REVIEWS

Cardiovascular risk in double diabetes

mellitus—when two worlds collide
Stephen J. Cleland
Abstract | Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused
on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes.
Although HbA1c level is an important contributor to increased macrovascular risk, several prospective studies
have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important
than HbA1c for the prediction of cardiovascular risk, especially for coronary heart disease events. ‘Double
diabetes mellitus’ describes a combination of T1DM with characteristics associated with type 2 diabetes
mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal
insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly
increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes
mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the
combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes
mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to
identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management
that might reduce their risk of future premature coronary disease.
Cleland, S. J. Nat. Rev. Endocrinol. advance online publication 10 April 2012; doi:10.1038/nrendo.2012.47

Introduction
Health-care professionals who manage patients with
type  1 diabetes mellitus (T1DM) usually take an
­e vidence-based approach to their treatment. In this
­glucose-centred approach to risk prediction, advice can
be given with confidence about strategies to optimize
glyca­e mic control, in the knowledge that increased
HbA1c levels are directly related to microvascular risk. 1
How­ever, the question of how to quantify an individual
patient’s macrovascular risk is far from being answered,
despite the results of several prospective cohort studies
showing that patients with T1DM are at much higher
risk of premature coronary disease and mortality than
healthy people.2–6 Indeed, patients with T1DM aged
30–40 years are thought to have a cardiovascular event
risk of 10–15% over their next decade of life.2–6 How­
ever, this figure masks a wide spectrum of individual
risk factors.
Only one randomized, controlled trial has examined
the effect of aggressive glycaemic control on macro-
vascular complications in patients with T1DM. In the
Diabetes Control and Complications Trial (DCCT),
1,441 patients with T1DM were randomly assigned to
either intensive or conventional glycaemic control over a
period of 6.5 years.1 This trial evolved into a prospective
cohort study, the Epidemiology of Diabetes Interventions
and Complications (EDIC) study, which reported on
cardiovascular complications in the DCCT participants
Competing interests
The author declares no competing interests.
after 17 years of follow-up.7 The EDIC study reported
an impressive 57% reduction in the relative risk of the
composite end point (nonfatal myocardial infarction,
stroke or death from cardiovascular causes) in the group
initially randomized to intensive glycaemic control.
This improvement was mainly driven by reduced HbA1c
levels during the 6.5 years of intensive glycaemic control
and highlights the importance of early imprinting and
metabolic memory in this context. Hyperglycaemia-
induced vascular damage is likely to be associated with
cumulative glucose exposure, and ‘area under the curve’
measure­ment could predict the extent of this damage.
The absolute event rate in the conventional glycaemic
control group was only 25, which corresponds to a
10-year cardio­vascular event risk of ~2%. By contrast,
in another prospective study (Pittsburgh Epidemiology
of Diabetes Complications [EDC]), the 10-year cardio-
vascular event rate was nearly 10%.6 The most probable
reason for this difference is the strict DCCT recruitment
criteria, which excluded patients with obesity, hyper­
tension, hypercholesterolaemia and established vascular
disease. The DCCT participants, by definition, had very
low baseline macrovascular risk and were, therefore,
unrepresentative of most ‘real life’ populations of patients
with T1DM.
Much more is understood about the mechanisms of Department of
Medicine, Glasgow
cardiovascular risk in type 2 diabetes mellitus (T2DM) Royal Infirmary,
and there could be overlaps with T1DM. At first it seems 84 Castle Street,
Glasgow G4 0SF, UK.
counterintuitive to translate knowledge of pathophysio­ steve.cleland@
logical mechanisms T2DM to T1DM when trying to ggc.scot.nhs.uk

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REVIEWS

Key points influences. For example, a study of 589 patients in the

Pittsburgh EDC cohort demonstrated a major upward
■■ Type 1 diabetes mellitus (T1DM) confers an increased risk of premature
coronary disease; however, markers of insulin resistance predict coronary risk
shift in BMI over a 20-year period, whereby the preva-
better than HbA1c levels lence of obesity (BMI ≥30 kg/m2) rose sevenfold to 22.7%
■■ HDL cholesterol levels are increased and liver fat stores are reduced in lean and of being overweight (BMI 25–30 kg/m2) increased
patients with T1DM, reflecting an altered hepatic physiology associated with from 26% to 42%, a rise of 47% (Figure 1).8 In 2007, the
relative portal insulinopaenia average BMI of patients with T1DM was similar to that
■■ Double diabetes mellitus describes a combination of T1DM with aspects of the general population. By contrast, in the pre-DCCT
of type 2 diabetes mellitus (especially central adiposity and features of era, the baseline BMI was lower than population norms
metabolic syndrome)
in patients with T1DM,8,9 probably owing to a combi-
■■ Insulin resistance and peripheral hyperinsulinaemia are features of treated
T1DM that are exaggerated in patients with double diabetes mellitus nation of weight loss prior to diagnosis and suboptimal
■■ The combination of chronic hyperglcaemia and abnormal lipid partitioning glycaemic control. Furthermore, one complication of
resulting from double diabetes mellitus accelerates the atherothrombotic intensive glycaemic control is weight gain. Subsequent
process, leading to premature coronary disease analyses of DCCT–EDIC subgroups have revealed
■■ Improvements in clinical strategies are required to identify and manage important concerns about some patients in the trial
patients at high risk of double diabetes mellitus who gained weight and began to exhibit features associ-
ated with increased cardiovascular risk.10 When patients
in the intensive-control group were split into quartiles
100 –
on the basis of weight gain, those in the highest quartile
(whose BMI increased from 24 kg/m2 to 31 kg/m2) had
higher blood pressure and LDL cholesterol levels than
those in the other three quartiles. In addition, patients
75 –
in the highest quartile required higher insulin doses to
achieve target HbA1c levels, had a higher waist:hip ratio
and a more atherogenic lipid profile (raised apolipo­
Prevalence (%)

