Researchers have defined five categories of diabetes patients, rather than the longstanding basic division into type 1 and type 2. That is an advance that could better enable health care providers to both combat the most aggressive forms of the disease as well as to help equip them to guide early treatment and prevention efforts in the lowest risk populations.

Physicians and researchers have long called for more precise categorization for the disease and the mechanisms involved. The hope is that this could prove a first step toward more tailored and effective diabetes treatment.

Rethinking categories

The researchers from Lund University in Sweden used six variables related to known factors in the trajectory of the disease, including insulin resistance, obesity and age. Using those, they established five clusters of kinds of diabetes patients. After one large initial study, the researchers replicated the results in three other datasets in Sweden and Finland prior to publishing recently in The Lancet Diabetes & Endocrinology.

"For 50 years, we have had type 1 and type 2 diabetes, which is based on one measurement method. Now, when we added the six variables to compute how many forms of diabetes did we have, the answer was five," Leif Groop, a physician and professor of diabetes and endocrinology at Lund University, told BioWorld. "This was in a very large cohort, more than 10,000. It covered more than 90 percent of patients in the region, so it was a very representative sample and it was replicated in three other cohorts.

"So, the clusters seem to be quite robust and I think all doctors should be treating patients using this," Groop added. "They have known that the disease is heterogeneous, but they have the tools to dissect the data."

The current distinction between type 1 and type 2 diabetes is based on the presence in type 1 of autoantibodies against pancreatic islet beta-cell antigens, with an absence of those autoantibodies in type 2 disease. Type 1 patients, of course, also tend to be younger. Under those criteria, roughly 75 percent to 90 percent of patients are classified as having type 2 disease.

More recently, a third subgroup known as latent autoimmune diabetes in adults (LADA) has emerged, which is present in less than 10 percent of people diagnosed with diabetes. It is defined by the presence of glutamic acid decarboxylase antibodies (GADA), but is phenotypically identical to type 2 diabetes at diagnosis. LADA becomes more similar to type 1 diabetes over time. Also, with the advent of gene sequencing in diagnostics, several rare monogenic forms of diabetes have been described.

Five, not two

The five new categories that have been discerned include three severe forms, which would benefit from extensive treatment in order to help prevent complications, as well as two mild forms that require fewer resources, but could help point the way toward prevention. The six variables used to identify the clusters were glutamate decarboxylase antibodies, age at diagnosis, body mass index (BMI), HbA1c, and homoeostatic model assessment estimates of beta-cell function and insulin resistance.

The first group is severe autoimmune diabetes (SAID); it corresponds to type 1 diabetes and LADA and has a young onset age as well as poor metabolic control, impaired insulin production and the presence of GADA antibodies. It ranged from roughly 6.4 percent to 10.1 percent of the study population, varying a bit between each of the four study populations.

The second group is severe insulin-deficient diabetes (SIDD), which is characterized by high HbA1C, impaired insulin secretion and moderate insulin resistance. That group had the highest incidence of retinopathy and was present in anywhere from 8.9 percent to 20.4 percent of the studied groups.

Group three is severe insulin-resistant diabetes (SIRD), which involves obesity and severe insulin resistance. That group had the highest incidence of kidney damage, which is the most costly secondary disease produced by diabetes. It accounted for anywhere from 11.2 percent to 15.3 percent of the study populations.

The mild forms are mild obesity-related diabetes (MOD), which is group four, and, finally, group five, which is mild age-related diabetes (MARD). The former includes obese patients who are relatively young when they become ill, while the latter is the largest group and consists of the most elderly patients. MOD was present in 18.3 percent to 22.8 percent, while MARD was by far the largest accounting for 34.3 percent to 47.3 percent depending on the study population.

Getting to guidelines

There are a few obvious treatment implications. SIDD patients stand to benefit the most by boosting insulin secretion, while for SIRD patients the target should be insulin resistance. Many of the SAID and SIDD patients are on insulin – 42 percent and 29 percent, respectively. But less than 4 percent of patients in the three remaining groups were on insulin. The shortest time to sustained insulin use was in the SAID patients.

Interestingly, metformin use was highest among SIDD patients, group two, and lowest among SAID patients, group one. But the cluster that stands to benefit the most from metformin is group three, or SIRD patients.

Groups one and two, SAID and SIDD patients, have substantially higher HbA1c at diagnosis than the other clusters. Ketoacidosis at diagnosis was most common in groups one and two, occurring in roughly one-third and one-quarter of those patients, respectively. Ketoacidosis at diagnosis was relatively uncommon, at less than 5 percent, of the other groups.

The researchers have already incorporated their work into an existing Asia cohort study, where they aim to replicate those findings. Groop anticipates they will find similar groups in the Asia study, but that the distribution of patients into those groups is likely to be different. Other research groups also are already working to replicate the study results. Eventually, enough data could accumulate to stimulate changes to diagnosis and treatment guidelines issued by groups such as the American Diabetes Association (ADA).

In addition, Groop anticipates further research into prediabetes. Those longitudinal cohort studies offer the opportunity to better characterize the onset and evolution of the disease over time as well. A clearer understanding of the transition from prediabetes into a disease state could aid prevention efforts.

"This is just the first step. We have assessed it in Europeans; now we have to replicate it in Asia. Clearly, we also want to implement this in the clinic. Therefore, we are developing a clinical support tool. So, in the clinic they will draw the blood sample and, at the end of the process, they will get a roadmap for the patient," said Groop.

"We are also doing a genetic screen of the clusters, because all of the genetic association studies that have been done in type 2 diabetes – they are no longer valid when you get into these groups," he concluded.