Women with prior gestational diabetes mellitus and prediabetes are characterised by a decreased incretin effect
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We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM).
In this cross-sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% × [AUCinsulin,OGTT − AUCinsulin,IIGI]/AUCinsulin,OGTT).
Sixty-three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01).
Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes.
KeywordsGestational diabetes mellitus Impaired glucose tolerance Incretin effect Isoglycaemic i.v. glucose infusion Oral glucose tolerance test Prediabetes Type 2 diabetes
Fasting plasma glucose
Good clinical practice
Gestational diabetes mellitus
Gastrointestinal-mediated glucose disposal
Glucose-dependent insulinotropic polypeptide
Impaired fasting glucose
Impaired glucose tolerance
Isoglycaemic i.v. glucose infusion
Insulin secretory rate
Normal glucose tolerance
Prior gestational diabetes mellitus
The authors are grateful to the participating women and for laboratory assistance from: N. Kjeldsen, J. Purtoft, S. M. Schmidt and I. A. Nachar at Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; L. Thielsen and L. Albæk from the Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; and Novo Nordisk, Bagsværd, Denmark for the supply of valine-pyrrolidide. Part of this work has been presented as an abstract at the Scientific Sessions of the ADA in San Francisco, June 2014, and Boston, June 2015, and at the Annual Meeting of the EASD in Vienna, September 2014, and Stockholm, September 2015.
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.
The study was initiated by the authors and supported as an investigator-initiated study by unrestricted grants from Novo Nordisk, the Novo Nordisk Foundation and the Danish Diabetes Academy. Research support was received from the AP Moeller Foundation and Danielsen Foundation. The study sponsor (Novo Nordisk) was involved in the design of the study; but not the collection, analysis, and interpretation of data; neither writing the report; nor the decision to submit the report for publication.
Duality of interest
SF, LV, CA, ESA, EB, JIB, TDC, JAS, ERM declare that there is no duality of interest associated with this manuscript. JJH is on the advisory panel of, consultant for, in the speaker bureau of and/or has received research support from AstraZeneca, GlaxoSmithKline, Hamni, Intarcia, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Zealand Pharma. PD is on the speaker bureau for Novo Nordisk and is participating in a multinational study with Novo Nordisk. FKK is on the advisory panel of, consultant for, in the speaker bureau of and/or has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, Gubra, Novo Nordisk, Merck Sharp & Dohme, Sanofi and Zealand Pharma. TV is on the advisory panel for, consultant for, in the speaker bureau of and/or has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Takeda.
All authors critically revised the manuscript for important intellectual content as well as approved the final version. SF and LV made contributions to conception and design, acquisition of data, and analysis and interpretation of data, and are responsible for the integrity of the data. CA, ESA and EB contributed to acquisition of data, and analysis and interpretation of data. JJH contributed to analysis and interpretation of data. JAS, TDC, ERM and PD were responsible for recruitment of patients and contributed to interpretation of data. JIB contributed to interpretation of data. FKK contributed to the design of the study and interpretation of data. TV is the guarantor of this work and made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, obtained funding and is responsible for the integrity of the data.
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