Eli Ipp, M.D.
In the past three years, Dr. Ipp has received grant/research support from Pfizer, Inc., R.W. Johnson, and Novo-Nordisk. He has served as a consultant for Novo-Nordisk, SmithKline Beecham Pharmaceutical and Hoechst Marion Roussel. Dr Ipp has also served on the Speakers' Bureau for Novo-Nordisk.
This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.
Release Date: 08/13/2000
Termination Date: 08/13/2003
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Learning ObjectivesUpon completion of this Cyberounds®, you should be able to:
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:
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, with the following results on an OGTT:
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.
This patient was discussed in two previous Cyberounds® conferences. In the first conference, we discussed a set of questions that covered aspects of the diagnosis of diabetes in the pregnant and non-pregnant states. In the second conference, the patient's young age raised questions about the etiology of her diabetes. Specifically, we discussed whether this could be Maturity Onset Diabetes of the Young (MODY)? But one question remains unanswered from the last discussion, If this is not MODY, what type of diabetes does this patient have?
This Cyberounds® will deal with a major, emerging problem in medicine in the U.S.; one that threatens particular sections of the population, and is likely to place enormous burdens on individuals, their families and a cost to society at large. This new problem is the entity known as "Non-insulin dependent diabetes of the Young" or "Type 2 diabetes in Childhood and Adolescence." (No formal name or abbreviation has been decided upon so far, so in this conference we will use "DM2C" to designate this condition). However, before we discuss DM2C, we will address the differential diagnosis in some more detail.
Ruling Out MODY
This young woman, as pointed out at the end of the previous Cyberounds®, does not have enough evidence to support a diagnosis of MODY. Although she is young enough and clearly has Type 2 diabetes, the patient does not have a family history consistent with dominant inheritance. In this case, we would therefore not pursue this diagnosis any further, i.e., there is no indication to go on to the next step, which would be genetic screening for MODY mutations. Although genetic screening is the only way to rule out a diagnosis of MODY with reasonable certainty, this is not altogether straightforward.
It is important to keep in mind that a negative finding upon genetic screening for MODY mutations does not completely rule out MODY. There are two reasons for this: First, as pointed out in the previous conference, not all causes of MODY have yet been identified.(1) Thus, unknown mutations in genes, not yet known to be associated with MODY, remain to be described. Second, not every method of mutation screening will detect all the MODY mutations. If one screens for known MODY mutations, it is likely but not certain that a mutation in any particular proband is one that has already been described, and is thus part of a screening package. DNA sequencing of the known MODY genes is the only way to exclude, for certain, if a novel mutation has occurred in one of these genes. If you are having a patient screened for MODY, make sure you know what method is being used.
Ruling Out Type 1 Diabetes
Why even bother with discussing Type 1 diabetes in this setting? The patient history provided us makes it unlikely that this is Type 1 diabetes. In addition, the patient was subsequently followed for long enough (>1 year) without change in the clinical picture, so we can be sure that this was not Type 1 diabetes going through a honeymoon phase. Does this completely rule out Type 1 diabetes? In fact it does not.
In recent years, it has become apparent that in older people Type 1 diabetes may not present as it does in childhood. In order to contrast the adult onset of Type 1 diabetes, let us briefly set up the typical scenario in childhood: a 10-15 year-old develops typical symptoms of progressively worsening polyuria and polydipsia and in the absence of medical intervention goes on to develop ketoacidosis. The course of the disease, up to this point, is often only a few weeks. However, we also know that the disease process itself is not as brief as this clinical scenario might suggest. This adolescent would have had an autoimmune process going on for years prior to the clinical presentation, but by the time he or she presents clinically, the beta cell mass is already sufficiently compromised that full-blown clinical diabetes is only a short time away. The honeymoon period that occurs in some patients represents only a short-lived recovery of sufficient beta cell function to permit a patient to manage with little or no insulin for a few months at best.
In adults who present with Type 1 diabetes, the presentation is different -- it is often a much slower process. The explanation for this difference is that the rate of autoimmune destruction of the beta cell mass is more protracted than in Type 1 diabetes in children.(2) The clinical presentation is, therefore, not as catastrophic. In this slow-moving scenario, an adult develops hyperglycemia over months or years and, thus, has prolongation of residual insulin secretion. This is demonstrated in a recent evaluation of Type 1 diabetes in patients under the age of 40 years.(3) Two years after diagnosis, 90% of patients whose diabetes began at less than 15 years of age had very low plasma C-peptide concentrations, compared with only 30% of those who developed Type 1 diabetes after age 15.(3) The older patients, with more insulin secretory capacity, may also do well on oral agent therapy to start out. To add to the confusion, adults may be overweight.
