The Pro12Ala polymorphism of PPARγ2 modulates beta cell function and failure to oral glucose‐lowering drugs in patients with type 2 diabetes

Abstract

Background We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator‐activated receptor γ2 (PPARγ2) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose‐lowering drugs. Methods We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA1c] 7.0%‐9.0%) with metformin 2 g/day and were randomly allocated to add‐on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA1c ≥8% on two consecutive visits, 3 months apart. Results Carriers or non‐carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2‐%S), and worse beta cell secretion (HOMA2‐%B) than non‐carriers. During 24 months of follow‐up, 32.5% among the Ala carriers and 8.6% among non‐carriers (P < 0.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6/100 person‐years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48 ± 10 vs 52 ± 7 years; P = 0.032), higher HbA1c (8.1 ± 0.5 vs 7.7 ± 0.5%; P < 0.001), and lower HOMA2‐%B (30 ± 12 vs 46 ± 29; P = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79‐11.1; P < 0.001); HbA1c at study entry was the other independent predictor of failure in this study population. Conclusion The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure.

Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression

“…The enzyme is a promising target for the treatment of metabolic diseases, and efforts have been made to develop liver-targeted SCD1 inhibitors 56 . Since genetic variations have a major impact on the efficacy of therapy 57 , 58 , SCD1 variants, including functional promoter polymorphisms, such as rs1054411, are likely to alter the effectiveness or even the need for medical treatment with SCD1 inhibitors. The development of individualized therapeutic protocols based on genetic profiling seems a reasonable future goal in the treatment of lipid metabolism-related diseases.…”

Molecular Mechanisms Underlying the Elevated Expression of a Potentially Type 2 Diabetes Mellitus Associated SCD1 Variant

“…Elevated expression of SCD1 is related to T2DM [ 9 , 10 ], and the enzyme might be a promising target in the treatment of the disease, and efforts have been made to develop liver-targeted inhibitors to decrease SCD1 activity [ 54 ]. It is notable, however, that polymorphic variants can influence the efficiency of therapy [ 55 , 56 ], thus, SCD1 polymorphisms including M224L SNP might alter the effect or even the need of such SCD1-inhibitors. This is another consideration supporting that the development of individualized therapeutic protocols based on genetic profiling would be the future objective in the treatment of T2DM, similarly to other diseases [ 55 ].…”