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Treatment strategy for type 2 diabetes

from the perspective of systemic vascular
protection and insulin resistance
This article was published in the following Dove Press journal:
Vascular Health and Risk Management
3 July 2012
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Kazunori Utsunomiya Abstract: This paper provides an update on the mechanisms of vascular impairment associated
Division of Diabetes, Metabolism and with insulin resistance and the pathogenesis of diabetic nephropathy and peripheral artery disease
Endocrinology, Jikei University School (PAD). It also considers the optimal treatment strategies for systemic vascular protection in light
of Medicine, Tokyo, Japan of recent findings. This area is of major clinical importance given the ongoing global epidemic
of type 2 diabetes and the pivotal role played by insulin resistance in the mechanism of vascular
impairment that manifests as macroangiopathy and microangiopathy. Timely diagnosis and
intervention is critical in patients with systemic arteriosclerotic disease. Therefore, treatment
strategies are aimed not only at targeting the presenting pathology, but also at reducing the risk
of cardiovascular events. These efforts can help reduce the risk of both cardiovascular events
and mortality. Treatment for PAD includes pharmacotherapy, endovascular treatment, and
vascular reconstruction, along with exercise therapy. Because PAD can cause ischemia in the
lower extremities, typical drug approaches include use of vasodilators and antiplatelet agents.
Beraprost sodium and cilostazol are common choices in Japan, and their risks and benefits are
discussed. Of note, beraprost has several therapeutic properties, including vascular endothelial
protection, and antiplatelet and anti-inflammatory effects, in addition to vasodilatory activity.
In patients with PAD, these activities improve the pathological process in the lower extremi-
ties and reduce the incidence of systemic vascular events. Recent preclinical findings indicate
that beraprost improves not only ischemic extremities through its vasodilatory properties, but
also reduces the insulin resistance which affects vascular endothelium. In this way, beraprost
may contribute to an overall systemic vascular protective action. The use of agents, such as
beraprost, which are capable of improving insulin resistance and resulting vascular endothelial
function at an earlier disease stage, may ultimately contribute to increasing the life expectancy
of patients with PAD.
Keywords: peripheral artery disease, insulin resistance, beraprost, vascular, protection

Introduction
In recent years, close links have gradually been revealed between insulin resistance
and the pathogenesis of a number of diseases. Vascular complications of diabetes
can be largely classified into macroangiopathy, eg, cardiovascular disease, stroke,
and peripheral artery disease (PAD), and microangiopathy, eg, diabetic nephropathy.
These two classes of diseases have traditionally been regarded as the result of dif-
Correspondence: Kazunori Utsunomiya
Division of Diabetes, Metabolism and ferent pathological mechanisms. However, the findings of recent research efforts
Endocrinology, Jikei University School show that these diseases share insulin resistance as the common primary pathological
of Medicine, Tokyo, Japan
Tel +81 3 3433 1111
pathway. The purpose of this review is to update physicians about recent progress
Email [email protected] on the mechanisms of vascular impairment associated with insulin resistance and

