"Nature": The 100th Anniversary of Insulin Discovery See Ten Monuments of Diabetes Treatment

This year marks the 100th anniversary of the discovery of insulin.

1922: The first discovery and first use of insulin

In 1921, Dr.

Subsequently, they worked with Canadian chemist James Bertram Collip to successfully purify insulin from pancreatic extracts and developed a method that can be mass-produced so that it can be used for patients

In 1922, Leonard Thompson, a 14-year-old patient with type 1 diabetes, received an insulin injection and his symptoms improved

This discovery inspired the rapid progress in the use of insulin to treat type 1 diabetes

1965: Study on the islet pathology of diabetes

Although the discovery of insulin has brought revolutionary changes to the treatment of diabetic patients, the pathophysiological mechanism of diabetes has still not been clarified in the following decades

This histological feature is different from that of late-onset diabetes (type 2 diabetes).

These studies of patients with early-onset diabetes helped to reveal the pathological process that occurs in the pancreatic islets of diabetic patients, and ultimately led to the birth of new therapies that improve the prognosis of patients

1978: Pioneer Study of Diabetes Complications

In the middle of the last century, people have realized the connection between diabetes and a series of degenerative diseases including neuropathy, retinopathy and kidney disease

1979: The birth of synthetic human insulin

After insulin was discovered in 1921, the use of pig or bovine insulin to control blood sugar has been widely used, saving the lives of many patients

With the development of recombinant DNA technology, in 1979, Genentech's research team published a paper on PNAS, reporting for the first time the successful synthesis of human insulin

The US FDA approved synthetic insulin for the market in 1982

1987: Reveal the role of incretin

The concept that the intestine can secrete factors that stimulate the release of insulin after ingestion of nutrients emerged in the beginning of the last century

In 1987, two important papers verified the relationship between glucagon-like peptide (GLP) and insulin secretion

We now know that GLP-1 has a variety of functions, including inhibition of glucagon secretion in pancreatic islets, gastric emptying and eating, and stimulation of beta cell proliferation

Research on incretin has stimulated the development of a variety of diabetes therapies based on increasing GLP-1 levels or simulating GLP-1 function.

1997: Daqing study reveals the impact of a healthy life>

Obesity is an important risk factor leading to type 2 diabetes
.
In the past half century, the outbreak of type 2 diabetes has been paralleled by the obesity epidemic
.
Although innovative therapies have shown significant effects in the control of type 2 diabetes, one of the important means to reduce the global burden of disease is to prevent the occurrence of diabetes
.

In 1986, the first large randomized controlled trial aimed at reducing the incidence of type 2 diabetes through behavioral interventions (including healthy eating and/or exercise) was launched in Daqing, China
.
The researchers enrolled 577 individuals with impaired glucose tolerance and randomly entered the control group (n=138), or received one of three life interventions (n=438): diet, exercise, or diet plus exercise, with an expectation of 6 years
.

After 6 years, the cumulative probability of developing type 2 diabetes in the control group was 67.
7%, compared with 43.
8% in the diet group, 41.
1% in the exercise group, and 46% in the exercise+diet group
.
This study shows that healthy eating and/or exercise can reduce the risk of type 2 diabetes
.

In 2019, the 30-year follow-up results of the Daqing Diabetes Prevention Study were published in The Lancet
.
The study showed that compared with the control group, the median delay time of diabetes onset in the combined intervention group was 3.
96 years, and the risk of onset was reduced by 39% (HR 0.
61, 95% CI 0.
45–0.
83; p=0.
0015)
.

2006: Towards stem cell therapy for the treatment of diabetes

In 1998, the birth of the first human embryonic stem cell line opened up the possibility of using stem cell therapy to treat many diseases
.
Type 1 diabetes is particularly suitable for this strategy.
Transplanting insulin-producing pancreatic β-cells into patients may provide long-term therapeutic treatments and even the possibility of cure
.

In 2006, the research team of Novocell (now Viacyte) published a paper in Nature Biotechnology, describing the process of differentiation of human embryonic stem cells into endocrine islet cells that can secrete various hormones such as insulin and glucagon
.

