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NEW YORK (Reuters Health) – Type 2 diabetes subtypes have partially distinct genetic backgrounds, suggesting etiological differences that may one day be targeted for treatment, genome-wide association analyses show.

“The key finding of this paper is that each of these diabetes subtypes show partially distinct genetic associations, augmentin 1g iv posologie which indicates that there are some differences in the disease etiologies of these subtypes,” Dr. Emma Ahlqvist of Lund University in Sweden told Reuters Health by email. “The severe insulin-resistant diabetes (SIRD) subtype stands out by being associated with variants that raise fasting insulin, but not with variants that affect insulin secretion.”

“We also identified a novel genetic variant that specifically increased the risk of the mild obesity-related subtype,” she said. “We will expand this study by including more individuals with diabetes, which we believe will enable us to identify more subtype-specific genetic risk variants.”

In previous work, Dr. Ahlqvist and colleagues performed a cluster analysis in a large Swedish cohort of adults with diabetes and identified five clusters of patients with different clinical characteristics, disease progression and outcomes, and suggested a new subclassification of adult diabetes. The subtypes are:

– Severe autoimmune diabetes (SAID, 6% of patients), defined by the presence of glutamic acid decarboxylase autoantibodies (GADA) and including patients traditionally referred to as type 1 diabetes and latent autoimmune diabetes in adults (LADA);

– Severe insulin-deficient diabetes (SIDD; 18%), characterized like GADA by early onset, low insulin secretion, relatively low BMI and poor metabolic control;

– Severe insulin-resistant diabetes (SIRD; 15%), characterized by late onset, obesity, insulin resistance and high risk of diabetic nephropathy and non-alcoholic fatty liver disease;

– Mild obesity-related diabetes (MOD, 22%), characterized by early onset, obesity and a relatively mild disease progression; and

– Mild age-related diabetes (MARD, 39%), characterized by late-onset diabetes and relatively good metabolic control.

For the current study, published in Nature Genetics, the team used genome-wide association and genetic risk score (GRS) analyses to compare the underlying genetic drivers of the various subtypes. They found that subtypes differ with regard to family history of diabetes and association with the GRS for diabetes-related traits.

As Dr. Ahlqvist noted, the SIRD subtype was uniquely associated with a GRS for fasting insulin but not with variants in the TCF7L2 locus or the GRS reflecting insulin secretion.

Further, a single nucleotide polymorphism (rs10824307) near the leucine rich melanocyte differentiation associated (LRMDA) gene was uniquely associated with MOD.

The authors conclude, “These results suggest translational potential in terms of intervention stratification, which is backed up with our previously published clinical data showing different treatment responses in the subtypes. This is an important public health aspect as what we think of as T2D is 80-90% of all diabetes; better knowledge of its pathogenesis, early detection and intervention in the face of heterogeneity is critical.”

Dr. Shailendra Patel, Director, Division of Endocrinology, Diabetes and Metabolism at the University of Cincinnati in Ohio told Reuters Health by phone, “This is a fantastic study! It provides scientific evidence for what we see in the clinic – namely, that diabetes is not one disease, and there are subtypes that may need to be treated differently. Clinicians can be reassured that what they’re doing now has robust science behind it.”

“The results also tell us not to be so glucose-centric – that diabetes is essentially a metabolic disease and we have to look at the bigger picture,” he said. “This approach may open the door to further subtypes and therapies based on the etiology.”

The study is funded in part by the Novo Nordisk Foundation, and two coauthors have received funds from Novo Nordisk.

SOURCE: Nature Genetics, online November 4, 2021.

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