Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy

Forbes, Shareen; Barr, Sarah M.; Reynolds, Rebecca M; Semple, Scott I.; Gray, Calum; Andrew, Ruth; Denison, Fiona C; Walker, Brian R.; Norman, Jane E.

doi:10.1007/s00125-015-3708-3

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Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy

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Author(s): Shareen Forbes , Sarah M. Barr , Rebecca M. Reynolds , Scott Semple , Calum Gray , Ruth Andrew , Fiona C. Denison , Brian R. Walker , Jane E. Norman

Publication date (Electronic): 7 August 2015

Journal: Diabetologia

Publisher: Springer Berlin Heidelberg

Keywords: Insulin resistance, MRI, Pregnancy, Stable isotope studies, Very severe obesity

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Abstract

Aims

Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies.

Methods

We recruited a longitudinal cohort of very severely obese ( n = 190) and lean ( n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case–control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic–euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6–9) and body fat distribution by MRI in late pregnancy ( n = 10/group).

Results

Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier ( p = 0.04).

Conclusions/interpretation

Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy.

Electronic supplementary material

The online version of this article (doi:10.1007/s00125-015-3708-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Most cited references 41

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Glucose clamp technique: a method for quantifying insulin secretion and resistance.

Christian R. Andres, Stephanie J. Tobin, R. DeFronzo (1979)

Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

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Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus.

Tara L. Huston, P Catalano, S Amini Kafi-abad … (1999)

This study prospectively evaluated the longitudinal changes in insulin sensitivity, insulin response, and endogenous (primarily hepatic) glucose production and suppression during insulin infusion in women with normal glucose tolerance (control) and gestational diabetes mellitus before and during a planned pregnancy. Eight control subjects and 7 subjects in whom gestational diabetes mellitus developed were evaluated with an oral glucose tolerance test, an intravenous glucose tolerance test, and hyperinsulinemic-euglycemic clamp with infusion of [6,6 (2)H2 ]glucose before conception and at 12 to 14 and 34 to 36 weeks' gestation. Insulin response was estimated as the area under the curve during the intravenous glucose tolerance test. Basal endogenous glucose production was estimated from isotope tracer dilution during steady state with [6,6 (2)H2 ]glucose and suppression during insulin infusion. Insulin sensitivity to glucose was defined as the glucose infusion rate required to maintain euglycemia during steady-state insulin infusion. Body composition was estimated with hydrodensitometry. Data were analyzed with 2-way analysis of variance with repeated measures for 2 groups. There were increases in first-phase (P =.006) and second-phase (P =. 0001) insulin responses in both groups with advancing gestation, but the increase in second-phase response was significantly greater (P =. 02) in the gestational diabetes mellitus group than in the control group. Basal glucose production increased significantly (P =.0001) with advancing gestation, and there was resistance to suppression during insulin infusion in both groups (P =.0001). There was less suppression of endogenous glucose production however, in the gestational diabetes mellitus group than in the control group (P =. 01). Insulin sensitivity decreased with advancing gestation in both groups (P =.0001), and there was lower insulin sensitivity in the gestational diabetes mellitus group than in the control group (P =. 04). Significant decreases in insulin sensitivity with time (P =. 0001) and between groups (P =.03) remained when the data were adjusted for differences in insulin concentration or residual hepatic glucose production. Obese women in whom gestational diabetes mellitus develops have a significant increase in insulin response but decreases in insulin sensitivity and suppression of hepatic glucose production during insulin infusion with advancing gestation with respect to a matched control group. These metabolic abnormalities in glucose metabolism are the hallmarks of type 2 diabetes, for which these women are at increased risk in later life.

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Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women.

E D Tyzbir, Anthony Roman, S Amini Kafi-abad … (1991)

To assess the longitudinal changes in insulin release and insulin sensitivity in nonobese normal women during gestation, six women were evaluated with oral glucose tolerance testing, body composition analysis, intravenous glucose tolerance tests, and the hyperinsulinemic-euglycemic clamp before conception, at 12 to 14 weeks, and at 34 to 36 weeks' gestation. There was a significant increase in the insulin/glucose ratio (p = 0.028) during the oral glucose tolerance test during gestation. There was also a significant 3.0- to 3.5-fold increase throughout gestation in first-phase (p = 0.001) and second-phase (p = 0.0001) insulin release during the intravenous glucose tolerance test. Peripheral insulin sensitivity was estimated as the glucose infusion rate (in milligrams per kilogram fat-free mass per minute) during the hyperinsulinemic-euglycemic clamp. There was a significant (p = 0.0003) 56% decrease in insulin sensitivity through 36 weeks' gestation. These results are the first to prospectively evaluate the longitudinal changes in maternal carbohydrate metabolism from the time before conception through late gestation with newer methods such as the hyperinsulinemic-euglycemic clamp.

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Author and article information

Contributors

Shareen Forbes: Shareen.Forbes@ed.ac.uk

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 7 August 2015

Publication date PMC-release: 7 August 2015

Publication date (Print): 2015

Volume: 58

Issue: 11

Pages: 2615-2626

Affiliations

[ ]Tommy’s Centre for Fetal and Maternal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

[ ]Endocrinology Unit, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ UK

[ ]Clinical Research Imaging Centre, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

Article

Publisher ID: 3708

DOI: 10.1007/s00125-015-3708-3

PMC ID: 4589551

PubMed ID: 26248646

SO-VID: 2b0efc9e-5362-43f1-bb07-bd21f7497666

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 31 March 2015

Date accepted : 3 July 2015

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: insulin resistance,mri,pregnancy,stable isotope studies,very severe obesity

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: insulin resistance, mri, pregnancy, stable isotope studies, very severe obesity

Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy

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GLUT4 biology

Most cited references 41

Glucose clamp technique: a method for quantifying insulin secretion and resistance.

Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus.

Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women.

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