Insulin Past, Present, and Future: 100 Years from Leonard Thompson

Round 1

Reviewer 1 Report

A very thorough review of the topic by an expert with a strong understanding of the history of the topic.  My only question is the copyright for the figures/images, but that is an editorial concern, not the reviewers.  Also, I assume that there is not a page limit as this was a requested submission.

Author Response

Thanks so much for your review and comments.  I believe all the figures and pictures were identified in the text and/or refences. The length has been less of a concern since this will be an e-publication where no added page costs involved vs print publication as well as potential for more widespread availability and sharing with medical students, residents, fellows and senior staff around the world.  

Reviewer 2 Report

Might need a bit of reworking. The historical paragraphs are a little heavy for the general reader . Could they be summarised by a shortr paragraph listing all these prior workers by name  and their contributions summarised as a table  

1890-1916 Nicolae Paulescu in Bucharest , extracted pancreatine but experiments not consistent / reproducible

1900, George Zuelzer in Berlin patented pancreatic extraction procedures after treating several dogs and then 5 humans - but feared hypoglycaemia ++ and stopped 

1906 De Meyer in Belgium,  proposed concept of "insuline " etc

prescribing practice : As a review paper, notwithstanding the fine work at NEDEC, maybe a broad sweep of how prescribing changes ensued after DCCT, and how they have not changed despite evidence ...so its also relevant to an international audience , and not so much on individual practices 

Development of insulins old and new : 

In this segment on the fast analogues  like the segment on super flat analogues, it would make sense to include insulins that have made it to market in major jurisdictions , whether or not they are sold in the USA

Short acting - you did not mention some of the newer insulins 

Lispro 

Aspart 

Insulin Glulisine

FiAsp

Fast Lispro

Halozyme 

Long acting - many younger docs did not realise that the zinc insulins were widely used and what their pros and cons were, or why the NPH was still not great compared to Lantus / Detemir ( eg as showed by the Hesse, 2004 paper ) 

PZI 

NPH

Lantus 

Detemir

Tresiba

Tujeo 

smart insulins ( glycemia controlled release 

Inhaled insulins 

Oral insulin 

======

For the section on pumps and CGMS ; 

this whole section could be done as a  review of the assistive technology to get the right amount of insulin to be delivered at the right time 

Eg CGMS helped fill in the data gaps and enabled patient and health care provide to realise where the highs and lows were clustering , so adjustments could be made

Pumps enabled more varied basals and more targetted boluses without having to give multiple injections a day , while the advent of first reactive, then  predictive auto stop and now the closed loop pumps further  reduce the risks of hypoglycemia 

Education is an enabler of right prescribing practice, without which the best insulins cannot have an effect... Dr Brink you as Sec Gen and then President of ISPAD awere responsible for promulgation of many education programmes to promote best pratices and the ISPAD guidelines in its many editions, not to mention the innumerable websites of national diabetes organisations, all of which draw on each other's best practices and modify for local use .

Author Response

Thanks for your review and commentary.  I've added some of the newer insulin and biosimilar information as suggested and will add a sentence, as suggested, about education (and psychosocial support) being enablers of improved prescribing practice to optimize insulin's efficacy. 

Reviewer 3 Report

This is a very timely and extensive review of the history of insulin treatment in a global perspective focusing particularly on issues related to pediatric diabetes at the time of the 100 years anniversary when the first child was treated. A couple aspects for improvement are suggested below in particular to include a couple more recent publications related to new developments in the field.

• The title appears to be truncated, consider change: Insulin Past, Present and Future: 100 Years from the after the first patient Leonard Thompson

• According to the instructions to the authors the abstract should be a total of about 200 words maximum and has currently 347. A shortened version with 226 words could look like this:

Before the discovery of insulin and the critical role of the pancreas vis-à-vis diabetes mellitus pathophysiology, childhood diabetes or what we now call type 1 diabetes mellitus was almost universally fatal. In limited resource countries around the world this remains sadly true because of the expense and unavailability of medical care, medical information and/or medications. Banting, Best, MacLeod and Collip in Toronto in 1921 successfully treated pancreatectomized dogs with an alcohol based pancreatic extract, and then were the first to do the same with children and adults with diabetes, starting with Leonard Thompson in early 1922. Progressive biopharmaceutical advances have modified insulin from pigs and cows and then genetically engineered insulin to work much faster and also much slower to provide more modernized ways of providing insulin. Insulin pens then replaced vial and syringe administration and then insulin pumps coupled with continuous blood glucose sensors have made delivery more physiologic in addition to more attention paid to nutrition advice, education and psychosocial support around the world. Programs to assist delivery of expensive insulin to limited resource countries administered by Insulin for Life, Life for a Child, Changing Diabetes in Children coupled with support by the International Society for Pediatric and Adolescent Diabetes have continued to make such advances available thorough wonderful philanthropy in insulin manufacturers and manufacturers of blood glucose monitoring equipment and insulin pump/sensor suppliers.