protein B and atherogenic lipoprotein subfractions,

50 –
and reduced apolipo­protein A1 levels) than those in the
other quartiles. These differences remained significant
after adjustment for HbA1c levels. A similar pattern was
observed through weight gain quartiles in the patients
25 –
assigned to conventional glycaemic control.10
These observations raise important concerns about
the value of aggressive glycaemic control in patients with
T1DM if it is accompanied by marked weight gain, espe-
0–
cially if driven by accumulation of central fat stores. We
8

7
98

99

99

99

99

99

00

00

00

know from many published studies on metabolic syn-

–1

–1

–1

–1

–1

–1

–2

–2

–2
86

88

90

92

94

96

98

00

04

drome and T2DM that increased body fat is associated

19

19

19

19

19

19

19

20

20

with a number of risk factors and markers linked with

Years
BMI <20 kg/m2 BMI 25–30 kg/m2
BMI 20–25 kg/m2 BMI >30 kg/m2
Figure 1 | Changing BMI profiles from 1986–2007 in 589 patients with T1DM in
the Pittsburgh EDC Prospective Cohort Trial. These profiles demonstrate a
consistent increase in the prevalence of both obesity and overweight in T1DM.
Whereas the 1986–1988 data reveal lower obesity and overweight prevalence
rates in patients with T1DM than in the general population, the 2004–2007 rates
are broadly similar. Permission obtained from John Wiley & Sons © Conway, B.
et al. Diabet. Med. 27, 398–404 (2010).
understand the drivers of coronary disease, particularly
as in many ways the two diseases are opposites. T1DM
is characterized by insulin deficiency, whereas T2DM is
usually associated with hyperinsulinaemia and insulin
resistance (with varying degrees of insulin secretory
defects in advanced phases of the disease) and prominent
vascular pathology, including hypertension, endothelial
dysfunction and arterial stiffness. However, compari-
son of the two diseases could be increasingly relevant
because of the changing demographics of populations of
patients with T1DM, as a result of societal and iatrogenic
cardiovascular disease. These include proinflammatory
adipocytokines, steatohepatitis, ectopic fat stores (pan-
creatic, muscle, cardiac, vascular, perivascular), insulin
resistance (muscle, hepatic, vascular), oxidative stress
and hypofibrinolysis or procoagulation.11–16 Obesity-
associated risk factors known to accelerate cardio­
vascular disease in patients with T2DM might, therefore,
also have an increasing role in some patients with T1DM.
If so, this phenotype could be described as double dia-
betes mellitus (the simultaneous presence of T1DM
and features of T2DM). As the prevalence of obesity and
metabolic syndrome in patients with T1DM continues to
increase, the notion that double diabetes mellitus is an
important driver of macrovascular risk in these patients
becomes a relevant public health issue.
By considering available knowledge on the patho­
physiology of T2DM, this Review will explore the evi-
dence that glycaemic control is just one of many factors
that contribute to the increased risk of premature cardio­
vascular disease and death in patients with T1DM.
Strategies to identify susceptible candidates early and to
manage them appropriately are highlighted.

