November 30, 2022

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24 important milestones in the fight against diabetes in the past 100 years

24 important milestones in the fight against diabetes in the past 100 years



 

24 important milestones in the fight against diabetes in the past 100 years

Today (November 14) is United Nations Diabetes Day. It is worth mentioning that this year coincides with the 100th anniversary of the discovery of insulin.

In the past 100 years, scientists have gained a more in-depth understanding of the pathogenesis of different types of diabetes, which has also brought considerable progress in patient care.

In June 2021, the “Nature” website introduced 24 important milestones in the history of diabetes research over the past 100 years.

 

This article will briefly introduce these important milestones to pay tribute to doctors, scientists, patients, biomedical companies and other people from all walks of life who have contributed to the treatment of diabetes!

 

1. 1922: The first discovery and first use of insulin

In the early 1920s, scientists identified and purified a pancreatic extract-insulin. In 1922, Leonard Thompson, a 14-year-old patient with type 1 diabetes, received an insulin injection and his symptoms improved.

Researchers pointed out in a paper published in 1922 that these results undoubtedly indicate that pancreatic extract has therapeutic value for some type 1 diabetes patients.

Subsequently, insulin was successfully used to regulate the blood sugar levels of patients with type 1 diabetes, completely changing the way these patients were treated.

In 1923, Dr. Frederick Banting and physiologist John Macleod won the Nobel Prize in Physiology or Medicine for their research on insulin.

 

2. 1965: Study on the islet pathology of diabetes

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

In 1965, an important histological study found that in patients with early-onset diabetes (later called type 1 diabetes), insulin-secreting β-cells were greatly reduced, and most patients with acute diseases had inflammation around and in the islets of the pancreas.

Sexual infiltration, which means that β cells are being attacked by “foreign factors”. This histological feature is significantly 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.

 

3. 1974: Revealing that HLA genes are genetically related to type 1 diabetes

In 1974, an article published in The Lancet proved that the types of HLA proteins present on white blood cells are related to the occurrence of type 1 diabetes and the occurrence of anti-pancreatic autoantibodies in patients, thus confirming that HLA genes are related to the inheritance of type 1 diabetes.

 

4. 1978: Discovered an animal model of type 1 diabetes

BB rats and non-obese diabetic (NOD) mice are two animal models of type 1 diabetes, and they will develop type 1 diabetes spontaneously. These animal models make it possible to study the underlying mechanisms of the onset and progression of type 1 diabetes, as well as the development of therapeutic interventions.

 

5. 1978: Groundbreaking research on complications of diabetes

In the middle of the 20th century, people have realized the connection between diabetes and a series of degenerative diseases including neuropathy, retinopathy and kidney disease.

However, the precise link between these complications and blood sugar control has not received enough attention. In 1977, Jean Pirart, a Belgian doctor, published the results of a 30-year pioneering longitudinal study.

The study analyzed the blood sugar control and complications of 4398 diabetic patients (this study was first published in French in 1977 and translated into English in 1978).

In the first 25 years of the study, a total of nearly 21,000 examinations were performed on these patients.

The results of this study reflect the association between blood sugar control status and complications, and show the promise of reducing the risk of complications by controlling blood sugar.

 

6. 1979: The birth of synthetic human insulin

The discovery of insulin The use of pig or bovine insulin to control blood sugar has been widely used, saving the lives of many patients. However, insulin extracted from animal pancreatic islets has many limitations. They have uneven effects in controlling blood sugar and may cause allergic reactions.

This is mainly due to the patient’s immune system producing antibodies against insulin.

In 1979, Genentech’s research team published a paper on PNAS, reporting for the first time the successful synthesis of human insulin. In subsequent clinical trials, artificially synthesized human insulin not only showed a blood sugar lowering effect similar to animal insulin, but also showed good safety.

In 1982, the US FDA approved the marketing of synthetic insulin, providing patients with a form of insulin with lower immunogenicity.

 

7. 1982: Discovery of insulin autoantibodies

In 1982, researchers identified the first autoantigen: the ~64kDa isoform of glutamate decarboxylase (GAD65). Using the immunoprecipitation experiment, the researchers at the time analyzed the sera of 10 newly diagnosed children with type 1 diabetes, and identified autoantibodies against this islet protein in 8 of them.

Insulin autoantibodies can be used for the prediction and diagnosis of type 1 diabetes.

