Complications of

Ty p e 1 D i a b e t e s
L. Yvonne Melendez-Ramirez, MD, Robert J. Richards, MD,
William T. Cefalu, MD*

KEYWORDS
 Type 1 Diabetes  Complications
 Retinopathy  Heart disease

The prevalence of diabetes is increasing worldwide, and the concern regarding the
number of new cases of diabetes relates to the development of chronic complications.
It has been recognized for years that the complications are a cause of considerable
morbidity and mortality worldwide and as such, negatively affect the quality of life in
individuals with diabetes with an increase in disability and death.1 Specifically, the
complications of diabetes have been classified as either microvascular (ie, retinop-
athy, nephropathy and neuropathy) or macrovascular (ie, cardiovascular disease
[CVD], cerebrovascular accidents, and peripheral vascular disease) (Table 1). In the
United States, diabetes is the leading cause of blindness and kidney failure in adults
aged 20 to 74 years and is implicated in approximately 60% of nontraumatic amputa-
tions. Adults with diabetes have an increased frequency and mortality from cardiovas-
cular disease. The total estimated financial burden of diabetes was $174 billion in 2007
and the cost to care for individuals with diabetes will only continue to increase dramat-
ically given the projected increase of 165% in new cases by the year 2050.1,2
In Type 1 Diabetes (T1D), the role of glycemic control in contributing to chronic
complications is not questioned and has been well established in epidemiologic
observations and prospective clinical studies. Complications are thought to be mainly
related to the degree of and length of exposure to hyperglycemia as assessed by
objective markers of glycemic control (ie, hemoglobin A1c [HbA1c] levels). As such,
standards of care are in place that are aimed to reduce the incidence and progression
of these complications by initiating early, aggressive treatment aimed at maintaining
a level of HbA1c as close to normal as possible as shown by the Diabetes Control
and Complications Trial (DCCT).3,4 Yet, despite tighter control of hyperglycemia, it

Support: None.
Joint Program on Diabetes, Endocrinology and Metabolism, Louisiana State University Health
Sciences Center School of Medicine, New Orleans, and the Pennington Biomedical Research
Center, Baton Rouge, LA, USA
* Corresponding author. Section of Endocrinology, Department of Medicine, Louisiana State
University School of Medicine, 1542 Tulane Avenue, New Orleans, LA 70112.
E-mail address: william.cefalu@pbrc.edu

Endocrinol Metab Clin N Am 39 (2010) 625–640

doi:10.1016/j.ecl.2010.05.009 endo.theclinics.com
0889-8529/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
626 Melendez-Ramirez et al

Table 1
Complications of diabetes

Ophthalmologic Neuropathic Nephropathic Cardiovascular

Retinopathy Sensory neuropathy Microalbuminuria Coronary heart
Moderate Acute sensory Macroalbuminuria disease
nonproliferative neuropathy Chronic kidney Cerebrovascular
retinopathy Chronic sensorimotor disease disease
Mild diabetic peripheral Peripheral vascular
nonproliferative neuropathy disease
retinopathy Focal and multifocal
Severe neuropathies
nonproliferative Autonomic neuropathy
retinopathy Cardiovascular
Proliferative autonomic
retinopathy neuropathy
Glaucoma Gastrointestinal
Cataracts neuropathy
Genitourinary
neuropathy

is apparent that other factors contribute to the development beyond glycemic control
in many individuals.4 For example, the role of proinflammatory and procoagulation
cascades as well as genetic variability and how they interact with the metabolic abnor-
malities is being further elucidated in the development of the vascular complications of
diabetes. A deeper understanding of these mechanisms will eventually translate into
clinical interventions that will further impact the prevention of diabetes complications.
A listing of complications related to T1D and clinical practice recommendations to
address the complications have been published in detail.3 For purposes of this article,
the authors focus on a brief review of the major complications.

BIOCHEMICAL AND MOLECULAR PATHWAYS OF DAMAGE

Given the data from prospective clinical research trials, elevated glucose levels are
thought to be the most important etiologic factor in the pathogenesis of microvascular
damage in T1D.4–7 It can be argued that all cells of the body are exposed to elevated
glucose levels in T1D; however, not all cells develop the changes associated with
vascular injury. The cells of the capillary endothelium of the retina, the mesangial
cell in the glomerulus, and the Schwann cells of the peripheral nerves are vulnerable
to the elevated extracellular concentration of glucose because they cannot efficiently
regulate the transport of glucose into the cell, leading to intracellular hyperglycemia,
which induces intracellular mechanisms that result in damage.8 The mechanisms by
which glucose induces the biochemical and metabolic changes that cause abnormal-
ities in the tissues, such as increasing endothelial permeability resulting in protein and
plasma extravasation, are not completely understood. Several mechanisms to explain
the development of the microangiopathy seen in diabetes have been proposed. In an
interesting review of the topic, Brownlee8 has reported on the mechanisms by which 4
biochemical and molecular pathways contribute to hyperglycemia-induced tissue
damage. These pathways were described as involving increased polyol flux, formation
of advanced glycation end products, activation of protein kinase C (PKC), and
increased flux through the hexosamine pathway.8 Even though the previously
 Complications and Diabetes 627

