presentation of gestational diabetes

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Gestational Diabetes Mellitus (GDM)

What is gestational diabetes mellitus.

Gestational diabetes mellitus (GDM)  is a condition in which a hormone made by the placenta prevents the body from using insulin effectively. Glucose builds up in the blood instead of being absorbed by the cells.

Unlike type 1 diabetes, gestational diabetes is not caused by a lack of insulin, but by other hormones produced during pregnancy that can make insulin less effective, a condition referred to as insulin resistance. Gestational diabetic symptoms disappear following delivery.

Approximately 3 to 8 percent of all pregnant women in the United States are diagnosed with gestational diabetes.

What causes gestational diabetes mellitus?

Although the cause of GDM is not known, there are some theories as to why the condition occurs.

The placenta supplies a growing fetus with nutrients and water, and also produces a variety of hormones to maintain the pregnancy. Some of these hormones (estrogen, cortisol, and human placental lactogen) can have a blocking effect on insulin. This is called contra-insulin effect, which usually begins about 20 to 24 weeks into the pregnancy.

As the placenta grows, more of these hormones are produced, and the risk of insulin resistance becomes greater. Normally, the pancreas is able to make additional insulin to overcome insulin resistance, but when the production of insulin is not enough to overcome the effect of the placental hormones, gestational diabetes results.

What are the risks factors associated with gestational diabetes mellitus?

Although any woman can develop GDM during pregnancy, some of the factors that may increase the risk include the following:

Overweight or obesity

Family history of diabetes

Having given birth previously to an infant weighing greater than 9 pounds

Age (women who are older than 25 are at a greater risk for developing gestational diabetes than younger women)

Race (women who are African-American, American Indian, Asian American, Hispanic or Latino, or Pacific Islander have a higher risk)

Prediabetes, also known as impaired glucose tolerance

Although increased glucose in the urine is often included in the list of risk factors, it is not believed to be a reliable indicator for GDM.

How is gestational diabetes mellitus diagnosed?

The American Diabetes Association recommends screening for undiagnosed type 2 diabetes at the first prenatal visit in women with diabetes risk factors. In pregnant women not known to have diabetes, GDM testing should be performed at 24 to 28 weeks of gestation.

In addition, women with diagnosed GDM should be screened for persistent diabetes 6 to 12 weeks postpartum. It is also recommended that women with a history of GDM undergo lifelong screening for the development of diabetes or prediabetes at least every three years.

What is the treatment for gestational diabetes mellitus?

Specific treatment for gestational diabetes will be determined by your doctor based on:

Your age, overall health, and medical history

Extent of the disease

Your tolerance for specific medications, procedures, or therapies

Expectations for the course of the disease

Your opinion or preference

Treatment for gestational diabetes focuses on keeping blood glucose levels in the normal range. Treatment may include:

Special diet

Daily blood glucose monitoring

Insulin injections

Possible complications for the baby

Unlike type 1 diabetes, gestational diabetes generally occurs too late to cause birth defects. Birth defects usually originate sometime during the first trimester (before the 13th week) of pregnancy. The insulin resistance from the contra-insulin hormones produced by the placenta does not usually occur until approximately the 24th week. Women with gestational diabetes mellitus generally have normal blood sugar levels during the critical first trimester.

The complications of GDM are usually manageable and preventable. The key to prevention is careful control of blood sugar levels just as soon as the diagnosis of diabetes is made.

Infants of mothers with gestational diabetes are vulnerable to several chemical imbalances, such as low serum calcium and low serum magnesium levels, but, in general, there are two major problems of gestational diabetes: macrosomia and hypoglycemia:

Macrosomia . Macrosomia refers to a baby who is considerably larger than normal. All of the nutrients the fetus receives come directly from the mother's blood. If the maternal blood has too much glucose, the pancreas of the fetus senses the high glucose levels and produces more insulin in an attempt to use this glucose. The fetus converts the extra glucose to fat. Even when the mother has gestational diabetes, the fetus is able to produce all the insulin it needs. The combination of high blood glucose levels from the mother and high insulin levels in the fetus results in large deposits of fat which causes the fetus to grow excessively large.

Hypoglycemia . Hypoglycemia refers to low blood sugar in the baby immediately after delivery. This problem occurs if the mother's blood sugar levels have been consistently high, causing the fetus to have a high level of insulin in its circulation. After delivery, the baby continues to have a high insulin level, but it no longer has the high level of sugar from its mother, resulting in the newborn's blood sugar level becoming very low. The baby's blood sugar level is checked after birth, and if the level is too low, it may be necessary to give the baby glucose intravenously.

Blood glucose is monitored very closely during labor. Insulin may be given to keep the mother's blood sugar in a normal range to prevent the baby's blood sugar from dropping excessively after delivery.

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• Staying Healthy During Pregnancy

Gestational Diabetes: Symptoms, Causes, and Treatments

• • A form of glucose intolerance that can affect the health of a pregnant mother and her fetus
• • Symptoms include fatigue, nausea, and blurred vision during pregnancy
• • Treatments usually include dietary changes and exercise
• • Involves maternal-fetal medicine
• Gestational Diabetes, Diabetes in Pregnancy

What is gestational diabetes?

Who is at risk for gestational diabetes, who should be tested for gestational diabetes, how is gestational diabetes treated, what are the risks for mothers and babies, what are the risks for labor and delivery, what makes yale medicine's approach to treating gestational diabetes stand out.

Approximately 10% of pregnant women in the United States have gestational diabetes, a form of glucose intolerance that can affect the health of both mother and baby. Not only is gestational diabetes common, its incidence has increased over the past 20 years.

The diagnosis may sound frightening to an expectant mother, but when caught early, this issue can be managed effectively without causing lasting health problems.

Gestational diabetes mellitus occurs only in women during pregnancy. Although the exact cause is unknown, the prevailing theory is that the placenta—the organ that delivers water and nutrients to the fetus—produces hormones that block the mother’s ability to use insulin effectively. Insulin is a hormone that the body needs to convert glucose, or sugar, into energy that the body’s cells can use.

As the pregnancy continues, the placenta grows and produces more and more of these hormones; the result is that glucose builds up in the blood, rather than being used by the mother's and fetus's cells.

Factors include:

· Women who have had gestational diabetes in the past

· Women with obesity

· Women with a family history of diabetes or prediabetes

About 90% of pregnant women have at least one risk factor for diabetes, but some risks are higher than others.

In the U.S., every woman is tested for gestational diabetes.

Testing is usually done between weeks 24 and 28 of gestation using an oral glucose tolerance test. The pregnant woman drinks 75 grams of a sugary solution and then blood samples are drawn to monitor glucose levels about two hours later.

For pregnant women in a high-risk group, testing should be done as early as possible, often in the first trimester.

The main goal of treatment is to keep the fetus from growing too large, which can harm both the mother and the baby. Patients will need to change how they eat and learn to monitor their blood sugar levels. In some cases, a patient may need to self-administer insulin injections or take oral medication.

A change in diet often helps the most. Recommendations may include:

• Avoiding high-sugar snacks and desserts, including soda, punch, candy, chips, cookies, cakes, and full-fat ice cream
• Eating at least five servings a day of fruits and vegetables
• Eating whole grains (whole-wheat bread, brown rice, and whole-wheat pasta)
• Switching to fat-free or low-fat dairy products
• Eating only small amounts of red meat

Gestational diabetes usually goes away after delivery.

Mothers with gestational diabetes are at a higher risk for preeclampsia (hypertension during pregnancy), problems with labor, and Cesarean delivery. A large baby (considered more than 9 pounds at delivery) may cause injury to the mother during a vaginal delivery. A very large baby may suffer broken bones or nerve damage during delivery. It may be necessary to deliver the baby via Cesarean section.

The child is also at a heightened risk of developing diabetes, obesity, and metabolism problems later in life. Likewise, a mother who has had gestational diabetes is also at greater risk of developing type 2 diabetes later in life.

If a patient can keep her blood sugar levels close to normal and has no other complications, the best time to deliver is at 39 or 40 weeks.

High blood glucose during labor can cause complications for the baby, including chemical imbalances. But one of the main concerns is hypoglycemia, or low blood sugar, in the baby immediately after delivery. This occurs if the mother's blood sugar levels have been high, which spikes the insulin level in the fetus’s circulation.

After delivery, the baby still has a high insulin level, but without the high sugar level from the mother. This causes the newborn’s blood sugar level to become too low, and glucose may need to be administered intravenously.

To avoid this, blood glucose is monitored very closely during labor. Insulin may be given to keep the mother's blood sugar in a normal range to prevent the baby's blood sugar from dropping excessively after delivery.

For most women, blood glucose levels return to normal after delivery. However, it is important for patients to take the glucose test again about six weeks postpartum. This is to ensure there is no sustained type 2 diabetes.