In 2008, the team transplanted human embryonic stem cell-differentiated pancreatic islet endoderm into mice, successfully differentiated glucose-sensitive endocrine cells in the animal body, and proved that these cells can help mice resist high blood sugar
.

2014: The "artificial pancreas" system changes the lives of patients

For patients with type 1 diabetes, controlling blood glucose levels within the normal range can delay or prevent complications
.
However, for patients, testing their blood sugar multiple times a day and calculating the insulin dosage based on the blood sugar level is a major burden of life
.

Continuous advances in blood glucose monitoring systems and advanced insulin delivery systems have allowed scientists to finally develop an "artificial pancreas" system that combines blood glucose monitoring and insulin delivery.
This system calculates the amount of insulin through an algorithm and automatically administers it.
Reduce the burden on patients
.

▲Illustration of "artificial pancreas" (picture source: reference [3])

In 2014, a randomized crossover clinical trial showed that a wearable "artificial pancreas" system that can automatically deliver insulin or glucagon provides better results for adolescents and adults with type 1 diabetes compared with insulin pumps.
Blood sugar control
.

There are already several "artificial pancreas" systems that have received regulatory approvals to be marketed in the United States and Europe
.
More systems are being tested in large-scale clinical trials, and it is expected that more patients will reduce their daily burden of managing diabetes
.

2016: The role of incretin drugs in controlling blood sugar

In the past 15 years, drugs targeting incretin (including GLP-1) have become a class of effective blood sugar control drugs
.
Based on the role of GLP-1 in regulating blood sugar, a variety of GLP-1 receptor agonists have been developed to lower blood sugar in patients with type 2 diabetes
.
They include albiglutide, liraglutide, dulaglutide and semaglutide based on GLP-1; and exendin 4 based exercise and lixisenatide
.

A systematic review and comparative analysis published in 2016 showed that GLP-1 receptor agonists are well tolerated
.
Moreover, the results of a number of clinical trials have shown that compared with placebo, GLP-1 receptor agonists can reduce the risk of atherosclerotic cardiovascular disease and the risk of kidney disease in patients with type 2 diabetes
.

The latest results show that these drugs also have the potential to treat type 2 diabetes
.
For example, semaglutide has recently received FDA approval for the treatment of obesity and overweight patients
.
It has also shown gratifying effects in clinical trials for the treatment of patients with non-alcoholic steatohepatitis
.

2019: The role of a new generation of hypoglycemic therapy in reducing cardiovascular disease

In 2008, the US FDA and EU EMA issued guidelines stating that diabetes drug developers need to more fully evaluate the cardiovascular safety of drugs under investigation during the development process
.

In 2015, the SGLT2 inhibitor empagliflozin was shown to significantly reduce the risk of composite cardiovascular outcomes in the EMPA-REG clinical trial
.
Since then, other SGLT2 inhibitors have also shown cardiovascular benefits in clinical trials
.

A meta-analysis published in 2019 showed that in 3 large clinical trials involving 34,322 patients, different SGLT2 inhibitors reduced the incidence of major adverse cardiovascular events (MACE) by 11%
.
In addition, SGLT2 inhibitors have also shown benefits in reducing the risk of chronic kidney disease (CKD)
.
These benefits were subsequently verified in patients with heart failure and chronic kidney disease who do not have type 2 diabetes
.

Another meta-analysis released in 2019 found that GLP-1 receptor agonists can also reduce the incidence of MACE by 12% in multiple clinical trials
.

These new benefits of the new generation of hypoglycemic therapy have brought revolutionary changes to the management of type 2 diabetes, provided patients and doctors with more choices, and reduced the burden of chronic complications caused by diabetes
.

The "Nature" website also lists other important breakthroughs in the course of diabetes research, including elucidating the autoimmune mechanism of type 1 diabetes, discovering genetic factors that affect type 2 diabetes, and so on
.

Reference materials:

[1] Milestones in diabetes.
Retrieved June 17, 2021, from https:// CLONING INSULIN.
Retrieved June 17, 2021, from https:// Boughton and Hovorka, (2019).
Advances in artificial pancreas systems.
Science Translational Medicine, DOI: 10.
1126/scitranslmed.
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