Commemorating insulin's centennial: engineering insulin pharmacology towards physiology

Pharmacokinetically tailored insulin has been rationally designed by molecular structural engineering and/or pharmaceutical formulation to improve glucose control and convenience for people with diabetes.Novel mechanisms protracted action based on reduced plasma clearance hold promise enable once-weekly subcutaneous once-daily oral basal delivery.Hepato-preferential analogs can be tailoring size receptor affinity provide more physiological replacement.Successful delivery achieved in early clinical trials but is still hampered low bioavailability.Clinical have initiated glucose-sensitive chemically engineered switch between active inactive conformations or undergo glucose-dependent clearance, thus giving hope that a 'smart insulin' within reach. The life-saving discovery of Toronto 1921 one the most impactful achievements medical history, at time being hailed as miracle treatment diabetes. molecule itself, however, poorly amenable pharmacological intervention, formidable challenge optimizing therapy ongoing century. We review academic insights into structure its relation self-association binding, well recombinant biotechnology, which all seminal drug design. Recent developments focused combining genetic chemical optimization generate ultra-rapid ultra-long-acting, tissue-selective, orally delivered analogs. further discuss these propose future scientific efforts include realizing dream glucose-responsive delivery. year 2021 marks centennial 1921, momentous event modern medicine. Over past 100 years we come know not only medicine diabetes also complex agent narrow therapeutic window (see Glossary). Every decade had innovative highlights, testifying across disciplines collectively brought us current state (Figure 1). These improvements driven inherent dosing (s.c.) precisely match constantly changing requirement over day, where rapid required during meals whereas slow steady necessary – especially night. Therefore, overarching goal century apply formulation, engineering, technology make it possible mimic natural patterns release from pancreatic β cells closely reduce spent either hyper- hypoglycemia. Nevertheless, despite innovations, overall level glycemic type 1 (T1D) 2 (T2D) far normalized (Box This calls continued research focus aiming optimize options diabetes.Box 1FAQs facts about therapyWho need therapy?As 2019, an estimated 463 million are living [101.International Diabetes Federation IDF Atlas.9th edn. IDF, 2019Google Scholar]. T1D condition autoimmune destruction insulin-producing cells. require treatment. vast majority (~90%) T2D due failing cell function, often linked resistance. initially managed lifestyle adaptations, antidiabetic agents, injectable GLP-1 However, because progressive nature T2D, many will eventually [2.Basu S. et al.Estimation global use diabetes, 2018–30: microsimulation analysis.Lancet Endocrinol. 2019; 7: 25-33Abstract Full Text PDF PubMed Scopus (53) Google 'rule halves' [102.Hart J.T. Rule halves: implications increasing diagnosis reducing dropout workload prescribing costs primary care.Br. J. Gen. Pract. 1992; 42: 116-119PubMed Scholar] illustrates optimal small fraction diagnosed achieve adequate IA) [48.Bain S.C. al.Evaluating burden poor associated inertia patients UK.J. Med. Econ. 2020; 23: 98-105Crossref (5) Scholar].Why challenging?Physiological secretion pancreas exquisitely regulated such right amount present exactly when needed IB). S.c. administration native human unable fast appearance meals, nor sufficiently flat long 24 h coverage. modified formulations give absorption injection site mealtime coverage, respectively. mismatches occur, opt miss their dose avoid hypoglycemia, leading less than control. In addition, who delay initiation (clinical inertia) owing perceived complexity, fear concerns weight gain daily [47.Russell-Jones D. al.Identification barriers approaches overcoming them.Diabetes Obes. Metab. 2018; 20: 488-496Crossref (87) Scholar].What consequences metabolic control?Whether result undiagnosed, receiving care, delaying intensification, adhering prescribed medications, leads long-term complications risk death. Poor microvascular affect organs, notably kidneys, eyes, nerves, while regulation, including dyslipidemia, results damage cardiovascular system macrovascular IC) Scholar,103.American Association Cardiovascular disease management: standards care 2021.Diabetes Care. 2021; 44: S125-S150Crossref (16) Scholar,104.American Microvascular foot care: S151-S167Crossref Scholar].Figure IComplexity treatment.Show full captionAbbreviation: Panel B adapted, permission, [105.Polonski K.S. al.Twenty-four-hour profiles pulsatile normal obese subjects.J. Clin. Invest. 1988; 81: 442-448Crossref Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) Who therapy? As Why challenging? Physiological What control? Whether revealed storage same applied modify pharmacokinetics pharmacodynamics. Hence, today's used millions [1.Mobasseri M. al.Prevalence incidence world: systematic meta-analysis.Health Promot. 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