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 results of an OGTT:

• 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 was first discussed in a previous Cyberounds^®, where we reviewed aspects of the diagnosis of diabetes in the pregnant and non-pregnant states. However, her young age raises interesting questions about the etiology of her diabetes. How does this fit with our preconceptions that older age persons usually develop Type 2 diabetes? And could this be Maturity Onset Diabetes of the Young (MODY)? Or is there another explanation for the appearance of diabetes in this young woman? There were five questions that remain unanswered from the last discussion, four of which will be discussed in this conference.

Part Two

Q6. 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?

Q7. What is MODY diabetes and how do we diagnose it?

Q8. Is MODY a homogeneous molecular and clinical entity?

Q9. What is the underlying mechanism(s) of MODY?

Part Three

Q10. If this is not MODY, what is it?

This question will be addressed in the third and final section of this multipart conference.

Introduction to Part Two

MODY (Maturity Diabetes of the Young) represents a small fraction of all Type 2 diabetes. It has been estimated that only 1-5% of all Type 2 diabetes may have MODY. So why is it important to discuss this relatively rare disorder? There are a number of reasons:

First, in the west and southwest of the U.S., where there are large numbers of Hispanic patients with Type 2 diabetes, we are increasingly seeing younger people with Type 2 diabetes. Although considered to be a disease of people above the age of forty, it is now frequently seen in the third and fourth decades and extends to include teenagers and even children. Our pediatric endocrine colleagues are becoming increasingly familiar with the use of oral agents, when previously their experience was entirely with Type 1 diabetes and insulin therapy. So, "could this be MODY?" is a question that is quite frequently raised in the practice of diabetic medicine in this part of the country.

Second, we should, periodically, look at our progress in the understanding of complex diseases such as diabetes. Type 2 diabetes is a disorder with multiple etiologies, including genetic and environmental causes, with hyperglycemia as a final common pathway. In other words, a pie that can be divided into many parts - each representing a different etiology. Using this metaphor, cutting out small slices as we discover their causes (e.g., MODY) leaves us with less of the unknown pie to understand. Thus, each small slice, though it represents only a relatively small part of the diabetic population, is an important piece of the pie. In the case of MODY, it also provides important information about how genetic mutations cause diabetes.

Third, advances in molecular genetics have made the last three years particularly eventful in discovering mutations responsible for MODY and, therefore, make this a relevant subject for update at this time. Keep in mind, though, that MODY is not a model for Type 2 diabetes - because, as outlined in more detail below, MODY is a monogenic disorder and Type 2 diabetes is likely multigenic.

Q6. Does this Woman Have MODY Diabetes (Maturity Onset Diabetes of the Young)?

This is, indeed, a young age for somebody to develop Type 2 diabetes, which is ostensibly how this young woman has presented, considering her initial diagnosis and subsequent management. She has none of the features of Type 1 diabetes, aside from her age. She has features that suggest Type 2 diabetes, such as her (over)weight and that she was managed on diet therapy alone during the earlier part of her pregnancy and, again, postpartum. In fact, the patient had never been symptomatic; she was diagnosed by routine screening, rather than because of severe symptoms. Also, at no time did she demonstrate evidence of ketosis. In her pregnancy, no ketosis was reported despite the hyperglycemia that was the basis for a diagnosis of diabetes. Pregnancy is a physiological state associated with 'accelerated starvation' and, thus, there is an increased tendency towards ketosis that occurs in all (including non-diabetic) pregnancies(1) -- even so, ketosis was not a part of this patient's clinical course. All these factors suggest that we are dealing with Type 2 diabetes rather than Type 1 diabetes, despite her young age. Having said that, we now have to deal with whether this young woman has a special form of Type 2 diabetes and, thus, the most intriguing question is whether this is the disorder described in the 70s as Maturity Onset Diabetes of the Young, or MODY.

Q7. What Is MODY Diabetes and How Do We Diagnose It?

MODY was originally described as a separate entity by Fajans(2),(3),(4) and Tatersall.(5) Since its original description, the definition of this disorder has changed and developed, as advances in molecular biology and careful clinical observation over time have allowed us to understand and define this disorder more precisely. The diagnosis of MODY today is based on three characteristic features: clinical, genetic and physiological:

A. Clinical: a triad of findings! The information required for the diagnosis of MODY for the first two decades after its original description was purely clinical. It comprised three clinical features:

• diagnosis of diabetes in the proband (that is not Type 1 diabetes)
• age < 25 years
• positive family history with a dominant mode of inheritance.

