PATHOPHYSIOLOGY AND BIOCHEMISTRY OF GESTATIONAL DIABETES

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF GESTATIONAL DIABETES

INTRODUCTION

Diabetes mellitus (DM) is a metabolic disorder thatis characterized by hyperglycemia and glucose intolerance. It is known to be associated with impairedinsulin secretion and peripheral sensitivity, as wellas eventualb-cell dysfunction (Donovan and McIntyre, 2010).Diabetes mellitus is one of theoldest diseases worldwide2. The International Diabetes Federation report of 2017 suggested that 451million adults globally had diabetes in 2017, and 693million individuals are expected to suffer from DMby 2045. The World Health Organization (WHO)also estimates that more than 19% of the world’s total adult population will suffer from DM by the year2030.  Diabetes mellitus has been a problem of great concern overthe years due to its high incidence and mortality rates,as well as its high management and treatment costs(Donovan and McIntyre, 2010).

Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it does increase the risk of pre-eclampsia, depression, and requiring a Caesarean section. Babies born to mothers with poorly treated gestational diabetes are at increased risk of being too large, having low blood sugar after birth, and jaundice.If untreated, it can also result in a stillbirth.Long term, children are at higher risk of being overweight and developing type 2 diabetes (American Diabetes Association, 2004).

Gestational diabetes can occur during pregnancy because of insulin resistance or reduced production of insulin. Risk factors include being overweight, previously having gestational diabetes, a family history of type 2 diabetes, and having polycystic ovarian syndrome.Diagnosis is by blood tests.For those at normal risk, screening is recommended between 24 and 28 weeks’ gestation.For those at high risk, testing may occur at the first prenatal visit.

Prevention is by maintaining a healthy weight and exercising before pregnancy.  Gestational diabetes is treated with a diabetic diet, exercise, medication (such as metformin), and possibly insulin injections.^[2] Most women are able to manage their blood sugar with diet and exercise.Blood sugar testing among those who are affected is often recommended four times a day.Breastfeeding is recommended as soon as possible after birth type 2 diabetes (American Diabetes Association, 2004).

Gestational diabetes affects 3–9% of pregnancies, depending on the population studied. It is especially common during the last three months of pregnancy.^[2] It affects 1% of those under the age of 20 and 13% of those over the age of 44.  A number of ethnic groups including Asians, American Indians, Indigenous Australians, and Pacific Islanders are at higher risk.In 90% of cases, gestational diabetes will resolve after the baby is born. Women, however, are at an increased risk of developing type 2 diabetes (White, 2019)

CLASSIFICATION OF GESTATIONAL DIABETES

Gestational diabetes is formally defined as “any degree of glucose intolerance with onset or first recognition during pregnancy”.This definition acknowledges the possibility that a woman may have previously undiagnosed diabetes mellitus, or may have developed diabetes coincidentally with pregnancy. Whether symptoms subside after pregnancy is also irrelevant to the diagnosis.A woman is diagnosed with gestational diabetes when glucose intolerance continues beyond 24 to 28 weeks of gestation.

The White classification, named after Priscilla White, who pioneered research on the effect of diabetes types on perinatal outcome, is widely used to assess maternal and fetal risk.It distinguishes between gestational diabetes (type A) and pregestational diabetes (diabetes that existed prior to pregnancy). These two groups are further subdivided according to their associated risks and management (Gabbe et al., 2002).

The two subtypes of gestational diabetes under this classification system are:

• Type A1: abnormal oral glucose tolerance test (OGTT), but normal blood glucose levels during fasting and two hours after meals; diet modification is sufficient to control glucose levels
• Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is required

Diabetes which existed prior to pregnancy is also split up into several subtypes under this system:

• Type B: onset at age 20 or older and duration of less than 10 years.

• Type C: onset at age 10–19 or duration of 10–19 years.
• Type D: onset before age 10 or duration greater than 20 years.
• Type E: overt diabetes mellitus with calcified pelvic vessels.
• Type F: diabetic nephropathy.
• Type R: proliferative retinopathy.
• Type RF: retinopathy and nephropathy.
• Type H: ischemic heart disease.
• Type T: prior kidney transplant.

An early age of onset or long-standing disease comes with greater risks, hence the first three subtypes.

Two other sets of criteria are available for diagnosis of gestational diabetes, both based on blood-sugar levels.