mentioned pathways were established in the pathogenesis of diabetic complications

and multiple animal experimental studies showed that inhibition of the individual path-
ways resulted in prevention of microvascular damage to the cells of the nerves, retina,
and kidney, clinical trials where single pathways were blocked proved to be disap-
pointing.8–12 Also, how these pathways interacted or were activated in relation to
the common injury of hyperglycemia was not understood. However, a hypothesis
unifying all these pathways as a common downstream effect of overproduction of
superoxide-anion by the mitochondrial electron transport chain was proposed
(Fig. 1).8

METABOLIC MEMORY

One of the strongest predictors of microvascular complications during the DCCT was
the A1c value at study entry, which reflected the glycemic control before randomiza-
tion. It was suggested that prior glycemic control exerted a long-term effect on the
development of diabetic complications.5 Following the active clinical intervention of
the DCCT, the cohort was followed longitudinally as the DCCT/EDIC (Epidemiology
of Diabetes Interventions and Complications).13 During the DCCT/EDIC cohort
follow-up study, a statistically significant decrease in the rate of microvascular and
cardiovascular complications was noted in the previously intensively treated cohort
years after the completion of the DCCT. This decrease occurred despite the fact

Fig. 1. Potential mechanism by which hyperglycemia-induced mitochondrial superoxide

overproduction activates 4 pathways of hyperglycemic damage. Excess superoxide partially
inhibits the glycolytic enzyme, GAPDH, thereby diverting upstream metabolites from glycol-
ysis into pathways of glucose overutilization. This overutilization results in increased flux of
dihydroxyacetone phosphate (DHAP) to DAG, an activator of PKC, and of triose phosphates
to methylglyoxal, the main intracellular advanced glycation end product (AGE) precursor.
Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine increases modification
of proteins by O-linked N-acetylglucosamine (GlcNAc) and increased glucose flux through
the polyol pathway consumes NADPH and depletes GSH. (From Brownlee M. Biochemistry
and molecular cell biology of diabetic complications. Nature 2001;414:813–20; with
permission.)
628 Melendez-Ramirez et al

that there was no significant difference between measured A1c levels between treat-
ment groups during the observation period.4,5,7,14 The convergence of the A1c during
the observational period essentially meant that any difference in the rate of develop-
ment of complications between the two groups would be the result of the early differ-
ences in glucose control achieved during the DCCT. The concept that an improvement
in glycemic control that is observed many years earlier results in a significant reduction
in the development of complications when assessed many years later is supported by
DCCT and DCCT/EDIC data in T1D and has been termed metabolic memory.15

MICROVASCULAR COMPLICATIONS
Retinopathy
One of the more disabling complications affecting quality of life for individuals with dia-
betes is the progressive loss of vision resulting from diabetic retinopathy. Diabetic reti-
nopathy is a highly specific vascular complication of both Type 1 and Type 2 diabetes
and the prevalence is highly associated to the duration of diabetes.16 Unfortunately,
this condition appears to represent the most frequent cause of new cases of blindness
among adults aged 20 to 74 years.16
Stages and development
The development of retinopathy has been described as occurring in at least 4
stages.17 It is described that at the initial stage microaneurysms (ie, small areas of
balloon-like swelling in the retina’s tiny blood vessels) occur. This stage is referred
to as mild nonproliferative retinopathy. As the disease progresses, some blood
vessels that nourish the retina are blocked leading to moderate nonproliferative reti-
nopathy. As the process continues, many more blood vessels are blocked, depriving
several areas of the retina with their blood supply. These areas of the retina send
signals to the body to grow new blood vessels for nourishment leading to a stage
referred to as severe nonproliferative retinopathy. The final and most advanced stage
is referred to as proliferative retinopathy.17 At this advanced stage, the growth of new
blood vessels occur secondary to the signals sent by the retina for nourishment.
Unfortunately, the new vessels that are formed grow along the retina. However, given
that they are abnormal in that they have thin fragile walls, they are predisposed to leak
blood.16,17 At this stage, if there is no successful intervention, bleeding from vessels
can leak into the center of the eye resulting in severe vision loss and blindness can
be a resulting outcome. It has been described that fluid can also leak into the center
of the macula, making the macula swell and blurring vision (ie, macular edema).
Macular edema is reported to occur at any stage of diabetic retinopathy. In addition
to the previously mentioned conditions, other eye conditions, such as cataracts and
glaucoma, occur earlier and more frequently in people with diabetes.16
As previously outlined, the duration of disease is associated with the prevalence of
retinopathy. However, several other clinical factors increase the risk. As discussed in
the subsequent section, chronic hyperglycemia is a major factor and intensive therapy
to improve glycemia is a major objective.18 In addition to hyperglycemia, the preva-
lence of retinopathy appears to be related to both nephropathy19 and hypertension.20
To evaluate the relationship to clinical and metabolic factors, Klein and colleagues21
examined the 25-year cumulative progression and regression of diabetic retinopathy
(DR). Observations suggested that progression of DR was more likely with less severe
DR, male sex, higher glycosylated hemoglobin, an increase in glycosylated hemo-
globin level, and an increase in diastolic blood pressure level from the baseline to
the 4-year follow-up.21 An increased risk of incidence of proliferative diabetic retinop-
athy was associated with higher glycosylated hemoglobin, higher systolic blood
 Complications and Diabetes 629