Committed to a deep understanding of the causes and treatment of diabetes, researchers affiliated with the Yale Medicine Diabetes Center and the Yale Diabetes Research Center conduct a wide variety of studies.

From the first successful studies of insulin pump technology in the 1970s to current investigations directed at understanding the cellular mechanisms underlying type 2 diabetes and the immunologic basis of type 1 diabetes, Yale Medicine has long been at the forefront of diabetes research and has been committed to providing our patients the finest treatment options available.

Visit the Yale Medicine Diabetes Content Center for more diabetes-related articles and videos.

Gestational diabetes

On this page, coping and support, preparing for your appointment.

If you're at average risk of gestational diabetes, you'll likely have a screening test during your second trimester — between 24 and 28 weeks of pregnancy.

If you're at high risk of diabetes — for example, if you're overweight or obese before pregnancy; you have a mother, father, sibling or child with diabetes; or you had gestational diabetes during a previous pregnancy — your health care provider may test for diabetes early in pregnancy, likely at your first prenatal visit.

Routine screening for gestational diabetes

Screening tests may vary slightly depending on your health care provider, but generally include:

Initial glucose challenge test. You'll drink a syrupy glucose solution. One hour later, you'll have a blood test to measure your blood sugar level. A blood sugar level of 190 milligrams per deciliter (mg/dL), or 10.6 millimoles per liter (mmol/L), indicates gestational diabetes.

A blood sugar level below 140 mg/dL (7.8 mmol/L) is usually considered within the standard range on a glucose challenge test, although this may vary by clinic or lab. If your blood sugar level is higher than expected, you'll need another glucose tolerance test to determine if you have gestational diabetes.

• Follow-up glucose tolerance testing. This test is similar to the initial test — except the sweet solution will have even more sugar and your blood sugar will be checked every hour for three hours. If at least two of the blood sugar readings are higher than expected, you'll be diagnosed with gestational diabetes.

More Information

• Glucose challenge test
• Glucose tolerance test

Treatment for gestational diabetes includes:

Lifestyle changes

Blood sugar monitoring.

• Medication, if necessary

Managing your blood sugar levels helps keep you and your baby healthy. Close management can also help you avoid complications during pregnancy and delivery.

Your lifestyle — how you eat and move — is an important part of keeping your blood sugar levels in a healthy range. Health care providers usually don't advise losing weight during pregnancy — your body is working hard to support your growing baby. But your health care provider can help you set weight gain goals based on your weight before pregnancy.

Lifestyle changes include:

• Healthy diet. A healthy diet focuses on fruits, vegetables, whole grains and lean protein — foods that are high in nutrition and fiber and low in fat and calories — and limits highly refined carbohydrates, including sweets. A registered dietitian or a certified diabetes care and education specialist can help you create a meal plan based on your current weight, pregnancy weight gain goals, blood sugar level, exercise habits, food preferences and budget.
• Staying active. Regular physical activity plays a key role in every wellness plan before, during and after pregnancy. Exercise lowers your blood sugar. As an added bonus, regular exercise can help relieve some common discomforts of pregnancy, including back pain, muscle cramps, swelling, constipation and trouble sleeping.

With your health care provider's OK, aim for 30 minutes of moderate exercise on most days of the week. If you haven't been active for a while, start slowly and build up gradually. Walking, cycling and swimming are good choices during pregnancy. Everyday activities such as housework and gardening also count.

While you're pregnant, your health care team may ask you to check your blood sugar four or more times a day — first thing in the morning and after meals — to make sure your level stays within a healthy range.

If diet and exercise aren't enough to manage your blood sugar levels, you may need insulin injections to lower your blood sugar. A small number of women with gestational diabetes need insulin to reach their blood sugar goals.

Some health care providers prescribe an oral medication to manage blood sugar levels. Other health care providers believe more research is needed to confirm that oral medications are as safe and as effective as injectable insulin to manage gestational diabetes.

Close monitoring of your baby

An important part of your treatment plan is close observation of your baby. Your health care provider may check your baby's growth and development with repeated ultrasounds or other tests. If you don't go into labor by your due date — or sometimes earlier — your health care provider may induce labor. Delivering after your due date may increase the risk of complications for you and your baby.

Follow-up after delivery

Your health care provider will check your blood sugar level after delivery and again in 6 to 12 weeks to make sure that your level has returned to within the standard range. If your tests are back in this range — and most are — you'll need to have your diabetes risk assessed at least every three years.

If future tests indicate type 2 diabetes or prediabetes, talk with your health care provider about increasing your prevention efforts or starting a diabetes management plan.

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Clinical trials

Explore Mayo Clinic studies  testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

It's stressful to know you have a condition that can affect your unborn baby's health. But the steps that will help control your blood sugar level — such as eating healthy foods and exercising regularly — can help relieve stress, nourish your baby and help prevent type 2 diabetes in the future.

You may feel better if you learn as much as you can about gestational diabetes. Talk to your health care team, or read books and articles about gestational diabetes. You may find a support group for people with gestational diabetes helpful. Ask your health care team for suggestions.

You'll likely find out you have gestational diabetes from routine screening during your pregnancy. Your health care provider may refer you to additional health professionals who specialize in diabetes, such as an endocrinologist, a certified diabetes care and education specialist, or a registered dietitian. One or more of these care providers can help you learn to manage your blood sugar level during your pregnancy.

You may want to take a family member or friend along to your appointment, if possible. Someone who accompanies you may remember something that you missed or forgot.

Here's some information to help you get ready for your appointment and know what to expect from your health care provider.

What you can do

Before your appointment:

• Be aware of pre-appointment restrictions. When you make your appointment, ask if you need to fast for lab tests or do anything else to prepare for diagnostic tests.
• Make a list of symptoms you're having, including those that may seem unrelated to gestational diabetes. You may not have noticeable symptoms, but it's good to keep a log of anything unusual you notice.
• Make a list of key personal information, including major stresses or recent life changes.
• Make a list of all medications, including over-the-counter drugs and vitamins or supplements you're taking.
• Make a list of questions to help make the most of your time with your health care provider.

Some basic questions to ask your health care provider include:

• What can I do to help control my condition?
• Can you recommend a registered dietitian or certified diabetes care and education specialist who can help me plan meals, an exercise program and coping strategies?
• Will I need medication to control my blood sugar?
• What symptoms should prompt me to seek medical attention?
• Are there brochures or other printed materials I can take? What websites do you recommend?

What to expect from your doctor

Your health care provider is also likely to have questions for you, especially if it's your first visit. Questions may include:

• Have you experienced increased thirst or excessive urination? If so, when did these symptoms start? How often do you have them?
• Have you noticed other unusual symptoms?
• Do you have a parent or sibling who's ever been diagnosed with diabetes?
• Have you been pregnant before? Did you have gestational diabetes during your previous pregnancies?
• Did you have other problems in previous pregnancies?
• If you have other children, how much did each weigh at birth?

Apr 09, 2022

• American College of Obstetricians and Gynecologists. Practice Bulletin No.190: Gestational diabetes mellitus. Obstetrics & Gynecology. 2018; doi:10.1097/AOG.0000000000002501.
• Diabetes and Pregnancy: Gestational diabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/pregnancy/diabetes-gestational.html. Accessed Dec. 31, 2019.
• Gestational diabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/gestational/all-content. Accessed Dec. 31, 2019.
• AskMayoExpert. Gestational diabetes mellitus. Mayo Clinic; 2021.
• Durnwald C. Gestational diabetes mellitus: Screening, diagnosis, and prevention. https://www.uptodate.com/contents/search. Accessed Nov. 30, 2021.
• American Diabetes Association. Standards of medical care in diabetes — 2021. Diabetes Care. 2021. https://care.diabetesjournals.org/content/44/Supplement_1. Accessed Nov. 11, 2021.
• Mack LR, et al. Gestational diabetes — Diagnosis, classification, and clinical care. Obstetrics and Gynecology Clinics of North America. 2017; doi:10.1016/j.ogc.2017.02.002.
• Tsirou E, et al. Guidelines for medical nutrition therapy in gestational diabetes mellitus: Systematic review and critical appraisal. Journal of the Academy of Nutrition and Dietetics. 2019; doi:10.1016/j.jand.2019.04.002.
• Rasmussen L, et al. Diet and healthy lifestyle in the management of gestational diabetes mellitus. Nutrients. 2020; doi:10.3390/nu12103050.
• Caughey AB. Gestational diabetes mellitus: Obstetric issues and management. https://www.uptodate.com/contents/search. Accessed Nov. 30, 2021.
• Castro MR (expert opinion). Mayo Clinic. Jan. 14, 2022.
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The Lancet Series on gestational diabetes

Executive summary.

