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Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis

  • Domenico TricòEmail author
  • Alessandro Mengozzi
  • Lorenzo Nesti
  • Mensud Hatunic
  • Rafael Gabriel Sanchez
  • Thomas Konrad
  • Katarina Lalić
  • Nebojša M. Lalić
  • Andrea Mari
  • Andrea Natali
  • for the EGIR-RISC Study Group



Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or ‘lipokine’) to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans.


Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic–euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance.


Circulating palmitoleate was proportional to fat mass (r = 0.21, p < 0.0001) and total NEFA levels (r = 0.19, p < 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. β] = 0.16, p < 0.0001), liver insulin resistance (std. β = −0.14, p < 0.0001), beta cell function (potentiation: std. β = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. β = −0.24, p < 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. β = 0.07, p = 0.04).


We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism.


Adipokine Beta cell function Glucose tolerance Insulin sensitivity Lipokine Monounsaturated fatty acid NEFA Palmitate Palmitoleic acid Subcutaneous adipose tissue 



Fat-free mass


Percentage fat mass


Impaired fasting glucose


Impaired glucose tolerance


Monounsaturated fatty acid


Normal glucose tolerance


Oral glucose insulin sensitivity index


Percentage palmitoleate enrichment in the total NEFA pool


Polyunsaturated fatty acid


Relationship between Insulin Sensitivity and Cardiovascular disease study


Stearoyl-CoA desaturase-1


Saturated fatty acid

std. β

Standardised regression coefficient



Preliminary study findings were presented as an abstract at the 55th EASD Annual Meeting in Barcelona, Spain, in 2019.

Contribution statement

DT contributed to study design, data analysis and interpretation and writing the manuscript. AMe, LN, MH, RGS, TK, KL and NML contributed to data collection and edited the manuscript. AM undertook the mathematical modelling of insulin secretion and beta cell function variables, contributed to data interpretation and edited the manuscript. AN contributed to study design and supervision, securing of funding, and data collection, analysis and interpretation, and edited and critically revised the manuscript. All authors read and approved the final submitted version of the manuscript. DT and AN are the guarantors of this work and, as such, have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.


The RISC study was partly supported by European Union grant QLG1-CT-2001-01252. DT is funded by the European Foundation for the Study of Diabetes (EFSD) Mentorship Programme.

Duality of interest

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

Supplementary material

125_2019_5013_MOESM1_ESM.pdf (169 kb)
ESM Figures (PDF 168 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Domenico Tricò
    • 1
    • 2
    Email author
  • Alessandro Mengozzi
    • 1
  • Lorenzo Nesti
    • 1
  • Mensud Hatunic
    • 3
  • Rafael Gabriel Sanchez
    • 4
  • Thomas Konrad
    • 5
  • Katarina Lalić
    • 6
  • Nebojša M. Lalić
    • 6
  • Andrea Mari
    • 7
  • Andrea Natali
    • 1
  • for the EGIR-RISC Study Group
  1. 1.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Institute of Life SciencesSant’Anna School of Advanced StudiesPisaItaly
  3. 3.Department of EndocrinologyMater Misericordiae University Hospital, University College Dublin School of MedicineDublinIreland
  4. 4.Unidad de InvestigacionHospital Universitario de la PrincesaMadridSpain
  5. 5.Institute for Metabolic ResearchGoethe UniversityFrankfurt am MainGermany
  6. 6.Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  7. 7.Institute of NeuroscienceNational Research CouncilPaduaItaly

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