Serum Non-Esterified Fatty Acid (NEFA) Concentrations are Associated - PowerPoint PPT Presentation

Serum Non-Esterified Fatty Acid (NEFA) Concentrations are Associated with Longitudinal Progression of Beta-Cell Dysfunction: Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort Luke W. Johnston Christine Lee Stewart Harris Ravi Retnakaran Bernard Zinman Richard P. Bazinet Anthony J. Hanley Department of Nutritional Sciences, University of Toronto 0 / 10

Disclosures • Presenter: Luke W. Johnston • Relationships with commercial interests: • None to disclose 1 / 10

Total NEFA: a risk factor for type 2 diabetes • Higher total NEFA associate with incidence of diabetes 1 • Potentially through lipotoxicity and/or inflammation 2 1 B. T. Steffen et al. (2015); Djoussé et al. (2012); Il’yasova et al. (2010) 2 Giacca et al. (2011); Newsholme et al. (2007) 2 / 10

Total NEFA: a risk factor for type 2 diabetes • Higher total NEFA associate with incidence of diabetes 1 • Potentially through lipotoxicity and/or inflammation 2 • However, NEFA comprised of physiologically diverse species (eg: saturated vs omega-3) • Limited data in humans on: • Role in progression of underlying disorders • Role of individual NEFA species 1 B. T. Steffen et al. (2015); Djoussé et al. (2012); Il’yasova et al. (2010) 2 Giacca et al. (2011); Newsholme et al. (2007) 2 / 10

Objective: • Examine the longitudinal associations of NEFA concentrations and individual NEFA species with 6-yr trends in insulin sensitivity (IS) and beta-cell function. 3 / 10

Prospective Metabolism and Islet Cell Evaluation cohort • Adults at-risk for diabetes • Recruited from Toronto and London, Ontario • Followed every 3-yrs 3 Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4 Wareham et al. (1995); Retnakaran et al. (2009) 4 / 10

Prospective Metabolism and Islet Cell Evaluation cohort • Adults at-risk for diabetes • Recruited from Toronto and London, Ontario • Followed every 3-yrs • OGTT at each visit (0, 30, 120 min), • Insulin sensitivity : 1/HOMA-IR and ISI (Matsuda Index) 3 • Beta-cell function : Insulinogenic index over HOMA-IR (IGI/IR) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) 4 • Fasting NEFA at baseline (n=478) • Thin layer chromatography (TLC) and gas liquid chromatography (GC) coupled to flame ionization detector (FID) 3 Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4 Wareham et al. (1995); Retnakaran et al. (2009) 4 / 10

Prospective Metabolism and Islet Cell Evaluation cohort • Adults at-risk for diabetes • Recruited from Toronto and London, Ontario • Followed every 3-yrs • OGTT at each visit (0, 30, 120 min), • Insulin sensitivity : 1/HOMA-IR and ISI (Matsuda Index) 3 • Beta-cell function : Insulinogenic index over HOMA-IR (IGI/IR) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) 4 • Fasting NEFA at baseline (n=478) • Thin layer chromatography (TLC) and gas liquid chromatography (GC) coupled to flame ionization detector (FID) • Generalized estimating questions (GEE) • Adjusted for waist (WC), physical activity (MET), alcohol intake, and sex. 3 Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4 Wareham et al. (1995); Retnakaran et al. (2009) 4 / 10

Outcomes declined by 14.4% to 27.5% over 6-yrs A: Insulin sensitivity C: Beta−cell function (1/HOMA−IR) (IGI/IR) 2.75 −0.25 2.50 log(1/HOMA−IR) −0.50 p < 0.001 p = 0.001 log(IGI/IR) 2.25 −0.75 2.00 −1.00 1.75 −1.25 1.50 0−yr 3−yr 6−yr 0−yr 3−yr 6−yr Clinic visit Clinic visit B: Insulin sensitivity D: Beta−cell function (ISI) (ISSI−2) 6.8 2.00 p < 0.001 p < 0.001 log(ISSI−2) 1.75 6.6 log(ISI) 1.50 6.4 1.25 6.2 1.00 0−yr 3−yr 6−yr 0−yr 3−yr 6−yr Clinic visit Clinic visit Figure 1:Trends over time, outcomes. 5 / 10

While clinical measures did not change A: Estimate of central C: Triacylglycerides adiposity (Waist) 110 Waist circumference (cm) 1.75 105 TAG (mmol/L) p = 0.188 p = 0.806 1.50 100 1.25 95 90 1.00 0−yr 3−yr 6−yr 0−yr 3−yr 6−yr Clinic visit Clinic visit B: Estimate of adiposity D: High−density (BMI) lipoprotein 1.6 1.5 34 p = 0.162 HDL (mmol/L) BMI (kg/m 2 ) p = 0.707 1.4 32 1.3 30 1.2 28 1.1 26 1.0 0−yr 3−yr 6−yr 0−yr 3−yr 6−yr Clinic visit Clinic visit Figure 2:Trends over time, clinical measures. 6 / 10

Higher total NEFA predicts 25% 5 greater risk for dysglycemia 5 RR = 1.25 (95% CI 1.05 to 1.43) per SD over the 6-yrs 7 / 10

Higher total NEFA predicts 25% 5 greater risk for dysglycemia ... and with declines in beta-cell function Insulin sensitivity & Beta−cell function log(1/HOMA−IR) log(ISI) log(IGI/IR) log(ISSI−2) 22:6 n−3 Non−esterified fatty acid species 20:5 n−3 ● 18:3 n−3 P−value 20:4 n−6 >0.05 ● 18:2 n−6 <0.05 ● ● 18:1 n−9 <0.01 18:0 16:0 ● Total −15−10 −5 0 5 −15−10 −5 0 5 −15−10 −5 0 5 −15−10 −5 0 5 Percent change (with 95% CI) for every 1 SD increase in fatty acids Figure 3:Forest plot of generalized estimating equation results. 5 RR = 1.25 (95% CI 1.05 to 1.43) per SD over the 6-yrs 7 / 10

Conclusion: • Total NEFA, rather than any individual species, predicts declines in beta-cell function 6 Giacca et al. (2011) 8 / 10

Conclusion: • Total NEFA, rather than any individual species, predicts declines in beta-cell function • Extends literature by showing strong association with beta-cell function rather than insulin sensitivity • Biologically plausible given beta-cells susceptible to lipotoxicity 6 6 Giacca et al. (2011) 8 / 10

Acknowledgements • Thanks to: • Study participants • Research nurses (Jan Neuman, Paula Van Nostrand, Stella Kink, Annette Barnie, Sheila Porter and Mauricio Marin) • LWJ received: • Canadian Diabetes Association Doctoral Student Research Award • University of Toronto Banting and Best Diabetes Centre Graduate Novo Nordisk Studentship • PROMISE supported by: • Canadian Institutes of Health Research • Canadian Diabetes Association Comments or questions? Please contact: luke.johnston@mail.utoronto.ca 9 / 10

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