Gestational diabetes is the most common medical pregnancy complication worldwide, affecting one in seven pregnancies. GDM cases are increasing globally alongside a parallel rise in obesity and diabetes in women of childbearing age. Without treatment, gestational diabetes can lead to high blood pressure, increased risk of Caesarean sections, mental health conditions, and complications for the baby at delivery, alongside health complications later in life for both mother and child, such as type 2 diabetes and cardiovascular disease. A new Series on gestational diabetes published in  The Lancet  calls for a greater focus on early gestational diabetes and a shift to a holistic life-course approach in how we manage the disease. The Series offers a comprehensive and inclusive analysis of the most current evidence on pathophysiology, screening, management, prevention, and long-term complications for mothers and their babies.

Non-communicable diseases in reproductive care

Pathophysiology from preconception, during pregnancy, and beyond, epidemiology and management of gestational diabetes, call to action for a life course approach.

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The Lancet Series on Gestational Diabetes

Gestational Diabetes Mellitus (GDM) is the most common medical pregnancy complication worldwide.

Related Content

Gestational diabetes: opportunities for improving maternal and child health, defining gestational diabetes: not just about cutoffs, is a new discussion about diagnosis of gestational diabetes needed.

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A Review of the Pathophysiology and Management of Diabetes in Pregnancy

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Abbreviations and Acronyms

• ACOG ( The American College of Obstetricians and Gynecologists )
• DKA ( diabetic ketoacidosis )
• GDM ( gestational diabetes mellitus )
• LGA ( large for gestational age )

Pathophysiology

Normal maternal glucose metabolism, pre-existing diabetes, early pregnancy hyperglycemia — fetal effects, fetal overnutrition, long-term offspring outcomes, impact of treatment on outcomes, pre-existing diabetes, preconception care.

• Open table in a new tab

Diagnosis of GDM

Glycemic Goals During Pregnancy

Gestational weight gain and diet.

Pharmacotherapy

Noninsulin agents, approach to management of hyperglycemia, dka during pregnancy, fetal monitoring and delivery planning, labor and delivery, postpartum care, supplemental online material, article metrics, related articles.

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The Pathophysiology of Gestational Diabetes Mellitus

Jasmine f plows.

1 Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA; ude.csu@swolp

Joanna L Stanley

2 Liggins Institute, University of Auckland, Auckland 1023, New Zealand; moc.liamg@ylntsoj (J.L.S.); [email protected] (C.M.R.)

Philip N Baker

3 University of Leicester, University Road, Leicester LE1 7RH, UK; [email protected]

Clare M Reynolds

Mark h vickers.

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist—including insulin and lifestyle interventions—there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.

1. Introduction

Gestational diabetes mellitus (GDM) is a common pregnancy complication, in which spontaneous hyperglycemia develops during pregnancy [ 1 ]. According to the most recent (2017) International Diabetes Federation (IDF) estimates, GDM affects approximately 14% of pregnancies worldwide, representing approximately 18 million births annually [ 2 ]. Risk factors include overweight/obesity, westernized diet and micronutrient deficiencies, advanced maternal age, and a family history of insulin resistance and/or diabetes. While GDM usually resolves following delivery, it can have long-lasting health consequences, including increased risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD) in the mother, and future obesity, CVD, T2DM, and/or GDM in the child. This contributes to a vicious intergenerational cycle of obesity and diabetes that impacts the health of the population as a whole. Unfortunately, there is currently no widely-accepted treatment or prevention strategy for GDM, except lifestyle intervention (diet and exercise) and occasionally insulin therapy—which is only of limited effectiveness due to the insulin resistance that is often present. While emerging oral antidiabetics, such as glyburide and metformin, are promising, concerns remain about their long-term safety for the mother and the child [ 3 , 4 ]. Therefore, safe, effective, and easy-to-administer new treatments are sought. In order to develop such treatments, a thorough understanding of the pathophysiology of GDM is required. This review will discuss what is known about the pathophysiology of GDM and what has yet to be elucidated. In order to do so, a contextual summary of glucose regulation during normal pregnancy, classification of GDM, forms of GDM, risk factors for GDM, and consequences of GDM is first required.

1.1. Glucose Regulation during Healthy Pregnancy

During healthy pregnancy, the mother’s body undergoes a series of physiological changes in order to support the demands of the growing fetus. These include adaptations to the cardiovascular, renal, hematologic, respiratory, and metabolic systems. One important metabolic adaptation is in insulin sensitivity. Over the course of gestation, insulin sensitivity shifts depending on the requirements of pregnancy. During early gestation, insulin sensitivity increases, promoting the uptake of glucose into adipose stores in preparation for the energy demands of later pregnancy [ 5 ]. However, as pregnancy progresses, a surge of local and placental hormones, including estrogen, progesterone, leptin, cortisol, placental lactogen, and placental growth hormone together promote a state of insulin resistance [ 6 ]. As a result, blood glucose is slightly elevated, and this glucose is readily transported across the placenta to fuel the growth of the fetus. This mild state of insulin resistance also promotes endogenous glucose production and the breakdown of fat stores, resulting in a further increase in blood glucose and free fatty acid (FFA) concentrations [ 7 ]. Evidence in animals suggests that, in order to maintain glucose homeostasis, pregnant women compensate for these changes through hypertrophy and hyperplasia of pancreatic β-cells, as well as increased glucose-stimulated insulin secretion (GSIS) [ 8 ]. The importance of placental hormones in this process is exemplified by the fact that maternal insulin sensitivity returns to pre-pregnancy levels within a few days of delivery [ 9 ]. For reasons that will be explored in this review, the normal metabolic adaptations to pregnancy do not adequately occur in all pregnancies, resulting in GDM.

1.2. Classification and Prevalence of Gestational Diabetes

The American Diabetes Association (ADA) formally classifies GDM as “diabetes first diagnosed in the second or third trimester of pregnancy that is not clearly either preexisting type 1 or type 2 diabetes” [ 1 ]. However, the exact threshold for a diagnosis of GDM depends on the criteria used, and so far, there has been a lack of consensus amongst health professionals. It is now advised by the ADA, the World Health Organization (WHO), the International Federation of Gynaecology and Obstetrics, and the Endocrine Society, that the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria be used in the diagnosis of GDM [ 10 ]. The IADPSG criteria was developed based on the results of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study—a large multinational and multicenter study of 23,000 pregnant women [ 11 ]. One major finding of the HAPO Study was a continuous risk of adverse maternal and fetal outcomes with increasing maternal glycaemia—even below the diagnostic threshold for GDM—suggesting the that criteria for intervention needed to be adjusted. The IADPSG therefore recommends that all women undergo a fasting plasma glucose (FPG) test at their first prenatal visit (where a reading ≥92 mg/dL is indicative of GDM), and that women with FPG <92 mg/dL undergo a 2-h 75 g oral glucose tolerance test (OGTT) between 24 and 28 weeks’ gestation. These glycemic cut-offs are lower than other guidelines, and only one abnormal glucose reading is required for diagnosis, which has resulted in a drastic increase in the number of cases of GDM and associated healthcare costs [ 12 ]. For this reason, there has been much discussion amongst experts as to whether the IADPSG criteria should be modified to only screen at-risk women (i.e., women of advanced maternal age, those who are overweight/obese, who are in high-risk ethnic groups, or with a family history of diabetes). However, some studies suggest that such efforts would miss a substantial number of GDM cases without significantly reducing the cost [ 13 , 14 , 15 ]. Therefore, the IADPSG criteria are the most widely recommended guideline today, although alternate criteria remain in some centers and countries ( Table 1 ).

Various criteria for gestational diabetes mellitus (GDM) diagnosis using oral glucose tolerance test (OGTT).

The inconsistencies in screening and diagnosis of GDM make worldwide estimates difficult. Using the IADPSG’s criteria, the International Diabetes Federation (IDF) estimated that 18 million live births worldwide (14%) were affected by gestational diabetes in 2017 [ 2 ]. South-East Asia had the highest prevalence of GDM at 24.2%, while the lowest prevalence was seen in Africa at 10.5%. Almost 90% of cases of hyperglycemia in pregnancy occurred in low- and middle-income countries, where access to maternal healthcare is limited. Even within-countries, GDM prevalence varies depending on race/ethnicity and socioeconomic status. Aboriginal Australians, Middle Easterners, and Pacific Islanders are the most at-risk groups for GDM [ 16 ]. Within the United States, Native Americans, Hispanics, Asians, and African-American women are at a higher risk of GDM than Caucasian women [ 17 ]. There is also some evidence that GDM prevalence varies by season, with more diagnoses of GDM in summer than winter [ 18 ].

