GDM, Lactation
Conditions
Brief summary
This purpose of this study is to investigate whether lactation improves insulin sensitivity and increases lipolysis in women.
Detailed description
There are two aims that this research will address. In Aim 1, the research question is Does lactation improve insulin sensitivity and increase lipolysis in women? In this Aim, researchers will assess whether lactation amongst women with a history of gestational diabetes mellitus (GDM) will improve whole body insulin sensitivity as well as increase whole body lipid turnover by using hyperinsulinemic-euglycemic clamps combined with \[6,6-2H\]-glucose and \[2H5\]-glycerol infusions. These stable, non-radiating isotopes have been used extensively and safely to study the mechanisms of insulin resistance amongst non-pregnant as well as pregnant humans; however, these techniques have not previously been applied to the study of insulin sensitivity during lactation. Therefore, the goals will be two-fold: 1) to determine whether lactation induces similar changes in insulin sensitivity in humans as in mice and 2) to pilot the feasibility of performing larger, more detailed metabolic studies in this population of women post-partum. The second aim (Aim 2) will use a retrospective chart review of women with a history of GDM who had an oral glucose tolerance test (OGTT) 6-8 weeks post-partum as part of standard of care. The focus of this protocol registration will be Aim 1.
Interventions
DIAGNOSTIC_TESTHyperinsulinemic-euglycemic clamp
After an overnight fast and an equilibration period lasting 2 hours, the 2-step euglycemic-hyperinsulinemic clamp study will be performed. A primed-continuous infusion of regular insulin will be given at 8 mU/(m2 × min) during the first 2 hours, and increased to 40 mU/(m2 × min) for the subsequent 2 hours. Plasma glucose levels will be measured every 5 min, and a variable glucose infusion will be initiated to maintain levels at ∼90 mg/dl. Plasma samples will be drawn at baseline and throughout the infusion period for measurement of isotope enrichment, insulin, NEFA, glycerol turnover, and additional hormones which may be altered with lactation. Approximately 160 mL of blood will be drawn at this visit.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* A history of GDM (as defined as the American Diabetes Association criteria) * Delivered a singleton, live birth at ≥ 35 weeks gestation within the past 18 months * HbA1C \< 6.5% at time of screening * Delivery within the past 18 months * Breast Feed Group: exclusively or mostly breast-fed (\< 6 ounces of formula/24 hours at 6-9 weeks of delivery) for at least 4-6 months
Exclusion criteria
* Currently lactating or lactation within the past 1 month at the time of the screening visit * Diagnosis of diabetes (T1D or T2D) prior to pregnancy * Current use of any glucose-lowering agents * Pregnancy related medical problems including preeclampsia * Major congenital fetal anomalies * Creatinine \> 1.5mg/dL, Hematocrit \< 35%, ALT and AST \> 2.5X upper limit of normal * Known psychiatric disorders, alcohol abuse, HIV, hepatitis, renal disease, hepatic disease, untreated heart disease, untreated thyroid disease, active systemic infection or malignancy * Illicit drug use (by the participant's self-report) * History of post-partum depression * Use of weight loss supplements or dieting 6 months prior to study * Corticosteroid or opiate use within 6 months of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate | 2 hours and 4 hours | The glucose infusion rate is determined by the amount of 20% dextrose given during the hyperinsulinemic-euglycemic clamp study, necessary to keep blood glucose levels at the target range (90-100 mg/dL). Higher rates of infused dextrose indicates greater sensitivity to infused insulin during the hyperinsulinemic-euglycemic clamp. Women with gestational diabetes are expected to be insulin resistant. |
| Endogenous Glucose Production | 4 hours | Determined with \[6,6-2H\] Glucose tracer given during the hyperinsulinemic-euglycemic clamp study. Lower values of endogenous glucose production indicates greater hepatic insulin sensitivity. |
| Whole Body Lipid Turnover Rates | 4 hours | Determined with \[2H5\] Glycerol tracer given during the hyperinsulinemic-euglycemic clamp study. Tracer levels in the plasma determinates how the body uses fat in the blood during the hyperinsulinemic-euglycemic clamp study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma NEFA | 4 hours | Measurement of non-esterified fatty acids levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. NEFA levels in the plasma are higher in individuals less sensitive to the effects of insulin. |
| Triglycerides | 4 hours | Measurement of triglycerides levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. Triglycerides levels in the plasma are higher in individuals less sensitive to the effects of insulin and with type 2 diabetes. |
| Insulin Levels | 4 hours | Measurement of insulin levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. Insulin levels in the plasma are higher in insulin resistant individuals. |
Countries
United States
Participant flow
Pre-assignment details
7 participants were screened and consented, 1 participant was screened and consented but did not qualify to be on study, demographics were collected from the 6 qualifying participants, with only 3 of those participants receiving intervention. The study could not be completed as planned due to difficulty to recruit moms during COVID.
