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

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Disclosures

• Presenter: Luke W. Johnston
• Relationships with commercial interests:
• None to disclose

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Total NEFA: a risk factor for type 2 diabetes

• Higher total NEFA associate with incidence of diabetes1
• Potentially through lipotoxicity and/or inflammation2
• 1B. T. Steffen et al. (2015); Djoussé et al. (2012); Il’yasova et al. (2010)

2Giacca 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 diabetes1
• Potentially through lipotoxicity and/or inflammation2
• 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
• 1B. T. Steffen et al. (2015); Djoussé et al. (2012); Il’yasova et al. (2010)

2Giacca 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.

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Prospective Metabolism and Islet Cell Evaluation cohort

• Adults at-risk for diabetes
• Recruited from Toronto and London, Ontario
• Followed every 3-yrs

3Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4Wareham 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)

3Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4Wareham 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.

3Matsuda and DeFronzo (1999); Matthews, Hosker, and Rudenski (1985) 4Wareham et al. (1995); Retnakaran et al. (2009) 4 / 10

Outcomes declined by 14.4% to 27.5% over 6-yrs

p < 0.001

−1.25 −1.00 −0.75 −0.50 −0.25 0−yr 3−yr 6−yr

Clinic visit log(1/HOMA−IR)

A: Insulin sensitivity (1/HOMA−IR) p < 0.001

1.00 1.25 1.50 1.75 2.00 0−yr 3−yr 6−yr

Clinic visit log(ISI)

B: Insulin sensitivity (ISI) p = 0.001

1.50 1.75 2.00 2.25 2.50 2.75 0−yr 3−yr 6−yr

Clinic visit log(IGI/IR)

C: Beta−cell function (IGI/IR) p < 0.001

6.2 6.4 6.6 6.8 0−yr 3−yr 6−yr

Clinic visit log(ISSI−2)

D: Beta−cell function (ISSI−2)

Figure 1:Trends over time, outcomes.

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While clinical measures did not change

p = 0.188

90 95 100 105 110 0−yr 3−yr 6−yr

Clinic visit Waist circumference (cm)

A: Estimate of central adiposity (Waist) p = 0.707

26 28 30 32 34 0−yr 3−yr 6−yr

Clinic visit BMI (kg/m2)

B: Estimate of adiposity (BMI) p = 0.806

1.00 1.25 1.50 1.75 0−yr 3−yr 6−yr

Clinic visit TAG (mmol/L)

C: Triacylglycerides p = 0.162

1.0 1.1 1.2 1.3 1.4 1.5 1.6 0−yr 3−yr 6−yr

Clinic visit HDL (mmol/L)

D: High−density lipoprotein

Figure 2:Trends over time, clinical measures.

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Higher total NEFA predicts 25%5 greater risk for dysglycemia

5RR = 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

log(1/HOMA−IR) log(ISI) log(IGI/IR) log(ISSI−2)

• Total

16:0 18:0 18:1 n−9 18:2 n−6 20:4 n−6 18:3 n−3 20:5 n−3 22:6 n−3 −15−10 −5 5 −15−10 −5 5 −15−10 −5 5 −15−10 −5 5

Percent change (with 95% CI) for every 1 SD increase in fatty acids Non−esterified fatty acid species

P−value

• >0.05

<0.05 <0.01

Insulin sensitivity & Beta−cell function

Figure 3:Forest plot of generalized estimating equation results.

5RR = 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

6Giacca 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 lipotoxicity6

6Giacca 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

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References

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