1.3. Forms of Gestational Diabetes

Outside of pregnancy, three distinct forms of diabetes mellitus are described: autoimmune diabetes (type 1), diabetes occurring on a background of insulin resistance (type 2), and diabetes as a result of other causes, including genetic mutation, diseases of the exocrine pancreas (e.g., pancreatitis), and drug- or chemical-induced diabetes (such as after organ transplantation or in the treatment of human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS)) [ 1 , 19 ]. While there is evidence that GDM can occur in all three settings [ 20 , 21 ], the vast majority (~80%) of GDM cases present as β-cell dysfunction on a background of chronic insulin resistance, to which the normal insulin resistance of pregnancy is partially additive [ 22 ]. Thus, affected women tend to have an even greater degree of insulin resistance than healthy pregnant women, and therefore have further reductions in glucose utilization and increased glucose production and FFA concentrations [ 23 ]. It is thought that β-cells deteriorate due to excessive insulin production in response to excess energy consumption and insulin resistance, exhausting the cells over time. The fact that this pathology closely resembles that of T2DM has spurred much debate about whether the two diseases should be considered to be etiologically indistinct [ 24 , 25 ]. As this form of GDM is by far the most common, it will be the focus of this review.

1.4. Risk Factors for Gestational Diabetes

Epidemiological studies of risk factors for GDM are limited and are typically afflicted by confounding factors [ 26 , 27 ]. In addition, inconsistencies in diagnostic criteria for GDM and measurements of risk factors make it difficult to compare findings across studies. Despite these concerns, several risk factors for GDM emerge consistently. These include overweight/obesity [ 28 ], excessive gestational weight gain [ 29 ], westernized diet [ 30 ], ethnicity [ 31 ], genetic polymorphisms [ 32 ], advanced maternal age [ 33 ], intrauterine environment (low or high birthweight [ 34 ]), family and personal history of GDM [ 35 ], and other diseases of insulin resistance, such as polycystic ovarian syndrome (PCOS) [ 26 ].

Each of these risk factors are either directly or indirectly associated with impaired β-cell function and/or insulin sensitivity. For example, overweight and obesity are intrinsically linked with prolonged, excessive calorie intake, which overwhelms β-cell insulin production and insulin signaling pathways. Even independently of body mass index (BMI) and overall caloric intake, diet and nutrition are associated with GDM. Diets that are high in saturated fats, refined sugars, and red and processed meats are consistently associated with an increased risk of GDM [ 36 , 37 ], while diets high in fiber, micronutrients, and polyunsaturated fats are consistently associated with a reduced risk of GDM [ 38 , 39 , 40 ]. Saturated fats directly interfere with insulin signaling [ 41 ], and they can also induce inflammation and endothelial dysfunction—both pathogenic factors in GDM [ 42 ]. On the other hand, n-3 polyunsaturated fatty acids, including those derived from fish and seafood, have anti-inflammatory properties [ 38 ]. The relationship between processed meat and GDM remains strong, even after adjustment for fatty acids, cholesterol, heme iron, and protein content [ 43 ]. It has been suggested that by-products related to the processing of meat could be responsible—such as nitrates (a common preservative in processed meats), or advanced glycation end products (AGEs), which have both been implicated in β-cell toxicity [ 44 , 45 ]. Interestingly, even independently of meat consumption, high protein diets are associated with GDM [ 46 , 47 , 48 ]. One theory for this is the role of amino acids as substrates for hepatic glucose production [ 49 ], and in hepatic lipotoxicity [ 50 ]. The inverse association between dietary fiber and GDM may be the result of reduced appetite or slowed glucose absorption, reducing demand on β-cells and insulin signaling mediators [ 39 ].

Low and high birthweight are likely risk factors for GDM because of their association with insulin resistance. Low birthweight is often the result of undernutrition in the womb, either as a result of maternal undernutrition or placental insufficiency. It is believed that the fetus compensates for undernutrition in the womb by epigenetically altering the expression of genes that are involved in fat storage, energy utilisation, and appetite regulation. Further, animal studies suggest that undernutrition in utero is associated with reduced β-cell number [ 51 ]. These alterations persist after birth—a phenomenon referred to as “developmental programming” [ 52 ]. While potentially beneficial in times of famine, a mismatch between nutritional status in the womb and nutritional status once born can contribute to the development of obesity and metabolic disease [ 53 , 54 ]. On the opposite end of the spectrum, overnutrition in the womb—such as can occur in GDM—can result in fetal overgrowth. These individuals are more likely to have experienced hyperglycemia and β-cell fatigue even before birth, predisposing them to hyperglycemia during times of later metabolic stress, such as during pregnancy [ 55 ].

1.5. Consequences of Gestational Diabetes

The importance of aiming to understand and effectively treat or prevent GDM is illustrated by the wide-ranging consequences of GDM for both the mother and the fetus.

Mother —GDM increases the risk of a number of short-term and long-term maternal health issues. In addition to the stress of normal pregnancy, GDM is associated with antenatal depression [ 56 ]. There is also an increased risk of additional pregnancy complications, including preterm birth and preeclampsia, and, in many cases, surgical delivery of the baby is required [ 57 ]. Approximately 60% of women with a past history of GDM develop T2DM later in life [ 58 ]. Each additional pregnancy also confers a threefold increase in the risk of T2DM in women with a history of GDM. Further, women with a previous case of GDM have a yearly risk of conversion to T2DM of ~2 to 3% [ 58 ]. Emerging evidence also suggests that the vasculature of women with a prior case of GDM is permanently altered, predisposing them to cardiovascular disease (CVD). A recent study reported a 63% increased risk of CVD amongst women with a history of GDM, which was partly, but not fully, explained by BMI [ 59 ]. This is of major concern, as CVD is the number one cause of death in the world [ 60 ].

Child —GDM also poses short- and long-term consequences for the infant. The aforementioned increase in placental transport of glucose, amino acids, and fatty acids stimulate the fetus’s endogenous production of insulin and insulin-like growth factor 1 (IGF-1). Together, these can cause fetal overgrowth, often resulting in macrosomia at birth [ 61 ]. As previously mentioned, excess fetal insulin production can stress the developing pancreatic β-cells, contributing to β-cell dysfunction and insulin resistance, even prenatally [ 62 ]. Macrosomia is also a risk factor for shoulder dystocia—a form of obstructed labor. Thus, babies of GDM pregnancies are usually delivered by caesarean section [ 63 , 64 ]. Once delivered, these babies are at increased risk of hypoglycemia, which is likely due to formed dependence on maternal hyperglycemia (fetal hyperinsulinemia), which can contribute to brain injury if not properly managed [ 65 ]. There is also evidence that GDM increases the risk of stillbirth [ 66 ]. In the long term, babies that are born of GDM pregnancies are at increased risk of obesity, T2DM, CVD, and associated metabolic diseases. Children born to mothers with GDM have almost double the risk of developing childhood obesity when compared with nondiabetic mothers, even after adjusting for confounders such as maternal BMI [ 67 , 68 ], and impaired glucose tolerance can be detected as young as five years old [ 69 ]. Females are therefore more likely to experience GDM in their own pregnancies, contributing to a vicious intergenerational cycle of GDM [ 70 ].

2. Pathophysiology of Gestational Diabetes

The remainder of this review will discuss molecular processes underlying the pathophysiology of GDM. GDM is usually the result of β-cell dysfunction on a background of chronic insulin resistance during pregnancy and thus both β-cell impairment and tissue insulin resistance represent critical components of the pathophysiology of GDM. In most cases, these impairments exist prior to pregnancy and can be progressive—representing an increased risk of T2DM post-pregnancy [ 71 ]. A number of additional organs and systems contribute to, or are affected by, GDM. These include the brain, adipose tissue, liver, muscle, and placenta.

2.1. β-Cell Dysfunction

The primary function of β-cells is to store and secrete insulin in response to glucose load. When β-cells lose the ability to adequately sense blood glucose concentration, or to release sufficient insulin in response, this is classified as β-cell dysfunction. β-cell dysfunction is thought to be the result of prolonged, excessive insulin production in response to chronic fuel excess [ 72 ]. However, the exact mechanisms underlying β-cell dysfunction can be varied and complex [ 73 , 74 ]. Defects can occur at any stage of the process: pro-insulin synthesis, post-translational modifications, granule storage, sensing of blood glucose concentrations, or the complex machinery underlying exocytosis of granules. Indeed, the majority of susceptibility genes that are associated with GDM are related to β-cell function, including potassium voltage-gated channel KQT-like 1 ( Kcnq1 ) and glucokinase ( Gck ). Minor deficiencies in the β-cell machinery may only be exposed in times of metabolic stress, such as pregnancy [ 75 ].

β-cell dysfunction is exacerbated by insulin resistance. Reduced insulin-stimulated glucose uptake further contributes to hyperglycemia, overburdening the β-cells, which have to produce additional insulin in response. The direct contribution of glucose to β-cell failure is described as glucotoxicity [ 76 ]. Thus, once β-cell dysfunction begins, a vicious cycle of hyperglycemia, insulin resistance, and further β-cell dysfunction is set in motion.

