Effect of the PPARG2 Pro12Ala Polymorphism on Associations of Physical Activity and Sedentary Time with Markers of Insulin Sensitivity in Those with an Elevated Risk of Type 2 Diabetes

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is an important regulator of metabolic health and a common polymorphism in the PPAR-γ2 gene (PPARG2) may modify associations between lifestyle behaviour and health. OBJECTIVE: To investigate whether the PPARG2 Pro12Ala genotype modifies the associations of sedentary behaviour and moderate-to-vigorous intensity physical activity (MVPA) with common measures of insulin sensitivity. METHODS: Participants with a high risk of impaired glucose regulation were recruited, United Kingdom, 2010-2011. Sedentary and MVPA time were objectively measured using accelerometers. Fasting and 2-hour post-challenge insulin and glucose were assessed; insulin sensitivity was calculated using Matsuda-ISI and HOMA-IS. DNA was extracted from whole blood. Linear regression examined associations of sedentary time and MVPA with insulin sensitivity and examined interactions by PPARG2 Pro12Ala genotype. RESULTS: 541 subjects were included (average age = 65 years, female = 33%); 18% carried the Ala12 allele. Both sedentary time and MVPA were strongly associated with HOMA-IS and Matsuda-ISI after adjustment for age, sex, ethnicity, medication, smoking status and accelerometer wear time. After further adjustment for each other and BMI, only associations with Matsuda-ISI were maintained. Every 30 minute difference in sedentary time was inversely associated with a 4% (0, 8%; p = 0.043) difference in Matsuda-ISI, whereas every 30 minutes in MVPA was positively associated with a 13% (0, 26%; p = 0.048) difference. The association of MVPA with Matsuda-ISI was modified by genotype (p = 0.005) and only maintained in Ala12 allele carriers. Conversely, sedentary time was not modified by genotype and remained inversely associated with insulin sensitivity in Pro12 allele homozygotes. CONCLUSION: The association of MVPA with Matsuda-ISI was modified by PPARG2 Pro12Ala genotype with significant associations only observed in the 18% of the population who carried the Ala12 allele, whereas associations with sedentary time were unaffected

Participant characteristics.

<p>Data displayed as median [IQR] or number (%)</p><p>* = higher values represent greater deprivation</p><p>^† = Fasting insulin data missing for 12 Ala12 carriers and 50 Pro12 homozygotes due to insufficient blood collection or cessation of bleeding</p><p>^‡ = 2-h insulin data missing for 14 Ala12 carriers and 59 Pro12 homozygotes due to insufficient blood collection or cessation of bleeding</p><p>^§ = Matsuda-ISI data missing for 21 Ala12 carriers and 89 Pro12 homozygotes; higher values indicate greater sensitivity</p><p>Participant characteristics.</p

Associations of moderate-to-vigorous physical activity (MVPA) and sedentary time with markers of insulin sensitivity.

<p>Coefficients represent the factor by which the measure of insulin sensitivity is multiplied by (95% Confidence Interval) for a 30 minute difference in sedentary time or MVPA</p><p>Model 1 adjusted for age, sex, ethnicity, smoking status, statin medication status, beta-blocker status and accelerometer wear time</p><p>Model 2 adjusted for above variables plus MVPA (for the sedentary time model) or sedentary time (for the MVPA model)</p><p>Model 3 adjusted for the above plus BMI</p><p>Associations of moderate-to-vigorous physical activity (MVPA) and sedentary time with markers of insulin sensitivity.</p