A Yoshida

AC Clermont

D. A. Schaumberg

D. M. Nathan

Diabetes Control and Complications Trial Research Group

E. Cagliero

ED Gilmore

F. Berisha

G. T. Feke

GL Trick

GT Feke

J. W. McMeel

K Guan

L. Pitler

M. Lorenzi

S Wolf

S-E Bursell

T Kawagishi

English

PubMed

Springer - Publisher Connector

SHORT COMMUNICATION
Retinal haemodynamics in individuals with well-controlled
type 1 diabetes
M. Lorenzi & G. T. Feke & E. Cagliero & L. Pitler &
D. A. Schaumberg & F. Berisha & D. M. Nathan &
J. W. McMeel
Received: 9 August 2007 /Accepted: 12 October 2007 / Published online: 20 November 2007
# The Author(s) 2007
Abstract
Aims/hypothesis Abnormalities in retinal haemodynamics
have been reported in patients with type 1 diabetes in
advance of clinical retinopathy. These abnormalities could
therefore be useful as early markers or surrogate endpoints
for studying the microangiopathy. Since the DCCT, the
increased focus on good glycaemic control is changing the
natural history of diabetic retinopathy. Based on this, the aim
of this study was to investigate whether patients with type 1
diabetes treated entirely or mostly in the post-DCCT era and
tested in the absence of confounding factors show retinal
haemodynamic abnormalities.
Methods We measured retinal haemodynamics by laser
Doppler flowmetry in 33 type 1 diabetic individuals with
no or minimal retinopathy (age 30±7 years, duration of
diabetes 8.8±4.6 years, 9% showing microaneurysms), and
31 age- and sex-matched non-diabetic controls. The study
participants were not taking vasoactive medications, and
blood glucose at the time of haemodynamic measurements
was required to be between 3.8 and 11.1 mmol/l.
Results HbA1c was 7.5±1.2% and blood glucose 7.7±
2.8 mmol/l in these type 1 diabetic individuals, indicating
relatively good glycaemic control. Retinal blood speed,
arterial diameter and blood flow were not different between
the diabetic individuals and the matched controls.
Conclusions/interpretation Type 1 diabetic patients with no
or minimal retinopathy who maintain relatively good
glycaemic control do not show abnormalities of the retinal
circulation at steady state, even after several years of
diabetes. In such patients it may be necessary to test the
vascular response to challenges to uncover any subtle
abnormalities of the retinal vessels.
Keywords Diabetic retinopathy . Retinal blood flow .
Retinal circulation . Type 1 diabetes
Abbreviations
MGH Massachusetts General Hospital
The DCCT proved that good glycaemic control is a
powerful means of preventing retinopathy or slowing its
course in many patients [1]. It also proved that today’s
means of achieving good control are imperfect, and that
some patients may still progress to sight-threatening stages
of retinopathy. With the latter finding, the DCCT encour-
aged continuation of the quest for therapies able to pre-
empt the effects of the residual hyperglycaemia; however,
by increasing the prevalence of good glycaemic control it
made any trial of such therapies extremely long and
expensive. For this reason, there is heightened interest in
early markers of retinopathy to be used as surrogates to test
adjunct therapies.
Diabetologia (2008) 51:361–364
DOI 10.1007/s00125-007-0872-0
M. Lorenzi (*) : L. Pitler
Schepens Eye Research Institute and Department
of Ophthalmology, Harvard Medical School,
Boston, MA, USA
e-mail: mara.lorenzi@schepens.harvard.edu
G. T. Feke : F. Berisha : J. W. McMeel
Schepens Retina Associates Foundation, Harvard Medical School,
Boston, MA, USA
E. Cagliero :D. M. Nathan
Diabetes Center and Department of Medicine at the Massachusetts
General Hospital, Harvard Medical School,
Boston, MA, USA
D. A. Schaumberg
Division of Preventive Medicine and Department of Medicine
at Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA, USA
Retinal haemodynamics have been investigated exten-
sively in the quest for early functional markers of diabetic
retinopathy [2]; some of the changes detected appear to be a
function of the duration of diabetes and the severity of
retinopathy [2–4]. In patients with type 1 diabetes and
absent or minimal retinopathy, several investigators using
different techniques have observed decreased retinal blood
speed [3–7]. These studies, performed in the early and
mid-1990s, were in patients with rather poor glycaemic
control by today’s standards, yet the decreased retinal blood
speed could not be attributed solely to elevated blood
glucose levels at the time of measurement because hyper-
glycaemia actually increases blood speed [2, 3, 7]. We
investigated whether patients with type 1 diabetes treated
entirely or mostly in the post-DCCT era and tested in the
absence of confounding factors show retinal haemodynamic
abnormalities.
Methods
The institutional review boards of the Schepens Eye
Research Institute and Massachusetts General Hospital
(MGH) approved this study. We recruited, from the MGH
