is, it can be administered immediately before or after the meal (Garnock-Jones and Plosker, 2009). Insulin glargine is marketed as Lantus, is most widely used as long-acting insulin analogue. It contains two basic arginine residues at the end of the B-chain that shifts the isoelectric point to neutrality, hence resulting in precipitation when injected subcutaneously in an unbuffered pH-4 formulation form. The precipitation results in its prolonged actions (Goykhman et al., 2009). Insulin detemir sold by Novo-Nordisk as Levemir, contains a prosthetic fatty acyl group on Lys 29 of B-chain, which causes its binding to serum albumin and results in circulating depot. This analog also exhibits more stable hexameric structure in comparison to natural insulin (Vigneri et al., 2010). Levemir is administered twice a day, as its actions are not as prolonged as that of Lantus.
Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial
Published in Current Medical Research and Opinion, 2022
Jun Yao, Xiaohui Guo, Li Sun, Ping Han, Xiaofeng Lv, Xiuzhen Zhang, Zhaohui Mo, Wenying Yang, Lihui Zhang, Zhanjian Wang, Lvyun Zhu, Quanmin Li, Tao Yang, Wenbo Wang, Yaoming Xue, Yongquan Shi, Juming Lu, Yongde Peng, Fan Zhang, Dewen Yan, Damei Wang, Xuefeng Yu
Over the last few decades, specialized insulin analogs have been developed by altering the amino acid structure of recombinant human insulin to provide additional benefits in terms of stability and speed of action3. Insulin aspart, a rapid-acting insulin analog, has an amino acid substitution at position B28 (proline substituted with aspartic acid)6. This substitution decreases insulin hexamer formation and promotes depolymerization, resulting in peak glucose infusion rates that are higher and occur earlier compared with human insulin, allowing administration immediately before a meal7,8. Typical onset of action for insulin aspart is 10–30 min following administration, with peak efficacy at 1–2 h and duration of effect of 3–6 h8,9. Most commonly, fast-acting analogs are administered using insulin pens, but can also be given via syringe and insulin pumps3. Treatment with rapid-acting insulin analogs, including insulin aspart, leads to improved blood glucose management without increasing the rate of hypoglycemia. However, the expense of currently available insulin analogs can be prohibitive for many patients, particularly in middle and lower-income countries3,10.
A case of asymmetric insulin-derived localised amyloid deposition associated with long-acting insulin analog administration
Published in Amyloid, 2022
Keiji Hirai, Shigeki Imamura, Aizan Hirai, Naoka Umemoto, Hisashi Oshiro, Fuyuki Kametani, Nagaaki Katoh, Masahide Yazaki, Susumu Ookawara, Yoshiyuki Morishita
The absorption rates of insulin after subcutaneous injection differ according to the analog used. Insulin glargine, a long-acting insulin analog, forms stable oligomers of hexameric insulin in subcutaneous tissue, from which insulin monomers are slowly released over 24 h [4]. In contrast, insulin aspart, a rapid-acting insulin analog, dissociates rapidly into monomers in subcutaneous tissue and is absorbed within 5 h [5]. In this case, the patient had injected insulin glargine on his left side for 15 years and insulin aspart on his right side for 14.5 years, which resulted in subcutaneous amyloid deposition only in his left abdominal wall. Therefore, the difference in the disappearance time of the insulin analogs from the subcutaneous tissue might explain the discrepancy in the formation of insulin-derived amyloid in his subcutaneous tissue. In the previous reports, the type of insulin involved was not identified because of the complex history of insulin use [1]. In contrast, specific type of insulin was identified as culprit for subcutaneous amyloid deposition in our case. Further accumulation of similar cases is needed to clarify the relationship between the type of insulin and the formation of insulin-derived amyloid.
Improving the treatment of patients with diabetes using insulin analogues: current findings and future directions
Published in Expert Opinion on Drug Safety, 2021
Eveline Lefever, Joke Vliebergh, Chantal Mathieu
The PRONTO-Pump study compared the compatibility and safety of ultra-rapid-acting lispro versus insulin lispro in CSII and showed a trend to a higher time in range (3.94 − 10.0 mmol/L) for ultra-rapid-acting lispro (65.7% ± 1.3%) versus insulin lispro (63.0% ± 1.3%) with no difference in severe hypoglycemia [119]. In the Onset 5 study, the efficacy and safety of faster-acting insulin aspart were compared to insulin aspart in CSII. Non-inferiority was proven for faster-acting insulin aspart regarding change from baseline HbA1c but it was superior to insulin aspart in controlling change from baseline 1 h PPG increment after a meal test (ETD −16.4 mg/dL [95% CI] [−25.7; −7.0], p = 0.001) and reductions at 30 min and 2 h were statistically significant with similar rates of severe hypoglycemia [120].