If the description of diabetes in a particular patient met these criteria, this was sufficient to make the diagnosis. Absence of Type 1 diabetes was defined as non-insulin requiring for at least two years. This triad of clinical features, that was part of the original description in the 1970s, seemed to carve out a separate form of diabetes. Clearly, these were people with what looked like Type 2 diabetes ('adult onset diabetes'; this nomenclature was dropped in 1979), yet they were too young and they had a mode of inheritance that was clearly autosomal dominant when examined in large pedigrees.

The genetics of Type 2 diabetes is not well understood, (nor was it in those days) and clinical experience suggested that the disease was often familial. Consequently, many diabetologists remained skeptical that the newly-described MODY form of diabetes was, indeed, a separate entity. Today, there is no doubt whatsoever that MODY is a distinct genetic and clinical disease process.

B. Genetic: monogenic mutations underlie all MODY. The precise genetic defects are now known for most forms of MODY (see below) and, thus, the method of diagnosis has essentially evolved so that it is performed primarily by genetic means today. However, clinical suspicion is still required to initiate a genetic evaluation. The rapid identification of the genetic defects in MODY were a result of the fine work that had been done in the early clinical descriptions of dominant inheritance in families with 'early onset' Type 2 diabetes. Clinical suspicion still remains the primary screening tool, using the clinical criteria described above, with confirmation by genetic tests.(6),(7),(8)

C. Physiological: impaired insulin secretion. Early on, it was apparent that many of the patients with MODY were lean and did not appear to be insulin resistant. Studies evaluating insulin secretion in these subjects revealed that all forms of MODY, so far described, have a defect in insulin secretion.(9),(10),(11) In each case, glucose-stimulated insulin secretion has been found to be reduced below normal. In the case of MODY2, the mutation in the glucokinase gene, the mechanism is best understood (see below) but the precise cellular mechanisms responsible for abnormal insulin secretion in the other forms of MODY remain to be elucidated. In the early clinical descriptions, it was apparent that, in some forms of MODY, insulin secretion appeared to decrease over time, while, in others, though lower than normal, remained constant, despite the passage of many years. This difference has now also been explained (see below).

Q8. Is MODY a Homogeneous Molecular and Clinical Entity?

Molecular Genetics: Unlike Type 2 diabetes, MODY represented an ideal paradigm to study the genetics of diabetes. The late onset and early mortality of Type 2 diabetes makes it difficult to obtain large multigeneration pedigrees; in contrast, several enormous pedigrees have been identified with MODY. Add to that the fact that MODY is a single gene disorder with high penetrance and contrast this with Type 2 diabetes, which is multifactorial and polygenic, i.e., multiple genes -- each partially contributing to the phenotype. It is clear, then, that defining the genetic nature of MODY is a far simpler task.

It should be apparent from the discussion above that MODY is not a homogenous entity. Indeed, five different forms of MODY have been described and this is not the end of the list. Each MODY type is a result of mutations in five different genes that have been identified so far. The first was reported in 1992 and the others since 1996. The terminology is quite simple: the five different MODY subtypes have been named MODY1 to MODY5. In some families, the mutation has not yet been identified(12) and these have been termed by some MODY-X. Table 1 provides a brief outline of the known MODY subtypes, identifying the gene involved, its chromosomal location and some brief clinical comments.

HNF = genes coding for hepatocyte nuclear factors (transcription factors)

GCK = gene coding for glucokinase (an enzyme that phosphorylates glucose in the beta cell & liver)

IPF = gene coding for insulin promoter factor (an insulin gene transcription factor)

Clinical heterogeneity: The overall prevalence of MODY in the population is currently unknown. The best studied populations with MODY so far are Europeans and it is clear that there is heterogeneity in the subtypes within Europe. The most common cause of MODY in France is MODY2, the glucokinase gene mutation, which occurs in over 50% of MODY families;(8) in the United Kingdom, it is MODY3, involving the HNF1-alpha gene, and found in over 60% of MODY pedigrees.(7)

The two most common forms of MODY are MODY3 and MODY2; and it appears that MODY3 is the most frequently occurring subtype. Most of our clinical information, therefore, derives from these two forms of MODY. The diabetes found in the MODY2 families is a mild fasting hyperglycemia that probably begins at birth and persists without deterioration for many years of follow-up, keeping within a range of about 120-180 mg/dl (7-10 mmol /L). It is unusual for any of these affected individuals to develop the microvascular complications of diabetes.