• Line 383 add reference to the role of insulin also for autoimmunity and potential cure:

This review focusses on the impact of the development of human insulin, insulin analogs, devices, and the treatment and educational approaches eventually leading to automated insulin delivery. However, one should not forget that insulin is the primary autoimmune target of type 1 diabetes in children and novel approaches of immunotherapy using insulin for immune tolerance induction are investigated. Potentially modern vaccines could remove the need for another 100 years of insulin therapy in the future (Ziegler AG, Danne T, Daniel C, Bonifacio E. 100 Years of insulin: Lifesaver, immune target, and potential remedy for prevention, Med (2021),https://doi.org/10.1016/j.medj.2021.08.003)

• Line 1432. Add references to the recent clinical trials of ultrapid insulins:

Clinical trials of the two currently commercially available ultra-rapid insulins faster aspart (FiAsp® from Novo) (Bode BW, Iotova V, Kovarenko M, Laffel LM, Rao PV, Deenadayalan S, Ekelund M, Larsen SF, Danne T. Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec, in Children and Adolescents With Type 1 Diabetes: The onset 7 Trial. Diabetes Care 2019;42:1255-1262)and trepostinil lispro (from Lilly: Liumjev®) (Warren M, Bode B, ChoJI, Liu R, Tobian J, Hardy T, Chigutsa F, Phillip M, HorowitzB, Ignaut D^. Improved postprandial glucose control with ultra rapid lispro versus lispro with continuous subcutaneous insulin infusion in type 1 diabetes: PRONTO-Pump-2. Diabetes Obes Metab 2021;23:1552-1561) )have indicated better postprandial control.

• Remove the passage line 1472-1482 and remove Fig 62 (maybe replace with an icodec figure) as peglispro insulin development has been discontinued by Lilly.

• Instead consider adding a paragraph on third generation basal analogs:

Insulin icodec is a novel basal insulin analog intended for once-weekly administration. Although this is aimed primarily at treating type 2 diabetes (Rosenstock J, Bajaj HS, Janež A, Silver R, Begtrup K, Hansen MV, Jia T, and Goldenberg R.Once-weekly insulin for Type 2 diabetes without previous insulin treatment. N Engl J Med 2020; 383:2107-2116), studies in type 1 diabetes are also ongoing. The molecular engineering behind this analog includes three amino acid substitutions (A14Glu, B16His, B25His) which results in reduced insulin receptor affinity and clearance, and a 20-carbon fatty diacid moiety attached via a hydrophilic linker leading to durable binding to circulating albumin and very protracted release. With these modifications, the half-life of icodec has been extended to about 8 days with a flat and stable pharmacokinetic profile, low peak-to-trough variations and evenly distributed glucose-lowering efficacy within a weekly dosing interval (Kjeldsen TB, Hubalék F, Hjørringgaard CU, et al: Molecular engineering of insulin icodec, the first acylated insulin analog for once-weekly administration in humans. J Med Chem 2021; 64:8942-8950). Lilly also presented first data at the on their weekly basal insulin Fc (BIF), a fusion protein that combines a novel-signal chain variant of insulin with a human IgG Fc domain. It is claimed that BIF is a selective insulin receptor agonist with > 100fold selectivity versus the IGF1 receptor and leads to a prolonged glucose lowering effect for up to 10 days (Frias JP, Chien J, Zhang Q, et al: Once weekly basal insulin Fc (BIF) is safe and efficacious in patients with type 2 diabetes mellitus (T2DM) previously treated with basal insulin. J Endocrine Soc 2021; 5 (Suppl 1): p A448).

• Line 1509 add the aspect of diabetes registries:

The worldwide SWEET project was developed under the auspices of ISPAD and has now more than 150 participating centers on all continents with a vision to harmonizing care to improve outcomes on the basis of registry data. Twice yearly benchmarking over 10 years was associated with significantly improved HbA1c and reduced hypoglycemia rates on a background of increasing pump and sensor use in young persons with T1D (Gerhardsson P, Schwandt A, Witsch M, Kordonouri O, Svensson J, Forsander G, Battelino T, Veeze H, Danne T, on be half of the SWEET study group. The SWEET project: benchmarking over 10 years is associated with improved HbA1c and increased use of diabetes technology in youth with type 1 diabetes from 19 countries worldwide. Diab Tech Ther 2021 Feb 26. doi: 10.1089/dia.2020.0618.)

• Line 1516 consider to mention the issue of biosimilar insulins which are another approach to fight insulin cost:

In 2015, the first available biosimilar was launched in the EU and the US under the names Abasaglar^® (EU) and Basaglar^® (US). From a global perspective, biosimilar insulins are starting to have an impact on the insulin market as more companies come to the market with their biosimilar insulins although a number of barriers remain (Godman B, Haque M, Leong T, Allocati E, Kumar S, Islam S, et al. The Current Situation Regarding Long-Acting Insulin Analogues Including Biosimilars Among African, Asian, European, and South American Countries; Findings and Implications for the Future. Front Public Health. 2021;9:671961).

Author Response

Thanks for the comments and review.  Will remove peglispro and replace with icodec information as suggested. Also will enhance SWEET data as suggested, will add specific information on biosimilars vis-a-vis lower costs and potential greater availability and add information about the potential of autoimmune tolerance re: insulin currently under investigation.