Case Presentation

A 22-year-old Mexican American woman presented to an obstetrician with a recent history of amenorrhea, which was confirmed as a pregnancy, her first. She was found to be overweight and also had a family history of Type 2 diabetes. The patient had a screening glucose load performed with a one-hour blood glucose measurement of 165 mg/dl. A formal three-hour oral glucose tolerance test (OGTT) was ordered, and it showed the following results:

• Fasting plasma glucose = 102 mg/dl
• One hour post glucose = 220 mg/dl
• Two hour post glucose = 195 mg/dl
• Three hour post glucose = 181 mg/dl.

The patient was told she had gestational diabetes and was placed on a diabetic diet and later in the pregnancy was also placed on insulin therapy because diet alone was not sufficient to maintain adequate glucose control. A healthy 7.5 lb. baby boy was delivered during a normal delivery. Six weeks post-partum, an oral glucose tolerance test was repeated and the patient was diagnosed with diabetes, based on the following OGTT results:

• Fasting plasma glucose = 115 mg/dl
• One hour post glucose = 240 mg/dl
• Two hour post glucose = 225 mg/dl.

This was confirmed in another OGTT repeated six weeks later. She was told she had Type 2 diabetes and was placed on an American Diabetes Association weight loss diet.

Questions

This patient provides us with the opportunity to discuss two related issues. Gestational diabetes occurs in younger women (who are in the reproductive age range) and so does Maturity Onset Diabetes of the Young (MODY). The criteria for diagnosis of diabetes during and after pregnancy form the first part of this discussion. The second part deals with Type 2 diabetes in young people, including MODY.

Part One

1. Who should be screened for gestational diabetes in pregnancy?
2. What are the diagnostic criteria for gestational diabetes?
3. What are the new diagnostic criteria for diabetes in the non-pregnant state?
4. What are the indications for insulin treatment in women with gestational diabetes?
5. What is the risk of developing permanent Type 2 diabetes in a woman who has had gestational diabetes?

Part Two

6. Does this woman have MODY diabetes (Maturity Onset diabetes of the Young) because she developed what appears to be Type 2 diabetes before the age of 25 years?
7. What is MODY diabetes and how do we diagnose it?
8. Is MODY a homogeneous molecular and clinical entity?
9. What is the underlying mechanism(s) of MODY?
10. If this is not MODY, what is it?

The first five questions will be answered in this conference and the second five will be addressed in the next conference.

Q1. Who Should Be Screened for Gestational Diabetes in Pregnancy?

Since the 1970s, it has been recommended that all pregnant women have screening for diabetes at the end of the second trimester of pregnancy, between 24-28 weeks. Screening consists of a plasma glucose sample obtained one hour after a 50g glucose load, given at any time of the day, irrespective of the time of the last meal. If the results of the screening test is a glucose level > 140 mg/dl, gestational diabetes is considered highly likely and is, therefore, tested for (as a second step) with a full OGTT, which is given in the fasting state. This approach is justified by the high morbidity for the neonate associated with missing the diagnosis of diabetes during pregnancy.(1) This two-step screening process is effective because the first step only requires a single blood sample one hour after ingesting the glucose solution and, thus, is relatively simple for all concerned, i.e., patient and physician. The result of this screening process is a 4% incidence of diabetes in pregnancy, although this may vary between 1-14%, depending upon the population studied.(2) This incidence rate amounts to about 135,000 women with gestational diabetes (GDM) each year in the United States.(2) However, even with such large numbers who have GDM, most women test negative on the screen with a 50g glucose load -- yet all pregnant women are screened.

Given the large number of women who tested negative, a different approach has now been recommended in order to simplify screening. The American Diabetes Association (ADA) recommends that screening not be done in those women who were considered to be at very low risk for developing diabetes during pregnancy, i.e., those who are youngest and leanest.(3) The following procedures are suggested:

Do not screen women who are considered to be at very low risk for gestational diabetes. Screen women who have the following risk factors:(3)

1. Age 25 years or more
2. A previous pregnancy with gestational diabetes
3. Obesity
4. A member of a high-risk population (for diabetes), e.g., African-American, Hispanic, Native American, Asian-American.
5. A first degree relative with diabetes

Thus, any woman of 25 years or older, or, if younger, with one of the risk factors mentioned above, should have the two-step screening process with the initial 50g oral glucose load as screening and a full OGTT if necessary thereafter.(3)

Q2. What Are the Diagnostic Criteria for Gestational Diabetes?

The criteria for diagnosis of diabetes in pregnancy were originally developed by O'Sullivan.(4) This OGTT differs from the OGTT performed in the non-pregnant state in two ways: it lasts three hours (rather than two) and it is the only test that still uses a 100g load (rather than 75g).

Diabetes is diagnosed when any two of four plasma glucose levels exceed the following cutoff limits (American Diabetes Association and also the American College of Obstetricians and Gynecologists [ACOG]):

• Fasting plasma glucose = 105 mg/dl
• One hour post glucose = 190 mg/dl
• Two hour post glucose = 165 mg/dl
• Three hour post glucose = 145 mg/dl.