So, in the early stages of the disease, an obese patient with Type 1 diabetes, treated with oral agents, may be clinically indistinguishable from Type 2.(4) At this point, the diagnosis can be made in only one of two ways: (a) clinically, with time-delayed diagnosis -- if we wait long enough, the immune process will progress and the patient will become insulin dependent and susceptible to ketoacidosis, like other Type 1 patients; and (b) by laboratory means, measuring autoantibodies.
This is not the place to discuss the various autoantibody measurements that can be obtained to make a diagnosis of Type 1 diabetes, but suffice it to say that about 5% of adult Type 2 patients have positive autoantibodies. This puts them into a group known as latent autoimmune diabetes of adults or LADA.(5) LADA patients, if followed, will eventually require insulin therapy. This is the group that was sometimes described as Type 2 diabetes "converting" to type 1; in fact, they had Type 1 diabetes all the time but following a clinical course that resembled Type 2 diabetes.
In the past, it would not have made much difference whether a patient had the Type 1 or 2 form of the disease. After all, many Type 2 diabetic patients eventually go on to insulin therapy. However, today many would regard the presence of islet autoimmunity in "Type 2" diabetes, i.e., LADA, to be an indication for early insulin therapy. This was discussed in a previous conference on insulin therapy in type 2 diabetes. So, should we be screening all Type 2 patients for islet autoimmunity? There is no evidence that this will be cost-effective at this time. In patients who have an atypical presentation of diabetes, this should be done. This patient, because of her age, was screened. She was islet cell antibody negative.
Early Onset Type 2 Diabetes
This patient developed diabetes at the age of 22 years, or possibly earlier. While presentation at this young age is unusual in many parts of this country, especially in Caucasians, it has become a more frequent occurrence in the practice of physicians who treat patients that belong to minority groups. Type 2 diabetes is seen at increasingly earlier ages in Hispanics and African-Americans. This is most striking in its appearance in childhood and adolescence, which is the extreme end of a continuum of disease that affects patients in their 20s and 30s, as well as the middle aged and elderly. Although this patient is no longer an adolescent, she belongs on the lower end of the age spectrum and provides us with an opportunity to discuss an extremely important problem, the diabetes of childhood and adolescence (DM2C).
Type 2 Diabetes in Childhood (DM2C)
Type 2 diabetes was previously thought to be a disease of middle age and the elderly. It has now been recognized in childhood as well and is considered to be a major medical problem because of dramatic increases in prevalence in recent years.(6) Type 2 diabetes in childhood (DM2C) is now reaching epidemic proportions in certain ethnic groups and geographic areas of the United States. One of these areas is in the Southwest, where it is no longer a rare entity for pediatric endocrinologists or primary care physicians.
An increasing number of studies have documented this phenomenon in a series of reports from various localities.(7) It has reached the point where both the American Diabetes Association decided it was time to release a consensus statement on this issue(6) and NIH put out a request for grant proposals with the idea of funding more research in this emerging area of public health and medical concern. It should be noted that both of these efforts occurred in the year 2000.
This is a new and urgent problem -- imagine only the potential devastation of a childhood disease if it were to occur with the frequency of adult Type 2 diabetes (about 6% of the population), with its life-long accompanying risk for long-term complications.
What Evidence Is There for an Epidemic of DM2C?
Children presenting with diabetes are usually assumed to have Type 1. Less than 5% of children are generally thought to have Type 2 diabetes. While this assumption continues to be appropriate in certain communities, it can no longer be considered reasonable in children of African-American and Hispanic descent. The increase in incidence observed in the last decade has been concentrated in these minority populations. Few large population-based studies have so far emerged in the literature because this is only a recently recognized phenomenon. However, reports from a number of different sites in the U.S. provide evidence for what is shaping up to be a serious epidemic.
Studies in the 1980s suggested that the prevalence of childhood diabetes (not distinguishing between Type 1 and Type 2) was low in U.S. populations. The NHANES data(7) from 1988-1994 for diabetes in the 12-19 year age group estimated a prevalence of 0.4% (this compares with 0.03% for cystic fibrosis). In a 1992-1996 study, the Pima Indians, known to have one of the highest rates of Type 2 diabetes in the world, the prevalence of diabetes in 10-14 year olds was about 2%, and rose to 5% in the 15-19 year age bracket.(8) This is a 5-10 fold higher rate of diabetes than the NHANES figure from the late 1980s but this increased prevalence is not restricted to the Pimas. In First Nation adolescents studied in Canada, the prevalence is 3.6% among 10-19-year-old girls. A series of clinic-based studies in different parts of the country showed similar results. This included clinics in Cincinnati OH, Charleston SC, Little Rock AR, San Antonio TX, Diego and Ventura CA, where there was as much as a 10-fold increase in Type 2 diabetes in patients 10-19 years old.(9) All of these clinic-based reports appeared in the 1990s. DM2C tended to occur in minority populations; in California and Texas mainly Hispanics and in the other clinics, a predominance of African-Americans.