Diabetes Center and the greater Boston area, type 1 diabetic
patients with the clinical characteristics of patients previ-
ously reported [3–7] to show decreased retinal blood speed:
18–45 years of age, 1–15 years of insulin dependence, and
absent or minimal retinopathy. The non-diabetic partici-
pants, matched for age and sex, had no history of diabetes
and had HbA1c levels lower than 6%. Exclusion criteria
were pregnancy, smoking, systemic diseases other than type 1
diabetes, other retinal diseases, hypertension and renal
insufficiency; also excluded were users of angiotensin-
converting enzyme inhibitors, angiotensin receptor antago-
nists, vitamin E at doses greater than 400 IU/day, aspirin or
other antiplatelet drugs, and ibuprofen. After giving informed
consent, all participants in the study underwent a complete
eye examination. Diabetic individuals were excluded if they
had diabetic retinopathy greater than level 20 in the Early
Treatment Diabetic Retinopathy Study severity scale (micro-
aneurysms only). HbA1c was measured by the MGH HbA1c
laboratory; a level >10% was an exclusion criterion.
The retinal haemodynamic parameters were measured
when capillary blood glucose levels were between 3.8 and
11.1 mmol/l in order to avoid the confounding effects of
acute hypo- or hyperglycaemia on retinal blood flow [7].
The investigator performing the laser Doppler measure-
ments (G. T. Feke) was masked to the diabetes status of the
participants. The study eye was chosen on the basis of
vascular anatomy. The superior temporal retinal arteries are
preferred because temporal arteries are larger than nasal
arteries, and the lesions of diabetic retinopathy are more
prevalent in the superior temporal than in the other
quadrants. The arterial blood column diameter and centre-
line blood speed were measured using a Canon laser
Doppler retinal blood flow instrument (CLBF 100; Canon,
Tokyo, Japan) [8]. The blood flow rate in units of μl/min is
calculated automatically as the product of the cross-
sectional area of the artery at the laser Doppler measure-
ment site and the average blood speed, assuming a circular
arterial cross-section [8].
Data are presented as means±SD. Parameters were
compared between diabetic and control participants using
the non-paired t test.
Results
Table 1 summarises the characteristics of the study
population. The diabetic and control groups differed only
in the levels of HbA1c and blood glucose. The diabetic
participants received insulin through multiple daily injec-
tions or an external pump. The mean HbA1c level was 7.5%
and the range 5.2–9.3%, eight patients having HbA1c levels
above 8%. The mean duration of type 1 diabetes was
8.8 years. Only three patients manifested retinopathy, two
of them showing one microaneurysm and one several
microaneurysms. Of note, no diabetic individual who
sought participation in the study was excluded because of
advanced retinopathy, and only one diabetic individual was
not included because of HbA1c greater than 10% (10.8%).
Figure 1 presents the retinal haemodynamic measure-
ments in 27 diabetic and 26 control participants in whom
Table 1 Characteristics of the study population
Diabetic
individuals
(n=33)
Controls
(n=31)
p value
Age (years) 30±7.0 30±5.6 0.86
Sex (% female) 48 58 0.44
HbA1c (%) 7.5±1.2 5.0±0.3 <0.0001
Diabetes duration
(years)
8.8±4.6 n/a n/a
Blood glucose
level (mmol/l)a
7.7±2.8 5.4±0.8 <0.0001
Systolic blood
pressure (mmHg)
106±11 109±7 0.27
Diastolic blood
pressure (mmHg)
65±8 66±7 0.47
Retinopathyb (%) 9 n/a
Data are means±SD or percentages
aMeasured immediately before the retinal haemodynamic studies
b Assessed using the Early Treatment Diabetic Retinopathy Study
severity scale. Individuals with a score of greater than 20 were
excluded from the study
n/a, not applicable
362 Diabetologia (2008) 51:361–364
the measurements could be performed at the major superior
temporal artery. Arterial diameter and blood speed were not
significantly different between the diabetic patients and the
controls (diameter: patients 116±12 μm, controls 112±
10 μm, p=0.18; blood speed: patients 32.9±6.0 mm/s,
controls 34.6±6.8 mm/s, p=0.34). Accordingly, retinal
blood flow was the same in the two groups (patients
10.4±2.4 μl/min; controls 10.4±3.2 μl/min, p=0.98). In the
remaining six diabetic and five control participants there
was early bifurcation of the artery, and one of the branches
was used for the measurements; again, no differences were
noted between the two groups. The sample size provided
80% power (α=0.05) to detect differences as low as
0.75 SD between diabetic and control participants. This
translates into differences of 7, 15 and 24% for retinal
artery diameter, blood speed and blood flow, respectively.
None of the haemodynamic measurements showed a
significant correlation with coincident blood glucose levels,
