Abstract
Objectives PPARγ variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between PPARγ genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.Methods PPARγ2 exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by in vitro assays. Additionally, a review of the literature was performed to obtain all reported cases with rare PPARγ2 variants to evaluate the characteristics of variants in different functional domains.ResultsSix (0.6%) patients had PPARγ2 variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare PPARγ2 variants in AF1 of PPARγ2 had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.ConclusionThe prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of PPARγ2 had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients via genetic testing and suggest that thiazolidinediones might be a good choice for these patients.
Highlights
Peroxisome proliferator-activated receptor g (PPARg) is a liganddependent transcription factor with key roles in adipocyte differentiation, adipogenesis, glucose homeostasis, and inflammation [1]
We obtained the following novel findings: 1) we obtained the first estimate of the prevalence of PPARG-DM in a Chinese population with early-onset type diabetes (EOD), i.e., 0.6%. 2) A hotspot diabetesrelated variant (p.Tyr95Cys) was identified in activation function 1 (AF1); this variant suppressed the differentiation of 3T3-L1 preadipocytes in vitro
Because we found that most reported patients with PPARG-DM were diagnosed before the age of 40, we estimated the prevalence of PPARG-DM in this population to ensure that our results are clinically meaningful
Summary
Peroxisome proliferator-activated receptor g (PPARg) is a liganddependent transcription factor with key roles in adipocyte differentiation, adipogenesis, glucose homeostasis, and inflammation [1]. Several rare PPARg variants have been reported as causes of familial partial lipodystrophy (FPLD3, OMIM 604367), insulin resistance, diabetes, and hypertriglyceridemia. In some patients with FPLD3, thiazolidinediones effectively ameliorate hyperglycemia and insulin resistance [2]. An additional 30 amino acids in N-terminal ligand-independent AF1 of PPARg2 results in a 5–10-fold increase in the activation function in vitro [3]. Patients carrying a rare variant, such as p.Pro113Gln, in the AF1 of PPARg2 show marked obesity and/or hyperglycemia [7]. Patients with rare variants in domains other than AF1 (non-AF1) consistently show a reduced fat mass and severe insulin resistance. We hypothesize that the effects of PPARg2 variants depend on the location of the variants
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