Diabetologia.: co-auth.: B.Thorens

Diabetologia. 2021 Jun 10. doi: 10.1007/s00125-021-05490-8. Online ahead of print.

Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study

Roderick C Slieker 1 2Louise A Donnelly 3Hugo Fitipaldi 4Gerard A Bouland 2Giuseppe N Giordano 4Mikael Åkerlund 4Mathias J Gerl 5Emma Ahlqvist 4Ashfaq Ali 6Iulian Dragan 7Andreas Festa 8 9Michael K Hansen 10Dina Mansour Aly 4Min Kim 6 11Dmitry Kuznetsov 7Florence Mehl 7Christian Klose 5Kai Simons 5Imre Pavo 8Timothy J Pullen 12 13Tommi Suvitaival 6Asger Wretlind 6Peter Rossing 6Valeriya Lyssenko 14 15Cristina Legido-Quigley 6 11Leif Groop 4 16Bernard Thorens 17Paul W Franks 4 18Mark Ibberson 7Guy A Rutter 13 19Joline W J Beulens 1 20Leen M ‘t Hart 21 22 23Ewan R Pearson 24Affiliations expand


Aims/hypothesis: Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic.

Methods: In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort’s cluster centres. Finally, we compared the time to insulin requirement for each cluster.

Results: Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression.

Conclusions/interpretation: Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration.

Keywords: C-peptide; Clusters; Cross-validation; HDL-cholesterol; Type 2 diabetes.