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Genetics May Affect Responses to Popular Diabetes and Weight Loss Drugs

An illustration of a DNA double helix.
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Patient responses to glucagon-like peptide 1 (GLP-1R) agonist drugs – used to treat type 2 diabetes and obesity – may depend on variations in GLP-1R genes, according to a new study. The research, published in Nature Genetics, also sheds light on the role of the digestive system in controlling blood sugar and reveals that high blood sugar may play a role in lung disease.

Exploring the biology underpinning diabetes

GLP-1R agonists are a popular class of drugs used to treat both type 2 diabetes and obesity. They help to keep blood sugar levels within a normal range and also help to facilitate weight loss.

Previous research has shown that lung conditions such as restrictive lung disease are more common in type 2 diabetics, but it was not known if diabetes directly damages the lungs or whether other factors may be linked to both conditions.

Now, researchers from the University of Surrey, as part of the Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC), have analyzed the genetics and linked random blood glucose levels of almost half a million people from 17 major studies. This provides new insight into the biology of diabetes, its potential complications and ways to make sure patients get the right treatments for them.

Drug treatments, impaired lung function and the role of the intestine

The researchers carried out a genome-wide association study (GWAS), scouring the participants’ genomes to characterize the effects of genetic variations on randomly tested blood glucose levels, which are frequently measured at different times throughout the day in clinical practice and research studies.

They also identified how variations in the gene that codes for the GLP-1 receptor influenced blood glucose levels and tested how some of the identified variants responded differently to GLP-1R agonist drugs in lab-cultured cells. This highlighted that these drugs may have differing effects on people depending on the variant they carry. Doctors should therefore match drugs to a patient’s unique makeup, the researchers suggest, to find treatments likely to work best for each individual.

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Next, they probed the relationship between blood sugar levels and lung disease using lung function test data linked to the study participants, revealing that high blood sugar did indeed directly impair lung function in people with type 2 diabetes. Data modeling suggested that an increase in average blood sugar from 4 mmol/L to 12 mmol/L could lead to a 20% decline in lung function and capacity.

"Our research provides the first evidence that high blood sugar levels in type 2 diabetes can directly lead to lung damage,” said Dr. Vasiliki Lagou, lead author of the study and postdoctoral scientist. “We hope our discovery that impaired lung function is a complication of type 2 diabetes is the first step towards increased awareness among healthcare professionals, leading to earlier diagnosis and treatment of lung conditions."

Lastly, the study identified roles for tissues not previously implicated in glucose metabolism – notably the ileum (the final section of the small intestine) and the colon. They show that the gut microbiome is related to glucose regulation, highlighting the role of glucose production by the gut flora, particularly microbiome species belonging to Collinsella and Lachnospiraceae-FCS020.

“This hugely important study, involving over a hundred scientists from around the globe, gives us new insights into the genetics of blood glucose levels and type 2 diabetes,” said Professor Inga Prokopenko, senior author of the study and head of statistical multi-omics at the University of Surrey. “Already now, we can act on better prevention from type 2 diabetes complications, including lung disease. We should improve treatment strategies for people with this condition, by studying individual DNA variants in relation to GLP-1R agonist response.”

Overall, the findings highlight the need for healthcare professionals to be vigilant about lung complications in people with type 2 diabetes and advances in the diagnosis and treatment of lung disorders early could potentially benefit thousands of people affected by the condition.

Reference: Lagou V, Jiang L, Ulrich A, et al. GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. Nat Genet. 2023;55(9):1448-1461. doi: 10.1038/s41588-023-01462-3

This article is a rework of a press release issued by the University of Surrey. Material has been edited for length and content.