The use of the OGTT in pregnancy, as a diagnostic measure of gestational diabetes, is receiving much attention at this time,(5) with calls for its replacement with a more standardized methodology and stricter cutoff values. However, until these issues are resolved the O'Sullivan criteria remain the gold standard.

Q3. What Are the New Diagnostic Criteria for Diabetes in the Non-pregnant State?

A higher than average risk for the development of Type 2 diabetes in women who have had gestational diabetes (GDM) requires increased vigilance for the subsequent appearance of diabetes. The diagnosis of diabetes in the non-pregnant state is, therefore, also an important issue in this young woman.

In 1997, the American Diabetes Association (ADA) put forward new criteria for the diagnosis of diabetes.(3) This was primarily designed to simplify the process of screening for diabetes in non-pregnant people. Until 1997, the OGTT was the formal method for screening and testing for diabetes in asymptomatic patients. In patients with classic symptoms of diabetes (polyuria, polydipsia and unexplained weight loss), a random plasma glucose of > 200mg/dl (11mmol/L) was sufficient to diagnose diabetes mellitus. However, for patients who were asymptomatic, more formal testing with an OGTT was always recommended. Unfortunately, the OGTT is not a good screening test because it is relatively inefficient. The OGTT is a cumbersome process that requires the patient fast and be willing to spend at least two hours having multiple blood samples drawn. It is not only time consuming for the patient but it is also relatively expensive, when costs of personnel time and multiple measurements are considered as well. For screening of large populations, this would obviously not be an ideal screening test.

However, widespread screening for diabetes is indeed a vitally important public health issue. An estimated 50% of all people in the United States, who have diabetes, are undiagnosed (NHANES II and III).(6) Furthermore, these persons do not necessarily have a milder form of diabetes, which might be benevolently ignored.(6) On the contrary, they seem to have as poor glucose control and as many macrovascular complications as patients with recognized diabetes.(6) If so many persons with unrecognized diabetes (estimates of up to six million persons in the U.S.) abound amongst us -- surely, we should screen more vigorously. Once diagnosed, treatment could be initiated without delay to diminish the likelihood of long-term complications.(7)

It is clear that the OGTT doesn't work as an easy, rapid efficient screening test and it has not been widely used for screening. An expert committee of the ADA, therefore, took another look at this issue and evaluated new data that has appeared in the literature recently.(8),(9),(10) These reports provide support for the concept that a fasting plasma glucose can be an acceptable epidemiological alternative to the OGTT for the diagnosis of diabetes. The diagnostic cutoff is a fasting plasma glucose of 126 mg/dl (7 mmol/L). Values equal to or above this figure on two separate occasions will diagnose diabetes. This is certainly a simple enough screening test that can immediately be put to use throughout the country whenever patients show up for routine visits to their health care providers.

It is important, however, to understand that there is a price to be paid for this increase in simplicity in screening: the fasting plasma glucose is not as sensitive a test as the two hour plasma glucose measurement after a 75g glucose load (i.e., the OGTT).(8),(9),(10) This means that some patients, whose diabetes might have been diagnosed with an OGTT, may be missed (estimates of 20-30%) using fasting glucose measurements only. However, from an epidemiological perspective, this does make sense for the following reason: the OGTT is used very infrequently to screen people who are at lower risk for diabetes (e.g., the general population). It is anticipated that the increase in the number of people being screened, by virtue of the simplification of the process to a single fasting blood sample, will justify this change. The anticipated increased identification of newly diagnosed diabetic persons, among the so-called "undiagnosed" diabetic group, will far outweigh the numbers that might be missed due to the lower sensitivity of this screening tool.

This case gives us the opportunity to discuss one caveat about the use of the fasting measurement that was not specifically addressed by the ADA committee. Our concern is the patient that falls into one of the high-risk populations, such as the patient under discussion. If we know that there is a greater risk for diabetes in a given person, it seems to us that this individual is best served by having an OGTT for screening in the non-pregnant state. Why take on a 30% chance of having the diagnosis missed if you are already at high risk? Based on our own unpublished data, we recommend that the OGTT still be performed in populations that have a high risk for diabetes. Many patients in high-risk populations will be willing to undergo an OGTT if we are willing to request it.

Who should be evaluated with an OGTT rather than an FPG (Fasting Plasma Glucose)? The classification of high-risk patients for diabetes was discussed above. However, in which of these conditions is an OGTT preferable to an FPG as a screening tool has not been addressed systematically. We suggest that women who have had gestational diabetes, who have parents with diabetes or any combination (two or more) of the risk factors previously mentioned, should have an OGTT. Until more data are available to address this issue, the decision involves good clinical judgement. In this patient, the OGTT was done, despite the fact that her FPG was not in the diabetic range, because she is Hispanic and obese. The fasting plasma glucose was less than the diagnostic value of 126 mg/dl (7 mmol/L), yet we did an OGTT and this enabled us to make a diagnosis of Type 2 diabetes, based on a clearly elevated glucose at 120 minutes. If the OGTT had turned out non-diabetic, we would have continued to screen the patient at one year intervals thereafter with repeated OGTT's.