Animal studies suggest that β-cell number is also an important determinant of glucose homeostasis. For example, Zucker fatty (ZF) rats that were subjected to 60% pancreatectomy mostly recover β-cell mass by one week post-surgery, but still develop hyperglycemia. In these cases, the short-term but dramatic reduction in β-cell mass overburdens the remaining β-cells, resulting in severely reduced glucose-stimulated insulin secretion and the depletion of internal insulin granule stores [ 77 ]. Sprague Dawley rats, which are usually very resistant to the development of diabetes, experience substantial loss of β-cell mass (50% reduction) by 15-weeks old when growth-restricted in utero via bilateral uterine artery ligation [ 78 ]. This loss of β-cell mass has been linked to epigenetic downregulation of pancreatic homeobox transcription factor ( Pdx1 ), which is essential for normal β-cell differentiation in the embryo [ 79 ]. Prolactin is also essential for adequate β-cell proliferation, as demonstrated in mouse knockouts of the prolactin receptor (PrlR −/− ) [ 80 ]. In addition, glucotoxicity is also thought to result in β-cell apoptosis over time [ 76 ]. Pancreatic samples from T2DM patients can show a reduction of β-cell mass by 40–60% [ 81 ], but less than 24% loss after five years of disease has also been reported [ 82 ]. Reduced β-cell hyperplasia may also play a role in GDM, based on animal studies and limited post-mortem human studies [ 83 ]. Therefore, reduced β-cell mass, reduced β-cell number, β-cell dysfunction, or a mix of all three contribute to GDM, depending on the individual.

2.2. Chronic Insulin Resistance

Insulin resistance occurs when cells no longer adequately respond to insulin. At the molecular level, insulin resistance is usually a failure of insulin signaling, resulting in inadequate plasma membrane translocation of glucose transporter 4 (GLUT4)—the primary transporter that is responsible for bringing glucose into the cell to use as energy ( Figure 1 ). The rate of insulin-stimulated glucose uptake is reduced by 54% in GDM when compared with normal pregnancy [ 84 ]. While insulin receptor abundance is usually unaffected, reduced tyrosine or increased serine/threonine phosphorylation of the insulin receptor dampens insulin signaling [ 85 ]. In addition, altered expression and/or phosphorylation of downstream regulators of insulin signaling, including insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), and GLUT4, has been described in GDM [ 84 ]. Many of these molecular changes persist beyond pregnancy [ 86 ].

Simplified diagram of insulin signaling. Binding of insulin to the insulin receptor (IR) activates IRS-1. Adiponectin promotes IRS-1 activation through AMP-activated protein kinase (AMPK), while pro-inflammatory cytokines activate protein kinase C (PKC) via IκB kinase (IKK), which inhibits IRS-1. IRS-1 activates phosphatidylinositol-3-kinase (PI3K), which phosphorylates phosphatidylinositol-4, 5-bisphosphate (PIP2) to phosphatidylinositol-3, 4, 5-phosphate (PIP3). PIP3 activates Akt2, which promotes GLUT4 translocation and glucose uptake into the cell.

Several of the previously discussed risk factors for GDM are thought to exert their effects by interfering with insulin signaling. For example, saturated fatty acids increase intracellular concentrations of diacylglycerol within myocytes, activating protein kinase C (PKC) and inhibiting tyrosine kinase, IRS-1 and PI3K [ 41 ]. Pro-inflammatory cytokines and adiponectin also modify this process, as discussed below.

A diagram of the relationship between β-cell dysfunction, insulin resistance, and GDM is provided in Figure 2 .

β-cell, blood glucose, and insulin sensitivity during normal pregnancy and GDM. During normal pregnancy, β-cells undergo hyperplasia and hypertrophy in order to meet the metabolic demands of pregnancy. Blood glucose rises as insulin sensitivity falls. Following pregnancy, β-cells, blood glucose, and insulin sensitivity return to normal. During gestational diabetes, β-cells fail to compensate for the demands of pregnancy, and, when combined with reduced insulin sensitivity, this results in hyperglycemia. Following pregnancy, β-cells, blood glucose, and insulin sensitivity may return to normal or may remain impaired on a pathway toward GDM in future pregnancy or T2DM. Pancreas image obtained from The Noun Project under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ), by artist Arif Fajar Vulianto.

2.3. Neurohormonal Networks

Neurohormonal dysfunction has been implicated in the pathogenesis of diseases of insulin resistance, such as that present in GDM. This network regulates appetite, active energy expenditure, and basal metabolic rate, and it is made up of a complex network of central (e.g., cortical centers that control cognitive, visual, and “reward” cues) and peripheral (e.g., satiety and hunger hormones) signals [ 87 , 88 ]. These contribute to GDM by influencing adiposity and glucose utilization. This network is highly regulated by the circadian clock, which may explain why pathological sleep disorders or those individuals undertaking shift work are correlated with GDM rates [ 89 , 90 ]. Neural networks controlling body weight are most likely set in early life, as demonstrated in animal studies. For example, rats that are both under- and over-fed in early life experience epigenetic alteration of the regulatory set-point of hypothalamic neurons [ 91 , 92 ]. This adds to the previously mentioned suggestion that predisposition to GDM may be set in the womb.

Some of the most important regulators of neurohormonal metabolic control are adipokines—cell signaling proteins that are secreted primarily by adipose tissue. These include leptin and adiponectin:

2.3.1. Leptin

Leptin is a satiety hormone secreted primarily by adipocytes in response to adequate fuel stores. It primarily acts on neurons within the arcuate nucleus of the hypothalamus to decrease appetite and increase energy expenditure. Specifically, leptin inhibits appetite-stimulators neuropeptide Y (NPY) and agouti-related peptide (AgRP), and it activates the anorexigenic polypeptide pro-opiomelanocortin (POMC) [ 93 ]. When leptin was first discovered, it was lauded as a potential treatment for obesity [ 94 ]. However, it was soon revealed that the majority of obese individuals do not respond to leptin, and instead demonstrate leptin resistance. While leptin treatment is effective in obesity that is caused by leptin and leptin receptor genetic polymorphisms, these are rare (<5% of obese individuals) [ 95 ]. Therefore, obesity is associated with excessive plasma leptin concentration (hyperleptinemia) as a result of leptin resistance, and plasma leptin concentrations are generally proportional to the degree of adiposity [ 96 ]. Leptin resistance can occur either as a defect in blood-brain barrier leptin transport, or through intracellular mechanisms that are similar to insulin resistance [ 97 ]. Like insulin resistance, a degree of leptin resistance occurs in normal pregnancy, presumably to bolster fat stores beyond what would usually be required in the non-pregnant state. Leptin resistance is further increased in GDM, resulting in hyperleptinemia [ 98 ]. However, pre-pregnancy BMI is a stronger predictor of circulating leptin than GDM per se [ 99 ].

The placenta also secretes leptin during human pregnancy. In fact, the placenta is responsible for the majority of plasma leptin during pregnancy [ 100 ]. Placental leptin production is increased in GDM, probably as a result of placental insulin resistance, and this further contributes to hyperleptinemia. This is also thought to facilitate amino acid transport across the placenta, contributing to fetal macrosomia [ 101 ].

2.3.2. Adiponectin

Similar to leptin, adiponectin is a hormone that is primarily secreted by adipocytes. However, plasma adiponectin concentrations are inversely proportional to adipose tissue mass, with low concentrations in obese individuals. GDM is similarly associated with decreased adiponectin [ 102 ]. In contrast to leptin, there is a stronger association of adiponectin with insulin resistance than with adiposity [ 103 ]. This suggests that adiponectin plays an important role in the pathogenesis of GDM, independent of obesity. Adiponectin enhances insulin signaling and fatty acid oxidation, and it inhibits gluconeogenesis [ 104 ]. It does so by activating AMP-activated protein kinase (AMPK) within insulin-sensitive cells, which facilitates the action of IRS-1 ( Figure 1 ), and by activating the transcription factor peroxisome proliferator-activated receptor alpha (PPARα) in the liver. Furthermore, adiponectin stimulates insulin secretion, by upregulating insulin gene expression and exocytosis of insulin granules from β-cells [ 105 ].

Adiponectin is also expressed at low concentration from the syncytiotrophoblast of the placenta where it is regulated by cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, interferon gamma (IFN-γ), and leptin [ 106 ]. The role of placental adiponectin in normal and GDM pregnancy is unclear [ 107 ]. However, emerging evidence suggests adiponectin impairs insulin signaling and amino acid transport across the placenta, limiting fetal growth. Therefore, adiponectin gene methylation in the placenta is associated with maternal glucose intolerance and fetal macrosomia [ 108 ].

2.4. Adipose Tissue

Originally believed to exist only as a passive depot of energy, the discovery of leptin in 1994 established adipose tissue as an essential endocrine organ. Adipose tissue both ensures that energy is partitioned safely and it actively secretes circulatory factors, including adipokines (the aforementioned leptin and adiponectin) and cytokines (such as TNF-α, IL-6, and IL-1β), which have wide-ranging metabolic effects.

