, Volume 61, Issue 4, pp 821–830 | Cite as

Association of NEFA composition with insulin sensitivity and beta cell function in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort

  • Luke W. Johnston
  • Stewart B. Harris
  • Ravi Retnakaran
  • Adria Giacca
  • Zhen Liu
  • Richard P. Bazinet
  • Anthony J. Hanley



Our aim was to determine the longitudinal associations of individual NEFA with the pathogenesis of diabetes, specifically with differences in insulin sensitivity and beta cell function over 6 years in a cohort of individuals who are at risk for diabetes.


In the Prospective Metabolism and Islet Cell Evaluation (PROMISE) longitudinal cohort, 477 participants had serum NEFA measured at the baseline visit and completed an OGTT at three time points over 6 years. Outcome variables were calculated using the OGTT values. At each visit, insulin sensitivity was assessed using the HOMA2 of insulin sensitivity (HOMA2-%S) and the Matsuda index, while beta cell function was assessed using the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion-sensitivity index-2 (ISSI-2). Generalised estimating equations were used, adjusting for time, waist, sex, ethnicity, baseline age, alanine aminotransferase (ALT) and physical activity. NEFA were analysed as both concentrations (nmol/ml) and proportions (mol%) of the total fraction.


Participants’ (73% female, 70% with European ancestry) insulin sensitivity and beta cell function declined by 14–21% over 6 years of follow-up. In unadjusted models, several NEFA (e.g. 18:1 n-7, 22:4 n-6) were associated with lower insulin sensitivity, however, nearly all of these associations were attenuated in fully adjusted models. In adjusted models, total NEFA, 16:0, 18:1 n-9 and 18:2 n-6 (as concentrations) were associated with 3.7–8.0% lower IGI/IR and ISSI-2, while only 20:5 n-3 (as mol%) was associated with 7.7% higher HOMA2-%S.


Total NEFA concentration was a strong predictor of lower beta cell function over 6 years. Our results suggest that the association with beta cell function is due to the absolute size of the serum NEFA fraction, rather than the specific fatty acid composition.


Beta cell function Diabetes pathogenesis Fatty acid composition Insulin sensitivity Longitudinal cohort Non-esterified fatty acids 



Alanine aminotransferase


Eicosapentaenoic acid


False discovery rate


Generalised estimating equations


HOMA2 of insulin sensitivity


Impaired fasting glucose


Insulinogenic index over HOMA-IR


Impaired glucose tolerance


Insulin sensitivity index (Matsuda index)


Insulin secretion-sensitivity index-2


Modified activity questionnaire


Metabolic equivalent of task


Partial least squares regression


Prospective Metabolism and Islet Cell Evaluation Cohort


Polyunsaturated fatty acids


Quasi-likelihood information criterion




Waist circumference



The authors thank J Neuman, PV Nostrand, S Kink and A Barnie (all of the Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Canada) and S Porter and M Marin (both of the Centre for Studies in Family Medicine, University of Western Ontario, Canada) for their expert technical assistance and dedication in their work for PROMISE.

Contribution statement

The authors had the following responsibility: LWJ analysed and interpreted the data and drafted the article; RR and SBH contributed to the conception and design and revised the article intellectual content; ZL acquired the data and revised the article intellectual content; AG assisted with interpretation of the data and revised the article intellectual content; AJH and RPB substantially contributed to the study conception and design, assisted with interpretation of the data and revised the article intellectual content. All authors read and approved the final version. LWJ and AJH have primary responsibility for final content and are the guarantors of this work.


This study was supported by grants from the Canadian Diabetes Association (CDA; Grant number: OG-3-14-4574-AH), the Canadian Institutes for Health Research (Grant number: MOP-130458) and the University of Toronto Banting and Best Diabetes Centre. LWJ was supported by a CDA Doctoral Student Research Award; RR was supported by a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award; SBH holds the CDA Chair in National Diabetes Management and the Ian McWhinney Chair of Family Medicine Studies at the University of Western Ontario; RPB holds a Tier II Canada Research Chair in Brain Lipid Metabolism and AJH holds a Tier II Canada Research Chair in Diabetes Epidemiology.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2017_4534_MOESM1_ESM.pdf (1.4 mb)
ESM (PDF 1478 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Luke W. Johnston
    • 1
  • Stewart B. Harris
    • 2
  • Ravi Retnakaran
    • 3
    • 4
  • Adria Giacca
    • 5
  • Zhen Liu
    • 1
  • Richard P. Bazinet
    • 1
  • Anthony J. Hanley
    • 1
    • 3
    • 6
  1. 1.Department of Nutritional Sciences, Faculty of MedicineUniversity of TorontoTorontoCanada
  2. 2.Centre for Studies in Family MedicineUniversity of Western OntarioLondonCanada
  3. 3.Division of EndocrinologyUniversity of TorontoTorontoCanada
  4. 4.Lunenfeld Tanenbaum Research InstituteMount Sinai HospitalTorontoCanada
  5. 5.Department of PhysiologyUniversity of TorontoTorontoCanada
  6. 6.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada

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