Gestational Diabetes: Opportunities and Challenges

Running Head: GESTATIONAL DIABETES

Gestational Diabetes: Challenges and Opportunities

Nicole Dummann

Bethel University

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GESTATIONAL DIABETES

Introduction

Gestational Diabetes Mellitus (GDM) is defined as newly

occurring abnormalities in carbohydrate metabolism and

glucose intolerance first recognized during pregnancy

(Varney et al., 2014). With GDM, there is resolution of

abnormal blood glucose tolerance soon after the baby is

delivered. The American Diabetes Association reports an

estimate of 9% of pregnancies in the U.S. that are currently

affected by gestational diabetes (American Diabetes

Association [ADA], 2013). Distinguishing between pre-

existing diabetes and gestational DM shows that

approximately 90% of diabetes in pregnancy is gestational

while the remaining 10% is attributable to pre-existing T1

or T2 diabetes mellitus (DM) (Moore, 2014).

The detrimental health implications resulting from

hyperglycemia during the gestational period, as well as the

potential for later development of T2DM for both the mother

and the baby, present both challenges and opportunities.

Health care providers and researchers need to be providing

informed clinical guidance to women at risk of GDM before,

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during, and after the period of gestation. It is important

to understand why gestational diabetes develops and to take

seriously the need to manage it effectively during

pregnancy. It is equally important to recognize the need

for health promotion and further research for both women who

experienced GDM during pregnancy, and the children that

result from those pregnancies.

Etiology

The etiology leading up to the development of GDM is

essentially two-fold with genetics playing a major role and

nutritional status, namely obesity, being a second major

contributor. The problem of insulin resistance without

adequate compensation in insulin production is a hallmark

feature of GDM. Insulin resistance is present in pregravid

women and is unmasked during pregnancy when the normal

physiologic movement to a state of insulin resistance

expresses in later pregnancy (Catalano et al., 2003). In

an article published in 2009 in Diabetologia, the authors

state that evidence indicates obesity is tied to the

development of insulin resistance because of chronic

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subclinical inflammation and dysregulated amounts of the

insulin sensitizing proteins collectively called adipokines

that are produced exclusively by adipocytes (Retnakaran et

al, 2009).

In normal pregnancy there is an approximate 50%

decrease in insulin-mediated glucose processing in the

mother’s body, and a 200-250% increase in insulin in order

to keep a euglycemic state (Barbour et al., 2007).

Additionally in the latter part of gestation in normal

pregnancy, there is a shift in the mother’s body to increase

lipolysis to use fat for energy rather than glucose. This

lipolysis is normally accompanied by a reduction in insulin

sensitivity of the mother’s cells and both physiologic

processes together aim to ensure the growing fetus receives

adequate nutrition during this high growth phase of

gestation (Boyle et al., 2014). Interestingly, women with

GDM, as compared to women with normal glucose tolerance,

have a lower rate of this shift to lipid oxidation and use

of the energy stored in fat. Skeletal muscle cells serve as

the primary tissue in the body where both glucose and lipids

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are metabolized in the body and thus play a big role in

determining if glucose is used by maternal cells or

ultimately transported across the placenta to the developing

fetus (Boyle et al., 2014). If more glucose is shunted

across the placenta, the risk of macrosomia increases.

Insulin resistance creates problems with glucose uptake,

metabolism, and storage at the cellular level. In summary,

pre-existing genetically mitigated maternal insulin

resistance and obesity, coupled with the normal

hyperinsulinemia and insulin resistance of later pregnancy,

set the stage for development of GDM.

Pathogenesis

At a cellular level, it is known that insulin

resistance and inadequate compensatory secretion of insulin

from the maternal beta cells are the reasons GDM develops.

The question, then, is what events trigger insulin

resistance to the degree that diabetes ensues? The answer

is not yet fully understood and is multifactorial.

First, it is known that the hormones produced and

released by the placenta, including human placental lactogen

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(hPL), send the message to maternal tissues to initiate

lipid oxidation and cellular insulin resistance to preserve

more nutrients and glucose for the growing fetus. In a

healthy pregnancy, the pancreatic beta cells of the mother

are able to compensate to release more insulin to prevent

hyperglycemia. For GDM, this then points to both

abnormalities of maternal skeletal muscle and fat cells and

possibly dysfunction of beta cells. Human placental growth

hormone (hPGH) has also been implicated in triggering

insulin resistance of maternal cells, and if overexpressed

may contribute to “severe peripheral insulin resistance.”

(Barbour et al., 2007).