HbA1c, age, diabetes duration, systolic or diastolic blood
pressure in either the diabetic or the control participants
(data not shown).
Discussion
The important finding of this study is that in young patients
with relatively well-controlled type 1 diabetes and no
complications the baseline retinal circulatory parameters
are within the normal range, even after several years of
diabetes. These results differ from those of studies
completed before the publication and widespread applica-
tion of the DCCT results. In these earlier studies [3–7] the
average HbA1c levels were 8, 10 or 12% compared with
7.5% in our diabetic individuals. Although we did not
observe a correlation of HbA1c with retinal blood speed or
flow, most likely because of the narrow range of HbA1c
values, it was previously shown that retinal blood flow
decreased with increasing HbA1c in type 1 diabetic patients
without retinopathy [4].
The relation between HbA1c and retinal circulatory
parameters must be interpreted with the knowledge that
acute elevations [2, 7] or coincident high levels [2, 3] of
blood glucose increase retinal blood flow, by increasing
blood speed. Thus, the decreased blood speed and blood
flow found in type 1 patients in previous studies indicated
the presence of chronic effects of hyperglycaemia on retinal
vessels in advance of clinical retinopathy. Elevated plasma
glucose levels at the time of haemodynamic measurements
could actually have masked, to some extent, such chronic
effects of hyperglycaemia, contributing to the inconsistency
with which retinal circulatory abnormalities were detected
in diabetic patients without retinopathy [2]. The design of
our study, requiring relatively normal glucose levels prior to
the laser Doppler measurements (Table 1), limited such
potential confounding effects, and the normal retinal
haemodynamics that we recorded in diabetic participants
should be informative of the status of retinal vessels.
Our results are empowering for patients with type 1
diabetes and those who care for them, for two reasons.
First, it is apparent that good glycaemic control is attainable
in a non-clinical trial setting, and is sustainable over time.
Second, such good control not only delays or prevents
retinopathy, as shown by the DCCT, but also delays or
prevents abnormalities in the retinal circulation that may be
prodromes to the development of retinopathy. Normal
retinal haemodynamics were also reported recently in
patients with type 2 diabetes with no retinopathy and mean
HbA1c of 7.2% [9] or 7.7% [2].
From the standpoint of finding early markers of retinopa-
thy, our observations indicate that measurements of retinal
circulatory parameters in the unperturbed state may not be
sufficiently sensitive in patients with absent or minimal
Fig. 1 Retinal haemodynamic parameters in type 1 diabetic individ-
uals and matched non-diabetic controls. The box plots present the data
for the 27 diabetic and 26 control participants in whom the measure-
ments could be performed at the major superior temporal artery. Each
box plot shows the 10th, 25th, 50th (median), 75th and 90th percentiles
of the indicated parameter. Values above the 90th and below the 10th
percentile are plotted as points
Diabetologia (2008) 51:361–364 363
retinopathy and well-controlled diabetes. Insofar as the HbA1c
levels in such patients are often still greater than normal, the
residual hyperglycaemia is likely to leave signs on the retinal
vessels, but these may be uncovered only when a functional
challenge is applied to the vessels. In response to hyperoxia,
used as a stimulus to test vascular reactivity, patients with
well-controlled type 2 diabetes showed normal retinal
haemodynamics [9], but type 1 patients in another study
did not [10]. Unfortunately, the latter study did not report
levels of glycaemic control. The next step will be to com-
pare in the same well-controlled type 1 diabetic individuals
the behaviour of retinal haemodynamics at steady state and
in response to a challenge. In this way we will begin to
reconstruct systematically the history of retinal micro-
angiopathy in the post-DCCT era.
Acknowledgements The study was supported by Public Health
Service grant EY014812 to M. Lorenzi, funded through the Special
Statutory Funding Program for Type 1 Diabetes Research, and by the
Massachusetts Lions Research Fund. D. M. Nathan is supported in
part by the Ida S. Charlton Charity Fund.
Duality of interest The authors declare that there is no duality of
interest associated with this manuscript.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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Retinal haemodynamics in individuals with well-controlled type 1 diabetes

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Retinal haemodynamics in individuals with well-controlled type 1 diabetes

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