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Cardiovascular risk factors in T1DM
Prospective cohort studies of macrovascular event inci-
dence in patients with T1DM have some common find-
ings. Age and duration of diabetes mellitus are clearly
important drivers of coronary heart disease (CHD)
events and mortality.17 After correction for these vari-
ables, however, the main risk factor is albuminuria. In
the Pittsburgh EDC prospective cohort study, involving
658 patients who were followed up for nearly 20 years,
mortality in patients with T1DM without albuminuria
was not significantly different to that in a control popula-
tion, emphasising the importance of this risk marker.18
Similar results have been reported in the FinnDiane
study, in which over 4,000 patients with T1DM were
followed up for 7 years. In the subgroup without albu-
minuria, no increase in mortality was observed (standar­
dized mor­tality ratio 0.8, 95% CI 0.5–1.1).19 BMI is not
an independent risk factor for cardiovascular disease
in T1DM cohorts, probably because BMI exhibits a
U‑shaped relationship with mortality in this setting.
Con­founding influences that lead to a low BMI include
smok­i ng, nephropathy and autonomic neuropathy,
which are all associated with increased mortality in
patients with T1DM.20
The degree to which established cardiovascular risk
factors, such as hypertension, hypercholesterolaemia and
smoking should be addressed in patients with T1DM
depends on the threshold of absolute cardiovascular
risk used to prompt treatment. All patients with T1DM
who smoke should be encouraged to quit and be given
adequate assistance. In patients aged >40 years, standard
risk calculators could be appropriate to guide the use of
primary prevention therapy such as anti-­hypertensive
drugs and statins, using a threshold of 15–20% 10-year
cardiovascular risk. However, in a generally younger
population of patients who have T1DM with a wide
spectrum of cardiovascular risk, the difficulty is to
identify those who should receive early and aggressive
primary prevention therapy. Given the importance of
albuminuria as an indicator of generalized vascular
dysfunction,21,22 it is advisable to treat these traditional
risk factors aggressively, possibly even in patients with
sustained microalbuminuria who are aged 20–40 years.
Applying knowledge of T2DM to T1DM
Several large glucose-lowering trials in patients with
T2DM were published in 2008‑2009. 23 Over 25,000
patients were recruited to the Action to Control Cardio­
vascular Risk in Diabetes (ACCORD) trial, Action in
Diabetes and Vascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation (ADVANCE)
trial and Veterans Affairs Diabetes Trial (VADT).24–26
Despite an aggressive approach to lowering HbA 1c to
<7.0%, their results showed no statistically significant
reduction in cardiovascular events. The ACCORD
study had to be stopped early because of increased
mortality in the intensively treated group, which was
probably attributable to an increased frequency of
hypoglycaemia. A 10-year follow-up of participants in
the UK Prospective Diabetes Study showed a reduced
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Box 1 | Potential features of double diabetes mellitus
Double diabetes mellitus should be considered in patients
with T1DM accompanied by the following features:
■■ Relatively high total daily insulin doses are required to
achieve glycaemia targets33
■■ Family history of type 2 diabetes mellitus, especially if
two or more relatives are affected33,34
■■ Progressive weight gain, especially associated
with central adiposity, while receiving insulin
treatment10,35,36,58
■■ Hypertension (even if borderline)35
■■ Low estimated glucose disposal rate (a surrogate
measure of insulin resistance)35,36
■■ Low HDL cholesterol levels (compared with high levels
typically found in patients with T1DM)17
Abbreviation: T1DM, type 1 diabetes mellitus.
incidence of cardio­vascular events in the intensively
treated group, especially in the patients who took met-
formin,27 but overall, in patients with T2DM, intensive
glycaemic control might only confer a minimal improve-
ment in macrovascular outcomes, and could in certain
circumstances be harmful. Moreover, HbA1c measure-
ments only reflect the average glycaemic control over
the preceding 3 months rather than the cumulative
total glucose exposure, which could be more relevant
than short-term exposure to long-term cardiovascular
outcome. Furthermore, HbA1c levels do not reflect the
variability of glucose levels, which are a robust predictor
of cardiovascular outcome28 and coronary artery calcifi-
cation, a surrogate measure of cardiovascular outcome.29
HbA1c levels were not an independent predictor of hard
(that is, permanent or irrevocable) CHD events in
either the Pittsburgh EDC cohort 30 or the EURODIAB
cohort.31 Interestingly, glycaemia status is better for the
prediction of stable occlusive peripheral vascular disease
than embolic vascular complications, 32 which raises
the intriguing question of whether glucose-unrelated
factors, such as lipid abnormalities, might contribute
to the pathophysiology of coronary plaque rupture
in T1DM. Of course, patients with T2DM are usually
older and generally have a higher prevalence of hyper­
tension and dyslipidaemia than patients with T1DM,
and these comorbidities are considered the predominant
drivers of macrovascular disease in T2DM.
Double diabetes mellitus
The term ‘double diabetes mellitus’ is not new. It was first
used in 1991 to account for the observation that patients
with T1DM who had a family history of T2DM often
required higher insulin doses to achieve similar glycae-
mic control targets than those without a family history of
T2DM (Box 1).33 The more penetrant the family history
(that is, the higher the number of family members with
diabetes mellitus), the higher the insulin dose required,
which indicated underlying resistance to its effects. The
hypothesis emerged that a subgroup of patients with
T1DM existed who were at risk of developing T2DM in
later life but would never be diagnosed as having T2DM
because they had already developed hyperglycaemia as a
REVIEWS
result of T1DM. These patients might, therefore, accrue
additional cardiovascular disease risk, beyond that