Participants by arm
| Arm | Count |
|---|---|
| Breast Feeding This group will consist of women who exclusively or mostly breast-fed for at least 4-6 months (\< 6 ounces of formula/24 hours at 6-9 weeks of delivery)1 and who delivered within the past 18 months.
Hyperinsulinemic-euglycemic clamp: After an overnight fast and an equilibration period lasting 2 hours, the 2-step euglycemic-hyperinsulinemic clamp study will be performed. A primed-continuous infusion of regular insulin will be given at 8 mU/(m2 × min) during the first 2 hours, and increased to 40 mU/(m2 × min) for the subsequent 2 hours. Plasma glucose levels will be measured every 5 min, and a variable glucose infusion will be initiated to maintain levels at ∼90 mg/dl. Plasma samples will be drawn at baseline and throughout the infusion period for measurement of isotope enrichment, insulin, NEFA, glycerol turnover, and additional hormones which may be altered with lactation. Approximately 160 mL of blood will be drawn at this visit. | 4 |
| Formula Feeding This group will consist of women who exclusively or mostly formula-fed (no breastfeeding or \< 3 weeks of breastfeeding)1 and who delivered within the past 18 months.
Hyperinsulinemic-euglycemic clamp: After an overnight fast and an equilibration period lasting 2 hours, the 2-step euglycemic-hyperinsulinemic clamp study will be performed. A primed-continuous infusion of regular insulin will be given at 8 mU/(m2 × min) during the first 2 hours, and increased to 40 mU/(m2 × min) for the subsequent 2 hours. Plasma glucose levels will be measured every 5 min, and a variable glucose infusion will be initiated to maintain levels at ∼90 mg/dl. Plasma samples will be drawn at baseline and throughout the infusion period for measurement of isotope enrichment, insulin, NEFA, glycerol turnover, and additional hormones which may be altered with lactation. Approximately 160 mL of blood will be drawn at this visit. | 2 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not qualify after consented | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Breast Feeding | Formula Feeding | Total |
|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 1.5 | 33 years STANDARD_DEVIATION 1.4 | 35 years STANDARD_DEVIATION 2.8 |
| Body Fat percentage | 43 percentage of body fat STANDARD_DEVIATION 9.2 | 46.8 percentage of body fat STANDARD_DEVIATION 3.6 | 44.2 percentage of body fat STANDARD_DEVIATION 6.4 |
| Body Mass Index (BMI) | 32 kg/m^2 STANDARD_DEVIATION 7.9 | 34.8 kg/m^2 STANDARD_DEVIATION 2.5 | 32.9 kg/m^2 STANDARD_DEVIATION 5.3 |
| Cholesterol High-Density Lipoprotein (HDL) | 55.8 mg/dL STANDARD_DEVIATION 9.9 | 42 mg/dL STANDARD_DEVIATION 11.3 | 51.2 mg/dL STANDARD_DEVIATION 11.6 |
| Cholesterol Low-Density Lipoprotein (LDL) | 104.3 mg/dL STANDARD_DEVIATION 24.7 | 124.5 mg/dL STANDARD_DEVIATION 28.9 | 111 mg/dL STANDARD_DEVIATION 25.3 |
| Cholesterol Total Cholesterol | 171.3 mg/dL STANDARD_DEVIATION 18.9 | 185 mg/dL STANDARD_DEVIATION 49.5 | 175.8 mg/dL STANDARD_DEVIATION 27 |
| Cholesterol Triglycerides | 57.8 mg/dL STANDARD_DEVIATION 19.2 | 92.5 mg/dL STANDARD_DEVIATION 46 | 69.3 mg/dL STANDARD_DEVIATION 31.1 |
| Diastolic BP | 78 mmHg STANDARD_DEVIATION 4 | 81 mmHg STANDARD_DEVIATION 4 | 79 mmHg STANDARD_DEVIATION 4 |
| Fat Free Mass (FFM) | 61.4 kilograms STANDARD_DEVIATION 22.9 | 47.1 kilograms STANDARD_DEVIATION 0.2 | 56.6 kilograms STANDARD_DEVIATION 17.4 |
