New Review: Research Status and Future Development of Precision Medicine in Type 2 Diabetes

Type 2 diabetes accounts for nearly 90%
of the estimated 537 million cases of diabetes worldwide.
And the number of cases is increasing rapidly, and the rate of growth among children and young people (under 40 years of age) is even more alarming
.
In the treatment and management of type 2 diabetes, precision medicine (including multiomics and pharmacogenomics) has the potential to improve the understanding of disease heterogeneity and find more precise therapeutic targets for type 2 diabetes, so as to achieve precise treatment
of diabetes.

On November 1, 2022, The Lancet published an authoritative review "Type 2 diabetes" online, Professor Ehtasham from the Diabetes Research Center of the University of Leicester and the NIHR Biomedical Research Center of Leicester focused on the current new therapeutic targets of type 2 diabetes, described the research status and future development of precision medicine in type 2 diabetes, and took us to understand the treatment and management
of type 2 diabetes from a new perspective.
1.
The "twelve" of the pathophysiology of type 2 diabetes mellitus

The pathophysiology of type 2 diabetes mellitus is complex, and at least eight pathophysiological abnormalities are known in the past, also known as "octet" (Figure 1).

Figure 1.
The "octet" of the pathophysiological mechanism of type 2 diabetes mellitus and therapeutic drugs for the above mechanisms

In this paper, Professor Ehtasham adds 4 latest pathophysiological mechanisms that can lead to type 2 diabetes on the basis of the original "octet":

1) Activation of chronic inflammation: therapeutic drugs against targets: GLP-1 receptor agonists, SGLT-2 inhibitors, anti-inflammatory drugs;

2) Immune function deficiency: therapeutic drugs for targets: GLP-1 receptor agonists, immunomodulators, SGLT-2 inhibitors;

3) intestinal dysbacteriosis; Targeted therapeutics: GLP-1 receptor agonists, DPP-4 inhibitors, α-glucosidase inhibitors, amylase analogues, metformin;

4) Excessive deposition of pancreatic amylin (IAPP): Drugs targeting this target are still under development and are one of the important therapeutic targets in the
future.
The new pathophysiological "Dodecano" of type 2 diabetes will help researchers to reposition existing diabetes drugs in view of the above potential pathophysiological defects, target the causes of diabetes, and carry out the research and development of new drugs for type 2 diabetes, so as to realize true precision medicine (Figure 2).

Figure 2.
Twelve pathophysiological defects lead to type 2 diabetes mellitus β cell failure and therapeutic drugs that target these mechanisms

2.
Development status of precision medicine for type 2 diabetes

As a multifactorial heterogeneous disease, the development of type 2 diabetes involves a fusion
of predisposing genetic factors and susceptibility environmental factors.
With the advancement of genome-wide association studies (GWAS), about 400 genetic variants associated with type 2 diabetes have been identified
.
Many genetic variants have also been found to have strong genetic associations
with cardiometabolic features such as obesity, hypertriglyceridemia, coronary artery disease, unhealthy sleep behavior, and depression.
However, many of the genetic mutations currently detected are low-frequency, rare variants whose role in the overall risk of developing the disease has not been fully elucidated
.

GWAS can help develop precision medicine models for type 2 diabetes, where an individual's own genetic data can help with the prevention, diagnosis, and development of
targeted therapies for diabetes.
Using GWAS, a large biobank study in the UK has identified 202 independent genetic variants
associated with higher waist-to-hip ratios.
The study found that hip-specific polygenic scores were associated with lower buttock fat and higher belly fat (Figure 3).

Figure 3.
Relationship between high waist-hip ratio polygenic score and fat mass

However, implementing precision medicine in type 2 diabetes requires not only a better understanding of genomics, but also other types of whole genomics, including epigenomics, proteomics, metabolomics, and pharmacogenomics, must be integrated into the
precision medicine model for type 2 diabetes.
At the same time, large-scale studies are needed to show the full potential and clinical benefits
of this approach.
The current future role of precision medicine in diabetes management has also been recognized by the ADA, which in 2018 partnered with EASD to launch the Diabetes Precision Medicine Initiative
.

3.
For precision medicine, the choice of future therapeutic drugs

Precision medicine focuses on targeting key therapeutic pathways and organs such as the brain, kidneys, and especially the gastrointestinal system
, which plays an important role in glucose regulation.
AI may also help to precisely redefine treatments in the management of type 2 diabetes, matching patients with the drugs that work best for them through techniques such as large-scale predictive models
.

Some drugs that mimic the hormonal effects of the gut to control appetite and weight are being developed
.
In this regard, dual agonists, including GLP-1 receptor agonists and GIP combinations or triple agonists, such as GLP-1 receptor agonists-GIP-glucagon, and long-acting amylase derivatives are in various stages of research and development, and have achieved exciting hypoglycemic effects, and it is believed that they may play a key role
in the treatment of type 2 diabetes in the near future.
In addition, oral insulin and new insulin (also known as smart insulin) have shown good hypoglycemic efficacy and safety in early clinical trials, and are expected to be launched
in the near future.