2.4.1. Energy Storage

The storage capability of adipose tissue is essential for metabolic health. This is exemplified through two extremes: rare disorders in which white adipose tissue is absent lead to severe metabolic syndrome, whereas some obese individuals (with excessive white adipose tissue) do not develop metabolic syndrome at all [ 109 ]. Therefore, the ability to partition excess calories into adipose tissue rather than ectopically in the liver, muscle, or pancreas, appears to serve as a protective measure. Non-diabetic obese individuals exhibit adequate adipose tissue expansion in response to fuel surfeit, and therefore maintain healthy blood glucose concentrations, sufficient β-cell compensation, and avoid chronic insulin resistance [ 110 , 111 ]. In this way, key organs avoid glucose and fatty acid-induced tissue damage. As previously mentioned, early pregnancy is marked by an increase in adipose tissue mass, while later pregnancy promotes the mobilization of fats from adipose tissue in order to fuel fetal growth. Both of these processes are thought to be limited in GDM [ 112 ]. GDM is associated with reduced adipocyte differentiation and increased adipocyte size (hypertrophy), accompanied by downregulated gene expression of insulin signaling regulators, fatty acid transporters, and key adipogenic transcription factors, such as PPARγ [ 113 ]. The combination of insulin resistance and reduced adipocyte differentiation hinders the tissue’s ability to safely dispose of excess energy, contributing to gluco- and lipo-toxicity in other peripheral organs. Indeed, both T2DM and GDM are associated with lipid deposition in muscle and liver [ 114 , 115 ].

2.4.2. Adipose Tissue Inflammation

Obesity, T2DM and GDM are associated with an increased number of resident adipose tissue macrophages (ATM) that secrete pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β. The importance of a low-grade inflammatory state in the pathogenesis of insulin resistance has recently become apparent. Pro-inflammatory cytokines have been discovered to both impair insulin signaling and inhibit insulin release from β-cells. These factors induce insulin resistance either by diminishing insulin receptor (IR) tyrosine kinase activity, increasing serine phosphorylation of IRS-1, or through the STAT3-SOCS3 pathway, which degrades IRS-1 [ 85 , 116 ]. Circulating concentrations of pro-inflammatory cytokines are increased in GDM [ 107 , 117 ]. Plasma TNF-α, in particular, is strongly correlated with insulin resistance [ 118 ]. Similarly, placental gene expression of TNF-α, IL-1β and their receptors has been reported to be increased in GDM [ 118 , 119 ]. However, the relationship between pregnancy and inflammation is complex. For example, Lappas et al. (2010) reported that GDM placentae secrete fewer pro-inflammatory cytokines (3 of 16 studied: IL-1β, TNF-α and M1P1B) than healthy placentae (13 out of 16 studied) [ 120 ]. This suggests that, while chronic low-grade inflammation appears to be important in the pathogenesis of GDM, the relationship may not be straightforward.

GDM is associated with upregulated hepatic glucose production (gluconeogenesis). Gluconeogenesis is increased in the fasted state, and not adequately suppressed in the fed state [ 84 ]. This is not believed to be entirely the result of inaccurate glucose sensing due to insulin resistance, as the majority of glucose uptake by the liver (~70%) is not insulin dependent. Common factors between the insulin signaling pathway and the pathways controlling gluconeogenesis, such as PI3K, might contribute to these effects [ 121 ]. Increased protein intake and muscle breakdown may also stimulate the process by providing excess gluconeogenesis substrate [ 122 ]. Despite this, the liver does not seem to be a primary pathogenic driver of T2DM or GDM [ 123 ].

2.6. Skeletal and Cardiac Muscle

Traditionally, skeletal muscle insulin resistance was believed to play a causal role in T2DM. However, skeletal muscle insulin resistance now appears to be a consequence of hyperglycemia—a protective measure to prevent metabolic stress and steatosis [ 124 ]. Even following a short period of overfeeding, cardiac and skeletal muscle develop insulin resistance in order to divert the excess energy into adipose tissue [ 125 ]. This is an important distinction when considering potential treatments for GDM: attempts to directly reverse skeletal muscle insulin resistance, without reducing plasma glucose concentrations, could be detrimental [ 123 ].

Separate to insulin sensitivity, T2DM and GDM are associated with a reduced number and function of mitochondria within skeletal muscle cells [ 126 ]. This could be the result of genetics, early-life programming, or chronic inactivity. Therefore, decreased number and function of mitochondria is likely an additional contributor to reduced glucose utilization in GDM.

2.7. Gut Microbiome

There is emerging evidence that microbial organisms within the gut—the “gut microbiome”—might contribute to metabolic diseases, including GDM. The gut microbiome can be influenced by early-life events, such as preterm delivery and breastfeeding, and by events in later life, such as diet composition and antibiotic use. The gut microbiome has been consistently reported to differ between metabolically healthy and obese individuals, including during pregnancy [ 127 ]. Furthermore, a study of stool bacteria in women with a past case of GDM reported a lower proportion of the phylum Firmicutes and higher proportion of the family Prevotellaceae as compared with normoglycemic pregnancy [ 128 ]. Similar associations have been observed in obesity [ 129 ], T2DM [ 130 ], fatty liver disease [ 131 ], and elevated total plasma cholesterol [ 132 ]. Firmicutes metabolize dietary plant polysaccharides. This may explain some of the dietary risk factors for GDM that are discussed earlier. Both red meat and animal protein decrease levels of Firmicutes , while high dietary fiber increase them [ 133 ]. However, the findings by Fugmann et al. (2015) remained after adjustment for dietary habits [ 128 ]. Therefore, Firmicutes appear to be relevant to pathogenesis of GDM independent of diet, although the mechanisms underlying this are unknown. Prevotellaceae are mucin-degrading bacteria that may contribute to increased gut permeability. Gut permeability is regulated by tight junction proteins, such as zonulin (ZO-1). Increased “free” plasma/serum ZO-1 is associated with type 1 diabetes (T1DM), T2DM [ 134 ], and GDM [ 135 ]. Increased gut permeability is thought to facilitate the movement of inflammatory mediators from the gut into the circulation, promoting systemic insulin resistance [ 134 , 136 ].

2.8. Oxidative Stress

Oxidative stress describes an imbalance between pro-oxidants and antioxidants in cells. Oxidative stress can lead to cellular damage by interfering with the state of proteins, lipids and DNA, and has been implicated in the pathogenesis of many diseases, including GDM [ 137 ]. Reactive oxygen species (ROS) are described as free radical and nonradical derivatives of oxygen, and include superoxide anion (O 2 − ), hydroxyl radical (•OH) and hydrogen peroxide (H 2 O 2 ) [ 138 ]. A hyperglycemic environment is associated with oxidative stress, and GDM women have been reported to overproduce free radicals and have impaired free-radical scavenging mechanisms [ 139 ]. ROS inhibit insulin-stimulated glucose uptake by interfering with both IRS-1 and GLUT4 [ 140 ]. ROS also slow glycogen synthesis in the liver and muscle. Pro-inflammatory cytokines, such as TNF-α, may also contribute to oxidative stress by increasing the expression and the activation of ROS precursors, like NADPH oxidase 4 (NOX4) [ 141 ].

Interestingly, iron supplementation in women already replete in iron is associated with GDM [ 142 ]. Several studies suggest that this relationship is the result of increased oxidative stress. Iron is a transitional metal and it can catalyze the reaction from O 2− and H 2 O 2 to the extremely reactive •OH within mitochondria [ 143 ]. On the contrary, selenium and zinc are transitional metals that are necessary for the activity of some antioxidant enzymes, which may explain their inverse association with GDM [ 144 ].

Homocysteine—a non-protein α-amino acid that is formed by the demethylation of methionine—is also thought to contribute to GDM via oxidative stress. Exposure of β-cells to even small amounts of homocysteine results in dysfunction and impaired insulin secretion [ 145 ]. A recent meta-analysis examined the relationship between serum homocysteine concentration and GDM in ten eligible studies. The authors reported significantly higher homocysteine concentrations among women with GDM as compared with those without GDM [ 146 ]. B vitamins, including folic acid, B2, B6, and B12 are essential for homocysteine homeostasis, and this may be one reason why deficiencies and imbalances of these micronutrients are associated with GDM [ 147 ].

2.9. Placental Transport

The placenta contributes to insulin resistance during pregnancy via its secretion of hormones and cytokines. As the barrier between the maternal and fetal environments, the placenta itself is also exposed to hyperglycemia and its consequences during GDM. This can impact transport of glucose, amino acids, and lipids across the placenta:

Glucose— Glucose is the primary energy source for the fetus and the placenta, and therefore must be readily available at all times. For this reason, insulin is not required for the placental transport of glucose. Instead, glucose transport occurs via GLUT1, by carrier-mediated sodium-independent diffusion [ 148 ]. However, the placenta still expresses the insulin receptor, and insulin signaling can influence placental metabolism of glucose [ 149 ]. The receptiveness of the placenta to glucose uptake means that it is particularly sensitive to maternal hyperglycemia, and this directly contributes to increased fetal growth and macrosomia.