pressure, proteinuria, greater body mass index at baseline, and an increase in the gly-
cosylated hemoglobin between the baseline and 4-year follow-up examinations.
Lower glycosylated hemoglobin and male sex, as well as decreases in glycosylated
hemoglobin and diastolic blood pressure during the first 4 years of follow-up, were
associated with improvement in DR.21

Screening
One of the more important aspects of care for individuals with T1D is the timely detec-
tion and treatment of underlying eye conditions. As such, it is imperative that providers
are vigilant regarding standards of care as related to suggested screening guidelines.
Standards of care in this regard have been recommended by the American Diabetes
Association3,16 (ADA) in its yearly Clinical Practice Guidelines. The current recommen-
dations as suggested by the ADA are that adults and children aged 10 years or older
with T1D have an initial dilated and comprehensive eye examination by an ophthalmol-
ogist or optometrist within 5 years after the onset of diabetes.16 Examinations should
be performed by an ophthalmologist or optometrist who is knowledgeable and expe-
rienced in diagnosing the presence of diabetic retinopathy and is aware of its manage-
ment. It is also recommended that subsequent examinations be repeated annually.
The suggested examinations may be less frequent (ie, every 2–3 years following one
or more normal eye evaluations by a qualified provider).16

Management
The successful treatment of retinopathy should be based on treating the underlying
metabolic conditions that contribute to the development of the retinopathy and effec-
tively treating the specific abnormalities identified in the eye. As such, intensive dia-
betes management with the goal of achieving near normoglycemia is considered
one of the most important aspects of treatment. Improvement in glycemia has clearly
been shown to prevent or delay the onset and progression of diabetic retinopathy in
individuals with both Type 1 and Type 2 diabetes.4–7,22,23 Given these findings, the
provider caring for patients with T1D will suggest insulin regimens that may include
multiple injections on a background of basal therapy or may suggest insulin pump
therapy if indicated. Clinical regimens that address both premeal and postmeal
glucose are needed to achieve the desired glycemic goals. Patients and providers
should have a clear understanding of the suggested A1c goal and communication
should be in place with the diabetes support team to achieve the goal. In addition
to glycemia, addressing blood pressure is recommended to decrease the progression
of retinopathy.24
A second aspect of prevention and treatment of retinopathy is to effectively address
any specific abnormality already present in the eye. Specifically, the provider should
promptly refer patients with any level of macular edema, severe nonproliferative dia-
betic retinopathy (NPDR), or any proliferative diabetic retinopathy (PDR) to an ophthal-
mologist who is knowledgeable and experienced in the management and treatment of
diabetic retinopathy.16 Diabetic retinopathy may occur first in the peripheral retina,
which can only be adequately examined by an eye professional. The patient requires
dilation and the examiner must use the hand lens. Laser photocoagulation may be
indicated in the treatment for the individual with T1D.
It is now well established that laser photocoagulation surgery has considerable efficacy
in the effective prevention of diabetic retinopathy. In this regard, both the Diabetic Reti-
nopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS),25,26
two large scale clinical trials, provide considerable data supporting the tremendous clin-
ical benefits of photocoagulation surgery. In the DRS,25 Panretinal photocoagulation
630 Melendez-Ramirez et al

surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to
6.4% in treated eyes. It appeared that the greatest benefit was observed among subjects
whose baseline evaluation revealed high-risk characteristics, such as disc neovasculari-
zation or vitreous hemorrhage.25 Panretinal laser surgery is primarily recommended for
eyes with PDR approaching or having high-risk characteristics.
Another major trial (ETDRS26) established the benefit of focal laser photocoagulation
surgery in eyes with macular edema. This study demonstrated a reduction of doubling
of the visual angle (eg, 20/50–20/100) from 20% in untreated eyes to 8% in treated
eyes. The ETDRS also verified the benefits of panretinal photocoagulation for high-
risk PDR, but not for mild or moderate NPDR. In older-onset patients with severe
NPDR or less-than-high-risk PDR, the risk of severe vision loss or vitrectomy was
reduced 50% by early laser photocoagulation surgery at these stages.
Thus, the results of both trials demonstrate that laser photocoagulation surgery was
beneficial in reducing the risk of further vision loss. However, the data suggest that
laser photocoagulation was generally not beneficial in reversing already diminished
acuity. These observations are critically important and given the fact that patients
who have findings consistent with retinopathy or macular edema may be asymptom-
atic, the importance of screening, early detection, and effective treatment can have
a significant effect to improve quality of life for the individual with T1D by preventing
further vision loss.
As outlined earlier, there have been tremendous advances made in the intervention
and management of retinopathy in individuals with T1D. However, it still appears that
the cumulative rates of diabetic retinopathy and incidence of diabetic retinopathy is
high. Specifically, Klein and colleagues21 reported high 25-year cumulative rates of
progression of DR and incidence of PDR (ie, 25-year cumulative rate of progression
of DR was 83%, progression to PDR was 42%, and improvement of DR was
18%).27 However, they also reported lower risk of prevalent PDR in more recently
diagnosed persons, which possibly reflects improvement in care over the period of
the study.21 Additional evidence that management strategies may be working to
reduce progression to diabetic retinopathy has come from a meta-analysis reported
by Wong and colleagues.27 A total of 28 studies comprising 27,120 subjects with dia-
betes (mean age 49.8 years) were included. After 4 years, pooled incidence rates for
PDR and severe vision loss (SVL) were 11.0% and 7.2%, respectively. Rates were
lower among participants in 1986 to 2008 than in 1975 to 1985. After 10 years, similar
patterns were observed. Participants in the 1986 to 2008 studies had lower propor-
tions of PDR and non-PDR at all time points than participants in 1975 to 1985 studies.
The investigators concluded that since 1985, patients with diabetes have lower rates
of progression to PDR and SVL. These findings may reflect an increased awareness of
retinopathy risk factors; earlier identification and initiation of care for patients with reti-
nopathy; and improved medical management of glucose, blood pressure, and serum
lipids. Differences in baseline characteristics, particularly in the prevalence and
severity of retinopathy, could also have contributed to these temporal differences.27

Nephropathy
Another major complication of diabetes that develops secondary to metabolic abnor-
malities is diabetic nephropathy. Nephropathy has been reported to occur in 20% to
40% of patients with diabetes and is the single leading cause of end-stage renal
disease.16,28 Generally, diabetic nephropathy is defined on clinical grounds as an
increased urinary albumin excretion in the absence of other renal diseases.16 As
currently suggested, the earliest stage of diabetic nephropathy in T1D is microalbumi-
nuria defined as albumin excretion of 30 to 299 mg/24 h, and is a marker for
 Complications and Diabetes 631

development of nephropathy in Type 2 diabetes.16 Microalbuminuria is important on

clinical grounds because it is also a well-established marker of increased CVD
risk.29,30 A more advanced stage of nephropathy (ie, macroalbuminuria) represents
persistent albuminuria in the range of greater than or equal to 300 mg/24 h.16 End-
stage renal disease is increased if patients with microalbuminuria progress to albumin
excretion rates consistent with macroalbuminuria.16
Diabetes nephropathy is known to be associated with increased risk of death,
mainly from cardiovascular causes.28 As is now well established, hyperglycemia,
hypertension, and genetic predisposition are the main risk factors for the development
of diabetic nephropathy.28 In addition, other risk factors, such as elevated serum
lipids, smoking, and dietary protein intake, provide a contribution.16,28 The importance
of the recognition of nephropathy at each stage of albuminuria is related to clinical
characteristics. Specifically, Gross and colleagues28 provided suggested clinical
characteristics to be expected at each stage of observed urine albumin excretion
(Table 2). Given the clinical significance of the findings, it is imperative that providers
understand the screening guidelines for detection of nephropathy.

Screening
To screen for diabetic kidney disease, urine albumin excretion is considered the
essential test and cornerstone of diagnosis. Currently, for patients with T1D, it is rec-
ommended that the provider obtain a urine albumin excretion in individuals with T1D

Table 2
Diabetic nephropathy stages

Cutoff Values of Urine Albumin for Diagnosis and Main Clinical Characteristics
Stages Albuminuria Cutoff Values Clinical Characteristics
Microalbuminuria 20–199 mg/min Abnormal nocturnal decrease of
blood pressure and increased blood
pressure levels
30–299 mg/24 h Increased triglycerides, total and LDL
cholesterol, and saturated fatty
acids
30–299 mg/ga Increased frequency of metabolic
syndrome components
Endothelial dysfunction
Association with diabetic retinopathy,
amputation, and cardiovascular
disease
Increased cardiovascular mortality
Stable GFR
Macroalbuminuriab R200 mg/min Hypertension
R300 mg/24 h Increased triglycerides and total and
LDL cholesterol
>300 mg/ga Asymptomatic myocardial ischemia
Progressive GFR decline

