The history of insulin development is seen from the intrinsic dynamics of new drug development

*For medical professionals only

After a hundred years of development, insulin is gorgeously "upgraded", and the future can be expected
.



In recent years, the incidence of diabetes has been increasing and has become a global health problem[1].

According to the International Diabetes Alliance[2], the total number of diabetic patients aged 20-79 in China will reach 140 million in 2021, ranking first in the world; the number of diabetes-related deaths in 2021 will reach 1.
4 million; and the total medical cost of diabetes will reach US$165.
3 billion.


As the most important endocrine hormone in the normal glucose metabolism process in the body, insulin occupies an important position in the treatment of diabetes [3
].
Nowadays, the treatment of diabetes has achieved remarkable results, on the one hand, new oral hypoglycemic drugs are emerging in an endless stream, and drug choices are gradually diversified; On the other hand, insulin is also developing innovations, from animal insulin to human insulin to insulin analogues, its effectiveness, safety and convenience are constantly improving
.
Although the rapid development of new target oral hypoglycemic drugs in recent years, the role and status of insulin in the treatment of diabetes is still irreplaceable, insulin is still the treatment method for patients with type 1 diabetes to survive, and it is also an effective means to control blood glucose and reduce the risk of complications in patients with type 2 diabetes (especially patients with a long course of illness) [4-5].


Times are changing, and the pace and spirit of exploration of medical research never stop
.
Professor Yang Wenying of China-Japan Friendship Hospital and Professor Mu Yiming of the PLA General Hospital will take us back to the history
of the development of insulin.








In 1921, the journey of insulin diabetes treatment officially began, and the journey of insulin diabetes treatment officially began
。 Canadian physician Frederick Banting and others successfully obtained insulin extract from the dog's pancreas and injected the extract into the dog whose pancreas was removed, and found that its blood sugar was reduced
.
In 1922, Frederick Banting et al.
first applied extracted insulin to the human body, and after more than 10 days of insulin treatment by 14-year-old diabetic patient Leonard Thompson, blood sugar dropped to normal levels, urine glucose and urine ketone bodies disappeared, and patients became happy and more energetic.
[6]
Since then, insulin has entered the stage of diabetes treatment, the history of diabetes treatment has been rewritten, and Frederick Banting and others have won the 1923 Nobel Prize
in Physiology or Medicine for the discovery of insulin.








The successful clinical application of the first revolution, the upgrade of animal insulin to human insulin, has
。 However, there is a significant deficiency
in insulin in animals.
For example, due to the inconsistency between animal insulin and the insulin molecular structure secreted by the human body, it is highly immunogenic, and it is easy to induce insulin antibodies, resulting in a large proportion of patients with fat atrophy at the injection site, and the individual difference in the hypoglycemic effect is large and unstable[7], in addition to the problem of insufficient production capacity [8].

With the advent and development of recombinant DNA technology, biosynthesis and mass production of human insulin have been made possible
.
In 1982, the first biosynthetic human insulin was approved for clinical use [9].

At this point, animal insulin gradually withdrew from the historical stage, and the era of clinical application of human insulin officially opened
.

Professor Yang Wenying pointed out that compared with animal insulin, human insulin is completely consistent with the molecular structure of insulin secreted by the human body itself, which greatly reduces immunogenicity and significantly reduces
local and systemic allergic reactions.








Another breakthrough - the leap from human insulin to insulin analogues, although human insulin makes up for the lack of insulin in animals, it is still unable to simulate physiological insulin secretion
。 Conventional human insulin is given subcutaneously relative to endogenous insulin, which has a slower onset of action as insulin at mealtime and cannot fully meet the needs of glucose control at mealtime; As basal insulin action time is short, it does not cover the need for basal glycemic control throughout the day [9].


In order to solve the above human insulin deficiency, insulin analogues came into being
.
Insulin analogues are based on human insulin, by altering amino acid structure or related modifications, changing the pharmacokinetic properties of insulin (including onset, peak, and duration of action), while preserving the biological properties and stability of insulin [10].









Gorgeous metamorphosis - the wisdom of combining the two into one, fish and bear paws can also be combined to obtain the ideal basic insulin should have a long action time and a flat pharmacodynamic curve, Basal insulin currently commonly used in clinical practice includes two dosage forms, medium and long acting [9,11-12
].

Ideal mealtime insulin should be as close as possible to the physiological pattern of insulin secretion during meals, with fast onset, rapid peaking, and short duration of action [3
].

Premixed insulin can provide both basal and prandial insulin, control postprandial blood glucose while taking into account the overall blood sugar, the scheme is simple and easy to operate, and it is widely used in diabetic patients in China [13].


Why do Chinese people have a special love for premixed insulin? Professor Yang Wenying said: "In the treatment process of diabetes, the number of injections and compliance are related, the more injections, the worse the compliance, and compliance directly brings about the improvement
of blood sugar.
" So, whether it is a doctor or a patient, we hope that we can ensure that the patient's compliance is good enough, but also reduce the number of injections, so that premixed insulin came into being
.
"
However, the emergence of premixed insulin meets the needs of clinical convenience, but there are also limitations such as the need for adequate mixing, short-acting/rapid-acting ingredients superimposed to produce a "shoulder effect", which needs to be further improved and improved
.
Clinically, there is also a desire to have a combination of insulin that can reduce the number of injections while providing longer-lasting and stable basal insulin with faster onset of action
.