Criteria for diagnosis of gestational diabetes, using the 100 gram Glucose Tolerance Test, according to Carpenter and Coustan:

• Fasting 95 mg/dl
• 1 hour 180 mg/dl
• 2 hours 155 mg/dl
• 3 hours 140 mg/dl

Criteria for diagnosis of gestational diabetes according to National Diabetes Data Group:

• Fasting 105 mg/dl
• 1 hour 190 mg/dl
• 2 hours 165 mg/dl
• 3 hours 145 mg/dl

Risk Factors OfGestational Diabetes

Classical risk factors for developing gestational diabetes are:

• Polycystic ovary syndrome
• A previous diagnosis of gestational diabetes or prediabetes, impaired glucose tolerance, or impaired fasting glycaemia
• A family history revealing a first-degree relative with type 2 diabetes
• Maternal age – a woman’s risk factor increases as she gets older (especially for women over 35 years of age).
• Paternal age – one study found that a father’s age over 55 years was associated with GD^[13]
• Ethnicity (those with higher risk factors include African-Americans, Afro-Caribbeans, Native Americans, Hispanics, Pacific Islanders, and people originating from South Asia)
• Being overweight, obese or severely obese increases the risk by a factor 2.1, 3.6 and 8.6, respectively.
• A previous pregnancy which resulted in a child with a macrosomia (high birth weight: >90th centile or >4000 g (8 lbs 12.8 oz))
• Previous poor obstetric history
• Other genetic risk factors: There are at least 10 genes where certain polymorphism are associated with an increased risk of gestational diabetes, most notably TCF7L2.

In addition to this, statistics show a double risk of GDM in smokers.Polycystic ovarian syndrome is also a risk factor,^[12] although relevant evidence remains controversial.Some studies have looked at more controversial potential risk factors, such as short stature.

About 40–60% of women with GDM have no demonstrable risk factor; for this reason many advocate to screen all women. Typically, women with GDM exhibit no symptoms (another reason for universal screening), but some women may demonstrate increased thirst, increased urination, fatigue, nausea and vomiting, bladder infection, yeast infections and blurred vision.

PathophysiologyOfGestational diabetes

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor on the cell membrane which in turn starts many protein activation cascades. These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose, glycogensynthesis, glycolysisand Fatty Acid synthesis

The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway beyond the insulin receptor. Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5–2.5 times more insulin is produced than in a normal pregnancy (Carpenter and Coustan, 2012).

Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which in cases of GDM progresses thereafter to levels seen in a non-pregnant woman with type 2 diabetes. It is thought to secure glucose supply to the growing fetus. Women with GDM have an insulin resistance that they cannot compensate for with increased production in the β-cells of the pancreas. Placentalhormones, and, to a lesser extent, increased fat deposits during pregnancy, seem to mediate insulin resistance during pregnancy. Cortisol and progesterone are the main culprits, but human placental lactogen, prolactin and estradiol contribute, too. Multivariate stepwise regression analysis reveals that, in combination with other placental hormones, leptin, tumor necrosis factor alpha, and resistin are involved in the decrease in insulin sensitivity occurring during pregnancy, with tumor necrosis factor alpha named as the strongest independent predictor of insulin sensitivity in pregnancy. An inverse correlation with the changes in insulin sensitivity from the time before conception through late gestation accounts for about half of the variance in the decrease in insulin sensitivity during gestation: in other words, low levels or alteration of TNF alpha factors corresponds with a greater chance of, or predisposition to, insulin resistance or sensitivity (Carpenter and Coustan, 2012).

It is unclear why some women are unable to balance insulin needs and develop GDM; however, a number of explanations have been given, similar to those in type 2 diabetes: autoimmunity, single gene mutations, obesity, along with other mechanisms.

Though the clinical presentation of gestational diabetes is well characterized, the biochemical mechanism behind the disease is not well known. One proposed biochemical mechanism involves insulin-producing β-cell adaptation controlled by the HGF/c-MET signaling pathway. β-cell adaption refers to the change that pancreatic islet cells undergo during pregnancy in response to maternal hormones in order to compensate for the increased physiological needs of mother and baby. These changes in the β-cells cause increased insulin secretion as a result of increased β-cell proliferation.HGF/c-MET has also been implicated in β-cell regeneration, which suggests that HGF/c-MET may help increase β-cell mass in order to compensate for insulin needs during pregnancy. Recent studies support that loss of HGF/c-MET signaling results in aberrant β-cell adaptation.

c-MET is a receptor tyrosine kinase (RTK) that is activated by its ligand, hepatocyte growth factor (HGF), and is involved in the activation of several cellular processes. When HGF binds c-MET, the receptor homodimerizes and self-phosphorylates to form an SH2 recognition domain. The downstream pathways activated include common signaling molecules such as RAS and MAPK, which affect cell motility, and cell cycle progression.

Studies have shown that HGF is an important signaling molecule in stress related situations where more insulin is needed. Pregnancy causes increased insulin resistance and so a higher insulin demand. The β-cells must compensate for this by either increasing insulin production or proliferating. If neither of the processes occur, then markers for gestational diabetes are observed. It has been observed that pregnancy increases HGF levels, showing a correlation that suggests a connection between the signaling pathway and increased insulin needs. In fact, when no signaling is present, gestational diabetes is more likely to occur.(Carpenter and Coustan, 2012).