The Effect of Lactation on Insulin Sensitivity and Lipolysis in Women

This purpose of this study is to investigate whether lactation improves insulin sensitivity and increases lipolysis in women.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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