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      In Utero Exposure to Maternal Hyperglycemia Increases Childhood Cardiometabolic Risk in Offspring

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          Abstract

          OBJECTIVE

          The objective of this study was to evaluate the effect of maternal hyperglycemia during pregnancy on cardiometabolic risk in offspring during early childhood.

          RESEARCH DESIGN AND METHODS

          A total of 970 mothers who had joined the Hyperglycemia and Adverse Pregnancy Outcome study were reevaluated, together with their child born during the study period, 7 years after delivery.

          RESULTS

          Offspring born to mothers diagnosed with gestational diabetes mellitus (GDM), as defined by the World Health Organization 2013 GDM criteria, had higher rates of abnormal glucose tolerance (4.7% vs. 1.7%; P = 0.04), higher rates of overweight or obesity, greater BMI, higher blood pressure (BP), lower oral disposition index, and a trend toward reduced β-cell function compared with those born to mothers without GDM. For each SD increase in maternal fasting, 1-h, and 2-h glucose levels on oral glucose tolerance tests (OGTTs) between 24 and 32 weeks of the index pregnancy, the risk of abnormal glucose tolerance in the offspring showed a corresponding increase (adjusted odds ratio [OR] 1.85–2.00). The associations were independent of BMI before pregnancy, childhood obesity, or being born large for gestational age. The area under the curve for glucose levels during the five-point OGTT increased to a similar extent in boys and girls with each SD increase in maternal 1-h and 2-h plasma glucose on OGTTs during pregnancy. All three maternal glucose levels were also associated with increased adjusted ORs for childhood overweight or obesity and adiposity among girls, but not boys.

          CONCLUSIONS

          Maternal hyperglycemia in pregnancy is independently associated with offsprings’ risk of abnormal glucose tolerance, obesity, and higher BP at 7 years of age. Its effect on childhood adiposity was apparent only in girls, not boys.

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          Most cited references26

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          Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.

          Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
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            Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships.

            Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.
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              High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia.

              The role of intrauterine hyperglycemia and future risk of type 2 diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) was evaluated in 597 subjects, primarily Caucasians, aged 18-27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4) offspring of women from the background population (O-BP). The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58-23.39) in O-GDM and 4.02 (1.31-12.33) in O-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was significantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04-1.91) per mmol/l. A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either diet-treated GDM or type 1 diabetes during pregnancy.
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                May 2017
                09 March 2017
                : 40
                : 5
                : 679-686
                Affiliations
                [1] 1Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Hong Kong
                [2] 2Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong
                [3] 3Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong
                [4] 4Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong
                [5] 5Department of Paediatrics, Chinese University of Hong Kong, Hong Kong
                [6] 6Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong
                [7] 7Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
                Author notes
                Corresponding author: Wing-Hung Tam, tamwh@ 123456cuhk.edu.hk .
                Author information
                http://orcid.org/0000-0003-1189-740X
                Article
                2397
                10.2337/dc16-2397
                5399651
                28279981
                536b14af-a4de-4ca7-b618-6b2bc8ec4c70
                © 2017 by the American Diabetes Association.

                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.

                History
                : 10 November 2016
                : 10 February 2017
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 37, Pages: 8
                Funding
                Funded by: National Institute of Child Health and Human Development, DOI http://dx.doi.org/10.13039/100000071;
                Award ID: R01-HD34242
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases, DOI http://dx.doi.org/10.13039/100000062;
                Award ID: R01-HD34243
                Funded by: Research Grants Council of the Hong Kong SAR, China
                Award ID: CUHK 473408
                Award ID: CUHK 471713
                Categories
                Cardiovascular and Metabolic Risk

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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