Scientists who performed the largest-ever genetic study of a puzzling type of adult-onset diabetes have uncovered new connections to the two major types of diabetes, offering intriguing insights into more accurate diagnosis and better treatment.
Latent autoimmune diabetes in adults (LADA), which is informally called “type 1.5 diabetes,” is a relatively common disorder that shares features of type 1 diabetes and type 2 diabetes.
LADA is commonly misdiagnosed as type 2 diabetes, as it presents in adulthood but doesn’t initially require insulin treatment.
New research reveals details of the underlying genetic influences in LADA, while leaving open many questions about how to classify the disorder.
“This study lends support to the idea that LADA is a hybrid of type 1 and type 2 diabetes, but doesn’t settle the question of the best way to precisely define the disorder,” said co-first author Dr. Diana L. Cousminer in a press release, “Correctly characterizing LADA is important, because it may determine whether a patient receives the most appropriate treatment.”
The new research, which is the first genome-wide association study of LADA, represents a large international effort from nine countries.
The study, along with analysis in 2017, found the strongest genetic signals in LADA were associated with type 1 diabetes, the autoimmune form of diabetes that usually presents in childhood and requires treatment with insulin.
The current analysis also found genetic signals linked to type 2 diabetes, the metabolic type of diabetes, more typically appearing first in adults, and by far the most common type of diabetes.
The new study performed genetic analyses in cohorts of European ancestry.
The primary analysis compared 2,634 LADA cases to 5,947 control subjects. Secondary analyses consisted of the LADA cases vs. 968 T1D cases and the LADA cases vs. 10,396 T2D cases.
What were the Findings?
The team found that the strongest genetic signals in LADA were mainly shared with established variants known to be linked to T1D.
However, the researchers discovered a novel locus with genome-wide significance near the gene PFKFB3.
This gene codes for a protein that regulates both insulin signaling and glycolysis, the chemical reaction that yields energy from glucose.
“This finding points to how variants at PFKFB3 may help to drive LADA,” said Cousminer, who added that because the gene’s product not only impacts metabolism (a key feature of T2D) but also regulates inflammation in autoimmune disease (a key feature of T1D), “this protein, therefore, appears to sit at the intersection of both major types of diabetes,” she explains.
Researchers say further study of underlying genetic interactions in LADA may reveal better biomarkers of the disease, which will aid in better diagnosis.
“Currently, as high as 5 to 10 percent of patients diagnosed as adults with type 2 diabetes may actually be misdiagnosed, and in fact have a late-onset form of autoimmune diabetes,” says Dr. Rajashree Mishra, another author of the study.
“More accurate diagnosis may guide better clinical management. For instance, patients with LADA may require close monitoring, to detect the optimal point at which they require insulin.”
Better knowledge of the underlying genetics and biology of LADA could potentially lead to new treatments, the researchers indicate.
“The interaction of genes in LADA may modify the disease process by delaying the onset of more severe autoimmune diabetes into adulthood,” Cousminer says.
“If further research uncovers those mechanisms, we may be able to develop therapeutic methods to delay more severe disease,” she adds.
The research has been published in Diabetes Care.
First GWAS analysis of ‘type 1.5 diabetes’ reveals links between immune and metabolic disease. 2018, October 17. Retrieved: https://www.eurekalert.org/pub_releases/2018-10/chop-fga101718.php