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the pathology of diabetic nephropathy and PAD, and to with cardiovascular disease (Figure 1). In contrast with
discuss current therapeutic strategies for systemic vascular type 1 ­diabetes, vascular complications arise from highly
protection. complicated pathophysiology in type 2 diabetes where vascu-
lar damage due to an insulin-resistant state can be worsened
Paradigm shifts by diabetes-induced hyperglycemia.
Diabetic vascular complications consist of microangiopathy
causing abnormalities at the capillary level, and macroan- PAD as a cardiovascular risk factor
giopathy which is primarily the result of arteriosclerosis. PAD is a macroangiopathy that can develop as arterio-
Macroangiopathy is associated with pathophysiological sclerotic progresses, suggesting a strong causal relation
conditions, including insulin resistance and metabolic with insulin resistance. This is supported by study findings
syndrome,1–3 whereas microangiopathy, including diabetic showing that the higher the HOMA-IR (homeostatic model
nephropathy, is considered to be vascular failure secondary to assessment of insulin resistance) value becomes, the more
hyperglycemia. As such, the pathophysiological mechanisms the prevalence of PAD increases to a clinically significant
of these two types of vascular disease have been tradition- extent (Figure 2).6 PAD is a peripheral vascular disease
ally recognized as different. This is true in the case of type 1 involving ischemia to the lower extremities followed by
diabetes, where only a hyperglycemic state contributes to the intermittent claudication and ultimately necrosis during
development of diabetic nephropathy. However, recent studies progression of the disease. This typically requires amputa-
have clearly demonstrated that accumulation of clinical traits tion of the affected extremity, which invariably compro-
in the metabolic syndrome (MetS) (Figure 1) could be a risk mises patient quality of life to a devastating extent. This
factor for development of chronic kidney disease (CKD), macroangiopathy is characterized not only by substantial
suggesting a contribution of insulin resistance to progression deterioration in quality of life secondary to lower extremity
of CKD.4 It was also recently been reported that mice lacking ischemia, but, also importantly, by a poor prognosis and a
insulin receptors in glomerular podocytes show glomerular worse long-term outcome.7
­sclerosis.5 These findings suggest that insulin resistance may During the time course of development of PAD, along with
play a crucial and common pathophysiological role not only symptomatic PAD, less intensive, asymptomatic conditions
in cardiovascular disease, ie, macroangiopathy, but also in are also associated with a high incidence of cardiovascular
CKD, ie, microangiopathy. events (Figure 3).8 This underscores the necessity of timely
Diabetes is a major cause of CKD, but the risk for CKD diagnosis and earlier treatment intervention because these
may already be elevated during the prediabetes phase asso- efforts can greatly determine the extent of any reduction in
ciated with insulin resistance, as is known to be the case risk of both cardiovascular events and mortality. These fac-

[Microangiopathy] [Microangiopathy]
Cardiovascular Diabetic
disease CKD nephropathy
Risk

MetS Diabetes mellitus

Pathological progression
Figure 1 Risk of disease aggravation with diabetes progression.
Abbreviations: CKD, chronic kidney disease; MetS, metabolic syndrome.

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Dovepress Systemic vascular protection and insulin resistance

9
P trend = 0.037 (χ2 test)
8

PAD prevalence (%)

6
7.8%
5 (n = 891)

4 6.1%
(n = 827)
3 5.4%
5.0% (n = 802)
(n = 722)
2

0
<1.08 1.08–1.86 1.86–3.34 >3.34

HOMA-IR

Figure 2 Relationship between insulin resistance and PAD.

Reena L, et al. Circulation. 2008;118:33–41. © 2008 Wolters Kluwer Health.
Abbreviations: HOMA-IR, homeostatic model assessment of insulin resistance; PAD, peripheral artery disease.

tors indicate that insulin-resistant patients should be checked Furthermore, a separate study into the possible relationship
for the possibility of PAD, followed by correct diagnosis and between CKD and PAD in Asian patients revealed that the
appropriate treatment. prevalence of PAD increases with CKD progression stage.
In addition to the earlier discussion on the potential rela- Patients with concurrent CKD and PAD demonstrated
tionship between CKD and insulin resistance, a correlation elevated cardiovascular mortality and an overall mortality
between PAD and CKD has also, and perhaps more intrigu- higher compared with patients with either PAD alone or CKD
ingly, been established. Data from the US National Health alone, indicating that the complication of CKD in the pres-
and Nutrition Examination Survey conducted from 1999 to ence of PAD may strongly increase the risk of cardiovascular
2002 documented that a reduction of estimated glomerular disease (Figure 5).10
(eGFR) (Figure 4) filtration rate, especially below 60 mL/ Overall, these findings illustrate a strong association
min/1.73 m2 (the diagnostic threshold for CKD stage 3), between PAD and CKD, both of which share the common
markedly increased the risk of developing PAD (Figure 4).9 underlying pathophysiology of insulin resistance leading to

1.0

0.9
Event-free survival

0.8

0.7

No PAD/unknown
Asymptomatic PAD
0.6
Symptomatic PAD

0.5
0 1 2 3 4 5
Time after baseline (year)

Figure 3 Life expectancy in PAD patients.