expected if they had T1DM alone. Whether this risk is
simply additive or more complex (that is, synergistic) is
not clear.
Assessing the insulin dose needed in patients with
T1DM and/or their family history of T2DM is unlikely
to provide accurate, adequate screening to identify this
high-risk subgroup of patients, although if the patient
has more than one first-degree relative with T2DM
their CHD risk seems to be fivefold higher than if no
relatives have T2DM.34 In clinical practice, insulin dose
is unreliable for identification of patients with double
diabetes mellitus, not only because it is inaccurately
reported by patients, but also because individuals with
T1DM have varying amounts of residual endogenous
insulin secretion, which contributes to their glycaemic
control, and also reduces peripheral hyperinsulinaemia
and insulin resistance (S. J. Cleland, unpublished obser-
vation). For this reason, more reliable tests are required
for epidemiologic­al and clinical purposes.
Pathogenetic factors
The vasculotoxic effects of T1DM could be accelerated
in patients who also have central obesity and insulin
resistance produced by a combination of genetic and
lifestyle factors. These factors might help to explain why
such vari­ability in the risk of CHD occurs in patients
with T1DM.
Insulin resistance
The gold standard test for measuring insulin resistance
is the euglycaemic hyperinsulinaemic clamp, although
this procedure is impractical for routine use in clinical
practice because it requires specialist research facilities
and takes >3 h to perform. However, this measurement
was made in 24 patients participating in the Pittsburgh
EDC prospective study,35 and used to generate a best-fit
model of insulin sensitivity on the basis of readily acces-
sible patient data, which has been proposed as a surro-
gate measurement of the whole-body estimated glucose
disposal rate (eGDR).35
The performance of eGDR as a surrogate marker of
insulin resistance was tested in 603 patients with T1DM
(baseline age 28 years and disease duration 19 years) who
were followed up over 10 years.30 During this period 109
CHD events occurred, of which 42 were hard events. A
number of independent predictors of hard CHD events
were revealed, including eGDR, disease duration,
nephropathy, non-HDL cholesterol levels and leukocyte
count. HbA1c was not predictive of hard CHD events.
In support of this finding, eGDR was retrospectively
calculated from data on participants in the DCCT–EDIC
trial, but using BMI instead of waist:hip ratio.36 A high
eGDR was a significant predictor of both cardio­vascular
events (HR 0.70, 95% CI 0.56–0.88) and any macro­
vascular event (HR 0.83, 95% CI 0.73–0.96). Total insulin
dose, however, was not predictive of these outcomes,
underlining its unreliability as a surrogate measure of
insulin resistance. Interestingly, a high eGDR was also
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predictive of microvascular events, a finding that is also
supported by data on the incidence of retinopathy and
nephropathy in the EURODIAB study.37
In a 2011 study, insulin sensitivity in patients with
T1DM was measured directly using the clamp tech-
nique.38 Patients with T1DM were more insulin-resistant
(6.2 mg·kg–1/min) than control individuals (12.7 mg·kg–1/
min), and this measurement also correlated significantly
with the volume of coronary artery calcification, a surro-
gate measure of atherosclerosis. In the same study, coro-
nary artery calcification was not associated with HbA1c.38
As this study demonstrated, insulin resistance is a feature
of T1DM even in the absence of obesity and metabolic
syndrome, a finding that has been consistently demon-
strated in the literature over the past 30 years.39,40 This
association is based on evidence from clamp and tracer
studies, in which hepatic glucose output and peripheral
glucose uptake (mainly in skeletal muscle) were meas-
ured directly in response to systemic insulin infusion.39,40
However, reduced insulin-mediated glucose uptake in
patients with T1DM might be predominantly driven by
abnormal lipid partitioning, rather than by dysfunctional
insulin–glucose signalling. This notion is supported by
the consistent demonstration of increased rates of lipo­
lysis (usually secondary to the effects of insulinopaenia on
adipocytes and hepatocytes) with consequent increased
levels of circulating nonesterified fatty acids and intra­
myocellular lipid.41–43 Furthermore, patients with T1DM
have increased peripheral hyper­insulinaemia compared
with individuals without diabetes mellitus, owing to sub-
cutaneous injection of exogenous insulin, which might
exacerbate peripheral insulin resistance, partly through
downregulation of insulin receptors44 and GLUT‑4, the
main intracellular insulin-mediated glucose transporter
in skeletal muscle. 45 In addition, supra­physiological
insulin levels have long been known to cause adverse
cardiovascular effects, such as sodium retention, vascu-
lar smooth muscle hypertrophy and sympathetic nervous
system stimulation, and any associated vascular insu­
lin resistance might cause raised blood pressure due to
blunted insulin-mediated peripheral vaso­dilata­tion.16,46
Patients with double diabetes mellitus could, there­
fore, have multiple causes of insulin resistance with a
c­onsequent elevation of cardiovascular disease risk.
HDL cholesterol levels
Patients with T1DM generally have high HDL cho-
lesterol levels and normal levels of total cholesterol. A
group of 19 patients with T1DM (mean age 35 years,
HbA1c 8.7%, and BMI 23 kg/m2) were compared with a
carefully matched (for age and sex) nondiabetic control
group. The mean HDL cholesterol level of the case
patients was 1.32 mmol/l, compared with 1.22 mmol/l
in control indivi­duals. 41 In addition, the cholesterol
esterification rate is higher in patients with T1DM than
in control indivi­duals for a given level of tri­glycerides,
which possibly explains why the patients’ HDL cho-
lesterol concentration is increased. 47 Furthermore,
phospholipid transfer protein (PLTP) activity is mark-
edly raised in patients with T1DM and this activity
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correlates with HDL cholesterol levels. Which factors