Abbreviations: GFR, glomerular filtration rate; LDL, low-density lipoprotein.

a
Spot urine sample.
b
Measurement of total proteinuria (R500 mg/24 h or R430 mg/L in a spot urine sample) can
also be used to define this stage.
Data from Gross JL, de Azevedo MJ, Silveiro SP, et al. Diabetic nephropathy: diagnosis, preven-
tion, and treatment. Diabetes Care 2005;28(1):164–76.
632 Melendez-Ramirez et al

starting 5 years after diagnosis or earlier in the presence of puberty or poor metabolic
control.16 Screening for microalbuminuria can be performed by measurement of the
albumin-to-creatinine ratio in a random spot collection. A serum creatinine should
also be obtained at least annually in all adults with diabetes regardless of the degree
of urine albumin excretion and is used to estimate glomerular filtration rate (GFR) and
to stage the level of chronic kidney disease.
In the past, GFR has been measured by specific techniques, such as inulin clear-
ance, 51Cr-ethylenediaminetetraacetic acid, 125I-iothalamate, and iohexol.31 In addi-
tion, the clearance of endogenous creatinine has been commonly used although
there are recognized limitations.32 In clinical practice, GFR can be estimated by
prediction equations that take into account serum creatinine concentration and
some or all of the following variables: age, sex, race, and body size.28 Estimated
GFR (eGFR) is commonly co-reported by laboratories or can be estimated using
formulae, such as the Modification of Diet in Renal Disease (MDRD) study equation.33
Specifically, the recommended equation by the National Kidney Foundation is that of
the MDRD, which calculates GFR as follows: GFR (ml $ min 1 $ 1.73 m 2) 5 186 
(serum creatinine [mg/dl] 1.154  age [years] 0.203  [0.742 if female]  [1.210 if
African American]).33 Another way to calculate GFR is by the Cockroft-Gault equation
(ie, creatinine clearance [ml/min] 5 [(140 age (years)]  weight [kg]/[72  serum
creatinine (mg/dl)  (0.85 if female)]).34 Recent reports have indicated that the
MDRD is more accurate for the diagnosis and stratification of chronic kidney disease
(CKD) in patients with diabetes than the Cockcroft-Gault formula.34 The level of GFR,
in addition to information on abnormal urine albumin excretion, can then be used to
stage the degree of CKD (Table 3).

Management
The screening procedures previously outlined are important when one considers
whether the treatment regimen will be primarily one of prevention of kidney disease
or one that will consist of aggressive treatment to prevent further progression of kidney
disease. The general principles involved for the prevention of diabetic nephropathy are
effective treatment of its known risk factors contributing to diabetic nephropathy (ie,
hypertension, hyperglycemia, smoking, and dyslipidemia).16,28 If patients are found

Table 3
Stages of chronic kidney disease

GFR (ml/min per 1.73 m2

Stage Description Body Surface Area)
1 Kidney damagea with normal or R90
increased GFR
2 Kidney damagea with mildly decreased 60–89
GFR
3 Moderately decreased GFR 30–59
4 Severely decreased GFR 15–29
5 Kidney failure <15 or dialysis
a
Kidney damage defined as abnormalities on pathologic, urine, blood, or imaging tests.
Data from American Diabetes Association. Standards of medical care in diabetes - 2010. Diabetes
Care 2010;33:S11–63; and Levey AS, Coresh J, Balk E, et al. National Kidney Foundation. National
Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and
stratification. Ann Intern Med 2003;139:137–47.
 Complications and Diabetes 633

to have evidence of nephropathy, the goal of treatment would then be one to prevent the
progression from micro- to macroalbuminuria, to attenuate the decline of renal function
in patients with macroalbuminuria, and to reduce the occurrence of cardiovascular
events. In general, the strategy for treatment is similar to the strategies of prevention,
but involve multiple and more intensive strategies.28 The goals of management include
achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg
or <125/75 mmHg if proteinuria is >1.0 g/24 h and increased serum creatinine), using
drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating
dyslipidemia (low-density lipoprotein [LDL] cholesterol <100 mg/dL).16 These strate-
gies appear to be effective for preventing the development of microalbuminuria, in
delaying the progression to more advanced stages of nephropathy, and in reducing
cardiovascular mortality in patients with Type 1 and Type 2 diabetes.

Intensive blood glucose control The value of intensive blood glucose control cannot
be understated in the management of patients when trying to prevent progression
to microalbuminuria or progression of microalbuminuria. Landmark studies, such as
the Diabetes Control and Complications trial, have demonstrated that A1c levels
less than 7% are associated with decreased risk for clinical and structural manifesta-
tions of diabetic nephropathy in patients with Type 1 diabetes.4–7 Intensive treatment
of diabetes reduced the incidence of microalbuminuria by 39%. The benefit of the
intensive intervention in patients randomized to strict glycemic control appeared to
have a long-lasting effect. Specifically, there was a reduction of approximately 40%
in the risk for development of microalbuminuria and hypertension 7 to 8 years after
the end of the DCCT.35 Thus, based on the evidence, insulin regimens should be
designed to achieve the best glucose control while minimizing hypoglycemia in
patients. As suggested for individuals with retinopathy, use of intensive insulin regi-
mens (ie, basal/bolus therapy) with multiple insulin injections or insulin pumps needs
to be strongly considered.

