Pregnancy Outcomes and Maternal Insulin Sensitivity

Diabetes Mellitus, Type 2 Clinical Trial

— PROMIS  

Official title:

Pregnancy Outcomes and Maternal Insulin Sensitivity

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04315545
• Other study ID #: 68845
• Status: Recruiting
• Start date: February 6, 2020
• Est. completion date: December 2023

Study information

• Verified date: April 2023
• Source: University Medical Center Groningen
• Contact: Anoush Kdekian, MSc
• Phone: +31641743476
• Email: a.kdekian[@]umcg.nl
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The PROMIS study will focus on maternal insulin sensitivity thourghout pregnancy and postpartum in a moderate to high risk population (BMI ≥25 kg/m2) in developing adverse pregnancy outcomes. Next to the OGTT, the meal tolerance test (MTT) will be used as a tool for metabolic testing.

The investigators hypothesize that (early) pregnancy assessment of maternal glucose-insulin metabolism with a MTT in a moderate to high risk group identify more mothers at risk for adverse pregnancy outcomes compared with standard OGTT testing at 24-28 weeks.

Description:

The worldwide prevalence of overweight and obesity is rapidly increasing, also affecting women of reproductive age. The prevalence of overweight women between 30-40 years in the Netherlands in 2017 was 39%. Women with a BMI ≥25 kg/m2 have excess adipose tissue which reduces insulin sensitivity and explains the correlated adverse outcomes for both mother and child.

Insulin sensitivity changes over the course of pregnancy due to the effect of placental hormones and is therefore normally decreased by the end of the second trimester to ensure a continuous supply of nutrients towards the growing fetus. Insulin resistance leads to beta-cell proliferation and larger volume of individual beta-cells, returning to non-pregnant levels after parturition. When beta-cell proliferation is not or inadequately increased, this may lead to hyperglycemia. It is shown that small increases in maternal glucose levels have a linear relationship with adverse outcomes. Maternal adverse outcomes are pre-eclampsia, caesarian section and gestational diabetes mellitus (GDM) on the short term and increased risk of weight retention and non-communicable diseases like cardiovascular diseases and diabetes mellitus type 2 (DM2) on the longer term. Adverse outcomes in infants are macrosomia, large for gestational age (LGA), small for gestational age (SGA) on the short term and a higher risk on childhood obesity and non-communicable diseases on the longer term. Adequate maternal insulin sensitivity throughout pregnancy is therefore critical.

Small maternal glucose increases could already be detected in an early stage of pregnancy. In the Netherlands hyperglycemia is standardly examined at the end of the second trimester in an at risk population by an oral glucose tolerance test (OGTT). This test is less suitable to detect mild hyperglycemia in early stages of pregnancy, with merely blood glucose levels as a result, and shows a lot of within subject variability. However markers of insulin sensitivity and related metabolic adaptations, for instance in lipid metabolism, may be a more straightforward measure that could potentially be detected earlier and allow for early intervention. An integration of postprandial responses of glucose/insulin following a meal challenge combined with lipid markers could provide clearer insights in maternal metabolic function. A test that could be used to examine this in more detail is a liquid meal tolerance test (MTT) which contains a balanced macro- and micronutrient composition. Assessing glucose homeostasis is not possible by only measuring glucose concentrations as there are numerous perturbations where glucose production and its utilization increases or decreases to the same extent without any changes in concentrations. For the understanding of the physiology and pathophysiology of glucose uptake and metabolism during pregnancy, glucose tracers should be followed.

The PROMIS study will specifically focus on the associations between insulin sensitivity in the mother in early pregnancy and fetal and neonatal outcomes with emphasis on growth and body composition. The investigators therefore hypothesize that when overweight pregnant women are challenged in early pregnancy with a MTT, the group of women with disturbed insulin sensitivity could be identified much earlier, and can therefore have a predictive role in adverse outcomes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2023
• Est. primary completion date: July 2023
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Healthy singleton pregnant women (10-12 weeks of gestation)

• BMI =25 kg/m2

• FPG =7.0 mmol/l

• Dutch or English speaking

• Written informed consent

Exclusion Criteria:

• Serious health complications (Hypertension, Hyperlipidemia, Asthma, Haemochromatosis) or medication use that influence the glucose metabolism or fetal growth (e.g. corticosteroids).

• Multiple pregnancy

• pre-existing Diabetes type 1 and 2 defined as FPG =7.0 mmol/l or use of diabetes medication

• Participation in any other studies involving the investigation of medication or nutritional products or severe illness or antibiotic use in the two weeks prior to entry into the study

• HIV/Hepatitis

• Expectation of non-compliance to the study protocol, among others, a fear of needles

• Known allergies or intolerances for one or more nutritional ingredients in the MTT

• Psychological dysfunctions

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diabetes, Gestational
• Gestational Diabetes
• Hypersensitivity
• Insulin Resistance
• Other Heavy-For-Dates Infants
• Small for Gestational Age Infant

Intervention

Diagnostic Test:
• meal tolerance test
In addition to the standard oral glucose tolerance (which is normally performed between 24-28 weeks of pregnancy), is used to test the metabolic resilience capacity of glucose, we will provide our participants with a different diagnostic tool named 'meal tolerance test' in an earlier stage of pregnancy (12-16 weeks), mid pregnancy (24-28 weeks) and 3 months postpartum.