However, it must be stressed that screening of the general population should certainly begin with fasting measurements as an effective way of diagnosing unsuspected diabetes. The ADA recommends that people aged 45 and above should have periodic fasting plasma glucose measurements performed at three year intervals.(4) If an OGTT is not being done in high risk groups, the FPG is better then no screening at all.

Q4. What Are the Indications for Insulin Treatment in Women with Gestational Diabetes?

Data from the well-conducted tight glucose control in pregnancy trials(11) have clearly shown the benefit of normoglycemia in diabetic pregnancy, whether gestational or pregestational (pre-existing diabetes). In pregestational diabetes, glucose control in the first trimester is also critical because this is the time of organogenesis in the fetus. Elevated Hemoglobin A1c has been clearly associated with congenital defects in the neonate and conception with a HbA1c <7% can markedly decrease this problem.(12) This is not an issue in gestational diabetes because the diabetes does not generally occur during the first trimester. On the other hand, in order to prevent the complications associated with the neonate of a diabetic mother, it is essential that tight glucose control be maintained during the remainder of the pregnancy. Goals for glucose control in pregnancy are:

Preprandial: <105 mg/dl (5.8 mmol/L)

Postprandial: <120 mg/dl (6.7 mmol/L), measured 1-2 hours after meals

If the preprandial and postprandial levels are not maintained with diet alone, a woman with gestational diabetes should be treated with insulin. Oral agents are not recommended in pregnancy, even though this patient does not have Type 1 diabetes. Sulfonylureas have been classified as category C agents in pregnancy and they appear to cross the placenta. There simply is not enough experience with metformin or troglitazone (category B agents) at this time to evaluate their safety in pregnancy. Keep in mind that as pregnancy progresses, the total daily dose of insulin needs to be increased as peripheral insulin resistance increases.

Q5. What Is the Risk of Developing Permanent Type 2 Diabetes in a Woman Who Has Had Gestational Diabetes?

This is a critical question for any woman who has been through pregnancy with diabetes. Most of these women do not have diabetes prior to the pregnancy, though one cannot always be sure. If diabetes persists directly after delivery, the presumption is that pregestational diabetes is the correct diagnosis. An FPG of >120 mg/dl, at the first screening for gestational diabetes, suggests pregestational diabetes.(13) This is based upon the two-fold higher incidence of major congenital abnormalities in these women who were thought to have gestational diabetes at the time of diagnosis but would not be expected to have had babies with congenital abnormalities at birth if this were the case. This observation suggests that, in fact, the blood glucose was elevated during the first trimester and Type 2 diabetes, prior to pregnancy, most likely accounts for the elevation. However, most women can rely on the fact that they will return to a non-diabetic state after delivery. This defines gestational diabetes, since it can be assumed that the diabetes did not precede the pregnancy.

What is the risk for developing Type 2 diabetes in these women? First, we should address the question of the risk for gestational diabetes in a subsequent pregnancy in the same mother? One third of women will not have gestational diabetes in a following pregnancy.(14) The risk factors are discussed in section 1 and are similar to those that predispose to gestational diabetes on the first go around. Protective factors are weight loss and care to prevent excess weight gain in a subsequent pregnancy.

O'Sullivan followed up his cohort of gestational diabetic women for thirty years and showed that there was close to a 60% cumulative risk for developing Type 2 diabetes.(15) Again, the factors most likely to bring out the diabetes earlier are the high risk factors mentioned in the answer to Q. 1 above. We keep coming back to these risk factors, which, in general, are those that will put any individual in the population at greater risk for diabetes. Recent data in a high-risk population in Southern California indicate that, for Hispanics, the long-term incidence rates will be even higher. Buchanan and colleagues have shown that the likelihood of developing Type 2 diabetes after gestational diabetes is about 10% per year in their five-year follow-up study.(16) The factor that places a woman at highest risk is impaired glucose tolerance at the standard six-week post-partum visit (plasma glucose >140 but <200 mg/dl at 120 minutes during an OGTT). These data suggest that gestational diabetes, in very high-risk populations, is almost certainly going to lead to Type 2 diabetes and, therefore, should be an indication for early intervention to prevent this outcome.

At this point, diet and exercise interventions should be considered. Whether medications should also be used as preventive strategies, in addition to life-style changes, must await the results of the Diabetes Prevention Project (DPP). DPP is an NIH-funded multicenter study of people with impaired glucose tolerance, designed to prevent the onset of Type 2 diabetes; some of their subjects have had gestational diabetes, and, thus, may be able to provide specific answers to this important issue.