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Emerging insights into the heterogeneity of type 2 diabetes include 6 distinct subphenotypes of prediabetes


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Robert Wagner, MD
Robert Wagner, MD

Research continues to increase understanding of the heterogeneity of type 2 diabetes and prediabetes.

“Maybe there is no one homogenous disease group—type 2 diabetes—but rather several subentities, all manifesting with the same phenomenon of hyperglycemia. This hypothesis is supported by clinical experience,” said Robert Wagner, MD, endocrinologist and diabetologist at the German Diabetes Center and University Hospital Düsseldorf, Germany. “We all know that disease courses in diabetes can be very different; glucose is only one aspect of the disease, and poorly predictive. We have patients with different risk situations—some of them develop neuropathy and diabetic foot syndrome, others develop nephropathy or retinopathy, while others develop macrovascular complications.

Dr. Wagner was among the panelists in the Friday, June 3, session, Heterogeneity of Diabetes—Underlying Mechanisms, Epidemiology, and Intervention Response. He discussed how pathophysiology-based subgrouping in diabetes and prediabetes could lead to more individualized diabetes treatment.

The session was livestreamed and can be viewed on-demand by registered meeting participants at If you haven’t registered for the 82nd Scientific Sessions, register today to access the valuable meeting content.

In a paper published last year, Dr. Wagner and colleagues described six distinct subphenotypes of people with prediabetes based on a number of core metabolic features, including blood glucose levels, amount of fat in the liver, overall fat distribution, blood lipid levels, and genetic risk of diabetes.

Melina Claussnitzer, PhD
Melina Claussnitzer, PhD

The investigators found that three of the identified subphenotypes have increased glycemia, but that only individuals in two of those clusters have imminent diabetes risks. By contrast, Dr. Wagner said they identified another cluster of individuals with prediabetes who have only moderate risk of type 2 diabetes but an increased risk of kidney disease and all-cause mortality.

While more study is needed, he said this proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes.

“We want to prevent diabetes and its complications, and perhaps the identification of such subphenotypes can help us guide precision prevention and therapy of diabetes in the future,” Dr. Wagner said.

Melina Claussnitzer, PhD, Assistant Professor at Harvard Medical School and Massachusetts General Hospital, discussed ongoing research exploring molecular heterogeneity underlying type 2 diabetes genetic variation in adipocytes.

Using an experimental image-based profiling tool (LipocyteProfiler) to identify phenotypic profiles in lipid-accumulating cells, she and her colleagues have been able to link genome-wide polygenic risk scores to genetically anchored cellular programs in adipocytes.

“We have a tool that allows us to extract highly granular representations of morphological and cellular functions in adipocytes,” Dr. Claussnitzer said. “We are learning about their cellular programs by extracting information out of microscopic images to basically map the molecular heterogeneity of type 2 diabetes,”

Kristina Utzschneider, MD
Kristina Utzschneider, MD

An advantage of image-based profiling is that it allows the detection and quantification of very subtle changes, which Dr. Claussnitzer said is particularly relevant in the context of the interpretation of common natural genetic variation.

“When we think about the variant-to-function framework—variants to regulatory elements to genes to proteins to cellular function—this tool might allow us to test whether these connecting roads might actually converge on a few cellular pathways that might contribute eventually to the onset and progression of disease,” she said.

Kristina Utzschneider, MD, Director of Diabetes Care, VA Puget Sound, and Assistant Professor of Medicine at the University of Washington, addressed how the growing understanding of heterogeneity in type 2 diabetes translates to the clinic, particularly in terms of treatment and medication decisions.

“Clinical trials mainly focus on comparing the averages or mean responses between treatment intervention arms in their patient populations; however, we have to remember that within each treatment there is also variability,” Dr. Utzschneider said. “As we better understand this heterogeneity of response to treatment, there may be specific characteristics or features of our patients that will help us know if they are going to respond better to this drug versus another drug.”