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Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort
  1. Zhila Semnani-Azad1,
  2. Luke W Johnston2,
  3. Christine Lee1,
  4. Ravi Retnakaran3,4,5,
  5. Philip W Connelly6,
  6. Stewart B Harris7,
  7. Bernard Zinman3,4,5,
  8. Anthony J Hanley1,3,5
  1. 1Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
  2. 2Department of Public Health, Aarhus Universitet, Aarhus, Denmark
  3. 3Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
  4. 4Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  5. 5Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
  6. 6Keenan Research Centre for Biomedical Science, St Michael’s Hospital, Toronto, Ontario, Canada
  7. 7Centre for Studies in Family Medicine, Western University, London, Ontario, Canada
  1. Correspondence to Dr Anthony J Hanley; anthony.hanley{at}


Objective To evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D).

Research design and methods Adults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (ICFASTING) and areas under the curve of C peptide-to-insulin (ICAUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC.

Results IC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in ICFASTING and ICAUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia.

Conclusions Our findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

  • clearance and action
  • beta cell function
  • insulin sensitivity
  • type 2 diabetes

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  • Contributors ZSA analyzed and interpreted the data and wrote the manuscript. LWJ contributed to data management, statistical guidance, and reviewed and approved the manuscript. CL, PWC, and RR reviewed and approved the manuscript. SBH, BZ, and AJH designed the study and reviewed and approved the manuscript. AJH is the guarantor of this work and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding PROMISE was supported by an operating grant from the Diabetes Canada (grant number: OG-3-14-4574-AH) and Canadian Institutes of Health Research (CIHR) (grant number: MOP130458). ZSA was funded by the CIHR Graduate Scholarships, Ontario Graduate Scholarship and the University of Toronto Banting and Best Scholarship. AJH was supported in part through a Tier II Canada Research Chair in Diabetes Epidemiology. RR holds the Boehringer Ingelheim Chair in Beta-Cell Preservation, Function and Regeneration at Mount Sinai Hospital.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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