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Vol. 17 Supplement 1

March 2020


The Discovery and Structure of Human Insulin

Chelsea Zimmerman, MD, Gregory Forlenza, MD, Desmond Schatz, MD



The isolation and purification of insulin nearly 100 years ago has been one of the most ground-breaking discoveries in the history of medicine. Subsequent determination of the specific structure of human insulin has permitted further developments and modifications of the formulations of insulin to allow improved quality of care and quality of life for patients with diabetes. In this
paper, we will review insulin structure and biosynthesis, treatment and prognosis of type 1 diabetes prior to insulin
therapy, experimentation leading to the discovery of insulin, and the first patients to be treated with insulin


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):131-137
doi: 10.17458/per.vol17.2020.zfs.discoverystructureinsulin


Eli Lilly and Company Insulins – A Century of Innovation

Malone JK, MD, Anderson JH, Jr., MD, Wolpert HA, MD, Ilag LL, MD, MS, Frank BH, PhD, De Felippis MR5, PhD, Paavola CD, PhD, Orr AL, MS, Beals JM, PhD



Eli Lilly and Company has played a pivotal role in the development of insulin products since its discovery in 1921. Through their dedication to pharmaceutical innovation, Josiah K. Lilly Sr. and George HA Clowes, in close collaborations with the University of Toronto, made insulin commercially available in 1923. Other innovations include the development and commercialization of the
first biosynthetic human insulin, a rapid-acting insulin analog and analog mixtures. Lilly has advanced the field
of knowledge with significant efforts toward developing a hepatic preferential basal insulin. Other important
insulin projects include the first concentrated rapid-acting insulin analog, clinical studies supporting the use of highly
concentrated human insulin, and an advanced clinical development program for an ultra-rapid insulin analog.
Lilly’s commitment to people affected with diabetes remains strong and will continue into the future through
collaborative research, innovative product development and investing in advanced technologies.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):138-160
doi: 10.17458/per.vol17.2020.jjh.elilillycompanyinsulin


Nearly a Century of Insulin at Sanofi: Looking Back Over the Decades of Production and Development

Zsolt Bosnyak, MD, PhD, Marcus Korn, PhD, Maximilian Bielohuby, PhD, Paulus Wohlfart, PhD, Norbert Tennagels, PhD



Almost a century ago, the first insulin was produced by Banting, Best, MacLeod and Collip in Toronto, thereby enabling life-saving treatment for people with diabetes. Since then, there have been many advancements in insulin production and development of new insulin analogues. In this article, we reflect on the rich heritage of Sanofi and its predecessor, Hoechst, in insulin production and development, from being one of the first companies to produce insulin in Europe in 1923, to modern-day insulin analogues and integrated care solutions at present-day Sanofi.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):161-169
doi: 10.17458/per.vol17.2020.bkb.sanoficenturyinsulin


Decision Support Systems for Insulin Treatment Adjustment in People with Type 1 Diabetes

Revital Nimri, MD



For people with type 1 diabetes, achieving optimal glycemic control requires use of intensive insulin therapy. To achieve this goal individuals are required to become proficient in accurately determining the appropriate amount of insulin needed to address a variety of situations throughout the day while considering numerous influencing factors. They also need to perform multiple tasks a day such as counting carbohydrates to accurately determine the required premeal bolus. There is also a need to periodically adjust insulin dosing as insulin sensitivity varies considerably over time. Sophisticated advanced technologies are being used by growing numbers
of individuals to manage diabetes. However, despite innovations in glucose monitoring technologies and new insulin formulations, many of these individuals are not achieving their glycemic goals. The new technologies provide ample amount of valuable diabetes related data that may complicate even further the insulin dosing decision making for people with diabetes as well as for the health care providers. Mobile health, digital tools and decision support systems can help to increase accurate, timely insulin dosing and insulin titration and holds the potential to improve glycemic control to a wide range of individuals with diabetes. The emerging mobile toolbox for insulin dosing adjustments that will be reviewed in this paper includes insulin management Apps; diverse range of Apps to guide insulin adjustments such as in times of physical activity and eating; data management systems which enable visualization and analysis of insulin and glucose data of various devices; real-time alarms and glucose prediction Apps that help to prevent hypoglycemia and hyperglycemia events; various bolus calculators for meal time dosing; sophisticated decision support algorithms for people using insulin pump, multiple insulin injections and closed loop systems for real-time and retrospective insulin dosing adjustments.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):170-182
doi: 10.17458/per.vol17.2020.n.insulintreatmenttype1diabetes


