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

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

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Cardiovascular risk factors in T1DM Box 1 | Potential features of double diabetes mellitus
Prospective cohort studies of macrovascular event inci-
Double diabetes mellitus should be considered in patients
dence in patients with T1DM have some common find- with T1DM accompanied by the following features:
ings. Age and duration of diabetes mellitus are clearly ■■ Relatively high total daily insulin doses are required to
important drivers of coronary heart disease (CHD) achieve glycaemia targets33
events and mortality.17 After correction for these vari- ■■ Family history of type 2 diabetes mellitus, especially if
ables, however, the main risk factor is albuminuria. In two or more relatives are affected33,34
the Pittsburgh EDC prospective cohort study, involving ■■ Progressive weight gain, especially associated
with central adiposity, while receiving insulin
658 patients who were followed up for nearly 20 years,
treatment10,35,36,58
mortality in patients with T1DM without albuminuria
■■ Hypertension (even if borderline)35
was not significantly different to that in a control popula- ■■ Low estimated glucose disposal rate (a surrogate
tion, emphasising the importance of this risk marker.18 measure of insulin resistance)35,36
Similar results have been reported in the FinnDiane ■■ Low HDL cholesterol levels (compared with high levels
study, in which over 4,000 patients with T1DM were typically found in patients with T1DM)17
followed up for 7 years. In the subgroup without albu- Abbreviation: T1DM, type 1 diabetes mellitus.
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 incidence of cardio­vascular events in the intensively
in T1DM cohorts, probably because BMI exhibits a treated group, especially in the patients who took met-
U‑shaped relationship with mortality in this setting. formin,27 but overall, in patients with T2DM, intensive
Con­founding influences that lead to a low BMI include glycaemic control might only confer a minimal improve-
smok­i ng, nephropathy and autonomic neuropathy, ment in macrovascular outcomes, and could in certain
which are all associated with increased mortality in circumstances be harmful. Moreover, HbA1c measure-
patients with T1DM.20 ments only reflect the average glycaemic control over
The degree to which established cardiovascular risk the preceding 3 months rather than the cumulative
factors, such as hypertension, hypercholesterolaemia and total glucose exposure, which could be more relevant
smoking should be addressed in patients with T1DM than short-term exposure to long-term cardiovascular
depends on the threshold of absolute cardiovascular outcome. Furthermore, HbA1c levels do not reflect the
risk used to prompt treatment. All patients with T1DM variability of glucose levels, which are a robust predictor
who smoke should be encouraged to quit and be given of cardiovascular outcome28 and coronary artery calcifi-
adequate assistance. In patients aged >40 years, standard cation, a surrogate measure of cardiovascular outcome.29
risk calculators could be appropriate to guide the use of HbA1c levels were not an independent predictor of hard
primary prevention therapy such as anti-­hypertensive (that is, permanent or irrevocable) CHD events in
drugs and statins, using a threshold of 15–20% 10-year either the Pittsburgh EDC cohort 30 or the EURODIAB
cardiovascular risk. However, in a generally younger cohort.31 Interestingly, glycaemia status is better for the
population of patients who have T1DM with a wide prediction of stable occlusive peripheral vascular disease
spectrum of cardiovascular risk, the difficulty is to than embolic vascular complications, 32 which raises
identify those who should receive early and aggressive the intriguing question of whether glucose-unrelated
primary prevention therapy. Given the importance of factors, such as lipid abnormalities, might contribute
albuminuria as an indicator of generalized vascular to the pathophysiology of coronary plaque rupture
dysfunction,21,22 it is advisable to treat these traditional in T1DM. Of course, patients with T2DM are usually
risk factors aggressively, possibly even in patients with older and generally have a higher prevalence of hyper­
sustained microalbuminuria who are aged 20–40 years. tension and dyslipidaemia than patients with T1DM,
and these comorbidities are considered the predominant
Applying knowledge of T2DM to T1DM drivers of macrovascular disease in T2DM.
Several large glucose-lowering trials in patients with
T2DM were published in 2008‑2009. 23 Over 25,000 Double diabetes mellitus
patients were recruited to the Action to Control Cardio­ The term ‘double diabetes mellitus’ is not new. It was first
vascular Risk in Diabetes (ACCORD) trial, Action in used in 1991 to account for the observation that patients
Diabetes and Vascular Disease: Preterax and Diamicron with T1DM who had a family history of T2DM often
Modified Release Controlled Evaluation (ADVANCE) required higher insulin doses to achieve similar glycae-
trial and Veterans Affairs Diabetes Trial (VADT).24–26 mic control targets than those without a family history of
Despite an aggressive approach to lowering HbA 1c to T2DM (Box 1).33 The more penetrant the family history
<7.0%, their results showed no statistically significant (that is, the higher the number of family members with
reduction in cardiovascular events. The ACCORD diabetes mellitus), the higher the insulin dose required,
study had to be stopped early because of increased which indicated underlying resistance to its effects. The
mortality in the intensively treated group, which was hypothesis emerged that a subgroup of patients with
probably attributable to an increased frequency of T1DM existed who were at risk of developing T2DM in
hypoglycaemia. A 10-year follow-up of participants in later life but would never be diagnosed as having T2DM
the UK Prospective Diabetes Study showed a reduced because they had already developed hyperglycaemia as a