Protein— Amino acid transport across the placenta is also an important determinant of fetal growth. GDM is associated with increased System A and L activity [ 150 ]. These can also be modulated by pro-inflammatory cytokines, such as TNF-α and IL-6 [ 151 ]. Altered amino acid transport may also be one mechanism by which excess protein intake contributes to GDM.

Lipids— Finally, while GDM has traditionally been described as a disease of hyperglycemia, the rise in obesity-associated GDM has prompted a greater focus on the role of hyperlipidemia in GDM. The majority of placental gene expression alterations in GDM occur in lipid pathways (67%), as compared with glucose pathways (9%) [ 152 ]. Preferential activation of placental lipid genes is also associated with GDM compared with T1DM [ 152 ]. These data correlate with the results of the HAPO Study, which revealed independent effects of maternal obesity and glucose on excessive fetal growth [ 153 ]. Therefore, it appears that GDM influences the placental transport of glucose, amino acids, and fatty acids, and that all three must be considered when discussing the impact of GDM on placental function and fetal growth.

In addition to these alterations in placental transport, GDM has been associated with other changes in the placenta. Some recent studies have reported that GDM is associated with placenta global DNA hypermethylation [ 154 ]. Similarly, studies of the placental proteome have identified differences in the expression of proteins between GDM and non-GDM placentas [ 155 ]. However, more research is required before the role of placental epigenetic and proteomic modifications in GDM is fully understood [ 156 ]. There has also been recent interest in small noncoding single-stranded segments of RNA, called microRNAs (miRNAs), expressed in placental trophoblast cells. miRNAs are involved in a number of cellular processes, including proliferation, differentiation, and apoptosis. Emerging evidence suggests that exosomes containing miRNAs are shed from the placenta during gestation and released into the maternal circulation, which can in turn influence the functioning of other cells, potentially contributing to the pathogenesis of GDM [ 157 , 158 ]. Interestingly, exposure to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA—found in food packaging materials and consumer products) has been associated with GDM, and it has been suggested that this could be because EDCs induce exosome signaling from the placenta [ 159 ]. Interestingly, EDCs including BPA have also been associated with alterations in methylation, perhaps linking the two mechanisms [ 160 ]. A summary diagram of the pathophysiology of GDM is presented in Figure 3 .

Organs involved in the pathophysiology of GDM (Images in this figure were obtained from The Noun Project under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ). Brain and Gut by Hunotika; Liver by Lavmik; Pancreas by Arif Fajar Vulianto; Placenta by Charmeleon Design; Muscle by Misha Petrishchev).

3. Opportunities and Considerations for Future Study

Uncovering the intricate molecular mechanisms underlying GDM is challenging, but necessary for our greater understanding of the disease and how these could assist in the design of new treatments. As β-cell dysfunction and insulin resistance are the hallmarks of GDM, the greatest emphasis should be placed on further understanding the mechanisms underlying these processes. For example, why do β-cells exhibit proper hyperplasia and hypertrophy in some pregnancies, but not others? How could we modify these processes to bolster pancreatic function and prevent hyperglycemia in at-risk individuals? As already mentioned, increasing insulin sensitivity could have unintended consequences by promoting uptake of glucose into tissue where energy should not be stored, such as the liver and skeletal muscle. Instead, investment into adipose-specific insulin sensitivity should be examined. While improving adipose capacity (and in theory increasing adipose tissue mass) might seem counterintuitive, in actuality, it should reduce hyperglycemia while ensuring that excess energy is stored safely. Of course, many of the mechanisms underlying GDM are not unique to GDM, encompassing other common disorders of insulin sensitivity, such as T2DM, prediabetes, and PCOS. Therefore, determination of pathways influencing development of these metabolic disorders may also shed light on GDM, and potentially accelerate opportunities for prevention and/or treatment. This is an important consideration, as the study of GDM (as a disorder of pregnancy) is limited for ethical reasons. Finally, the ability to study large amounts of data through computer technology is rapidly advancing the fields of genomics, epigenetics, proteomics, metagenomics (the microbiome), and metabolomics (the study of the small-molecule intermediates and products of metabolism). It is hopeful that the advancement of these large-scale techniques may assist in our understanding of the pathogenesis of GDM in the future.

4. Conclusions

Pregnancy is a state of high metabolic activity, in which maintaining glucose homeostasis is of upmost importance. When hyperglycemia is detected in the pregnant mother, this is referred to as GDM, although controversy remains over diagnostic criteria. It is likely that genetic, epigenetic, and environmental factors all contribute to the development of GDM, and that the mechanisms involved are complex and advance over a substantial period of time. However, in the majority of cases, pancreatic β-cells fail to compensate for a chronic fuel surfeit, leading to eventual insulin resistance, hyperglycemia, and an increased supply of glucose to the growing fetus. There is also evidence that adipose expandability, low-grade chronic inflammation, gluconeogenesis, oxidative stress, and placental factors contribute to the pathology of GDM. Greater understanding of these processes and their contribution to GDM is required in order to develop effective treatments and prevention strategies.

Author Contributions

J.F.P. primarily wrote the manuscript. J.L.S., C.M.R., P.N.B. and M.H.V. provided supervisory and editorial assistance.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Nooria Atta , Anuli Ezeoke , Clive J. Petry , Laura C. Kusinski , Claire L. Meek; Associations of High BMI and Excessive Gestational Weight Gain With Pregnancy Outcomes in Women With Type 1 Diabetes: A Systematic Review and Meta-analysis. Diabetes Care 20 September 2024; 47 (10): 1855–1868. https://doi.org/10.2337/dc24-0725

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The increased risk of pregnancy complications in type 1 diabetes is mainly attributed to maternal hyperglycemia. However, it is unclear whether other potentially modifiable factors also contribute to risk in this population.

We sought to assess whether high BMI and excessive gestational weight gain (GWG) are associated with perinatal complications in type 1 diabetes.

We searched Medline, Embase, PubMed, Scopus, Web of Science, and Cochrane databases to January 2024.

Studies examining associations between periconception BMI or GWG and perinatal complications in type 1 diabetes were included.

We used a predesigned data extraction template to extract study data including year, country, sample size, participants’ characteristics, exposure, and outcomes.

We included 29 studies (18,965 pregnancies; 1978–2019) in the meta-analysis. A 1 kg/m 2 /1 kg increase in preconception BMI or GWG was associated with a 3% and 11% increase, respectively, in perinatal complications (BMI odds ratio [OR] 1.03 [95% CI 1.01–1.06]; GWG OR 1.11 [95% CI 1.04–1.18]). Preconception BMI ≥ 25 kg/m 2 or excessive GWG was associated with a 22% and 50% increase, respectively, in perinatal complications (BMI OR 1.22 [95% CI 1.11–1.34]; GWG OR 1.50 [95% CI 1.31–1.73]). BMI was associated with congenital malformation, preeclampsia, and neonatal intensive care unit admission. Excessive GWG was associated with preeclampsia, cesarean delivery, large for gestational age, and macrosomia.

Limitations included retrospective study design, variable measurement for exposures and outcomes, small number of studies for some outcomes, and no data from Asia and Africa.

Addressing maternal BMI prepregnancy and preventing excessive GWG should be key clinical priorities to improve outcomes in pregnant women with type 1 diabetes.

Graphical Abstract

This article contains supplementary material online at https://doi.org/10.2337/figshare.26311525 .

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Gestational outcomes related to the occurrence of gestational diabetes mellitus: a cohort study.

1. Introduction

2. materials and methods, 2.1. type of study, sample characteristics, and data collection, 2.2. statistical analysis, 4. discussion, 5. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Share and Cite

Souza Stork, S.; Meurer Souza, C.; Somariva Prophiro, J.; Brownell, E.A.; Pinto Moehlecke Iser, B. Gestational Outcomes Related to the Occurrence of Gestational Diabetes Mellitus: A Cohort Study. Healthcare 2024 , 12 , 1905. https://doi.org/10.3390/healthcare12191905

Souza Stork S, Meurer Souza C, Somariva Prophiro J, Brownell EA, Pinto Moehlecke Iser B. Gestational Outcomes Related to the Occurrence of Gestational Diabetes Mellitus: A Cohort Study. Healthcare . 2024; 12(19):1905. https://doi.org/10.3390/healthcare12191905

Souza Stork, Samara, Claudia Meurer Souza, Josiane Somariva Prophiro, Elizabeth Ann Brownell, and Betine Pinto Moehlecke Iser. 2024. "Gestational Outcomes Related to the Occurrence of Gestational Diabetes Mellitus: A Cohort Study" Healthcare 12, no. 19: 1905. https://doi.org/10.3390/healthcare12191905

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Prediction of gestational diabetes mellitus by multiple biomarkers at early gestation

Affiliations.