Is this Different from Adult Type 2 Diabetes?
There is little information about the pathophysiology of diabetes in DM2C so far, but what exists suggests that the mechanisms are likely to be similar to Type 2 diabetes in adults. Epidemiological evidence from studies in the clinics mentioned above suggest that except for age, DM2C does resemble Type 2 diabetes in adults. In 578 children and adolescents, obesity and acanthosis nigricans were frequent concomitants of DM2C. Mean BMI ranged from 27-38 Kg/m.(2) The disease also appears to be more frequent in young women, with a female/male ratio of 1.3 to 3.0 at the different centers. The mean age was about 14 years and the youngest were 5-8 years old! Family history was positive in first degree relatives in an astonishing 74-95% of patients. Ketoacidosis at initial presentation was more common in African-American DM2C. Unfortunately, diabetes control is often poor in DM2C and there appears to be no protection from complications of diabetes, which may occur early.
Type 2 diabetes is a disease of both insulin resistance and impaired insulin secretion. One of the important differences between adults and children is that, even in the absence of obesity, normal childhood is associated with insulin resistance. This insulin resistance of childhood and adolescence has both physiological and pathological causes. The most important physiological cause of insulin resistance is normal puberty.(10) Puberty is accompanied by a transient physiological decrease in insulin sensitivity(10) that resolves in later adolescence. In non-diabetic adolescents, this manifests as fasting hyperinsulinemia and in Type 1 diabetic subjects as an increase in insulin requirements.
Although well defined as a clinical phenomenon, the mechanisms for the insulin resistance of puberty are not known. Factors that may play a role are the hormones of puberty -- growth hormone and IGFI in particular. Sex steroids may also play a role but are thought to be a less likely cause. Arslanian(10) found an increase in lipid oxidation in puberty that correlated with a decrease in glucose disposal that might explain insulin resistance. Polycystic ovarian disease also begins in puberty and is associated with insulin resistance, impaired glucose tolerance and a high propensity for Type 2 diabetes. It is a gender-specific cause of insulin resistance that has been better studied in young adults and further studies are necessary in adolescents. Another gender-specific cause of insulin resistance in young adults that is relevant to this case, is pregnancy. As discussed in a previous conference, pregnancy is associated with a marked degree of insulin resistance and in adults results in diabetes in 3-4% of pregnancies, where the beta cell response is inadequate to maintain normal glucose homeostasis.
However, despite these causes for insulin resistance in childhood and adolescence, Type 2 diabetes has not been common. There must be other factors that explain the changing incidence of this disorder.
What Is the Reason for this Changing Incidence of DM2C?
The most likely factor contributing to such an early appearance of this disease, with the change occurring over one generation, is probably environmental rather than genetic. Most fingers point towards obesity as the major factor in the development of this emerging epidemic. The evidence that obesity can play this role is largely epidemiological but appears to be overwhelming -- in the same period of time that the incidence of diabetes is increasing, the prevalence of obesity in North America has increased dramatically, especially in children.
It is clear that environmental/behavioral factors, such as obesity, are required to convert genetic susceptibility into clinical diabetes. Therefore, the alarming increase in the percentage of clinically obese American school children revealed in a 1987 landmark study may have presaged this increase in the incidence of diabetes in the 1990s. Called the National Children and Youth Fitness Study (NCYFS), this survey compared data from several previous national surveys on health and fitness. By one analysis, the incidence of obesity had gone up by 54% from 1977 to 1984 in children, ages 12-17 years.(11) The findings showing that 25% of all children studied had triceps skinfold thickness greater than the 85th percentile as established in the 1960s-70s.
Obesity is now thought to affect as many as one out of every three children. The finding of increased obesity in children in the 1980s may well be the underlying explanation for the increase in Type 2 diabetes seen in the next decade. The explanation of this relationship is most likely based on the concept that, when early, severe insulin resistance develops in a subject who has a genetic propensity for beta cell failure, this will result in diabetes at an early age because there is insufficient insulin to respond to the increased need.
In summary, the earlier onset of Type 2 diabetes, as exemplified by our case in this series of Cyberounds® conferences, presents us with a major public health problem in the North America. It is important that we begin to address this urgent problem with studies to understand its mechanisms better and attempts to prevent diabetes in populations much younger than ever anticipated.