The mildness of the diabetes, its stability over time and the absence of microvascular complications is different from other forms of MODY that have been well characterized and followed for many years. A good example is the famous RW pedigree that has been followed since 1958 (6) and is now known to have a MODY3 mutation. MODY3 has a more variable phenotype. Diabetes begins in late childhood or early adulthood. It manifests as a progressive deterioration in insulin secretion over time, so that about one third of patients become insulin requiring eventually. Glucosuria, due to an altered renal threshold, may mitigate the degree of hyperglycemia. Typical microangiopathic and macrovascular disease, similar to Type 2 diabetes, may be seen in these subjects. MODY3 behaves, over time, more like regular Type 2 diabetes, which is also associated with progressive declining beta cell function(18) and the development of long term complications.

We can explain the differences between the clinical course of MODY2 and MODY3, now that we have a better understanding of the underlying molecular defects.

Q9. What Is the Underlying Mechanism(s) of MODY?

Although the genes and gene products of most of the mutations have been identified, the underlying biochemical and physiological mechanisms for many of the MODY subtypes have not yet been determined. An exception to this is MODY2, which is caused by a mutation in the glucokinase gene and has been better defined than any of the others because the biochemistry and cellular physiology of the glucokinase enzyme had been well worked out prior to its discovery as a cause of MODY. In fact, it is one of the few stories of a successful candidate gene strategy for exploring the cause of disease. Once the glucokinase gene had been cloned, it became an obvious candidate gene for causing diabetes and so it was tested and shown to have mutations in a subset of MODY families.

The altered gene product in MODY2 is glucokinase, which was long suspected to be a glucose sensor in the beta cell. This enzyme phosphorylates glucose after it enters the beta cell and is a rate-limiting step in the metabolism of glucose. Glucose metabolism is essential for stimulation of insulin secretion. Thus, if glucokinase is deficient, so that the rate of entry of glucose into the system that couples the stimulus to secretion of insulin were decreased, one might expect that less insulin would be secreted for a given level of glucose presented to the beta cell. In fact, this is what happens. Raising glucose concentrations overcomes this defect and, consequently, insulin secretion can increase proportionately. Unfortunately, the end result is a requirement for higher glucose levels to achieve this effect. A new steady state develops in vivo, in which higher circulating glucose levels are associated with 'normal' plasma insulin concentrations, i.e., a re-setting of the glucose sensing system of the beta cell. Essential to understanding this new steady state is to realize that once you deliver enough glucose to the beta cell to induce a higher level of glucokinase, enough insulin will be secreted to maintain a new "physiological" state so that the normal feedback endocrine system still works at the expense of mild hyperglycemia. There is only a slight deterioration of this new steady state that accompanies aging and, thus, the patients do not become insulin requiring, nor do they develop microvascular complications. A diagrammatic explanation of the defect in glucokinase activity in MODY2 is provided in Figure 1.

Figure 1. Diagram of Pathophysiology of Defective Insulin Secretion in MODY2, Glucokinase Gene (GCK) Mutations.

A. Normal beta cell. Glucose stimulates insulin secretion (white arrows), with a negative feedback loop (in white) that maintains glucose homeostasis.

B. GCK mutation. Glucose in similar concentrations, as in A, but the glucose sensor is defective, thus insulin secretion is diminished (thin white arrow). B is a theoretical, interim phase.

C. New steady state. Glucose concentrations increase (fat white arrow) until insulin secretion is normalized (normal white arrow). Negative feedback system maintains glucose homeostasis at expense of elevated basal glucose.

What about the other molecular defects? These are less well understood. The names of the transcription factors found to be mutated in MODY reflect the fact that they were not expected to be associated with a disease of the pancreatic islets (e.g., hepatocyte nuclear factors, HNF1 or HNF4). What these molecules do in the beta cell and how they are tied into insulin secretion needs to be clarified. Thereafter, it will become clearer, as with glucokinase, how the molecular defect is responsible for the development of the insulin-deficient type of diabetes that characterizes all of the MODY subtypes.

Q10. If This Is Not MODY, What Is It?

This patient developed her diabetes before the age of 25 years and has what appears to be Type 2 diabetes. She, therefore, has two of the three characteristics of MODY. What can family history, the third in the triad of criteria for MODY, tell us about her diagnosis? Her family history reveals that her mother has Type 2 diabetes that was first diagnosed at age 55 years. A paternal uncle has diabetes as well. The grandparents are still alive and are known not to have diabetes. Although she has a positive family history, there is, therefore, no clear evidence for an autosomal dominant inheritance of diabetes in this family -- this patient is unlikely to have MODY diabetes.

If this is not MODY, what is it? In the third and last Cyberounds^® on this case, we will provide some answers and discuss young onset diabetes that is not classical MODY.