• 1 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Department of Pediatrics, Xinhua Hospital, Early Life Health Institute, Shanghai Jiao-Tong University School of Medicine, Kong-Jiang Road, Shanghai, 200092, China.
• 2 Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, University of Toronto, L5-240, Murray Street 60, Toronto, ON, M5T 3H7, Canada.
• 3 Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200030, China.
• 4 Clinical Skills Center, School of Clinical Medicine, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China.
• 5 Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200092, China.
• 6 Department of Clinical Assay Laboratory, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200092, China.
• 7 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Department of Pediatrics, Xinhua Hospital, Early Life Health Institute, Shanghai Jiao-Tong University School of Medicine, Kong-Jiang Road, Shanghai, 200092, China. [email protected].
• 8 State Key Laboratory of Reproductive Medicine, Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
• 9 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Department of Pediatrics, Xinhua Hospital, Early Life Health Institute, Shanghai Jiao-Tong University School of Medicine, Kong-Jiang Road, Shanghai, 200092, China. [email protected].
• 10 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Department of Pediatrics, Xinhua Hospital, Early Life Health Institute, Shanghai Jiao-Tong University School of Medicine, Kong-Jiang Road, Shanghai, 200092, China. [email protected].
• 11 Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, University of Toronto, L5-240, Murray Street 60, Toronto, ON, M5T 3H7, Canada. [email protected].
• PMID: 39285345
• PMCID: PMC11406857
• DOI: 10.1186/s12884-024-06651-4

Background: It remains unclear which early gestational biomarkers can be used in predicting later development of gestational diabetes mellitus (GDM). We sought to identify the optimal combination of early gestational biomarkers in predicting GDM in machine learning (ML) models.

Methods: This was a nested case-control study including 100 pairs of GDM and euglycemic (control) pregnancies in the Early Life Plan cohort in Shanghai, China. High sensitivity C reactive protein, sex hormone binding globulin, insulin-like growth factor I, IGF binding protein 2 (IGFBP-2), total and high molecular weight adiponectin and glycosylated fibronectin concentrations were measured in serum samples at 11-14 weeks of gestation. Routine first-trimester blood test biomarkers included fasting plasma glucose (FPG), serum lipids and thyroid hormones. Five ML models [stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, support vector machine and k-nearest neighbor] were employed to predict GDM. The study subjects were randomly split into two sets for model development (training set, n = 70 GDM/control pairs) and validation (testing set: n = 30 GDM/control pairs). Model performance was evaluated by the area under the curve (AUC) in receiver operating characteristics.

Results: FPG and IGFBP-2 were consistently selected as predictors of GDM in all ML models. The random forest model including FPG and IGFBP-2 performed the best (AUC 0.80, accuracy 0.72, sensitivity 0.87, specificity 0.57). Adding more predictors did not improve the discriminant power.

Conclusion: The combination of FPG and IGFBP-2 at early gestation (11-14 weeks) could predict later development of GDM with moderate discriminant power. Further validation studies are warranted to assess the utility of this simple combination model in other independent cohorts.

Keywords: Early gestation; Fasting plasma glucose; Gestational diabetes; IGFBP-2; Predictive biomarker.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

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• 81930095/National Natural Science Foundation of China
• 81961128023/National Natural Science Foundation of China
• 82073570/National Natural Science Foundation of China
• 21410713500/Shanghai Municipal Science and Technology Commission
• 2020CXJQ01/Shanghai Municipal Health Commission
• 2019YFA0802501/Ministry of Science and Technology of China
• 155955/CAPMC/ CIHR/Canada

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Being pregnant and managing gestational diabetes during the COVID-19 Pandemic

Patient Stories

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Being pregnant during a global pandemic is something I couldn’t have imagined in my wildest dreams, but here I am. On top of the uncertainty that comes along with a pregnancy during this time, I was also diagnosed with gestational diabetes, which added another level of fear and uncertainty.

We had just celebrated our unborn son at a baby shower with my entire family and friends the week before COVID-19 started to affect businesses and employees were being told to work from home. I was 23 weeks pregnant and went from feeling joyous and excited to the stark contrast of feeling confused and scared. My mind was flooded with questions: What would happen if I got sick? How could it affect my baby? Will this situation go into July when our son is due? Will my family and friends be able to visit when he is born?

Though the latter half of my pregnancy was not like I imagined it would be, the staff at Texas Children’s Pavilion for Women has been incredibly helpful and supportive. I’ve been able to convert some of my appointments into virtual visits which has been convenient and still allows me to ask all of my questions. I have also found my care team to be very responsive via MyChart when I have additional questions.

When I went to the Pavilion for Women for my 3-hour glucose test, the hospital seemed rather empty when I arrived, but I expected this as I knew the goal was to reduce overall traffic to avoid spread COVID-19. I also expected to go through a screening process before going to my appointment because the staff called me in advance and explained what my visit would look like.

I was politely greeted by a security guard who escorted me to the first floor where I was to be screened. They asked me several questions about exposure to the virus, etc., took my temperature and gave me a visitor badge. I was then escorted to the elevators that took me to the 15th floor. I took my glucose test and was poked and prodded by needles several times. The results came back through MyChart a day later that I failed the test and was diagnosed with gestational diabetes.

At first I thought the diagnosis was my fault. I should have eaten better while I was pregnant or lost more weight before I even became pregnant. But I soon found out from a gestational diabetes counselor that it has more to do with a hormonal issue with the placenta and how my body processes glucose during pregnancy. I will say, having this diagnosis is just one more thing to manage as I have to track what I eat and test my blood every four hours – on top of remembering to wear a mask, wipe down everything that comes into the house and keep 6 ft. away from anyone who’s not my husband. But it’s not difficult to manage as long as I stay on top of it.

After learning about my diagnosis, I was grateful to have the option to have a virtual visit with the gestational diabetes counselor. The counselor walked me through some of the information about how to manage my condition and also called in a prescription for a glucose test kit called Accu-Check, so I could start testing and logging my blood glucose levels.

I tested my blood four times a day and logged my levels for about a week and a half and then had my “official” first phone call with another GD counselor. They helped me understand what adjustments I could make to my meals to help lower my glucose levels and walked me through the handouts again to make sure I didn’t have any questions. They instructed me to submit my glucose logs every Monday so they can evaluate my levels. If they are too high then I will need to take medication. If I can manage my levels with diet and exercise, no medication is needed.

I recently had my 28-week appointment at the Pavilion for Women with Dr. Longerot, which included a growth scan with our maternal-fetal medicine team (MFM). I knew in advance that my husband would not be able to attend this appointment due to the new hospital policies put in place to protect patients and staff, and was grateful he had been there for my previous ultrasounds.

My growth ultrasound went well and my friendly sonographer texted me a link to download the images and video clips from the exam so I could show my husband! After my appointment, I tried explaining to my husband what the MFM detailed to me and didn’t do a very good job. So I asked via MyChart if they could send me the written ultrasound summary so I could share it with him. They sent it the next day and my husband was happy and felt “in the loop.” The staff is really going above and beyond to ensure everyone feels cared for and informed.

As I near my delivery date, I anticipate thinking more about my birth experience. With things evolving so rapidly due to COVID-19, I have worries about what my experience might look like. However, as long as I have my husband by my side, that’s all I need. In fact, it may be best if it’s just the two of us so we can focus on learning how to take care of our newborn, and not having a ton of visitors may be a good thing!

Overall, I’m very grateful for the time I’ve had at home and the extra time with my husband. I also think being home while pregnant with gestational diabetes has helped me stay on track with my diet as there are no distractions. We’ve been social distancing by avoiding gatherings - even on Easter - and host Zoom calls with family instead. We’ve been working from home during the week so the only time we get out of the house are our walks around the neighborhood to get some fresh air. Even on walks, we make sure to keep 6 ft. away from anyone else on the sidewalk. We continuously wash our hands, use hand sanitizer religiously and wipe down any surfaces items from the “outside world” have touched. And, if either of us venture out to the grocery store (my husband typically goes), we make sure to wear a mask and gloves. Having to remember to do all of this is pretty stressful. Especially when I have pregnancy brain and am much more forgetful than I normally am.

Through these difficult times, I try to remind myself how exciting life will be once our baby boy is born. I’ve been decorating the nursery, my husband and I selected a name that we’re really excited about – William Wyatt Herbst – and I’ve been making a list of everything I need to monogram with his initials. These are the things that I focus on to bring positive vibes into our daily lives!

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Though the latter half of my pregnancy was not like I imagined it would be, the staff at Texas Children’s Pavilion for Women has been incredibly helpful and supportive. I’ve been able to convert some of my appointments into virtual visits which has been convenient and still allows me to ask all of my questions.