In 2019, soluble double insulin - Degupton double insulin was approved for marketing in China and applied to the clinic, which is composed
of a fixed ratio of insulin deuterotonin and insulin aspart (7:3).
。 Professor Yang Wenying said that the half-life of insulin deuterotonin is up to 25 hours, the effect is flat, aspart insulin is a rapid-acting insulin analogue, whether in the preparation, or subcutaneously, the two components are independent and play their respective roles, simulating the biphasic monomodal of physiological secretion (Figure 1), which can avoid the "shoulder effect" of premixed insulin preparations, reduce the occurrence of hypoglycemia, and 1 to 2 injections per day can take into account fasting and postprandial blood sugar control, and there is no need to mix well when injecting [3].


Figure 1.
Degumendong double insulin glucose infusion rate curve biphasic single peak, two components do not interfere with each other "I once had a type 2 diabetic patient, nearly 80 years old, 4 injections of insulin per day, there is always hypoglycemia, I tried to replace him with
2 injections of degupton double insulin per day, the effect is very good, the patient no longer has hypoglycemia, blood sugar can basically reach the standard, no longer as much
fluctuation as before 。 This case left a deep impression on Professor Mu Yiming, and also made him affirm
the efficacy of Tokugamidon double insulin.

The Expert Guidance on the Clinical Application of Insulin Degutenton[14] states that Degustrostondiinin can provide basal and mealtime insulin in a single injection, with better glycemic control and no increased risk of hypoglycemia compared with basal insulin; The risk of hypoglycemia, the number of injections and doses is lower while achieving considerable efficacy compared to the basal-meal-time dosing regimen
.
Clinical evidence supports the use of insulin deuterotonate in a variety of clinical settings and can be used for initiation or intensification of insulin, and it is recommended that insulin degustor be used as one of the options for patients who initiate insulin therapy at the beginning of
oral drug failure or require insulin intensive therapy.

The latest edition of the 2020 edition of the China Guidelines for the Prevention and Treatment of Type 2 Diabetes[4] includes for the first time a double insulin analogue, alongside basal insulin and premixed insulin, while the only double insulin analogue currently on the market is TegumentonDouble insulin
.








The road to tomorrow - the road is obstructive and long, and the line is approachingAlthough insulin preparations have made great progress, insulin therapy still faces many challenges in clinical practical applications, In order to bring more effective treatment and a more comfortable experience to patients, the development of insulin is still moving forward [3].


Professor Mu Yiming sighed: "For diabetic patients, 3-4 injections of insulin every day, eat a lot of drugs, patient compliance is difficult to guarantee, in the long run, the incidence of chronic diseases will increase, we are eager for the future development of new drugs, so as to drive the improvement
of the entire diabetes treatment rate.
" "
The development of insulin preparations has been a 100-year walk
since the discovery of insulin in 1921.
The therapeutic philosophy, efficacy and safety of insulin are constantly being updated and developed
.
While inheriting the past, the development of new insulin preparations continues to run in many directions, trying to provide patients with more effective, safer and more convenient treatment options
.

We believe that with the further deepening of human understanding of diabetes, the research and development direction of new insulin preparations will become more and more colorful
.
At the same time, we also believe that one day, the treatment of diabetes will surpass all existing drug treatments, and human beings will eventually explore ways to cure the
disease.

Create a new pattern of diabetes treatment, the road is obstructive and long, the line is coming, we will forge ahead
.

References:

[1] GGE Mengjia,LIU Wanting,SUN Zhongzhong.
Evaluation and Analysis of Insulin in Hospitals,2021,21(09):1148-1152.
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1672-2124.
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030.

[2] International Diabetes Federation.
IDF Diabetes Atlas 10th edition[EB/OL].
[2022-05-12].
https：//diabetesatlas.
org/atlas/tenth-edition/.

Yu Xuefeng.
The Past, Present and Future of Insulin: Development and Application of Insulin Preparation[J].
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[4] Diabetes Branch of Chinese Medical Association.
Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)[J].
International Journal of Endocrinology and Metabolism,2021,41(05):482-548.

[5] American Diabetes Association; 9.
Pharmacologic Approaches to Glycemic Treatment:Standards of Medical Care in Diabetes—2021.
Diabetes Care 1 January 2021; 44(Supplement_1):S111-S124.
https://doi.
org/10.
2337/dc21-S009.

[6] Banting FG,Best CH,Collip JB,et al.
Pancreatic extracts in the treat-ment of diabetes mellitus[J].
Can Med Assoc J,1922,12(3):141-146.

GUO Xiaohui.
Educational management norms for insulin use in diabetic patients in China[M].
Tianjin:Tianjin Science and Technology Press,2011.

[8] Mu Yiming, Zhao Jiajun, Zhu Dalong, et al.
Expert opinion on the clinical use of human insulin and animal insulin[J].
Drug Review,2014,11(15):8-10.

[9] HIRSCH I B,JUNEJA R,BEALS J M,et al.
The Evolution of Insulin and How it Informs Therapy and Treatment Choices[J].
Endocr Rev,2020,41(5):733-755.

[10] KAHN C R,WEIR G C,KING G L,et al.
Joslin Diabetes[M].
14 edition.
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Beijing:People's Medical Publishing House,2007.
]

Ji Linong, Lu Juming, Zhu Dalong, et al.
Chinese expert guidance and recommendations on the clinical application of basal insulin in adult type 2 diabetes[J].
Chinese Journal of Diabetes,2017,25(1):2-9.

[12] Wang Xiaonan, Fu Ran, Li Ying, et al.
Research Progress in the Clinical Application of Degumann Double Insulin[J].
International Journal of Pharmaceutical Research,2020,47(10):809-813.

Liu Chao,Shi Lixin,Zhao Zhigang.
Expert consensus on clinical application of premixed insulin (2016 edition)[J].
Drug Review,2016,13(09):5-11.

Zhu Dalong, Zhao Weigang, Kuang Hongyu, et al.
Expert guidance on the clinical application of insulin degumenton[J].
Chinese Journal of Diabetes,2021,13(07):695-701.

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