Diehm, et al. Circulation. 2009;120:2053–2061. © 2008 Wolters Kluwer Health.
Abbreviation: PAD, peripheral artery disease.

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431
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Utsunomiya Dovepress

0.6
eGFR (given by simplified MDRD equation)

eGFR (serum cystatin C, univariate)

eGFR (serum cystatin C, multivariate)

PAD prevalence
0.4

0.2

15 30 45 60 75 90 105 120 135

eGFR (mL/min/17.3 m2)

Figure 4 Relationship between eGFR levels and PAD prevalence.

Selvin E, et al. Eur Heart J. 2009;30:1918–1925. © 2010 SAGE Publications.
Abbreviation: PAD, peripheral artery disease; eGFR, estimated glomerular filtration rate.

vascular impairment. This fact warrants not only a therapeu- for improvement of intermittent claudication in patients
tic approach targeting PAD, but also effective and timely with PAD.12
management of cardiovascular risk in patients with systemic Treatment with a phosphodiesterase 3 inhibitor is also
arteriosclerotic disease. indicated to prevent recurrence in the post-cerebral infarction
stage, and is positioned as a compound effective for vascular
Drugs for PAD and approaches protection in the brain and lower extremities. ­However, of
to vascular protection note, phosphodiesterase 3 also exists abundantly in myo-
Current treatment for PAD includes drugs, endovascular cardial cells and, therefore, requires caution with regard to
treatment, and vascular reconstruction, in addition to possible adverse events, such as arrhythmia. It should be
exercise therapy. Because PAD causes ischemia in the noted that beraprost is derived from an endogenous substance,
lower extremities secondary to arteriosclerotic stenosis prostaglandin I2, and has several therapeutic properties,
and occlusion, typical drug approaches include vasodila- including vascular endothelial protection and antiplatelet
tors and antiplatelet agents. In Japan, frequent choices are and anti-inflammatory effects, in addition to vasodilatory
beraprost and cilostazol, amongst others.11 Table 1 provides activity.13 In PAD, the clinical benefits of beraprost include
a list of oral agents currently used in the clinical setting in improving impaired circulation in the lower extremities.14
Japan. Cilostazol is a phosphodiesterase 3 inhibitor, and is The role of beraprost is in reduction of the incidence of sys-
recommended by the TASC-II PAD treatment guideline temic vascular events, as demonstrated by meta-analysis of

38.5
40 All -cause death

35 Cardiovascular death

30 P < 0.001 (chi-squared test)

23.5
Death (%)

25
19.0 18.5
20

15 12.5 12.0
10.5
10
5.6
5

0
CKD + PAD PAD alone CKD alone Non-complicated
complication (n = 651) (n = 398) CKD/PAD
(n = 287) (n = 2,274)

Figure 5 Relationship between CKD/PAD complication and cardiovascular death.

Luo Y, et al. Vasc Med. 2010;15:107–112. © 2010 SAGE Publications.
Abbreviations: CKD, chronic kidney disease; PAD, peripheral artery disease.

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 Table 1 Oral drugs of PAD
Nonproprietary Trade Pharmacological Indication Dosage and administration
class PAD Other (for adult)
Dovepress

ASO TAO
Beraprost Dorner Oral prostacyclin 1) Improvement of ulcer, pain, and feeling 2) Primary pulmonary 1) 120 μg/day in three doses postprandially
sodium Procylin derivative product of coldness associated with PAD hypertension 2) 60 μg/day in three doses postprandially
dose escalation: in case of dose
escalation, thrice to four times/day up to
a daily maximum dose of 180 μg
Cilostazol Pletal Antiplatelet Improving ischemic symptoms secondary Inhibiting recurrence A dose of 100 mg for twice a day, with
to PAD, such as ulceration, pain, and coldness in post-cerebral infarction phase adjustment as needed
(except cardioembolic form)