regulate, or are associated with, PLTP activity is not yet
known, but candidates include hepatic triacylglycerol
lipase (also known as hepatic lipase [HL]), lipoprotein
lipase, p­hosphatidylcholine-sterol acyltransferase and
cho­lesterol ester transfer protein.48 In the EDC trial,
patients with TIDM who experienced CHD events had
lower HDL cholesterol levels than those who had no
CHD events (1.31 mmol/l versus 1.42 mmol/l). However,
no significant difference in HDL cholesterol levels was
detected when similar analyses were carried out on
patients in the DCCT–EDIC and EURODIAB cohorts.
In all three cohorts, however, triglycerides and LDL cho-
lesterol levels were consistently increased in the patients
with coronary events.17 Interestingly, albuminuria was
associated with both reduced HDL cholesterol levels 49
and raised triglyceride levels, 50,51 but whether these
as­sociations represent causal relationships is unclear.
The ‘Golden Years’ cohort comprises 400 patients with
T1DM for at least 50 years.52 Detailed characteristics of
this cohort were published in 2003.53 The mean age
of the patients at the time of this report was 69 years,
and the mean age at diagnosis was 14 years. In general,
their BMI was normal (mean 25 kg/m2) and, compared
with younger patients with T1DM, their insulin dose was
rela­tively low (0.52 U/kg), which is consistent with low
under­lying levels of insulin resistance. Albuminuria was
evi­dent in 36% of patients, and antihypertensive drugs
were prescribed to 29%. The most striking finding,
how­ever, was a very high HDL cholesterol level (mean
1.84 mmol/l). Possible reasons for this finding include
genetic factors (these patients tended to have long-lived
parents), high physical activity levels and moderate
alcohol consumption.
These studies clearly show that high levels of HDL
cholesterol (which are traditionally regarded as ‘pro-
tective’ from CHD) are present in most patients with
T1DM, but that a subgroup of patients who go on to
develop premature CHD tend to have decreased levels of
HDL cholesterol associated with increased triglycerides
and LDL cholesterol levels, resembling the atherogenic
dyslipidaemia characteristic of patients with T2DM.
Hepatic triacylglycerol lipase
Studying portal vein insulin levels could provide some
insight into why HDL cholesterol levels (and hence
cardio­v ascular risk) differ so much in patients with
T1DM and those with T2DM. In patients with T2DM,
portal vein insulin levels are usually high because
increased secretion is required to overcome insulin
resistance and high portal insulin levels result in high
hepatic exposure to this hormone. Insulin stimulates
the activity of HL, which facilitates the exchange of
tri­glycerides for LDLs (mediated by cholesteryl ester
transfer protein), resulting in a reduction in the HDL
cholesterol content of lipoprotein particles. The end
result is the low HDL cholesterol levels that are observed
in individuals with central obesity, metabolic syndrome
and T2DM.54,55 By contrast, patients with T1DM have
low portal vein insulin levels (and, therefore, low HL
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REVIEWS
activity) because exogenous insulin is delivered subcu-
taneously. As a result, the HDL cholesterol content of
lipoprotein particles is preserved.
Three studies have confirmed that HL activity is
reduced in patients with T1DM. In a study of 10 patients
with T1DM, HL activity was significantly lower in the
patients than in a group of matched control indivi­duals
(39.6 ± 35.2 U/l versus 87.0 ± 27.1 U/l).56 In another
study, HL activity increased in patients with T1DM who
switched from subcutaneous insulin to intraperitoneal
insulin, and this change was associated with decreased
levels of HDL2 cholesterol and increased levels of HDL3
cholesterol.57 In a subgroup of 61 DCCT participants,
increased HL activity accounted for most of the associa-
tion between increased intra-abdominal fat stores and
decreased HDL2 cholesterol levels in multivariate analy-
ses; furthermore, HbA1c levels were not associated with
any of these parameters.58 The results from this study
also suggest that increased HL activity in conjunction
with central weight gain in patients with T1DM could
be important in switching the lipid profile to an athero-
genic pattern that resembles the dyslipidaemia of T2DM.
It is tempting to speculate, therefore, that T1DM confers
an atheroprotective phenotype due to reduced hepatic
insulin exposure and the subsequent beneficial effects
on lipid profile.
A number of studies in patients with T1DM on
perito­neal dialysis who received insulin by the portal
vein route also support these findings. In all patients,
despite this administration route seeming to offer a
more physio­logical method of delivering insulin than
subcutaneous injec­tion, serum lipid profiles switched
to an atherogenic pat­tern, with significant reductions in
HDL cholesterol and increases in the LDL cholesterol:
HDL cholesterol ratio.57,59–61
The advent of pancreatic transplantation provides
another potential model to test these ideas. In a study of
44 patients with T1DM who received simultaneous pan-
creas and kidney transplants, the lipid profile changed
after transplantation to a more atherogenic pattern in
the group with portal drainage rather than pancreatic
venous drainage (namely, higher total cholesterol, LDL
cholesterol and triglyceride levels but lower HDL cho-
lesterol levels). This change reflected increased hepatic
insulin exposure.62
Hepatic fat content and metabolism
In patients with obesity, metabolic syndrome and T2DM,
the pathological significance of nonalcoholic fatty liver
disease has been emerging.63 Strong associations are
evident between intra-abdominal fat, intrahepatic fat,
an atherogenic lipid profile, atherosclerosis and systemic
inflammation (measured by levels of C‑reactive protein,
IL‑6 and TNF). In the liver, hyperinsulinaemia promotes
deposition of fat and stimulates expression of sterol regu­
latory element-binding protein 1c (SREBP1c), which has
a crucial role in the regulation of hepatic tri­glyceride
accumulation.54 Enzymes involved in de novo lipo­genesis
(namely fatty acid synthase and acetyl-­coenzyme A car-
boxylase) are activated by SREBP1c, and in parallel,
REVIEWS