There are multiple areas where cellular communication

can be altered or interrupted when considering

pathophysiology of insulin resistance. A combination of

downregulation of cell receptors, interruptions in signaling

pathways, altered transcription factors, proteins, and

hormonal messengers, and issues with cellular

phosphorylation all contribute to the development of insulin

resistance. These problems appear to occur because of

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genetic predisposition, triggers of obesity and normal

processes of pregnancy, and possibly some yet to be

discovered causes. Nutrient deficiencies or inefficiencies

may also contribute to the development of insulin

resistance.

Colomiere et al. set out to look more closely at the

insulin signaling pathway in pregnant women with GDM who

were both obese and non-obese. They note that normally

insulin binds to an insulin receptor on cells called IR-β

which is implicated in signaling other insulin receptor

substrates (2010). IR-β starts the cascade that

communicates with an enzyme (P13-K) that translocates one of

the primary glucose transporters (GLUT4) to the cell

membrane by phosphorylation, which is a process that

transfers energy appropriately within a cell. They go on to

note that studies have shown reduced levels of the protein

associated with the P13-K enzyme as well as reduced GLUT4

transporters in muscle and adipose cells of obese pregnant

women (Colomiere, 2010). Furthermore, Reece et al. note

that the downregulation of one of the insulin receptor

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substrates, known as IRS-1, is implicated in decreased

glucose uptake by muscle cells (2009). Defects in

expression of proteins involved with turning glucose into

glycogen for storage in cells has also been implicated in

insulin resistance (Colomiere, 2010).

Excessive lipid turnover has also been found in states

of insulin resistance and increases free fatty acids that

circulate in the mother’s bloodstream which ties in with an

increase in hepatic glucose output (Barbour et al., 2007).

This finding connects to a study by Retnakaran et al. that

found that low levels of adiponectin, the insulin

sensitizing proteins produced by adipose cells, increased

leptin (the satiety hormone), and increased C-reactive

protein are found to exist in women with GDM and are

possible contributors to insulin resistance (2009).

Very recent research by Boyle et al. points

additionally to the role of calcium in insulin mediated

glucose processing. Their preliminary data show that there

may be disruption in the intracellular calcium signaling in

skeletal muscle cells affecting mitochondrial functioning in

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cells of women with GDM; they suggest further investigation

(2014). Interestingly, Catalano et al. found that zinc

deficiency of the mother may play a role in insulin

resistance as zinc is needed for proper signaling of the

insulin pathway and in animals, zinc was needed for

effective glucose metabolism (2003). A direct cause and

effect relationship was not made, but this look at the role

of zinc does call out for further research and speaks to the

multitude of cellular events at play when considering

glucose disposal and insulin resistance in the body.

Clinical Manifestations

Clinical manifestations are typically not readily

apparent when problems with glucose intolerance begin. Much

like the start of T2 DM, hyperglycemia can be quite silent.

It is therefore important that women are screened during

pregnancy to test that the body is able to compensate for

the insulin resistance of later pregnancy. Women have long

been screened for GDM between weeks 24-28 of gestation as

this is the time when the normal insulin resistance of

pregnancy sets in.

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The standard screening timeline and process, though,

has recently been challenged and international controversy

exists between different organizations.

In brief, the American College of Obstetricians and

Gynecologists (ACOG) recommends a two-step oral glucose

tolerance test. Women are given 50 grams of glucose and if

blood glucose (BG) one hour later is greater than 130-140

mg/dl they are then given a second oral glucose tolerance

test. The second test gives 100 grams of oral glucose and

BG is checked three hours later. There are two sets of

recommendations for interpreting the results of the three

hour oral glucose test but both say that BG should be less

than 140-145 mg/dl. A second test is done to ultimately

rule out a false-positive first test (Varney et al., 2014).

This two-step process has been the prevailing screening

method until recently.

With the rise of obesity and Type 2 DM, the American

Diabetes Association (ADA) and the International Association

of the Diabetes and Pregnancy Study Groups (IADPSG)

recommend consideration of earlier screening of all women,

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or at least high-risk women, at the start of prenatal care

to rule out pre-existing DM (Varney et al., 2014). The rest

of the recommendation from the ADA and IADPSG coincides with

the recommendation from the World Health Organization (WHO)

which promotes use of one 75 gram oral glucose tolerance

test. The WHO recommends this in consideration of expense

and availability of medical care in developing nations

(Reece et al., 2014). GDM is diagnosed with the 75 gram

test if after 2 hours the blood glucose is >153 mg/dl.

