- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03860558
Impact of Metabolic Health on Sperm Epigenetic Marks in Humans
Study Overview
Status
Intervention / Treatment
Detailed Description
Parental history of diabetes confers substantial individual risk for development of obesity and diabetes. Obesity risk can be transmitted across generations, from parents or grandparents to children. Genomic variation explains only a portion of this risk. Epigenetic modulation through DNA methylation, histone modification, or by noncoding RNAs, provide mechanisms to regulate gene activity independent of DNA sequence by determining which genes are turned on or off in response to environment or disease. Epigenetic changes can be stable over the lifespan providing a mechanism through which environmental exposures may impart long-term effects on gene expression and phenotypic outcome.
The maternal intrauterine environment is now well recognized to modify obesity and T2D disease risk of offspring. Fetuses carried by women who are obese, have diabetes, or suffer from suboptimal nutrition are at increased risk of insulin resistance, obesity, T2D, and cardiovascular disease risk as adults. Studies in rodents also show that the health, metabolism, and prior environmental exposures of the male can also influence health of his offspring. Existing data provide powerful support for the hypothesis that current glucose levels and overall metabolic health of males can alter epigenetic marks in sperm and suggest a novel modifiable mechanism of transmission. However, much less is known about how human sperm epigenetic patterns change with nutritional and metabolic health, and whether these may ultimately impart differences in health of future generations. Thus, we are studying the impact of both type 1 and type 2 diabetes, and elevations in glucose common to both conditions, on human reproductive health and the sperm epigenome.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Mary E Patti, MD
- Phone Number: 6173092635
- Email: mary.elizabeth.patti@joslin.harvard.edu
Study Contact Backup
- Name: Elvira Isganaitis, MD
- Email: elvira.isganaitis@joslin.harvard.edu
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02215
- Recruiting
- Joslin Diabetes Center
-
Contact:
- Elvira Isganaitis, MD
- Email: elvira.isganaitis@joslin.harvard.edu
-
Sub-Investigator:
- Elvira Isganaitis, MD
-
Contact:
- Mary E Patti, MD
- Phone Number: 617-309-2635
- Email: mary.elizabeth.patti@joslin.harvard.edu
-
Principal Investigator:
- Mary E. Patti, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male, age 18-65 years
- Willing and able to provide informed consent and follow all study procedures, including providing sperm specimens 3 months apart.
- Type 1 or type 2 diabetes diagnosis confirmed by an endocrinologist (for participants in the diabetes groups)
- HbA1c > 7% (for participants in the diabetes groups)
- Overweight (BMI > 25 kg/m2) (for all groups, to ensure groups are similar)
Exclusion Criteria:
- Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
- Hepatic disease, including serum alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0;
- Severe diabetic retinopathy;
- Congestive heart failure, New York Heart Association (NYHA) class II, III or IV;
- History of myocardial infarction, unstable angina or revascularization within the past 6 months;
- Active genitourinary infection;
- Testicular volume <12 mL (assessed using Prader orchidometer);
- Hypogonadism, defined as total testosterone <250 ng/dl;
- Hyperprolactinemia, defined as prolactin >18 ng/ml;
- Hyperestrogenism, defined as estradiol >42 pg/ml;
- Cryptorchidism;
- Cigarette smoking;
- Active alcohol abuse or substance abuse;
- Cancer (except localized non-melanoma skin cancers) or use of chemotherapy agents within 5 years;
- Use of nitrates or guanylate cyclase stimulators;
- Use of steroid hormones (including testosterone), other than inhalers for reactive airway disease
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Lifestyle Intervention
20 overweight men with T1D or T2D will undergo an intensive 3 month lifestyle intervention program aimed at improving metabolic health, glycemic control, and body weight.
|
Participants will undergo a 12-week multidisciplinary program for weight control and intensive diabetes management.
The program includes adjustments to diabetes medications to enhance weight reduction and improve glycemia, dietary modification, and activity instructions.
|
Active Comparator: No-Intervention Controls
10 overweight men with T1D or T2D will be assessed at baseline and at 3 months.