Locations

Country	Name	City	State
Netherlands	University Medical Centre Groningen	Groningen
Netherlands	Medical Center Leeuwarden	Leeuwarden

Sponsors (1)

Lead Sponsor	Collaborator
University Medical Center Groningen

Country where clinical trial is conducted

Netherlands, 

References & Publications (26)

Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG. 2006 Oct;113(10):1126-33. doi: 10.1111/j.1471-0528.2006.00989.x. Epub 2006 Jul 7. — View Citation

Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999 Apr;180(4):903-16. doi: 10.1016/s0002-9378(99)70662-9. — View Citation

Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr. 2003 May;133(5 Suppl 2):1674S-1683S. doi: 10.1093/jn/133.5.1674S. — View Citation

Chen C, Xu X, Yan Y. Estimated global overweight and obesity burden in pregnant women based on panel data model. PLoS One. 2018 Aug 9;13(8):e0202183. doi: 10.1371/journal.pone.0202183. eCollection 2018. — View Citation

Cobelli C, Man CD, Sparacino G, Magni L, De Nicolao G, Kovatchev BP. Diabetes: Models, Signals, and Control. IEEE Rev Biomed Eng. 2009 Jan 1;2:54-96. doi: 10.1109/RBME.2009.2036073. — View Citation

Feig DS, Zinman B, Wang X, Hux JE. Risk of development of diabetes mellitus after diagnosis of gestational diabetes. CMAJ. 2008 Jul 29;179(3):229-34. doi: 10.1503/cmaj.080012. Erratum In: CMAJ. 2008 Aug 12;179(4):344. — View Citation

Ferrara A, Peng T, Kim C. Trends in postpartum diabetes screening and subsequent diabetes and impaired fasting glucose among women with histories of gestational diabetes mellitus: A report from the Translating Research Into Action for Diabetes (TRIAD) Study. Diabetes Care. 2009 Feb;32(2):269-74. doi: 10.2337/dc08-1184. Epub 2008 Nov 4. — View Citation

Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. Am J Obstet Gynecol. 1985 Feb 1;151(3):333-7. doi: 10.1016/0002-9378(85)90298-4. — View Citation

HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. — View Citation

Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002 Oct;25(10):1862-8. doi: 10.2337/diacare.25.10.1862. — View Citation

Ko GT, Chan JC, Woo J, Lau E, Yeung VT, Chow CC, Cockram CS. The reproducibility and usefulness of the oral glucose tolerance test in screening for diabetes and other cardiovascular risk factors. Ann Clin Biochem. 1998 Jan;35 ( Pt 1):62-7. doi: 10.1177/000456329803500107. — View Citation

Koning SH, Hoogenberg K, Lutgers HL, van den Berg PP, Wolffenbuttel BH. Gestational Diabetes Mellitus:current knowledge and unmet needs. J Diabetes. 2016 Nov;8(6):770-781. doi: 10.1111/1753-0407.12422. Epub 2016 Jul 28. — View Citation

Koning SH, Hoogenberg K, Scheuneman KA, Baas MG, Korteweg FJ, Sollie KM, Schering BJ, van Loon AJ, Wolffenbuttel BH, van den Berg PP, Lutgers HL. Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study. BMC Endocr Disord. 2016 Sep 29;16(1):52. doi: 10.1186/s12902-016-0136-4. — View Citation

Koning SH, van Zanden JJ, Hoogenberg K, Lutgers HL, Klomp AW, Korteweg FJ, van Loon AJ, Wolffenbuttel BHR, van den Berg PP. New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes. Diabetologia. 2018 Apr;61(4):800-809. doi: 10.1007/s00125-017-4506-x. Epub 2017 Nov 22. — View Citation

Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007 Dec;50(4):938-48. doi: 10.1097/GRF.0b013e31815a5494. — View Citation

Langer O, Umans JG, Miodovnik M. The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference. J Matern Fetal Neonatal Med. 2013 Jan;26(2):111-5. doi: 10.3109/14767058.2012.734874. Epub 2012 Oct 30. — View Citation

Maegawa Y, Sugiyama T, Kusaka H, Mitao M, Toyoda N. Screening tests for gestational diabetes in Japan in the 1st and 2nd trimester of pregnancy. Diabetes Res Clin Pract. 2003 Oct;62(1):47-53. doi: 10.1016/s0168-8227(03)00146-3. — View Citation

Malcolm J, Lawson ML, Gaboury I, Keely E. Risk perception and unrecognized type 2 diabetes in women with previous gestational diabetes mellitus. Obstet Med. 2009 Sep;2(3):107-10. doi: 10.1258/om.2009.080063. Epub 2009 Sep 1. — View Citation

NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017 Dec 16;390(10113):2627-2642. doi: 10.1016/S0140-6736(17)32129-3. Epub 2017 Oct 10. — View Citation

Noctor E, Dunne FP. Type 2 diabetes after gestational diabetes: The influence of changing diagnostic criteria. World J Diabetes. 2015 Mar 15;6(2):234-44. doi: 10.4239/wjd.v6.i2.234. — View Citation

Seshiah V, Cynthia A, Balaji V, Balaji MS, Ashalata S, Sheela R, Thamizharasi M, Arthi T. Detection and care of women with gestational diabetes mellitus from early weeks of pregnancy results in birth weight of newborn babies appropriate for gestational age. Diabetes Res Clin Pract. 2008 May;80(2):199-202. doi: 10.1016/j.diabres.2007.12.008. Epub 2008 Feb 4. — View Citation

Sonagra AD, Biradar SM, K D, Murthy D S J. Normal pregnancy- a state of insulin resistance. J Clin Diagn Res. 2014 Nov;8(11):CC01-3. doi: 10.7860/JCDR/2014/10068.5081. Epub 2014 Nov 20. — View Citation

Venkataraman H, Ram U, Craik S, Arungunasekaran A, Seshadri S, Saravanan P. Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians: more evidence for the 'thin-fat' baby. Diabetologia. 2017 Mar;60(3):399-405. doi: 10.1007/s00125-016-4166-2. Epub 2016 Dec 2. — View Citation

World Health Organization. World health statistics 2016: Monitoring health for the SDGs sustainable development goals. World Health Organization; 2016.

Yang X, Hsu-Hage B, Zhang H, Zhang C, Zhang Y, Zhang C. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002 Sep;25(9):1619-24. doi: 10.2337/diacare.25.9.1619. — View Citation

Zhu Y, Zhang C. Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective. Curr Diab Rep. 2016 Jan;16(1):7. doi: 10.1007/s11892-015-0699-x. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	FFQ	Food frequency questionnaire	between week 12-16 of gestation
Other	FFQ	Food frequency questionnaire	between 24-28 of gestation
Other	FFQ	Food frequency questionnaire	1 month postpartum
Other	FFQ	Food frequency questionnaire	3 months postpartum
Other	AEBQ	Adult eating behaviour questionnaire	between week 12-16 of gestation
Other	AEBQ	Adult eating behaviour questionnaire	between 24-28 of gestation
Other	AEBQ	Adult eating behaviour questionnaire	1 month postpartum
Other	AEBQ	Adult eating behaviour questionnaire	3 months postpartum
Other	BEBQ	Baby eating behaviour questionnaire	1 month postpartum in child
Other	BEBQ	Baby eating behaviour questionnaire	3 months postpartum in child
Other	EQ	EQ-5D questionnaire	Between week 12-16 of gestation
Other	EQ	EQ-5D questionnaire	between week 24-28 of gestation
Other	EQ	EQ-5D questionnaire	1 month postpartum
Other	EQ	EQ-5D questionnaire	3 months postpartum
Other	PA	Pregnancy physical activity questionnaire	between week 12-16 of gestation
Other	PA	Pregnancy physical activity questionnaire	between week 24-28 of gestation
Other	PA	International physical activity questionnaire	1 month postpartum
Other	PA	International physical activity questionnaire	3 months postpartum
Other	MP	Meal test preference questionnaire	In week 24 of gestation
Other	MP	Meal test preference questionnaire	In week 25 of gestation
Primary	fasting glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=0 min, before intake of test drink
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=10 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=20 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=30 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=45 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=60 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=90 min postprandial
Primary	postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	T=120 min postprandial
Primary	fasting and postprandial glucose	Bloood will be collected fasted and after intake of the MTT and OGTT	AUC and postprandial curve
Primary	fasting insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=0 min, before intake of test drink
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=10 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=20 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=30 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=45 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=60 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=90 min postprandial
Primary	postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	T=120 min postprandial
Primary	fasting and postprandial insulin	Blood will be collected fasted and after intake of the MTT and OGTT	AUC and postprandial curve
Secondary	Triglycerides	Blood will be collected fasted	T=0 min, before intake of test drink
Secondary	Total cholesterol	Blood will be collected fasted	T=0 min, before intake of test drink
Secondary	HDL-cholesterol	Blood will be collected fasted	T=0 min, before intake of test drink
Secondary	Free fatty acids	Blood will be collected fasted	T=0 min, before intake of test drink
Secondary	Hba1c	Blood will be collected fasted	T=0 min, before intake of test drink
Secondary	Fasting stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=0, before intake of test drink
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=10 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=20 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=30 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=45 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=60 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=90 min postprandial
Secondary	postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	T=120 min postprandial
Secondary	fasting and postprandial stable glucose isotopes	Blood will be collected fasted and after intake of the MTT and OGTT	AUC and postprandial curve