The discovery of pancreatic islet cell antibodies and their various targets provides evidence that type 1 diabetes is an autoimmune disease, and at the same time promotes the development of disease prevention research and antibody detection, and it is still used today.

 

8. 1986: Discovery of cytokines directly related to type 1 diabetes

In 1986, a study published in the journal Science showed that the cytokine IL-1 has a direct role in mediating β-cell death. This discovery heralds a new understanding of insulitis-related mechanisms and provides a new method for targeted therapy.

 

9. 1987: Reveal the role of incretin

In 1987, two important papers verified the relationship between glucagon-like peptide (GLP) and insulin secretion. Researchers used artificially synthesized and extracted GLP-1 fragments from animals and found in in vitro experiments that they can stimulate insulin secretion.

These studies laid the foundation for further exploration of the function of GLP-1 in glucose homeostasis, and ultimately promoted the application and development of incretin-based therapy in the treatment of type 2 diabetes.

 

10. 1988: Discovery of glucose transporter 4 (GLUT4)

A study published in the journal Nature in 1988 showed that the insulin-stimulated glucose transporter in muscle and adipose tissue is molecularly different from the previously reported glucose transport system.

The following year, the gene encoding this unique transporter was cloned, and several different laboratories mapped the location of its chromosomes. In order to reflect its similarity with the cloned GLUT1-3 glucose transporter, the protein is called GLUT4.

 

11. 1992: Discovery of monogenic diabetes

In the early 1990s, genetic linkage analysis studies identified a new form of diabetes-monogenic diabetes, which is a disease caused by a single gene mutation that interferes with the function of β cells.

This discovery is considered an important milestone in the field because it has a profound impact on the clinical care and prognosis of patients.

 

12. 1993: TNF can block insulin receptor signaling

In two papers published in 1993 and 1995, scientists found that the pro-inflammatory cytokine tumor necrosis factor (TNF) was up-regulated in the adipose tissue of obese animals and obese humans, and blocking TNF could improve insulin sensitivity in obese animal models sex.

After that, a 1996 study also established the molecular basis of TNF-driven insulin resistance.

 

13. 1993: Blood sugar control can prevent diabetes complications

Complications of type 1 “insulin-dependent” diabetes include sequelae of capillaries, nerves, and large vessels. In 1983, the Diabetes Control and Complications Trial (DCCT) began to recruit patients to check whether intensive treatment can improve the prognosis of patients with type 1 diabetes.

Intensive treatment is to use an external pump or inject insulin 3 or more times a day to keep blood sugar within the non-diabetic range as safely as possible. In 1993, the results of diabetes control and complications trials were announced.

The trial showed that intensive treatment significantly reduced the complications of diabetes.

The announcement of the results of this trial marks that intensive treatment has become the new standard treatment for patients with insulin-dependent diabetes.

 

14. 1995: The role of bariatric surgery in type 2 diabetes

A study published in 1995 showed that a group of obese patients who underwent bariatric surgery had significantly improved symptoms of type 2 diabetes. At present, bariatric surgery is still one of the most effective treatment options for this disease.

 

15. 1997: Daqing study reveals the influence of healthy lifestyle on the prevention 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, or received one of the three life intervention measures of diet, exercise, or diet plus exercise.

The intervention was expected to be 6 years. In 1997, a Daqing study reported that compared with placebo, individuals with impaired glucose tolerance had a statistically significant reduction in the incidence of type 2 diabetes after 6 years of diet and/or exercise behavior intervention.

In 2019, the 30-year follow-up results of the Daqing Diabetes Prevention Study were published in the sub-Journal of The Lancet. Studies have shown that, compared with the control group, the median delay in the onset of diabetes in the combined intervention group was 3.96 years, and the risk of onset was reduced by 39%.

 

16. 2000: Discovery of genetic genes for type 2 diabetes

In 2000, researchers published a groundbreaking gene association study, which confirmed that PPARG is a susceptibility gene for type 2 diabetes.

At present, research in this field has made great progress, and more than 550 risk signals of type 2 diabetes have been identified.

The valuable knowledge gained from these genetic factors has been used in the research of disease mechanisms and treatments, and may become the basis of precision medical methods in the future.

