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Design of Non-Standard Insulin Analogs for the Treatment of Diabetes Mellitus

  • Technological Development in Diabetes Therapies (S Russell, Section Editor)
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Abstract

Structure-based protein design has enabled the engineering of insulin analogs with improved pharmacokinetic and pharmacodynamic properties. Exploiting classical structures of zinc insulin hexamers, the first insulin analog products focused on destabilization of subunit interfaces to obtain rapid-acting (prandial) formulations. Complementary efforts sought to stabilize the insulin hexamer or promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus; Sanofi-Aventis, Paris, France) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir; Novo-Nordisk, Basværd, Denmark). In the past year second-generation basal insulin analogs have entered clinical trials in an effort to obtain ideal flat 24-hour pharmacodynamic profiles. The strategies employ non-standard protein modifications. One candidate (insulin degludec; Novo-Nordisk a/s) undergoes extensive subcutaneous supramolecular assembly coupled to a large-scale allosteric reorganization of the insulin hexamer (the TR transition). Another candidate (LY2605541; Eli Lilly and Co., Indianapolis, IN, USA) utilizes coupling to polyethylene glycol to delay absorption and clearance. On the other end of the spectrum, advances in delivery technologies (such as microneedles and micropatches) and excipients (such as the citrate/zinc-ion chelator combination employed by Biodel, Inc., Danbury, CT, USA) suggest strategies to accelerate PK/PD toward ultra-rapid-acting insulin formulations. Next-generation insulin analogs may also address the feasibility of hepatoselective signaling. Although not in clinical trials, early-stage technologies provide a long-range vision of “smart insulins” and glucose-responsive polymers for regulated hormone release.

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Acknowledgments

This work was supported by grants from the National Institutes of Health and American Diabetes Association to one of the authors (M.A.W.). V.P. is a predoctoral fellow of the NIH Medical Scientist Training Program at the CWRU School of Medicine and is supported by NIH Fellowship F30DK094685-02.

Disclosure

Conflicts of Interest: The intellectual property pertaining to zinc-stapled human insulin analogs and its long-acting formulations are owned by Case Western Reserve University and licensed to Thermalin Diabetes, LLC. M.A. Weiss: holds shares in and is Chief Scientific Officer of Thermalin Diabetes, LLC.; he has also been a consultant to Merck, Inc. and the DEKA Research and Development Corp.; V. Pandyarajan: none. The authors otherwise declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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  1. Department of Biochemistry, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    V. Pandyarajan & M. A. Weiss

  2. Department of Biomedical Engineering, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    M. A. Weiss

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Pandyarajan, V., Weiss, M.A. Design of Non-Standard Insulin Analogs for the Treatment of Diabetes Mellitus. Curr Diab Rep 12, 697–704 (2012). https://doi.org/10.1007/s11892-012-0318-z

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