Table 1 | Hepatic fat and portal insulin levels in patients with T1DM41 atherogenic serum lipid profile and increased p­roduction
of pr­oinflammatory cytokines.
Marker Patients with T1DM Matched nondiabetic
controls This metabolic shift could, therefore, be another
mechanism that leads to atheroprotection in patients with
Intrahepatic fat content (%) 2.2 ± 1.0* 1.5 ± 0.7
T1DM. To test this hypothesis, liver fat content could be
Fasting lipid oxidation (mg·kg–1/min) 0.8 ± 0.4* 1.5 ± 0.7
measured and compared between groups of pan­creatic
Insulin (pmol/l) 62 ± 46 44 ± 13 transplant recipients with portal drainage and pancre-
EHI (pmol/l) 60 ± 30* 94 ± 27 atic venous drainage, respectively, to determine whether
Glucagon (ng/l) 81 ± 52 84 ± 21 liver fat content is increased in the portal drainage group,
but such studies have not yet been performed. How­ever,
Glugagon:EHI ratio 1.7 ± 1.2* 0.9 ± 0.4
hepatic fat content, as measured by CT scan, has been
*Statistically significant difference versus controls. Abbreviations: EHI, estimated hepatic insulin; T1DM,
type 1 diabetes mellitus. assessed in patients with T2DM who required continu-
ous ambulatory peritoneal dialysis; five of eight patients
treated with peritoneal insulin had hepatic subcapsular
steatosis compared with none of the patients on subcuta-
neous insulin.64 No equivalent study has been carried out
in patients with T1DM.
Double
diabetes Effects on CHD risk
Double diabetes mellitus could have either an additive
or synergistic effect on CHD risk (Figure 2). Theoretical
patient profiles can be drawn up that help to predict
CHD risk in patients with double diabetes mellitus and
I have suggested four possible profiles on the basis of
clinical observations (Table 2). For example, patients who
are resistant to the adverse vascular effects of chronic
hyperglycaemia and are protected from abnormal lipid
partitioning by reduced liver fat content and an anti­
Resistant to Prone to Resistant to Prone to
glucotoxicity glucotoxicity glucotoxicity glucotoxicity
atherogenic lipid profile have a very low risk of CHD.
Normotensive Normotensive Hypertensive Hypertensive Con­versely, patients with T1DM who have a genetic
High HDL High HDL Low HDL Low HDL background that confers a poor defence against gluco­
toxic effects and have high levels of circulating non­
CHD risk esterified fatty acids and dyslipidaemia—caused by
Figure 2 | Proposed model of increasing coronary risk for patients with type 1 central obesity, increased liver fat and an atherogenic
diabetes mellitus. The risk of CHD is affected by factors such as resistance to lipid profile—have a high risk of CHD (Table 2).
glucotoxicity, obesity, HDL cholesterol and hypertension (excluding established The case for a synergistically increased CHD risk in
determinants of CHD risk: age, duration of diabetes mellitus and albuminuria). such individuals is illustrated by findings in a subgroup
Abbreviation: CHD, coronary heart disease. of 479 patients with T1DM enrolled in the DCCT. High
levels of LDL cholesterol modified by advanced glyca-
hepatic fatty acid oxidation is inhibited and the balance tion endproducts in circulating immune complexes con-
shifts to lipid storage as triglyceride is incorporated into ferred a 6.4-fold (95% CI 2.5–16.2-fold) increase in the
VLDL cholesterol. risk of high carotid intima–media thickness (a surrogate
Hepatic fat content in 19 patients with T1DM with marker for atherosclerosis).65 This observation might
low portal insulin levels (mean age 35 years, BMI represent an example of hyperglycaemia and abnormal
23 kg/m2, HbA1c 8.7%) was compared with a matched lipid partition­ing acting synergistically to accelerate
(for age and sex) control group without diabetes mel- vascular disease.
litus (Table 1).41 Patients with T1DM had significantly The largest prospective cohort of patients with T1DM
reduced intra­hepatic fat content on 1H magnetic reso- par­t icipated in the FinnDiane study. Measurement
nance spectro­scopy and increased fasting lipid oxida- of metabolic phenotypes, vascular complications and
tion. Fasting metabolic investigations and insulin clamp pre­mature deaths in a population of 4,197 patients fol-
studies showed that the estimated hepatic insulin level lowed up for 6.5 years, with 295 deaths, has yielded some
was lower and the glucagon:estimated hepatic insulin interest­ing results.66 The data were analysed to investi-
ratio was higher in patients than in control indivi­ gate associations between metabolic markers, diabetic
duals (Table 1).41 These results are consistent with the kidney disease, retinopathy, hypertension, obesity and
notion that low hepatic insulin exposure in patients with mortality. Two phenotypes seemed to be associated with
T1DM, along with glucagon stimulation, could shift the increased mortality: a combination of poor glycaemic
metabolic balance from lipid storage to oxidation.41 This control, an atherogenic lipid profile, central obesity and
pattern is the opposite to that observed in patients with insulin resistance; and a combination of raised HDL cho-
T2DM and might help to protect patients with T1DM lesterol levels, raised adipo­nectin levels, microvascular
from the pathological effects of fatty liver, such as an complications (especially albuminuria) and low BMI.

