All-cause mortality in people with type 2 diabetes and lipodystrophy-like metabolic phenotype

Aim We wanted to investigate whether the lipodystrophy (LD)-like phenotype increases mortality in type 2 diabetes. To this end we first developed and confirmed the triglyceride/BMI ratio (TBR index) as an inexpensive and widely available marker of the LD-like metabolic phenotype. The TBR index was then tested for association with all-cause mortality in patients with type 2 diabetes. Research Design and Methods Associations between TBR and mortality were assessed by Cox in three type 2 diabetes cohorts (n = 2,137, n = 960 and n = 5,060). A 20-SNP genotype risk score (GRS), associated with LD-like phenotype was investigated to identify the molecular basis of TBR variability. Main finding In all cohorts, the highest TBR decile showed features of LD-like phenotype, including atherogenic dyslipidemia, lower BMI, worse glycemic control, insulin resistance, elevated gamma-glutamyl transferase and hypoadiponectinemia. In the metanalysis, decile 10 had higher mortality risk (HR = 1.46, P < 0.0001). Finally, in a subset of one of the three cohorts, the LD-like GRS was significantly associated with TBR. Conclusions The TBR is a novel, inexpensive and easily available marker that identifies a subgroup of type 2 diabetes patients with a LD-like phenotype, partly explained by genetic factors. Our findings help disentangle the heterogeneity of death risk in diabetes, refine diagnostic and follow-up algorithms and enable specific treatments for improving long-term outcomes in LD-like individuals.