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result of T1DM. These patients might, therefore, accrue predictive of microvascular events, a finding that is also
additional cardiovascular disease risk, beyond that supported by data on the incidence of retinopathy and
expected if they had T1DM alone. Whether this risk is nephropathy in the EURODIAB study.37
simply additive or more complex (that is, synergistic) is In a 2011 study, insulin sensitivity in patients with
not clear. T1DM was measured directly using the clamp tech-
Assessing the insulin dose needed in patients with nique.38 Patients with T1DM were more insulin-resistant
T1DM and/or their family history of T2DM is unlikely (6.2 mg·kg–1/min) than control individuals (12.7 mg·kg–1/
to provide accurate, adequate screening to identify this min), and this measurement also correlated significantly
high-risk subgroup of patients, although if the patient with the volume of coronary artery calcification, a surro-
has more than one first-degree relative with T2DM gate measure of atherosclerosis. In the same study, coro-
their CHD risk seems to be fivefold higher than if no nary artery calcification was not associated with HbA1c.38
relatives have T2DM.34 In clinical practice, insulin dose As this study demonstrated, insulin resistance is a feature
is unreliable for identification of patients with double of T1DM even in the absence of obesity and metabolic
diabetes mellitus, not only because it is inaccurately syndrome, a finding that has been consistently demon-
reported by patients, but also because individuals with strated in the literature over the past 30 years.39,40 This
T1DM have varying amounts of residual endogenous association is based on evidence from clamp and tracer
insulin secretion, which contributes to their glycaemic studies, in which hepatic glucose output and peripheral
control, and also reduces peripheral hyperinsulinaemia glucose uptake (mainly in skeletal muscle) were meas-
and insulin resistance (S. J. Cleland, unpublished obser- ured directly in response to systemic insulin infusion.39,40
vation). For this reason, more reliable tests are required However, reduced insulin-mediated glucose uptake in
for epidemiologic­al and clinical purposes. patients with T1DM might be predominantly driven by
abnormal lipid partitioning, rather than by dysfunctional
Pathogenetic factors insulin–glucose signalling. This notion is supported by
The vasculotoxic effects of T1DM could be accelerated the consistent demonstration of increased rates of lipo­
in patients who also have central obesity and insulin lysis (usually secondary to the effects of insulinopaenia on
resistance produced by a combination of genetic and adipocytes and hepatocytes) with consequent increased
lifestyle factors. These factors might help to explain why levels of circulating nonesterified fatty acids and intra­
such vari­ability in the risk of CHD occurs in patients myocellular lipid.41–43 Furthermore, patients with T1DM
with T1DM. have increased peripheral hyper­insulinaemia compared
with individuals without diabetes mellitus, owing to sub-
Insulin resistance cutaneous injection of exogenous insulin, which might
The gold standard test for measuring insulin resistance exacerbate peripheral insulin resistance, partly through
is the euglycaemic hyperinsulinaemic clamp, although downregulation of insulin receptors44 and GLUT‑4, the
this procedure is impractical for routine use in clinical main intracellular insulin-mediated glucose transporter
practice because it requires specialist research facilities in skeletal muscle. 45 In addition, supra­physiological
and takes >3 h to perform. However, this measurement insulin levels have long been known to cause adverse
was made in 24 patients participating in the Pittsburgh cardiovascular effects, such as sodium retention, vascu-
EDC prospective study,35 and used to generate a best-fit lar smooth muscle hypertrophy and sympathetic nervous
model of insulin sensitivity on the basis of readily acces- system stimulation, and any associated vascular insu­
sible patient data, which has been proposed as a surro- lin resistance might cause raised blood pressure due to
gate measurement of the whole-body estimated glucose blunted insulin-mediated peripheral vaso­dilata­tion.16,46
disposal rate (eGDR).35 Patients with double diabetes mellitus could, there­
The performance of eGDR as a surrogate marker of fore, have multiple causes of insulin resistance with a
insulin resistance was tested in 603 patients with T1DM c­onsequent elevation of cardiovascular disease risk.
(baseline age 28 years and disease duration 19 years) who
were followed up over 10 years.30 During this period 109 HDL cholesterol levels
CHD events occurred, of which 42 were hard events. A Patients with T1DM generally have high HDL cho-
number of independent predictors of hard CHD events lesterol levels and normal levels of total cholesterol. A
were revealed, including eGDR, disease duration, group of 19 patients with T1DM (mean age 35 years,
nephropathy, non-HDL cholesterol levels and leukocyte HbA1c 8.7%, and BMI 23 kg/m2) were compared with a
count. HbA1c was not predictive of hard CHD events. carefully matched (for age and sex) nondiabetic control
In support of this finding, eGDR was retrospectively group. The mean HDL cholesterol level of the case
calculated from data on participants in the DCCT–EDIC patients was 1.32 mmol/l, compared with 1.22 mmol/l
trial, but using BMI instead of waist:hip ratio.36 A high in control indivi­duals. 41 In addition, the cholesterol
eGDR was a significant predictor of both cardio­vascular esterification rate is higher in patients with T1DM than
events (HR 0.70, 95% CI 0.56–0.88) and any macro­ in control indivi­duals for a given level of tri­glycerides,
vascular event (HR 0.83, 95% CI 0.73–0.96). Total insulin which possibly explains why the patients’ HDL cho-
dose, however, was not predictive of these outcomes, lesterol concentration is increased. 47 Furthermore,
underlining its unreliability as a surrogate measure of phospholipid transfer protein (PLTP) activity is mark-
insulin resistance. Interestingly, a high eGDR was also edly raised in patients with T1DM and this activity