Intensive blood pressure control Effective treatment of blood pressure abnormalities

is also a major strategy for both prevention and treatment of nephropathy. Treatment
of hypertension, as well described, has been shown to reduce the risk of cardiovas-
cular and microvascular events in patients with diabetes. With specific regard to indi-
viduals with T1D, about 40% of patients with Type 1 diabetes with normoalbuminuria
have been reported to have blood pressure levels greater than 140/90 mmHg.28 But
hypertension is common in patients with diabetes, even when renal involvement is
not present.28
The American Diabetes Association has also outlined in detail the recommendations
for treatment of high-normal blood pressure (systolic or diastolic blood pressure
consistently above the 90th percentile for age, sex, and height). It is currently recom-
mended that patients with diabetes be treated to a systolic blood pressure less than
130 mm Hg and to a diastolic blood pressure less than 80 mmHg.16 According to the
published guidelines, patients with a systolic blood pressure of 130 to 139 mmHg or
a diastolic blood pressure of 80 to 89 mmHg may be given lifestyle therapy alone for
a maximum of 3 months. If after 3 months the targets are not achieved, patients should
be advanced to treatment with pharmacologic agents. Lifestyle therapy for hyperten-
sion consists of weight loss if patients are overweight, and incorporating a Dietary
Approaches to Stop Hypertension (DASH)-style dietary pattern, including reducing
sodium and increasing potassium intake, moderation of alcohol intake, and increased
physical activity.16 It has also been recommended by the ADA that patients with more
severe hypertension (systolic blood pressure R140 mmHg or diastolic blood pressure
634 Melendez-Ramirez et al

R90 mmHg) at diagnosis or follow-up should receive pharmacologic therapy in addi-

tion to lifestyle therapy.
Current recommendations suggest that therapy for patients with diabetes and
hypertension be paired with a regimen that includes either an angiotensin-
converting (ACE) inhibitor or an angiotensin II receptor blocker (ARB). If one class is
not tolerated, the other should be substituted.16 If needed to achieve blood pressure
targets, consideration of diuretics may be in order and prescribed based on efficacy
given the measured GFR. As is well known for treatment of hypertension, multiple
drug therapy (2 or more agents at maximal doses) may be required to achieve blood
pressure targets.16 In addition to effective glucose and blood pressure control, it has
also been suggested to reduce protein intake to 0.8 to 1.0 g/kg body wt 1/day 1 in
individuals with diabetes and the earlier stages of CKD and to 0.8 g/kg body wt 1/
day 1 in the later stages of CKD.16 Also, when ACE inhibitors, ARBs, or diuretics
are used it is important to monitor serum creatinine and potassium levels for the devel-
opment of acute kidney disease and hyperkalemia. Finally, the provider caring for
patients with T1D should consider referral to a specialist experienced in diabetic
nephropathy when there is uncertainty about the etiology of kidney disease, if there
are difficult management issues, or if advanced kidney disease is present.16

Neuropathy
The diabetic neuropathies represent a heterogeneous group of disorders and the
specific neuropathic abnormality can present with diverse clinical manifestations.
Neuropathies may be present clinically as either focal or diffuse processes. The
most common neuropathic disorders are chronic sensorimotor diabetic peripheral
neuropathy (DPN) and autonomic neuropathy.16 As any provider who cares for individ-
uals with T1D will attest, DPN is viewed an extremely common disorder. Clearly,
because of the degree and type of presentation, estimates of the prevalence will
vary, but it is reported that at least 20% of adult patients with diabetes may present
with at least one manifestation of DPN.36 The etiologies of DPN are multiple, but the
condition has been associated with several modifiable and nonmodifiable risk factors,
including the degree of hyperglycemia, lipids, blood pressure, and diabetes dura-
tion.36 The prevalence data for diabetic autonomic neuropathy (DAN) has been
reported to range from 1.6% to 90% and clearly is dependent on the test used to
assess the condition. In addition, the differences in populations examined and type
and stage of disease play major roles in defining the prevalence.36 As reported, risk
factors for the development of DAN include diabetes duration, age, and long-term
poor glycemic control. DAN is also associated with factors predisposing to macrovas-
cular events (ie, hypertension and dyslipidemia).

