Most practitioners today would have assumed that this adolescent
had recent-onset type 2 diabetes. The risk factors include non-Caucasian
ancestry, positive family history, presence of acanthosis in someone
with an elevated BMI, and hyperglycemia without ketoacidosis.1
At her first follow-up visit 1 month later, R.M. was found to be positive
for islet cell autoantibodies (ICAs), glutamic acid decarboxylase
(GAD) antibodies, and ICA-512 antibodies. Her A1C was 7.8%. Her insulin
doses had been slowly decreased, with glucose levels consistently
<150 mg/dl and total daily insulin requirements of 0.5 units/kg/day.
Her metformin was discontinued given her positive antibody studies
and near-euglycemic blood glucose range.
At another follow-up 3 months later, R.M. was still off metformin,
and her blood glucose levels were in a euglycemic range on <0.4
units/kg/day (10 units of NPH with 4 units of lispro at breakfast
and 6 units of NPH with 3 units of lispro at dinner). Her A1C was
5.9%. She had not required any adjustments for high blood glucose
levels.
In the past, type 1 diabetes would account for the majority of diabetes
seen in this age-group. Yet, the national obesity epidemic has changed
the types of diabetes being seen, especially in pediatrics. The most
recent National Health and Nutrition Examination Survey noted that
30% of adolescents are now overweight,2 and there has been a commensurate
rise in the number of cases of type 2 diabetes found in adolescents.3
Recently, in a cohort of obese adolescents, 20% were noted to have
impaired glucose tolerance, and 4% had undiagnosed type 2 diabetes.4
In some pediatric diabetes practices, type 2 diabetes now accounts
for 25–50% of the patient population, and this continues to
increase.1
The incidence of type 2 diabetes in American adolescents is highest
among African-Americans, Latinos, and Asians.1 For the African American
population, this increased risk for type 2 diabetes results at least
in part from the fact that African-American prepubertal children and
adolescents have greater insulin resistance than their Caucasian counterparts,
even when matched for BMI.5,6
Given the increase of obesity in our society, we expect that many
children who present with new-onset diabetes will have evidence of
obesity and acanthosis, which are strongly suggestive of type 2 diabetes.
Yet, rather than assume that they have type 2 diabetes, clinicians
must test for autoantibodies to clarify the underlying etiology.
R.M. was found to have positive antibodies directed against the ß-cells
and thus, clearly, has autoimmune-mediated type 1 diabetes. However,
she also has evidence of insulin resistance, which is found in type
2 diabetes. Some have referred to this condition as "double diabetes,"
or "type 1.5 diabetes."
Multiple studies have shown that up to 90% of new-onset type 1 diabetic
patients will have evidence of at least one antibody at diagnosis,
and 40–50% will have two or more.7 Tests for four autoantibodies
are now available through commercial laboratories. The traditional
assay to measure ICAs involves incubating a patient’s serum
with a section of normal pancreas and assessing reactivity via indirect
immunoflurosence. The other three antibody tests now available are
for GAD, ICA-512 (also known as IA-2 or tyrosine phosphatase), and
insulin autoantibodies (IAAs). The IAA measurement must be obtained
within 10 days to 2 weeks from the initiation of exogenous insulin
therapy, because exogenous insulin may induce antibody positivity.
Although most patients with type 1 diabetes are autoantibody-positive,
ethnicity confers notable differences and may make confirmation of
type 1 diabetes more difficult. African-American adolescents with
new-onset type 1 diabetes have up to a fourfold greater chance of
exhibiting no autoantibodies compared to their Caucasian counterparts
(17.4 vs. 4.6%, respectively).8 Thus, African-American adolescents
with type 1 diabetes may initially present as antibody-negative, which
may prove misleading in making therapy decisions.
The presence of autoantibodies has important implications for patient
care. In the U.K. Prospective Diabetes Study, subjects presumed to
have type 2 diabetes, yet who were noted to have one or more autoantibodies,
progressed more rapidly to ß-cell failure and required insulin
therapy.9 Up to 90% of patients who were positive for ICA and GAD
antibodies required insulin within 6 years.9
In this case, had one assumed that this was a case of type 2 diabetes
and treated R.M. solely with metformin, the patient may have done
well initially, during her honeymoon phase. However, she would have
been at high risk for progression to diabetic ketoacidosis as her
honeymoon period waned or when faced with an intercurrent illness
or stress. Furthermore, intensive insulin therapy is one potential
means to prolong the honeymoon phase and protect endogenous insulin
secretion,10 and she would have been denied this potential benefit.
Despite the evidence that R.M. has type 1 diabetes, we must return
to considerations about type 2 diabetes. Although she tested positive
for autoantibodies, she did present with acanthosis nigricans, an
elevated BMI, a positive family history, and was from a higher-risk
ethnic group. If we had studied her formally, she would almost certainly
have exhibited increased insulin resistance, and she may have ultimately
developed type 2 diabetes later in life if she had not had earlier
autoimmune destruction of her ß-cells.
One question to consider is whether there is a role for insulin sensitizers
in such a situation. Metformin may be a useful addition to insulin
for adolescents with type 1 diabetes and insulin resistance.11 Preliminary
studies have found that metformin lowered A1C, decreased insulin dosage,
and caused no weight gain in adolescents with type 1 diabetes and
poor metabolic control.11 Clinicians initiating such therapy must
carefully inform the patient and family about the risks of lactic
acidosis and the increased risk for hypoglycemia with combined therapy.
Further studies with metformin and other insulin sensitizers (such
as thiazolidinediones) are needed before this will become established
therapy.
For R.M., we elected to continue her subcutaneous low-dose insulin
regimen at 0.4 units/kg/day during the honeymoon phase, but we may
consider adding metformin therapy in the future.
With the surge in obesity, we are witnessing a rise in type 2 diabetes,
especially among children and adolescents. These patients often present
in puberty, at a time of increased insulin resistance.
All pediatric patients who are diagnosed with new-onset diabetes need
antibody studies obtained to distinguish type 1 from type 2 diabetes
in order to provide appropriate therapies. Autoantibodies may not
always be positive in African Americans with new-onset type 1 diabetes.
Patients who have type 1 diabetes and evidence of insulin resistance
may benefit from the addition of metformin as an insulin-sensitizing
agent. However, the use of metformin in these patients is still under
investigation and has not yet gained approval from the Food and Drug
Administration.
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