Vascular Health and Risk Management 2012:8

Sarpogrelate Anplag 5-HT2 blocker Improving ischemic symptoms accompanying A dose of 100 mg for thrce a day
hydrochloride PAD, such as ulceration, pain, and coldness postprandially, with adjustment
as needed
Ticlopidine Panaldine Antiplatelet 1) Improving ischemic symptoms accompanying 2) Treating thrombosis/embolism 1) 300–600 mg in two to three doses
hydrochloride PAD, such as ulceration, pain and coldness and improving circulatory postprandially, with dose adjustment as
impairment secondary to needed
vasculopathy and extracorporeal 2) 200–300 mg in two to three doses
circulation postprandially, with dose adjustment as
3) Treating thrombosis/embolism needed
secondary to ischemic cerebrovascular 3) 200–300 mg in two to three doses
impairments (transient ischemic attack postprandially, with dose adjustment as
or TIA, or stroke) needed; a single dose is possible in the
4) Improving circulatory impairments case of 200 mg dose a day
associated with cerebrovascular 4) 300 mg in three doses postprandially,
spasm secondary to subarachnoid with dose adjustment as needed
cerebral hemorrhage
Limaprost Opalmon Oral prostaglandin 1) Improving ischemic 2) Improving subjective symptoms 1) 30 μg/day in three doses
alfadex Prorenal E1 derivative symptoms (pain, numbness in lower 2) 15 μg/day in three doses
product accompanying extremities) and ambulatory
TAO, such as function associated with
ulceration, acquired lumber spinal stenosis
pain and coldness (patients with normal SLR
testing, presenting with bilateral
intermittent claudication)
Ethyl- Epadel EPA product 1) Improving ischemic 2) Hyperlipidemia 1) 600 mg for three times a day
eicosapentaenoic symptoms accompanying postprandially, with dose adjustment as
acid ASO, such as ulceration, needed
pain and coldness 2) 600 mg for three times a day

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postprandiallyIn case of abnormal
triglycerides, increase dose up to
900 mg three times a day

433
Systemic vascular protection and insulin resistance

Abbreviations: ASO, arteriosclerosis obliterans; PAD, peripheral artery disease; EPA, eicosapentaenoic acid; TAO, thromboangiitis obliterans; SLR, straight leg raise.
Utsunomiya Dovepress

two double-blind, placebo-controlled studies. This analysis improved insulin transfer into skeletal muscles. These
included 594 patients who received beraprost and 590 who studies also demonstrated that beraprost not only improves
received placebo. Primary endpoints were defined as vascular ischemic extremities through its vasodilatory properties,
events, including lower limb deterioration and cardiovascu- but also reduces insulin resistance which affects vascular
lar and cerebrovascular events. The statistical analysis was endothelium, suggesting that beraprost may contribute to
performed using the Mantel-Haenszel Chi-square test based an overall systemic vascular protective action.
on intent to treat. The results showed that the risk ratio was One of the traditional goals of treatment for PAD is
0.608 (P = 0.012), demonstrating the beneficial effect of to improve the classical symptoms, including intermittent
beraprost on all vascular events.15 This effect is attributed to claudication and a sensation of coldness. Recent research
the multimodal pharmacodynamic properties of beraprost has indicated that PAD, even in the earlier asymptomatic
related to its antiplatelet activity and vascular endothelial stages, may increase the risk for cardiovascular diseases,
protection. underlying the importance of efforts not only to allevi-
A recent animal study demonstrated that insulin signaling ate the symptoms of PAD, but also to reduce the risks for
in vascular endothelium greatly contributes to insulin sensi- cardiovascular disease. In view of the strong association
tivity in peripheral skeletal muscles (Figure 6), and therefore between microangiopathy, macroangiopathy, and insulin
to pathogenesis of microangiopathy and macroangiopathy.16 resistance-induced vascular impairment or inflammation as
Kubota et al16 reported that reduced function of vascular discussed earlier, the focus of comprehensive treatment for
endothelium results in reduced insulin sensitivity; they PAD-induced vascular abnormalities should target not only
demonstrated that impaired insulin signaling in endothelial the site specifically affected, eg, the lower extremities, but
cells, due to reduced insulin receptor substrate 2 expression also the common underlying pathophysiology, specifically to
and insulin-induced phosphorylation of endothelial nitric improve the vascular endothelium and inhibit ­inflammation.
oxide synthase, caused attenuation of insulin-induced capil- This inclusive therapeutic approach has the potential to
lary recruitment and insulin delivery, which in turn reduced achieve the desired systemic vascular protection. In summary,
glucose uptake by skeletal muscle. Moreover, restoration of the use of drugs capable of improving insulin resistance and
insulin-induced phosphorylation of endothelial nitric oxide vascular endothelial function at an earlier stage of the disease
synthase in endothelial cells completely reverses reduction may ultimately contribute to increasing the life expectancy
in capillary recruitment and insulin delivery. Beraprost of patients with PAD. Therefore, consideration of their wider
ameliorated the permeability of skeletal capillaries and use at earlier stages of PAD is warranted.