Screening
The recognition and effective treatment of neuropathy is important at preventing
further loss in sensory function and improving the quality of life for patients with
T1D. The reasons for doing so are multiple but include the fact that up to half of indi-
viduals with DPN may be asymptomatic, and as such, may be at high risk for injury to
the foot.36 It is recognized that amputations are increased following a foot injury, so
early recognition and management is crucial. Current recommendations suggest
that providers screen all patients for distal symmetric polyneuropathy at diagnosis
and at least annually thereafter using simple clinical tests. Specifically, it is recommen-
ded that the provider assess patients with use of tests, such as pinprick sensation,
vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensa-
tion at the distal plantar aspect of both great toes and metatarsal joints, and
 Complications and Diabetes 635

assessment of ankle reflexes.16,36 It has been reported that by using combinations of

more than one test, sensitivity in detecting DPN can be as high as 87%.36 Further, it is
important to note that a loss of 10-g monofilament perception and reduced vibration
perception may actually predict foot ulcers.36 Electrophysiological testing is rarely
needed, except in situations where the clinical features are atypical.16
For the individual with T1D, screening for signs and symptoms of autonomic
neuropathy should be instituted at 5 years after the diagnosis.37 Further, autonomic
neuropathy can potentially involve most, if not all, systems in the body. Thus, the
specific symptoms and signs of autonomic dysfunction should be evaluated with
a careful history, and appropriately assessed and documented during the physical
examination. As suggested, special testing may not be needed and may not affect
management or outcomes.37 Cardiovascular autonomic neuropathy is the most clin-
ically important form of diabetic autonomic neuropathy because it is clearly a risk
factor for cardiovascular disease.38 A suggested diagnosis may be made clinically
by demonstrating resting tachycardia (>100 bpm) or orthostasis changes in blood
pressure. Gastrointestinal neuropathies should be evaluated with detailed history
that may uncover symptoms suggestive of esophageal enteropathy and gastropare-
sis. For example, patients should be specifically questioned regarding symptoms,
such as bloating after meals, explosive diarrhea and alternating constipation, and
vomiting of previously ingested food. If gastroparesis is suspected, gastric emptying
studies using double-isotope scintigraphy may be considered but in many cases, the
test results may correlate poorly with clinical symptoms.37 Diabetic autonomic
neuropathy may present clinically with symptoms suggestive of genitourinary tract
disturbances. For example, erectile dysfunction or retrograde ejaculation in men
may be caused by diabetic autonomic neuropathy. Recurrent urinary tract infections,
pyelonephritis, incontinence, or a palpable bladder may indicate the need for an eval-
uation of bladder dysfunction.

Management
Diabetic peripheral neuropathy Given the tremendous morbidity that can be caused
secondary to significant clinical neuropathy, one of the primary strategies in the
management of the individual with T1D is the prevention of neuropathy. We now
have definitive evidence from landmark studies, such as the DCCT, that the risk for
DPN and autonomic neuropathy can be significantly decreased with improved glyce-
mic control over a sustained time.4–6 Unfortunately, unlike for glycemic control, there
is a paucity of data regarding control of other risk factors and prevention of neuropathy
in T1D. But in general, improved lipid and blood pressure control, smoking cessation,
and avoidance of excessive alcohol consumption are already recommended as
preventive strategies for other diabetic complications.16,36,37
If patients are found to have DPN, the first step is not different from the overall
management strategy for retinopathy and nephropathy because the primary goal is
to obtain optimal glycemic control.36,39,40 Although there is not definitive evidence
from clinical trials and data is obtained from observational studies, it is thought that
control of extreme blood glucose fluctuations, in addition to improved glycemic
control, may reduce neuropathic symptoms.16,37 There are also practice recommen-
dations suggesting that patients with DPN may benefit clinically from pharmacologic
intervention. Examples of drugs that have been used have been tricyclic drugs, such
as amitriptyline, nortriptyline, and imipramine. Although tricyclic drugs may be useful,
the side effects may limit their use and compliance. Anticonvulsants, such as gaba-
pentin, carbamazepine and pregabalin, have been shown to be effective. Gabapentin
is shown to be effective for neuropathic pain and is reported to be one of the most
636 Melendez-Ramirez et al

commonly prescribed anticonvulsants for this purpose. Pregabalin has also been
confirmed to be useful in painful diabetic neuropathy in a randomized controlled trial.41
In addition, the 5-Hydroxytryptamine and norepinephrine uptake inhibitor duloxetine is
now indicated for use in DPN,16 and substance P inhibitor capsaicin cream has also
been used. It is important to note that with the exception of duloxetine and pregabalin,
none of the other pharmacologic classes are specifically licensed for the management
of painful DPN.
Autonomic neuropathy The treatments for autonomic neuropathy are generally
geared to the specific organ and tissue affected. For example, clinical symptoms,
such as postural hypotension and dizziness, may be treated with mechanical
measures or a trial of pharmacologic agents. Gastroparesis may be treated with
frequent small meals and prokinetic agents. Erectile dysfunction may be treated
with psychological counseling, sildenafil, vardenafil, tadalafil, prostaglandin E1 injec-
tion, device, or prosthesis.16 Given the multiple abnormalities and the complexity of
the condition, the reader is strongly encouraged to consult the latest recommenda-
tions by the American Diabetes Association.16