Higher risk is due to several factors but most notably

maternal age, having specific ethnic heritage, and a BMI

greater than 30.

If for some reason, GDM wasn’t caught by standard

screening, the woman would possibly and eventually manifest

symptoms that can come with hyperglycemia which include

polydipsia, polyuria, blurred vision, skin changes, and

fatigue. The risk of stillbirth is increased with

uncontrolled blood glucose and if a woman has an unexplained

stillbirth in her history, she is considered high risk which

warrants earlier screening in subsequent pregnancies (Varney

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et al., 2014). Additionally GDM predisposes women to higher

rates of pre-eclampsia (Boyle et al., 2014). Macrosomic, or

large for gestation infants (birth weight >4500 grams), is

also a typical clinical manifestation that results from

hyperglycemia in pregnancy.

Natural History

Large for gestation infant size (macrosomia) certainly

is an unfortunate result of untreated or undertreated GDM.

Additionally, Reece et al. note that infants exposed to a

hyperglycemic environment in utero can also suffer

respiratory distress syndrome, cardiomyopathy, hypoglycemia,

hypocalcemia, hypomagnesemia, polycythemia, and blood

hyperviscosity (2009).

The incidence of birth defects is not increased if

first trimester blood sugars are within normal limits and

GDM develops in later pregnancy. In contrast, the risk of

birth defects in babies born to mothers with undetected or

uncontrolled pre-existing DM in early pregnancy is

significantly increased (Varney et al., 2014).

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One of the most concerning aspects of GDM, especially

if poorly treated, is the increase in prevalence of T2 DM,

obesity, and metabolic syndrome in the children from those

pregnancies. As noted in an article in The Lancet from May

of 2009, a longitudinal study of Pima Indians showed that

“exposure to hyperglycemia in utero led to development of

Type 2 DM in 40% of children (5-19 years old) of Pima Indian

women” (Reece et al., 2009).

Also of great importance to note is that women who

develop GDM have a high risk for GDM in future pregnancies

and also for development of T2 DM and heart disease later in

life. As many as half of women with GDM will develop T2 DM

at some point (Boyle et al., 2014).

Prognosis

Prognosis overall is very good for women with GDM if

they are screened appropriately and follow treatment

recommendations to keep blood glucose as close to normal as

possible. There are some variations in recommendations for

BG levels during pregnancy, but the fifth annual

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international workshop conference of 2007, sponsored by the

ADA, put forth the following goals for BG for women with

GDM: fasting should be 90-99 mg/dl, 1 hour post-prandial

should be <140 mg/dl, and 2 hour post-prandial should be

<120 mg/dl (Reece. 2009).

Keeping mean glucose concentrations near normal

minimizes the potential for macrosomia (baby >4500 grams at

birth), birth injuries that may occur while delivering a

macrosomic baby, need for cesarean delivery, and the

potential medical issues noted above in the natural history

section.

Treatment Options

Goals for treatment are to keep blood glucose levels as

close to normal as possible. This is achieved by use of

diet, physical activity, insulin, and in some cases oral

antihyperglycemic medications. In a pregnancy not affected

by diabetes, the mother’s average fasting blood sugar is

right around 74 mg/dl and peak post meal blood sugars rarely

go above 120 mg/dl (Moore, 2014). Dietary recommendations,

termed Medical Nutrition Therapy (MNT), are to keep

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carbohydrate intake to 50% or less of total daily intake and

to avoid large, high carbohydrate meals. In practice, women

are taught to avoid highly processed cereal and fruit for

the breakfast meal as these are consistently shown to cause

post-prandial blood glucose spikes. Women are typically

advised to have three meals and three snacks daily and more

complex carbohydrates are recommended. Diabetes educators

(R.N. or R.D.) develop meal plans for women with specific

carbohydrate counts for all meals and snacks.

Physical activity as part of the treatment plan for

women with GDM has support from research and in a cohort

study of 22,000 women it was found that women affected by

GDM who exercised regularly were less likely to deliver

large for gestation babies (Reece et al., 2014). Generally

30 minutes a day of moderate level activity is recommended.

If blood sugars cannot be kept close to normal, then

insulin is indicated. The amount and type of insulin are

variable but often will involve multiple daily injections.

Continuous glucose monitors have been used successfully to

reveal post-prandial spikes in blood sugar and/or nighttime

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hypoglycemia not caught with multiple fingerstick blood

sugars. More commonly though, women are taught to monitor

their blood sugars using a home glucometer and should check

blood glucose levels at a minimum of twice daily – fasting

and 2 hours after a meal (Varney et al., 2014).

