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e-Letters: Observations

Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia

  1. Ravi Retnakaran1,2,3⇑,
  2. Chang Ye1,
  3. Philip W. Connelly2,4,
  4. Anthony J. Hanley1,2,5,
  5. Mathew Sermer6 and
  6. Bernard Zinman1,2,3
  1. 1Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
  2. 2Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada
  3. 3Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
  4. 4Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada
  5. 5Department of Nutritional Sciences, University of Toronto, Toronto, Canada
  6. 6Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Canada
  1. Corresponding author: Ravi Retnakaran, ravi.retnakaran{at}sinaihealthsystem.ca.
Diabetes Care 2017 Aug; 40(8): e101-e102. https://doi.org/10.2337/dc17-0781
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Adipokine dysregulation and subclinical inflammation are putative diabetogenic features of adiposity. However, while alterations in adipokines/inflammatory proteins can predict incident type 2 diabetes in longitudinal studies (1–3), evidence for causality is generally hindered by two limitations. First, there is a relative paucity of human data linking changes in adipokines/inflammatory proteins with changes in insulin sensitivity and β-cell function over time, as might be expected for causal mediators. Second, because obesity-induced changes in circulating proteins do not occur in isolation, the precise elucidation of causal mediators ideally requires consideration of multiple adipokines/inflammatory proteins simultaneously (as opposed to individually, as typically occurs in studies). Thus, to address these limitations, we evaluated changes over 2 years in adipokines (adiponectin, chemerin, retinol-binding protein 4 [RBP-4]) and inflammatory proteins (C-reactive protein [CRP], plasminogen activator inhibitor 1 [PAI-1]) in relation to changes in insulin sensitivity, β-cell function, and glycemia in women with varying degrees of recent gestational dysglycemia and hence a range of future risk of diabetes.

In this study, 339 women underwent a glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT and measurement of adiponectin (Millipore), chemerin (Millipore), RBP-4 (ALPCO), CRP (Dade Behring), and PAI-1 (Invitrogen) at both 1 year and 3 years postpartum. The study protocol has been previously described in detail (4,5). On each OGTT, insulin sensitivity/resistance was measured by Matsuda index and HOMA of insulin resistance (HOMA-IR), and β-cell function was measured by the Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-IR (4,5). The antepartum GCT/OGTT identified four gestational glucose tolerance groups (gestational diabetes mellitus, gestational impaired glucose tolerance, abnormal GCT with normal OGTT, normal GCT/OGTT), each of which predicts distinct trajectories of future risk of diabetes (5). On multiple linear regression analyses (Table 1), none of the adipokines/inflammatory proteins or their changes predicted β-cell function at 3 years (models A and B). Adiponectin at 1 year predicted insulin sensitivity (Matsuda index) at 3 years, while PAI-1 at 1 year and its change from 1 to 3 years were negative predictors (model C). The same predictors emerged for HOMA-IR, in addition to CRP at 1 year and its change from 1 to 3 years (model D). For both fasting and 2-h glucose at 3 years (models E and F), significant independent predictors were the respective glucose measurement at baseline, BMI at 1 year, and change in BMI from 1 to 3 years. Of note, although weight gain is associated with both increased CRP and insulin resistance, the change in CRP was itself independently and inversely associated with HOMA-IR and fasting glucose at 3 years, likely reflecting the impact of adjustment for concurrent change in BMI and the other adipokines/inflammatory proteins. Finally, on logistic regression analysis with the same covariates, the only predictors of prediabetes/diabetes at 3 years were glucose intolerance at 1 year (odds ratio 8.12, 95% CI 3.98–16.56), BMI at 1 year (1.09, 1.02–1.16), and change in BMI (1.30, 1.05–1.59).

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Table 1

Significant independent predictors of six metabolic outcomes at 3 years postpartum

Thus, in fully adjusted models simultaneously evaluating all of the adipokines/inflammatory proteins and their changes over time, the dominant independent predictors of all of the metabolic outcomes were BMI at 1 year and its change from 1 to 3 years. The impact of adiposity on risk of diabetes in this population does not appear to be mediated by changes in adiponectin, chemerin, RBP-4, CRP, or PAI-1.

Article Information

Funding. This study was supported by operating grants from the Canadian Institutes of Health Research (MOP-84206) and Canadian Diabetes Association (CDA-OG-3-15-4924-RR). R.R. is supported by a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award. A.J.H. holds a Tier-II Canada Research Chair in Diabetes Epidemiology. B.Z. holds the Sam and Judy Pencer Family Chair in Diabetes Research at Mount Sinai Hospital and University of Toronto.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. R.R., P.W.C., A.J.H., M.S., and B.Z. designed and implemented the study. R.R. and C.Y. contributed to the analysis plan and interpretation of the data. C.Y. performed the statistical analyses. R.R. wrote the first draft. All authors critically revised the manuscript for important intellectual content. All authors approved the final manuscript. R.R. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Received April 18, 2017.
  • Accepted May 15, 2017.
  • © 2017 by the American Diabetes Association.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

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    1. Pradhan AD,
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Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia
Ravi Retnakaran, Chang Ye, Philip W. Connelly, Anthony J. Hanley, Mathew Sermer, Bernard Zinman
Diabetes Care Aug 2017, 40 (8) e101-e102; DOI: 10.2337/dc17-0781

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Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia
Ravi Retnakaran, Chang Ye, Philip W. Connelly, Anthony J. Hanley, Mathew Sermer, Bernard Zinman
Diabetes Care Aug 2017, 40 (8) e101-e102; DOI: 10.2337/dc17-0781
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