MACROVASCULAR COMPLICATIONS

In contrast to microvascular disease, macrovascular complications have been less

studied and less is known about the specific determinants of disease particular to
T1D. However, as observed for individuals with Type 2 diabetes mellitus, macrovas-
cular complications in T1D impart significant morbidity and mortality. In contrast to
the general population, the macrovascular complications in T1D occur much earlier
in life, have a more diffuse, accelerated course and have a higher mortality, especially
in those aged less than 40 years.
There are several studies that have been published over the recent years that
provide an estimate of the incidence of cardiovascular disease in T1D. In the Pitts-
burgh Epidemiology of Diabetes Complications study (EDC), men and women with
T1D were shown to have a similarly increased risk of premature coronary artery
disease (CAD), although risk factors (predictors) appeared to vary by both sex and
type of CAD manifestation.42 It was also confirmed how clinically important renal
abnormalities were as a predictor, especially in men.43 In addition, hypertension,
smoking, and dyslipidemia were observed to be CAD predictors in T1D.43 One of
the more interesting findings as suggested from the Pittsburgh EDC study and the
DCCT was the observation that insulin resistance, the hallmark of Type 2 diabetes,
may also relate to CAD risk in T1D.44,45 Specifically, the data suggested all factors pre-
dicting total CAD or angina have been linked to insulin resistance.42
Other studies have demonstrated the risk for CVD is also increased for a primarily
African American cohort with T1D.46 Six-year incidence of any CVD was significantly
associated with older age and longer duration of diabetes when assessed at baseline.46
In addition, it was established that baseline older age, higher body mass index, higher dia-
stolic blood pressure, proteinuria, retinopathy severity, and being depressed were signif-
icant and independent risk factors for incidence of any CVD in this cohort. Thus, it is
apparent that regardless of race, CVD risk appears to be high in individuals with T1D.46
Evaluation and Management
As recently reviewed,47 the approach to glycemic control and its primary effect on
CVD outcomes was stated to be controversial. However, the observations suggest
clear benefit over a long-term period of observation resulting from intensive manage-
ment of glycemia as evidenced from the DCCT/EDIC.48 In fact, a 57% reduction in
 Complications and Diabetes 637

cardiovascular events was noted. As reviewed by Orchard and Costacou,47 it was

suggested that glycemia plays a significant role in the early atherogenic development
of lesions, a conclusion consistent with recent evidence from the Veterans Affairs Dia-
betes Trial (VADT) in Type 2 diabetes, showing that any cardiovascular mortality
benefit from intensification of glycemic therapy is limited to those diagnosed with dia-
betes 15 or fewer years earlier.
An important management strategy for individuals with T1D is the control of tradi-
tional risk factors as would be expected in the management for individuals with
Type 2 diabetes. As previously outlined, traditional risk factors appear to assist the
clinician in deciding what patients with T1D are at risk. Evidence of this comes from
observations from the EURODIAB study.49 Specifically, clinical risk factors, such as
waist-hip ratio, blood pressure, and dyslipidemia, contributed to the overall cardiovas-
cular mortality as did the presence of the complications (eg, albuminuria, retinopathy,
neuropathy).49 As reviewed, a major limitation for management of CVD in T1D is that
there is no risk engine developed in the general population or in individuals with Type 2
diabetes that is appropriate for T1D because of the younger age of diabetes onset and
interactions with complications, especially renal disease.47,50 However, work is under
way on developing a T1D cardiovascular disease risk engine.47
It has been suggested that other factors, such as genetic variation, may help identify
susceptible individuals in being predisposed to CVD. In recent years, there has been
great excitement with the haptoglobin (Hp) genotype.47 This genotype may help char-
acterize susceptible individuals with Type 2 diabetes.47,51 The potential role of this
genotype was evaluated in individuals with T1D as part of the Pittsburgh EDC study
of childhood onset T1D.52 It was observed that after statistical adjustment for traditional
CVD risk factors, a 2-fold greater risk was observed for individuals noted to carry the Hp
2-2 genotype as compared with those carrying the Hp 1-1. Clearly, such data provides
exciting new possibilities that allow a clinician to assess risk for individuals with T1D.
When one now considers what subject with T1D is at risk, we still have considerable
gaps in knowledge. However, over the past few years there have been significant new
findings. We do know that individuals with T1D with abnormalities in traditional risk factors
must be considered at high risk, and in particular, the presence of retinopathy and neurop-
athy increases the risk for CVD. It is also suggested that certain genotypes now put
patients at increased risk. For the clinician to design a regimen to reduce risk, intensive
glycemic control is clearly indicated as is control of dyslipidemia and blood pressure.

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