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correlates with HDL cholesterol levels. Which factors activity) because exogenous insulin is delivered subcu-
regulate, or are associated with, PLTP activity is not yet taneously. As a result, the HDL cholesterol content of
known, but candidates include hepatic triacylglycerol lipoprotein particles is preserved.
lipase (also known as hepatic lipase [HL]), lipoprotein Three studies have confirmed that HL activity is
lipase, p­hosphatidylcholine-sterol acyltransferase and reduced in patients with T1DM. In a study of 10 patients
cho­lesterol ester transfer protein.48 In the EDC trial, with T1DM, HL activity was significantly lower in the
patients with TIDM who experienced CHD events had patients than in a group of matched control indivi­duals
lower HDL cholesterol levels than those who had no (39.6 ± 35.2 U/l versus 87.0 ± 27.1 U/l).56 In another
CHD events (1.31 mmol/l versus 1.42 mmol/l). However, study, HL activity increased in patients with T1DM who
no significant difference in HDL cholesterol levels was switched from subcutaneous insulin to intraperitoneal
detected when similar analyses were carried out on insulin, and this change was associated with decreased
patients in the DCCT–EDIC and EURODIAB cohorts. levels of HDL2 cholesterol and increased levels of HDL3
In all three cohorts, however, triglycerides and LDL cho- cholesterol.57 In a subgroup of 61 DCCT participants,
lesterol levels were consistently increased in the patients increased HL activity accounted for most of the associa-
with coronary events.17 Interestingly, albuminuria was tion between increased intra-abdominal fat stores and
associated with both reduced HDL cholesterol levels 49 decreased HDL2 cholesterol levels in multivariate analy-
and raised triglyceride levels, 50,51 but whether these ses; furthermore, HbA1c levels were not associated with
as­sociations represent causal relationships is unclear. any of these parameters.58 The results from this study
The ‘Golden Years’ cohort comprises 400 patients with also suggest that increased HL activity in conjunction
T1DM for at least 50 years.52 Detailed characteristics of with central weight gain in patients with T1DM could
this cohort were published in 2003.53 The mean age be important in switching the lipid profile to an athero-
of the patients at the time of this report was 69 years, genic pattern that resembles the dyslipidaemia of T2DM.
and the mean age at diagnosis was 14 years. In general, It is tempting to speculate, therefore, that T1DM confers
their BMI was normal (mean 25 kg/m2) and, compared an atheroprotective phenotype due to reduced hepatic
with younger patients with T1DM, their insulin dose was insulin exposure and the subsequent beneficial effects
rela­tively low (0.52 U/kg), which is consistent with low on lipid profile.
under­lying levels of insulin resistance. Albuminuria was A number of studies in patients with T1DM on
evi­dent in 36% of patients, and antihypertensive drugs perito­neal dialysis who received insulin by the portal
were prescribed to 29%. The most striking finding, vein route also support these findings. In all patients,
how­ever, was a very high HDL cholesterol level (mean despite this administration route seeming to offer a