| Fat Mass | 45.1 kilograms STANDARD_DEVIATION 11.8 | 41.5 kilograms STANDARD_DEVIATION 5.9 | 43.9 kilograms STANDARD_DEVIATION 8.6 |
| Glucose Levels | 66.3 mg/dL STANDARD_DEVIATION 9.5 | 101.9 mg/dL STANDARD_DEVIATION 28.1 | 78.1 mg/dL STANDARD_DEVIATION 23.1 |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Systolic Blood Pressure (BP) | 117 mmHg STANDARD_DEVIATION 19 | 148 mmHg STANDARD_DEVIATION 27 | 127 mmHg STANDARD_DEVIATION 24 |
| Weight | 87.8 kg STANDARD_DEVIATION 26.7 | 88.6 kg STANDARD_DEVIATION 5.7 | 88.1 kg STANDARD_DEVIATION 17.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 2 |
| other Total, other adverse events | 0 / 4 | 0 / 2 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 |
Outcome results
Primary
Endogenous Glucose Production
Determined with \[6,6-2H\] Glucose tracer given during the hyperinsulinemic-euglycemic clamp study. Lower values of endogenous glucose production indicates greater hepatic insulin sensitivity.
Time frame: 4 hours
Population: Data not collected due to COVID.
Primary
Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate
The glucose infusion rate is determined by the amount of 20% dextrose given during the hyperinsulinemic-euglycemic clamp study, necessary to keep blood glucose levels at the target range (90-100 mg/dL). Higher rates of infused dextrose indicates greater sensitivity to infused insulin during the hyperinsulinemic-euglycemic clamp. Women with gestational diabetes are expected to be insulin resistant.
Time frame: 2 hours and 4 hours
Population: Data presented here is from the 3 participants that came to this appointment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Breast Feeding | Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate | Glucose Infusion Rate 2 hours | 2.1 mg/kg/min | Standard Deviation 1.2 |
| Breast Feeding | Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate | Glucose Infusion Rate 4 hours | 7.1 mg/kg/min | Standard Deviation 2.1 |
| Formula Feeding | Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate | Glucose Infusion Rate 2 hours | 1 mg/kg/min | — |
| Formula Feeding | Whole Body Insulin Sensitivity Measured by the Glucose Infusion Rate | Glucose Infusion Rate 4 hours | 2.5 mg/kg/min | — |
Primary
Whole Body Lipid Turnover Rates
Determined with \[2H5\] Glycerol tracer given during the hyperinsulinemic-euglycemic clamp study. Tracer levels in the plasma determinates how the body uses fat in the blood during the hyperinsulinemic-euglycemic clamp study.
Time frame: 4 hours
Population: Data not collected due to COVID.
Secondary
Insulin Levels
Measurement of insulin levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. Insulin levels in the plasma are higher in insulin resistant individuals.
Time frame: 4 hours
Population: Data not collected due to COVID.
Secondary
Plasma NEFA
Measurement of non-esterified fatty acids levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. NEFA levels in the plasma are higher in individuals less sensitive to the effects of insulin.
Time frame: 4 hours
Population: Data not collected due to COVID.
Secondary
Triglycerides
Measurement of triglycerides levels in the plasma at fasting and during the hyperinsulinemic-euglycemic clamp study. Triglycerides levels in the plasma are higher in individuals less sensitive to the effects of insulin and with type 2 diabetes.
Time frame: 4 hours
Population: Data not collected due to COVID.