Insulin Adverse Events

Johnny Ludvigsson, MD PhD



The negative consequencies of diabetes treatment are traditionally regarded as caused by a disastrous treatment rather than adverse events of the insulin preparations. However, hypoglycemia, changes at the injection site (lipatrophy, lipoma), insulin allergy, obesity and increased risk of certain forms of cancer can easily be regarded as adverse events of the drug, and needle-phobia, psychological problems, increased risk of suicide are adverse events related to insulin and its administration. Also macroangiopathy and even microangiopathy to some extent can be regarded as adverse events as the most crucial part of the treatment of Type 1 diabetes is the insulin treatment.
There is still room for improvments of insulin as a drug. We need insulins with more predictable absorption and kinetics, leading to more stable near-normal blood glucose, less risk of hypoglycemia, less effect in periphery and more effect on the liver, and less risk of vascular complications, obesity, cancer.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):183-190
doi: 10.17458/per.vol17.2020.l.insulinadverseevents

Insulin: A Growth Hormone and Potential Oncogene

Zvi Laron, MD PhD (hc), Haim Werner, PhD



Both in vitro and in vivo experimental studies proved that insulin has an important anabolic role. This physiological function of insulin is reflected in its well documented involvement in protein metabolism and in acceleration of cell proliferation. Support for a growth promoting action of insulin is further provided by clinical studies that revealed that children with hypoinsulinemia have a decreased growth rate whereas, on the other hand, children with hyperinsulinemia have an accelerated growth. While it was initially assumed that the growth activities of insulin are facilitated via cross-talk with the closely related insulin-like growth factor-1 receptor (IGF-1R), it is now clear that the vast majority of these activities are mediated via direct interaction with the insulin receptor (IR). The present article provides an overview of the growth and proliferative actions of insulin, with an emphasis on a number of pathological conditions, including cancer.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):191-197
doi: 10.17458/per.vol17.2020.lw.insulinghpotentialoncogene


Update on Worldwide Trends in Occurrence of Childhood Type 1 Diabetes in 2020

Jaakko Tuomilehtoת MD, MA, PhD, FRCP (Edin), Graham D. Ogle, MBBS, FRACP, Nicolai Lund-Blix, MSc, PhD, Lars C Stene, MSc, PhD



Epidemiological data on pediatric type 1 diabetes (T1D), mainly incidence, have become increasingly available since the second half of the 20th century. Comparative incidence data across populations were only obtained since the 1980s. The 2019 IDF Atlas provides T1D incidence, prevalence and mortality estimates for children <15 years for all 211 countries, but actual data were available for only 94 countries (only 3 low-income). The estimated prevalent cases were 600,900 and incident cases 98,200. Incidence remains highest in Finland (60/100,000/ year), Sardinia and Sweden, followed by Kuwait, some other northern European countries, Saudi Arabia, Algeria, Australia, New Zealand, USA and Canada. The lowest incidence is seen across East and South-East Asia. Globally, the average increase in incidence has been 3-4%/year over past decades, being steeper in low-incidence countries. Although T1D mortality has drastically decreased, there is still a higher risk compared with the non-diabetic population, especially in people with diabetic nephropathy.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):198-209
doi: 10.17458/per.vol17.2020.tol.epidemiologychildtype1diabetes


Global Inequality in Type 1 Diabetes: a Comparison of Switzerland and Low-and Middle-Income Countries

Nilson Almeida Marques, BA, Maria Lazo-Porras, MD, Valérie Schwitzgebel, MD, Montserrat Castellsague, Georges Cimarelli, Mirjam Dirlewanger, MD, Philippe Klee, MD, PhD, Luz Perrenoud, David Beran, PhD



Globally it is estimated that over 1 million children and adolescents have Type 1 diabetes with large variations in incidence between different contexts. Health systems need to provide a variety of elements to ensure appropriate diabetes care, such as service delivery; healthcare workforce; information; medical products and technologies; financing and leadership and governance. Describing these elements between Geneva, Switzerland, a high-income country with high spending on healthcare and a large density of doctors, and low- and middle-income countries this article aims to highlight the global inequality of diabetes care. Type 1 diabetes can serve as a litmus as we move towards the centenary of the discovery of insulin and beyond as there is a need for a global movement to ensure that innovation in the management of diabetes benefits the whole diabetes community and not just a select few.


Ref: Ped. Endocrinol. Rev. 2020;17(Supp1):210-219
doi: 10.17458/per.vol17.2020.mps.type1diabetescomparison


History of Insulin Treatment in Children and Adolescents with Diabetes in Japan

Tatsuhiko Urakami, MD, PhD



For the increasing number of type 1 diabetes in Japan, after 1960, a greater supply of insulin was required, accordingly the availability of insulin gradually improved, The National Health Insurance approved self-injections of insulin at home in 1981. Afterwards, intensive insulin treatment with short-acting insulin and intermediate-acting insulin became widely used. Recombinant rapid-acting insulin analog was introduced in 1986 and long-acting insulin analog was introduced in 2003. In recent years, basal-bolus insulin regimens using these insulin analogs have become popular in children and adolescents with type 1 diabetes in Japan, which can improve the metabolic state and quality of life. This also will contribute to prevent the occurrence and progression of micro- and macro-vascular complications later in life.


Ref: Ped. Endocrinol. Rev. 2020;17(Suppl1):220-221
doi: 10.17458/per.vol17.2020.u.insulintreatchildadolescentjapan



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