June 2012 - American Association for Clinical Chemistry

Rethinking ß-Cell Function After Type 1 Diabetes Onset
Ultrasensitive Assay Detects C-Peptide Decades Post-Diagnosis
By Genna Rollins
aaCC members enjoy many benefits, including a
members-only newsletter, Clinical Laboratory Strategies.
this online publication provides readers with insight
into new research of importance to laboratory practice.
each issue features a discussion of a recently published
study selected by the Strategies editorial advisory board,
with commentary by both a study author and outside
reviewer. articles also are available as podcasts.
this month, CLN is pleased to present a recent article
from Strategies.
In selecting the study discussed in this article,
the Editorial Advisory Board commented
that use of a new high-sensitive
assay broke down some long standing
opinions on the destruction of pancreatic
ß-cells. It also presents a paradigm shift in
thinking about treatment options for patients
with type 1 diabetes. With potential
therapies on the horizon for ß-cell stimulation,
this type of assay could be critical
to identifying patients who might benefit
from therapy, as well as monitoring treatment
effectiveness.
For decades, treatments for and clinical
trials involving type 1 diabetes have
been based on the understanding that
the disease’s autoimmune process rapidly
curtails pancreatic ß-cell function,
as measured by C-peptide levels. However,
research involving a new, ultrasensitive
C-peptide assay is providing fresh
insight into the course of diabetes. The
study findings are covered in this issue of
Strategies.
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20 CliniCal laboratory news June 2012
The conventional understanding of the
pathophysiology of type 1 diabetes is that
pancreatic ß-cell function drops off dramatically
and soon—within a few years—
after diagnosis. This well-described process
can be tracked through declines in C-peptide
values over the same period, C-peptide
being the protein clipped when A- and
B-chain proteins of proinsulin synthesized
by pancreatic ß-cells form insulin. Rapid
ß-cell death and the associated drop in insulin
production have led to what researcher
Denise Faustman, MD, PhD, has called
therapeutic nihilism. “The thought has
been that the pancreas is not functioning
after about one-to-two years, so our treatment
approach has been kind of fatalistic.
‘Oh, your pancreas is dead, we don’t have
anything to save the remaining pancreas’,”
she explained. Faustman is director of im-
munobiology at Massachusetts General
Hospital and an associate professor of medicine
at Harvard Medical School in Boston.
However, diabetologists also have recognized
that some residual ß-cell function
remains after diagnosis and that early, aggressive
treatment with insulin or immunosuppressive
drugs can slow the autoimmune
destruction of ß-cells, enabling
patients to go a little longer before they
need full doses of insulin routinely. Equally
well-known is that some newly diagnosed
diabetics run quickly into complications of
the disease, while others fare much better
clinically for years. Often this has been attributed
to the latter managing their disease
better, but new evidence is casting a
different light on this.
ß-Cell Function Endures
Faustman and her colleagues recently used
a new ultrasensitive C-peptide immunoassay
to measure serum C-peptide levels in
long-term type 1 diabetics (Diabetes Care
2012;35:465–70). To their surprise, the
subjects not only had detectible C-peptide
levels—including 10% of those who had
had diabetes 3–4 decades—but also functioning
ß-cells. “We found using a new
ultrasensitive assay that the time course
of the disease is totally altered. Even at
30 years out, 20 percent still have a pancreas
making some insulin, as assayed by
C-peptide,” said Faustman. “It’s a whole
new way to view the disease as it relates to
the pancreatic function two years out after
diagnosis. It’s all come about because of
this ultrasensitive assay, which has altered
understanding of the kinetics of this disease
in a good way.”
The study involved two components,
including 182 type 1 diabetics, who were a
median of 39 years, had had the disease a
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median of 15 years, and were a median of
age 13 at disease onset. C-peptide values for
all these subjects were measured first with
an ultrasensitive C-peptide assay, and
only those with values higher than the
detection range of the ultrasensitive assay
also were measured using a standard assay.
The second part of the study involved
four diabetics who provided serum
samples weekly for up to 20 consecutive
weeks. C-peptide values in these samples
were measured using a different standard
C-peptide assay but with the same
ultrasensitive assay that had been used to
measure samples from the 182 patients.
The standard C-peptide assays have lower
limits of detection of 15 pmol/L and
33.1 pmol/L, respectively, whereas the
ultrasensitive assay has a lower limit of
detection of 1.5 pmol/L with inter- and
intra-assay coefficients of variation of 5.5
and 3.8% at 37 pmol/L.
Researchers categorized the 182 samples
into six groups based on the patients’
years of disease duration and found declining
levels of C-peptide detection across the
groups; however, the decline was gradual
over decades, rather than a few years. Nearly
80% of samples in the 0–5 years’ duration
of disease group had C-peptide levels
above the ultrasensitive assay’s limit of detection,
versus 10% from patients who had
had diabetes for 31–40 years. C-peptide
was not detected in subjects who had had
diabetes 31–40 years. In the group of four
subjects who provided a total of 54 serial
samples, the standard C-peptide assay did
not detect C-peptide in any of the samples,
whereas the ultrasensitive assay detected
C-peptide in 63%.
The researchers also assessed subjects’
ß-cell functional capacity by evaluating
fasting and/or non-fasting glucose levels in
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