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New research highlights genetic differences between different forms of type 2 diabetes

Photo of one of the researchers behind the study in the lab.
Dina Mansour Aly, one of the main authors behind the study, has carried out several genetical analyses. Photo: Petra Olsson

Previous research from Lund University has shown that diabetes can be divided into five groups with different disease progression. A new study published in Nature Genetics demonstrates that there are also genetic differences between different groups of patients. An important goal of the research is to contribute with knowledge that will enable tailored treatments of patients with type 2 diabetes.

“In our new study, we have discovered that there are clear genetic differences between the groups. This suggests that there are somewhat different causes behind type 2 diabetes,” says Emma Ahlqvist, a researcher in genomic, diabetes and endocrinology at Lund University Diabetes Centre (LUDC), and one of the lead authors behind the study which was recently published in Nature Genetics.
 
In a study published in 2018, researcher Emma Ahlqvist and her colleagues showed that it is possible to divide diabetes into five groups, based on disease progression and the risk of complications (see fact box). In this classification system, type 2 diabetes is divided into four groups and type 1 diabetes patients into one group. 

Different genetic profiles

For the new study, the researchers have performed genome-wide association studies (GWAS) and a genetic risk score analysis (GRS) on around 10 000 individuals with diabetes from the population study All New Diabetics in Scania (ANDIS). Especially one group stands out in the new study – SIRD (Severe insulin-resistant diabetes). The group is characterized by obesity, severe insulin resistance and high risk of diabetic kidney disease.

“This group has a somewhat different genetic profile compared to the other groups. Our study demonstrates that individuals belonging to this subtype have genetic variants associated with insulin resistance, but are not associated with variants that affect insulin secretion,” says Emma Ahlqvist.

Another group that stands out in the study is MOD (Mild obesity-related diabetes), which is characterized by early onset and obesity. This was the only group uniquely associated with a single nucleotide polymorphism (SNP) near a gene called LRMDA. 

Tailored treatments

The study adds to the evidence base that different groups of patients may need individualized treatment. Patients with decreased insulin secretion may for example benefit from early insulin treatment. Individuals within the group SIRD may instead need a treatment focused on targeting the insulin resistance. 

“Patients in this group often have a normal insulin production but may instead have problems with insulin resistance. They can have a lot of insulin in the blood and may benefit from a treatment that increases the insulin sensitivity,” says Emma Ahlqvist.

The researchers behind the study are planning to carry out a larger study with more individuals to find out whether there are more genetic variations that are specific for the different groups.

“In the long-term perspective, we hope that our research will be clinically relevant and contribute to the development of individualized treatments of patients with type 2 diabetes. First, we need to see clear evidence that tailored treatments will lead to successful results in clinical trials. We also need to investigate how to apply the classification system to different ethnical groups,” says Emma Ahlqvist.
 

The five subgroups

SAID (Severe autoimmune diabetes)

SAID includes patients traditionally referred to as type 1 diabetes and latent autoimmune diabetes in adults (LADA). SAID is defined by the presence of GAD autoantibodies and characterized by early onset, poor metabolic control and low insulin secretion.

SIDD (Severe insulin-deficient diabetes)

SIDD is characterized by early onset, low insulin secretion, relatively low BMI and poor metabolic control. Patients with SIDD also have an increased risk of developing the eye condition retinopathy and neuropathy, a type of damage to the nervous system.

SIRD (Severe insulin-resistant diabetes)

SIRD is characterized by late onset, obesity, insulin resistance and high risk of non-alcoholic fatty liver disease and diabetic kidney disease.

MOD (mild obesity-related diabetes)

MOD has early onset, obesity and a relatively mild disease in terms of progression of hyperglycemia and complications.

MARD (mild age-related diabetes)

MARD is characterized by late-onset diabetes and relatively good metabolic control. 
 

Photo of the researcher behind the study.

Contact

Emma Ahlqvist, associate professor and researcher in genomics, diabetes and endocrinology 
emma [dot] ahlqvist [at] med [dot] lu [dot] se

Link to Emma Ahlqvist’s profile in Lund University Research Portal
 

Quick facts about the study

Subject: Genetics of diabetes 
Research area: Clinical research
Study design: Quantitative study, researcher-initiated study, register-based study, statistical link
Observational study (epidemiological): Cross-sectional study, cohort study
Number of groups in the study: Five diabetes subtypes and controls in two population studies – ANDIS and DIREVA
Number of patients in the study: 9486+4427
Patient group/s (state diagnosis): Diabetes (SAID, SIDD, SIRD, MOD, MARD)
Healthy volunteers: 2744 (MDC)+1683 (Botnia)
Case-control study

Link to the article in Nature Genetics