Fat-rich food fed

Normal
mouse

Insulin- Insulin-
inducted inducted
Akt p Akt p p
Capillary
Vascular Phosphorylation
endothelium

eNOS eNOS
Interstitium activity activity

Capillary recruitment
: Insulin
: Insulin receptor

Interstitial insulin concentrations

(insulin transfer into
skeletal muscle)

Skeletal Glucose uptake

muscle

Figure 6 Insulin transfer from vascular endothelial cells to skeletal muscle.

Kubota T, et al. Cell Metab. 2011;13:294–307. © 2011 Elsevier.

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Dovepress Systemic vascular protection and insulin resistance

Insulin resistance

• Hyperglycemia • Hypertension •Dyslipidemia

Vascular impairment Common pathological treatment

Blood glucose control

ARB/ACEI
Statin
Prostacyclin

Microangiopathy Macroangiopathy

Nephropathy PAD
Retinopathy Cardiovascular disease
Neuropathy Stroke

Figure 7 Development of vascular impairment in insulin-resistant state and treatment.

Abbreviations: PAD, peripheral artery disease; ARB, angiotensin receptor blocker; ACEI, angiotensin converting enzyme inhibitor.

Insulin resistance-targeted suggest that insulin resistance is the link between overweight/
treatment approach obesity and the adverse clinical syndromes related to excess
Insulin resistance is a serious pathophysiological condition adiposity.17,18
which can result in impairment of the entire vasculature Therefore, it would seem logical to interrupt these nega-
irrespective of vessel size, and thereby cause diabetes- tive associations at an earlier stage of the disease process
induced vascular complications. In addition, recent research using a treatment approach that takes into consideration
has revealed that CKD is closely associated with cardio- the extra dimension of systemic vascular protection. The
vascular disease risk in the presence of PAD. As shown in conventional therapeutic approach emphasizes, first of
Figure 7, these complications share a common underlying all, management of blood glucose levels, as well as blood
pathological mechanism in the form of insulin resistance. pressure control by the use of angiotensin receptor blockers
Indeed, disorders such as hypertension, insulin resistance, and angiotensin-converting enzyme inhibi­tors along with
type 2 diabetes, obesity, and subsequent cardiovascular lipid management through the use of statin therapy. How-
disease are intertwined at a pathological level and currently ever, for vascular impairment induced by insulin resistance,
represent epidemics that pose a major public health challenge prostacyclins may now be considered alongside the conven-
worldwide. ­Meeting this challenge requires an understanding tional options. It is anticipated that ongoing studies and emerg-
of the interplay between adipose tissue and the vasculature. ing evidence will demonstrate yet further beneficial effects of
Macrovascular and microvascular dysfunction is important the prostacyclins on reducing the incidence of vascular events
not only in the development of obesity-related target organ at an earlier stage of the disease.
damage, but also in the development of cardiovascular risk
factors, including hypertension and insulin resistance.17,18
Disclosure
The authors report no conflicts of interest in this work.
It should be noted that in cardiovascular disease, type 2
diabetes and hypertension are characterized by resistance
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