1.84 mmol/l). Possible reasons for this finding include more physio­logical method of delivering insulin than
genetic factors (these patients tended to have long-lived subcutaneous injec­tion, serum lipid profiles switched
parents), high physical activity levels and moderate to an atherogenic pat­tern, with significant reductions in
alcohol consumption. HDL cholesterol and increases in the LDL cholesterol:
These studies clearly show that high levels of HDL HDL cholesterol ratio.57,59–61
cholesterol (which are traditionally regarded as ‘pro- The advent of pancreatic transplantation provides
tective’ from CHD) are present in most patients with another potential model to test these ideas. In a study of
T1DM, but that a subgroup of patients who go on to 44 patients with T1DM who received simultaneous pan-
develop premature CHD tend to have decreased levels of creas and kidney transplants, the lipid profile changed
HDL cholesterol associated with increased triglycerides after transplantation to a more atherogenic pattern in
and LDL cholesterol levels, resembling the atherogenic the group with portal drainage rather than pancreatic
dyslipidaemia characteristic of patients with T2DM. venous drainage (namely, higher total cholesterol, LDL
cholesterol and triglyceride levels but lower HDL cho-
Hepatic triacylglycerol lipase lesterol levels). This change reflected increased hepatic
Studying portal vein insulin levels could provide some insulin exposure.62
insight into why HDL cholesterol levels (and hence
cardio­v ascular risk) differ so much in patients with Hepatic fat content and metabolism
T1DM and those with T2DM. In patients with T2DM, In patients with obesity, metabolic syndrome and T2DM,
portal vein insulin levels are usually high because the pathological significance of nonalcoholic fatty liver
increased secretion is required to overcome insulin disease has been emerging.63 Strong associations are
resistance and high portal insulin levels result in high evident between intra-abdominal fat, intrahepatic fat,
hepatic exposure to this hormone. Insulin stimulates an atherogenic lipid profile, atherosclerosis and systemic
the activity of HL, which facilitates the exchange of inflammation (measured by levels of C‑reactive protein,
tri­glycerides for LDLs (mediated by cholesteryl ester IL‑6 and TNF). In the liver, hyperinsulinaemia promotes
transfer protein), resulting in a reduction in the HDL deposition of fat and stimulates expression of sterol regu­
cholesterol content of lipoprotein particles. The end latory element-binding protein 1c (SREBP1c), which has
result is the low HDL cholesterol levels that are observed a crucial role in the regulation of hepatic tri­glyceride
in individuals with central obesity, metabolic syndrome accumulation.54 Enzymes involved in de novo lipo­genesis
and T2DM.54,55 By contrast, patients with T1DM have (namely fatty acid synthase and acetyl-­coenzyme A car-
low portal vein insulin levels (and, therefore, low HL boxylase) are activated by SREBP1c, and in parallel,

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

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

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