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Diabetes
Complications
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Macrovascular and microvascular complications of diabetes result
from the slow progression of vascular damage caused by chronic
hyperglycemia. The pathological manifestations of diabetes complications
include blindness, kidney failure, nerve damage, and heart disease.
Although high blood glucose is clearly associated with the development
or progression of complications, some patients with poor glucose
control never develop complications while some with apparently
good control develop severe complications. Also, susceptibility
to complications is higher in some families than others. This
suggests that there are factors other than glucose that influence
susceptibility to diabetes complications.
We and others have shown that there is biological variation in
glycated hemoglobin (HbA1c) levels in human populations that
is not attributable to blood glucose levels. In essence, people
with similar mean blood glucose levels can have different HbA1c
levels, some higher and some lower than average for the population.
Most recently we have also shown that the severity of vascular
complications of diabetes is related to biological variation
in HbA1c levels. The goal of this project is to understand genetic
and environmental factors in addition to glucose that influence
individual susceptibility to both hemoglobin glycation and diabetes
complications in humans and mouse models. Our prior studies are
outlined below. Study 1: Evidence of Biological
Variation in HbA1c - the Children’s
Hospital Study
High and low hemoglobin glycation phenotypes in type
1 diabetes: a challenge for interpretation of glycemic control. Hempe, J.M.,
Gomez R., McCarter R. & Chalew S.A. Journal of Diabetes and
its Complications 16:313-320, 2002.
Panel A shows the simple linear regression for all 682 pairs of
total MBG and HbA1c observations from all type 1 diabetic patients
in the study. There was significant correlation between MBG and
HbA1c (HbA1c=0.027×MBG
+ 5.8, r=0.71, p<0.0001) but also wide variability in the population
HbA1c response to MBG. We evaluated the results from individual
patients over time to determine if the population variation was
random or due to
between-individual variation. Panel B shows the paired HbA1c and
MBG results for three different patients over the 2.3 year study
with HbA1c levels that
consistently tracked above ( ),
near ( ), or below
( ) the population regression line.
To quantify individual effects we used the population regression
equation to calculate a Hemoglobin Glycation Index (HGI = observed
HbA1c – predicted
HbA1c) to quantify the magnitude and direction of the difference between
each patient’s set of observed and predicted HbA1c results. Likelihood
ratio tests and T-statistics showed that mean HGI were significantly different
among individuals, and that 29% of the patients had HbA1c levels that were
statistically significantly higher or lower than predicted by the regression
equation. These results show that MBG and HbA1c are not necessarily interchangeable
estimates of glycemic control. They also show that human populations are
made up of individuals with different hemoglobin glycation phenotypes,
i.e. high, moderate, or low “glycators” that can be identified
based on the relationship between HbA1c and MBG. Study 2: Biological Variation in HbA1c is Associated with Risk of Diabetes
Complications - Analysis of Data from the Diabetes Control and
Complications Trial
Biological Variation in Glycated Hemoglobin Predicts Risk of
Retinopathy and Nephropathy in Type 1 Diabetes. McCarter R.,
Hempe, J.M., Gomez R. & Chalew S.A. Accepted for publication in Diabetes Care.
Panel A shows the variability in the relationship between MBG and HbA1c
in the DCCT population. Panel B shows the paired HbA1c and MBG results
for three different patients over the 9 year study with HbA1c levels that
consistently tracked above (),
near (), or below
() the population
regression line. Panel C shows the relationship between HGI and risk of
retinopathy. Panel D shows the relationship between HGI and risk
of nephropathy. Using the DCCT data we developed a longitudinal multiple regression
model from MBG and HbA1c measured in the 1441 DCCT participants at quarterly
visits. As in the Children’s Hospital study, a Hemoglobin
Glycation Index (HGI = observed HbA1c – predicted HbA1c) was calculated for
each patient for each clinic visit to assess biological variation based
on the directional deviation of observed HbA1c from that predicted by
MBG in the model. The population was subdivided by thirds into high, moderate,
and low HGI groups based on mean participant HGI during the study. Cox
proportional hazard analysis compared risk for development or progression
of retinopathy and nephropathy between HGI groups controlled for MBG,
age, treatment group, strata, and duration of diabetes.
Likelihood ratio tests and T-statistics showed that mean HGI
were significantly different among individuals, and that 57% of the patients
had HbA1c levels that were statistically significantly higher or lower
than predicted by the regression equation. At seven years follow-up, patients
in the high HGI group (higher than predicted HbA1c) had three times greater
risk of retinopathy (30% vs. 9%, p<0.001) and six times greater risk
of nephropathy (6% vs. 1%, p<0.001) compared to the low HGI group.
We conclude that between-individual biological variation in HbA1c, distinct
from that attributable to MBG, was evident among type 1 diabetes patients
in the DCCT and was a strong predictor of risk for diabetes complications.
Identification of the processes responsible for biological variation in
HbA1c could lead to novel therapies to augment treatments directed at
lowering blood glucose levels and prevent diabetes complications.
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