Developmental ORIgins of Healthy and Unhealthy AgeiNg: the Role of Maternal Obesity (DORIAN)

The prevalence of obesity in the developed world has increased markedly over the last 20 years. Considering the prevalence of obese and overweight adult subjects, and the fact that pregnancy itself induces a state of insulin resistance and inflammation, maternal obesity may be the most common health risk for the developing fetus. It is well established that what we eat has a major impact on our health. However, there is growing evidence to suggest that diet during pregnancy and lactation may be particularly important as not only does it influence the health of the mother, it may have a permanent effect on the health of her children and even her grandchildren. The concept that environmental factors, such as nutrition during early development, influence both our health span and lifespan has been termed the developmental origins of health and disease hypothesis.

The objective of the study are:

• to compare subjects with frailty (condition developed with ageing) with controls and characterize the unhealthy aged condition with the measurements described below
• to examine if signs of frailty can be reversed by lifestyle induced modifications (exercise training programme) of its primary components (IR, sarcopenia, psychological profile) in offspring of overweight/obese (OOM) vs lean mothers (OLM).

The study consists of 37 frail old subjects, age ≥ 65 sub-grouped in 17 OOM, and 20 OLM and 11 non frail controls. These subjects will be studied with positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS) and ultra sounds (US). In addition functional MRI (fMRI) will be performed. Adipose tissue biopsies will be taken.

Subjects will undergo characterization of biohumoral markers, a 75 g oral glucose tolerance test, imaging biomarkers (PET/CT, US, fMRI-MRS), genetic biomarkers (DNA and telomere damage) and inflammatory biomarkers (macrophage infiltration) before and after the 4-month lifestyle intervention period (physical exercise). By PET/CT it will be measured tissue-specific IR in skeletal muscle, adipose tissue, liver, myocardium and targeted brain regions. MRS will be used to measure organ steatosis in the skeletal muscle and liver, MRI will be used to measure fat masses in abdominal areas, and fMRI will be performed to assess activation in brain regions regulating cognition and appetite/energy control. US will be used to assess cardiovascular markers (IMT, strain and function).

Study Overview

• Status: Completed
• Conditions: Muscle Weakness; Insulin Resistance; Maternal-Fetal Relations
• Intervention / Treatment: Behavioral: Exercise Training

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00014
    • University of Helsinki, Department of General Practice and Primary Health Care
  • Turku, Finland, 20521
    • Turku PET Centre (Turku University Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Subjects must be already participating the Helsinki Birth Cohort Study

Frailty Groups Inclusion Criteria:

• (Frailty) with lowest half of adult grip strength (measured 2001-2004)
• Group OM: (Offspring of Obese mothers) Highest quartile of maternal BMI
• Group LM: (Offspring of Normal weight/Lean mothers) Lowest two quartiles of maternal BMI

Control group Inclusion Criteria:

• (no Frailty) with highest half of adult grip strength (measured 2001-2004)
• Offspring of normal weight mothers

Exclusion Criteria:

• Subjects whose mothers were pre-eclamptic during pregnancy
• Oral corticosteroid or Warfarin therapy
• Recent myocardial infarction
• Severe chronic disorder that can prevent to participate the intervention
• Chronic atrial fibrillation and pacemaker
• Cancer less than 5 years ago
• Current smoking
• Diabetes requiring insulin treatment or fasting glucose more than 7 mmol/l
• Weight more than 170 kg and Waist circumference > 150 cm
• Inner ear implants
• Metal objects in body including metallic prostheses, artificial valve prostheses, surgical clips, braces, foreign fragments or tattoo

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise Training - 17 offspring of OM; 4 months exercise training, OM: Obese mothers	Behavioral: Exercise Training; Three times a week, for four months.
No Intervention: 11 non-frail controls (9 LM); Studied only at baseline
Experimental: Exercise Training - 20 offspring of LM; 4 months exercise training, LM:Lean/Normal Mothers	Behavioral: Exercise Training; Three times a week, for four months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline group comparison and Change from Baseline in Insulin-stimulated whole body and organ-specific glucose uptake at 4 months	Assessed via 18F-Fluorodeoxyglucose (FDG)-PET/CT+Clamp technique	At day 1 and after 4 months of intervention (for the 15 controls only at baseline)
Baseline group comparison and Change from Baseline in Epigenetic characterization of DNA samples (Telomere length, H2A.X phosphorilation, mtDNA deletion, p66) at 4 months	Telomere length, H2A.X phosphorilation, mtDNA deletion are measurements performed in Pisa, National Research Council p66 presence is measured in Rome, Istituto Superiore di Sanita'	At day 1 and after 4 months of intervention (for the 15 controls only at baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline group comparison and Change from Baseline in Fat masses and content via MRI and MRS at 4 months	Adipose tissue fat masses in different depots (subcutaneous, visceral, pericardial) Liver, skeletal muscle, vertebral fat content	At day 1 and after 4 months of intervention (for the 15 controls only at baseline)
Baseline group comparison and Change from Baseline in MRI brain anatomy and fMRI characterization of activation response to food stimuli of different brain regions at 4 months	MRI anatomy: White matter volume, Cortex thickness, Nerve tracks found with Diffusor Tension Imaging fMRI will be used to identify different brain regions activated by food stimuli while subjects perform three different task: watch the food, think of eating the food, control the urge to eat the food.	At day 1 and after 4 months of intervention

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: University of Turku; Istituto Superiore di Sanità; University of Helsinki; Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy
• Investigators: Principal Investigator: Pirjo Nuutila, MD PhD, Turku PET Centre (Turku University Hospital)

Publications and helpful links

General Publications

• Berry A, Bucci M, Raggi C, Eriksson JG, Guzzardi MA, Nuutila P, Huovinen V, Iozzo P, Cirulli F. Dynamic changes in p66Shc mRNA expression in peripheral blood mononuclear cells following resistance training intervention in old frail women born to obese mothers: a pilot study. Aging Clin Exp Res. 2018 Jul;30(7):871-876. doi: 10.1007/s40520-017-0834-4. Epub 2017 Sep 26.
• Huovinen V, Bucci M, Lipponen H, Kiviranta R, Sandboge S, Raiko J, Koskinen S, Koskensalo K, Eriksson JG, Parkkola R, Iozzo P, Nuutila P. Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers. PLoS One. 2016 Sep 26;11(9):e0163723. doi: 10.1371/journal.pone.0163723. eCollection 2016.
• Bucci M, Huovinen V, Guzzardi MA, Koskinen S, Raiko JR, Lipponen H, Ahsan S, Badeau RM, Honka MJ, Koffert J, Savisto N, Salonen MK, Andersson J, Kullberg J, Sandboge S, Iozzo P, Eriksson JG, Nuutila P. Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers. Diabetologia. 2016 Jan;59(1):77-86. doi: 10.1007/s00125-015-3780-8.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: August 26, 2013
• First Posted (Estimate): August 29, 2013

Study Record Updates

• Last Update Posted (Estimate): March 22, 2016
• Last Update Submitted That Met QC Criteria: March 21, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Obesity; Exercise Therapy; Epigenesis, Genetic
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Hyperinsulinism; Pregnancy Complications; Obesity; Muscle Weakness; Insulin Resistance; Obesity, Maternal
• Other Study ID Numbers: T55/2012b; EC-FP7-278603 (Other Grant/Funding Number: EC within the FP7 under the project DORIAN, GA n° 278603)