They will not participate in a lifestyle intervention.
|
Participants will not undergo an intervention.
|
Active Comparator: Healthy Controls
10 healthy men will be assessed at baseline and at 3 months.
They will not participate in a lifestyle intervention.
|
Participants will not undergo an intervention.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Spermatozoa concentration
Time Frame: 1 year
|
Sperm will be assessed for concentration, reported as total yield (millions per ml)
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Sperm DNA methylation, reported as genomic location of regions with methylation altered in response to intervention
Time Frame: 1 year
|
We will utilize purified DNA (1.5 μg), sheared by sonication to obtain 200-700 bp fragments for subsequent library preparation for methylation-dependent immunoprecipitation and sequencing.
Differentially methylated regions (DMR) are identified using methylated DNA immunoprecipitation coupled with next-generation sequencing (MEDIPS).
DNA methylation is assessed using sliding windows (500 bp size, 200 bp shift).
Regions with read ratios >1.5 or <0.67 and binomial p<0.0001 in independent biologically replicated comparisons are designated as DMR.
|
1 year
|
RNA Sequencing
Time Frame: 1 year
|
RNA will be isolated from sperm samples and subjected to RNA sequencing to analyze the content of both of large messenger ribonucleic acid (mRNA)/noncoding RNA and small RNAs.
Data will be analyzed to identify those species altered in response to intervention.
|
1 year
|
Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2015-40
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Overweight
-
University Hospital, LilleNational Research Agency, France; European Union; University of Lille Nord de... and other collaboratorsNot yet recruitingOverweight and Obesity | Overweight, Childhood | Overweight, Infant
-
Children's Hospital Los AngelesUniversity of Southern California; Tufts Medical CenterRecruitingOverweight and Obesity | Overweight AdolescentsUnited States
-
University of AarhusThe Danish Dairy Research Foundation, Denmark; Sygekassernes HelsefondCompletedOverweight and Obesity | Overweight Adolescents | Metabolic DiseaseDenmark
-
Memorial Sloan Kettering Cancer CenterRecruitingObesity | Overweight | Overweight and Obesity | Obese | Overweight or ObesityUnited States
-
University Hospital Bispebjerg and FrederiksbergUniversity of CopenhagenCompleted
-
Holbaek SygehusUniversity of Copenhagen; University of Florida; University of Minnesota; Hebrew... and other collaboratorsRecruitingChildhood Overweight and ObesityDenmark
-
Khyber Medical University PeshawarRecruitingObesity, OverweightPakistan
-
National Taiwan University HospitalCompleted
-
Institut Investigacio Sanitaria Pere VirgiliCompletedObesity, Childhood | Overweight and Obesity | Overweight, ChildhoodSpain
-
Children's Hospital SrebrnjakBelupo; Podravka d.d.RecruitingBody Weight | Overweight and ObesityCroatia
Clinical Trials on Lifestyle Intervention
-
Sheba Medical CenterD-Cure, Israel; Chief Scientist, The Israel Ministry of ScienceCompleted
-
Northwestern UniversityNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)CompletedHyperglycemia | Glucose Metabolism Disorders | Metabolic Diseases | Obesity | Diabetes Mellitus | Endocrine System Diseases | Overnutrition | Nutrition Disorders | Overweight | Body Weight | Signs and SymptomsUnited States
-
Baylor College of MedicineNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Michael... and other collaboratorsActive, not recruiting
-
Laval UniversityActive, not recruitingPhysical Activity | Weight Loss | Dietary Modification | BreastfeedingCanada
-
University of AdelaideCompletedInsulin Resistance | Type 2 DiabetesAustralia
-
Molde University CollegeNorwegian Labour and Welfare AdministrationCompletedObesity | Morbid Obesity | Work Related Illnesses | Life Style | Sick-leave
-
Mayo ClinicCompletedObesityUnited States
-
DongGuk UniversityNational Research Foundation of KoreaUnknown
-
Umeå UniversityActive, not recruitingHypertension,Essential | Lifestyle-related ConditionSweden
-
Beth Israel Deaconess Medical CenterCenter for Nutritional Research Charitable TrustCompletedObesity | Weight GainUnited States