Oral medications, specifically Metformin (a biguanide)

and Glyburide (a sulfonylurea) have been used in pregnancy

with success and without any obvious detriment to the fetus.

Glyburide when studied was not found in the cord serum of

infants and was very effective in managing post prandial

blood sugars (Reece et al., 2014). Metformin has not been

found to cause any fetal anomalies in several small studies

of women with polycystic ovarian syndrome (Reece et al.,

2014). In practice, Metformin tends to be used more commonly

if an oral agent is chosen. In general, oral medications

can increase compliance of the mother, but still remain

somewhat controversial depending on the region of practice

and training of the practitioner.

Women with GDM should be sure to have screening labwork

completed 6 to 12 weeks postpartum (Varney et al., 2014).

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Conclusion

The challenges of GDM arise from an incomplete

understanding of the causes of insulin resistance, the

growing trend of obesity of American women, disagreements

between authoritative organizations on criteria for

diagnosing GDM, and the knowledge that both the women who

develop GDM in pregnancy and their children have increased

risk for later development of T2 DM.

The opportunities exist for further research into why

and how insulin resistance develops, continued health

promotion around the negative health implications of

obesity, coming to consensus as a medical community to be

sure we don’t over-screen for or undertreat both pre-

existing DM or GDM, and to be sure we are having

conversations with women who develop GDM so they understand

their risk factors and need for follow up screening. It is

so important that we as a health care community not take

this disease of pregnancy lightly.

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References

American Diabetes Association (2013). Fast facts data and statistics

about diabetes.

Retrieved from

http://professional.diabetes.org/admin/UserFiles/0 -

Sean/FastFacts March 2013.pdf

Barbour, L.A., McCurdy C.E., Hernandez, T.L., Kirwan, J.P.,

Catalano, P.M., Friedman

J.E., (2007). Cellular mechanisms for insulin

resistance in normal pregnancy and gestational

diabetes. Diabetes Care, 30(2). doi:10.2337/dc07-s202

Boyle, K.E., Hwang, H., Janssen, R.C., DeVente, J.M.,

Barbour, L.A., Hernandez,

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http://professional.diabetes.org/admin/UserFiles/0%20-%20Sean/FastFacts%20March%202013.pdf

http://professional.diabetes.org/admin/UserFiles/0%20-%20Sean/FastFacts%20March%202013.pdf


T.L.,…Friedman, J.E. (2014). Gestational diabetes is

characterized by reduced mitochondrial protein

expression and altered calcium signaling proteins in

skeletal muscle. PLoS ONE, 9(9), e106872.

doi:10.1371/journal.pone.0106872

Catalano, P.M., Kirwan, J.P., Haugel-de Mouzon, S., King, J.

(2003). Gestational

diabetes and insulin resistance: role in short and long

term implications for mother and fetus. The Journal of

Nutrition, 133(5). Retrieved from http://jn.nutrition.org

/content/133/5/1674S.full.pdf+html

Colomiere, M., Permezel, M., Lappas, M. (2010). Diabetes and

obesity during pregnancy

alter insulin signalling and glucose transporter

expression in maternal skeletal muscle and

subcutaneous adipose tissue. Journal of Molecular

Endocrinology, 44, 213-223. doi:10.1677/JME-09-0091

Moore, T.R. (2014). Diabetes mellitus and pregnancy. Retrieved

from

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http://emedicine.medscape.com/article/127547overview?

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References

Reece, E.A., Leguizamon, G., Wiznitzer, A. (2009).

Gestational diabetes: need for a

common ground. The Lancet, 373, 1789-97. Retrieved from

http://search. proquest.com.

ezproxy.bethel.edu/docview/ 199044534?accountid=8593

Retnakaran, R., Qi, Y., Connelly, P.W., Sermer, M.,

Hanley, A.J., Zinman, B. (2009).

Low adiponectin concentration during pregnancy predicts

postpartum insulin resistance, beta cell dysfunction

and fasting glycaemia. Diabetologia: Journal of the EASD,

53: 268-276. doi:10.1007/s00125-009-1600-8

Varney, H., Kriebs, J., King, T., Brucker, M., Fahey, J., &

Gegor, C. (2014). Obstetric

complications in pregnancy. In Varney's midwifery (Fifth

ed.). Sudbury, Mass.: Jones and Bartlett Pub.

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http://emedicine.medscape.com/article/127547overview?src=emailthis#aw2aab62

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GESTATIONAL DIABETES 21

Gestational Diabetes: Opportunities and Challenges

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