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 REVIEWS

Table 2 | Proposed management of patients with T1DM according to hypothetical cardiovascular risk profile
Parameter Patient 1* Patient 2* Patient 3* Patient 4*
Complications No microvascular Microalbuminuria and early No microvascular Microalbuminuria
complications retinopathy complications and early retinopathy
Physical Lean and active Lean and active Overweight and inactive Overweight and
inactive
Family history None None Yes (mother and aunt) Yes (father)
of T2DM
Daily insulin dose 40 U 47 U 95 U 106 U
Blood pressure 122/73 128/76 143/86 147/88
(mmHg)
HDL cholesterol 1.62 1.43 1.16 1.08
level (mmol/l)
10‑year estimated 1–2% 2–10% 2–10% 10–20%
CHD risk (Low) (Medium) (Medium) (High)
Clinical Potentially lower CHD risk Presence of albuminuria Resistant to glucotoxic Susceptible to both
observations than matched nondiabetic (which reflects endothelial effects, but developing glucotoxic effects
controls owing to favourable dysfunction) and retinopathy metabolic syndrome and atherogenic
liver physiology and (which reflects susceptibility to Would have been at risk dyslipidaemia
atheroprotective lipid profile glucotoxic effects) associated of developing T2DM in Likely to develop
Might have mild peripheral with increased CHD risk the absence of T1DM double diabetes
hyperinsulinaemia and No evidence of mellitus
insulin resistance accompanying dyslipidaemia
Expected to have good that could accelerate the
long-term survival atherosclerotic process
Recommendations Usual care Threshold for considering CHD Threshold for Early and aggressive
for management primary prevention therapy considering CHD primary targeting of CHD risk
lowered prevention therapy factors
Main focus should be on good lowered Main focus should
glycaemic control Main focus should be on be on education and
education and healthy healthy lifestyle
lifestyle modification modification
*Based on patients who were nonsmokers, 35 years of age, who had T1DM for 20 years and a HbA 1c level ~8%. Abbreviations: CHD, coronary heart disease;
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

One interpretation of these results is that when abnor-
mal lipid partitioning—a feature of both obesity and the
metabolic syndrome—is combined with gluco­toxicity,
a characteristic of microvascular complications, the
process of atherosclerosis is accelerated and the risk of
premature mortality is greatly increased. As the research-
ers noted in their discussion, “when these two �������
[pheno-
types] collide, the risk of death peaks.”66 The overlap in
these two pheno­types can be considered to represent
double diabetes mellitus.
Reversing insulin resistance in T1DM
Lifestyle intervention
Patients with T1DM who show signs of developing
T2DM should be identified and treated appropriately
to prevent further progression of T2DM-associated
complications (Box 2). The concept of double diabetes
mellitus should be discussed with the patient to encour-
age them to make appropriate lifestyle modifica­tions.
Modifications to treatments and targets could also
be considered.
Similarly to nondiabetic individuals, patients with
T1DM who have high levels of physical fitness tend to
have greater insulin sensitivity than those who are not
physically fit. In a study of 27 adolescents with T1DM,
maximal oxygen consumption during cycle ergo­metry
was significantly correlated with insulin sensitivity,
which was assessed by the euglycaemic clamp technique.67
Increased levels of physical activity might be expected,
therefore, to improve insulin sensitivity. Par­ticipation
in a 45 min exercise session three times per week for
12 weeks resulted in a 23% increase in insulin sensitivity
in nine adolescents with T1DM,68 but these individuals
demonstrated no significant improvement in glycaemic
control. In another study, seven patients who used insulin
pumps were compared with a non­diabetic control group.
Insulin sensitivity was 40% lower in patients than control
individuals at baseline, but after the patients completed a
6‑week exercise intervention (cycling for 1 h per day on
4 days of the week) this difference between the groups
disappeared, meaning that patients’ insulin sensitivity
increased by 60% in response to exercise.69 To study the
mechanism underlying this exercise-mediated improve-
ment in insulin sensitivity, muscle biopsy samples were
obtained from seven patients with T1DM before and
after the 6‑week exercise intervention, and were com-
pared with samples from control individuals and a group
of patients with T1DM who did not participate in the
exercise programme. Insulin receptor density and glyco­
gen synthase activity were lower in the patients with
T1DM than in control individuals at baseline; however
only glycogen synthase activity increased in the exercise
group, with an accompanying improvement in HbA1c and
re­duction in insulin dose requirement.70