 

17. In 2002: CD3 specific antibodies were first shown to slow down the loss of β-cell function in type 1 diabetic patients

In 2002, Kevan Herold et al. published the results of a small clinical trial. The subjects of the study were patients who were recently diagnosed with type 1 diabetes. They received an escalating dose of the CD3-specific monoclonal antibody teplizumab within two weeks.

The study found that patients who received a single short-term treatment with CD3 monoclonal antibody showed a slower deterioration in β-cell function within 12 months. In addition, the study also found that relatively low-dose CD3 monoclonal antibody treatment seems to have a lasting effect on the immune response, indicating that it is possible to “reconnect” the immune response to a tolerable state.

In 2005, other researchers conducted a larger phase 2 study using another CD3-specific monoclonal antibody, otelixizumab, in newly diagnosed type 1 diabetes patients.

The study also showed that during an 18-month follow-up period, short-term CD3 monoclonal antibody treatment can improve the preservation of β-cell function.

Currently, researchers are still conducting research on CD3 specific antibodies in human type 1 diabetes.

 

18. 2006: Towards stem cell therapy for the treatment of diabetes

The birth of human embryonic stem cell lines opened up the possibility of using stem cell therapy to treat a variety of diseases, and 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 on Nature Biotechnology, describing the process of differentiation of human embryonic stem cells into endocrine islet cells that can secrete insulin and glucagon.

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

 

19. 2007: Discovery of pancreatic islet inflammation in type 2 diabetes

In 2007, a study from Marc Donath and colleagues showed that insulitis is a pathological feature of type 2 diabetes and type 1 diabetes.

This discovery paved the way for further exploration of inflammasome activation and anti-inflammatory therapy for type 2 diabetes. the way.

 

20. 2012: Published the first clinical data of Treg cell treatment of type 1 diabetes

Marek-Trzonkowska published the first clinical trial results of regulatory T cells (Treg cells) in patients with type 1 diabetes in 2012 and 2014.

In a small trial study of children with type 1 diabetes who had recently onset, it was found that the use of Treg cell therapy is safe and tolerable, and reduces the patient’s need for exogenous insulin.

One year later, the researchers further reported that repeated treatment of Treg cells is safe and can prolong the survival time of β cells.

Moreover, the follow-up results also showed that compared with the control group, the patients treated with Treg therapy had lower insulin requirements statistically.

 

21. 2014: The “artificial pancreas” system changes the lives of patients

In 2014, Russell et al. reported the first results of a randomized crossover trial using a wearable “artificial pancreas” drug delivery system compared with insulin pump therapy.

The “artificial pancreas” system can automatically deliver insulin or glucagon.

The test results show that the “artificial pancreas” system provides better blood sugar control for teenagers and adults with type 1 diabetes compared with insulin pumps. Today, several “artificial pancreas” systems have been approved for marketing in the United States and Europe, and more systems are being tested in large-scale clinical trials, which are expected to help more patients reduce their daily burden of managing diabetes.

 

22. 2016: The role of incretin drugs in controlling blood sugar

Incretin drugs include glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. These drugs can use GLP-1 to produce insulin Influence to improve blood sugar control.

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.

In addition, clinical studies have also shown that GLP-1RA drugs can promote weight loss and reduce the risk of atherosclerotic cardiovascular disease and kidneys in patients with type 2 diabetes.

 

23. 2019: reveal the infectious causes of type 1 diabetes?

In 2002, clinical centers in the United States and Europe began recruiting young children to study the environmental causes of type 1 diabetes (TEDDY study).

Based on this research, a paper published in 2019 pointed out that long-term enterovirus type B infection plays a role in the development of type 1 diabetes in young children.

This is a major advancement for humans to understand the link between the virus group and type 1 diabetes. 

 

24. 2019: The role of a new generation of hypoglycemic therapy in reducing cardiovascular disease

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 by 11%.

In addition, SGLT2 inhibitors have also shown benefits in reducing the risk of chronic kidney disease. 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 major adverse cardiovascular events 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. Today, with the continuous breakthroughs and innovations of scientists, diabetes has changed from a fatal emergency to a chronic disease that can be controlled.

Facing the future, we sincerely hope that more updated diabetes therapies will be available, effective treatment and even prevention for patients, and an early elimination of the threat of diabetes to human health.

 

 

 

24 important milestones in the fight against diabetes in the past 100 years

(source:internet, reference only)


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