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© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 2 | Managing patients with double diabetes mellitus
■■ Identify potential patients as early as possible
■■ Discuss the concept of double diabetes mellitus
with the patient and explain its potential importance
in terms of their risk of future cardiovascular
complications
■■ Focus on measures that promote a healthy lifestyle,
including advice on calorie reduction, increasing
exercise and activity levels and smoking cessation
■■ Consider lowering the threshold for initiation of primary
prevention of cardiovascular disease (blood pressure
and lipid levels)
■■ In some patients, consider a change in the insulin
regime or even a loosening of glycaemic targets to limit
central weight gain
Apart from potential improvements in glycaemia
and insulin sensitivity, exercise is associated with other
beneficial cardiovascular outcomes. Exercise increases
HDL cholesterol in patients with T1DM69,71 and reduces
other cardiovascular risk factors, such as LDL cholesterol
levels, blood pressure and waist circumference, as shown
in a study of 20 patients who participated in a 3-month
exercise programme.71
Little information is available on the potential effects
of diet on insulin resistance and other metabolic param-
eters in patients with T1DM. No studies have been pub-
lished on the effects of calorie-reduction diets, and only
one small crossover study has been conducted on the
effects of a low-fat, isocaloric diet in 10 patients with
T1DM.72 Insulin sensitivity, measured by the clamp tech-
nique, improved significantly in the patients assigned to
the low-fat diet but still remained 33% lower than in a
matched, nondiabetic control group.72
Metformin
A number of noncontrolled studies of metformin in
patients with T1DM reported that individuals receiving
this agent were able to reduce their insulin doses and
maintain a similar level of glycaemic control, which sug-
gested that this drug had an insulin-sensitising effect.73–77
A number of randomized, placebo-controlled trials have
since been conducted, using either a parallel-group or
crossover design,78–82 the largest of which had 100 partici-
pants.81 A systematic review that included these studies
on the use of metformin in patients with T1DM83 drew
four main conclusions: firstly, insulin dose decreased by
5–10 U daily in most studies; secondly, HbA1c decreased
by 0.6–0.9% in some studies; thirdly, participants’ weight
decreased by 1.7–6.0 kg in half of the studies; and,
fourthly, their cholesterol decreased by 0.3–0.41 mmol/l
in some studies. An earlier meta-analysis of these studies
drew similar conclusions.84 Metformin, therefore, has
considerable potential for both prevention and reversal
of the double diabetes mellitus phenotype.
Thiazolidinediones
Two studies have examined the use of thiazolidine­
diones in patients with T1DM. A randomized, placebo-­
controlled 6‑month trial of pioglitazone therapy in 35
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© 2012 Macmillan Publishers Limited. All rights reserved
adolescents with T1DM found no significant reductions
in either glycaemic control or insulin dose and a signifi-
cant BMI increase in patients who took thiazolidine­
diones. In addition, this treatment did not alter lipid
profiles.85 In a study with a similar design, conducted
in 50 overweight adult patients with T1DM, rosigli-
tazone use for 8 months was associated with reduced
insulin doses and reduced blood pressure.86 The largest
changes in these factors occurred in patients with the
greatest insulin resistance; both control groups and those
taking rosiglitazone experienced similar weight gains of
around 3 kg.
Conclusions
Patients with T1DM have a wide spectrum of macro-
vascular risk, and the evidence increasingly indicates
that glycaemic control only has a small role in predict-
ing an individual’s level of risk. The role of albumin­
uria as a marker of generalized endothelial dysfunction
and increased cardiovascular risk has been established.
Other factors being considered include obesity, markers
of insulin resistance, HDL cholesterol and intrahepatic
fat content.
Reducing the risk of premature cardiovascular dis­
ease in patients with T1DM might involve identifica-
tion of these risk factors at an early stage, and making
appropriate alterations to their management. These
changes could involve targeted lifestyle advice, includ-
ing encourage­ment to increase physical activity levels
and early use of primary prevention drugs, such as
statins and anti­hypertensive drugs, bearing in mind
that women of child-bearing age must have appropriate
advice on contra­ception before being prescribed statins
or angiotensin-converting-enzyme (ACE) inhibitors. In
some patients at particularly high cardiovascular risk,
for example those who experience substantial weight
gain as a complication of intensive insulin regimes,
relaxation of glycaemic targets might be appropriate to
facilitate manage­ment of their macro­vascular risk. Use
of metformin as an insulin-sensitizing agent could be
consider­ed in this context.
Clearly, further prospective studies, including interven-
tion trials, are required to explore the concept of double
diabetes mellitus. The outcomes of these studies will help
to improve the management of patients with T1DM and
reduce the burden of premature cardiovascul­ar events
and mortality in this setting.
Review criteria
OVID, MEDLINE and EMBASE were searched to identify
articles published between January 1980 and April
2011. Search terms included “type 1 diabetes”, “double
diabetes”, “insulin resistance”, “metabolic syndrome”,
“estimated glucose disposal rate”, “coronary heart
disease” and “cardiovascular risk”. In addition, citations
of key papers were explored for any additional relevant
studies. Finally, databases of authors and registry data
with a track record of publication in this area were used to
complete the search.
www.nature.com/nrendo

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