Endothelial dysfunction in diabetes mellitus

Figures & data

Table 1 Clinical identification of the metabolic syndrome

Risk factor	Defining level
Abdominalobesity*(waistcircumference)†	Men >102cm
	Women >88 cm
Triglycerides	≥150 mg/dL
High-density lipoprotein cholesterol	Men <40 mg/dL
	Women <50 mg/dL
Blood pressure	≥130/85 mm Hg
Fasting glucose	≥110 mg/dL

Diagnosis is made when three or more of the risk determinants are present (Hsueh et al 2004).

Figure 1 Progression of endothelial dysfunction in relation the progression of insulin resistance (Hsueh et al 2004).

Figure 2 Pathophysiology of hyperglycemia induced endothelial dysfunction (DeVriese et al 2000).

Table 2A Role of various modalities of therapy on endothelial dysfunction

Reference	Treatment	Patient	Result on endothelial function
	Role of ACEI and ARBs
Mancini et al 1996	ACEI (most studies)	NIDDM, CAD	+EDVD
O’Driscoll et al 1997, ^Citation1999
Mullen et al 1998
Anderson et al 2000
Prasad et al 2000
Hornig et al 2001
Cheetham et al 2000	ARBs	NIDDM, CAD	Debated results
Hornig et al 2001
Hermann et al 2006	Quinapril 2 /12 Tx	24 pt. NIDDM,	↑insulin-stimulated endothelial function , ↑vascular adiponectin gene expression
Sato et al 2003	candesartan(4–12 mg-day)	30 pt. DM2, 12 wks treatment	clinically improves oxidant stress
Chaturvedi et al 2001	lisinopril	IDDM	Circulating plasma VEGF concentration is not strongly correlated with risk factor status or microvascular disease
Cheetham et al 2001	50 mg of losartan daily for 4 wks	NIDDM	↑NO-mediated dilation in the conduit vessels
Pieper et al 2000	temocapril	Diabetic rat	+EDVD
Arcaro et al 1999	Captopril 25 mg tid	IDDM	+EDVD in the femoral artery of normotensive microalbuminuric Pt.
O’Driscoll et al 1999	enalapril (10 mg twice daily / 4 wks	NIDDM	↑stimulated and basal NO-dependent endothelial function.
McFarlane et al 1999	perindopril 4 for 12 wk	IDDM	improve arterial endothelial function
Gasic et al 1999	Fosinopril (10 mg/day) for 12 wks	11 microalbuminuric NIDDM pt.	↓cVCAM-1 levels and ↓ microalbuminuria
Nielsen et al 1997	lisinopril 10–20 mg dialy for 12/12	43 hypertensive NIDDM pts	reno- and vasculoprotective properties in hypertensive NIDDM nephropathy pts.
Bijlstra et al 1995	perindopril 4–8 mg OD/ 6 /12	10 pt. NIDDM	+EDVD
	Role of glitazones and other oral hypoglycemic agents
Sourij et al 2006	pioglitazone (30 mg/day for 12 wks	NIDDM	+EDVD
Caballero et al 2003	troglitazone treatment for 12 wks	NIDDM	+EDVD
Forst et al 2005	pioglitazone	179 pt. NIDDM	+EDVD
(Pistrosch et al 2005)	Rosiglitazone for 12 wks	19 pt. NIDDM with. microalbuminuria	↓ glomerular hyperfiltration and NO Bioavailability and ↓end-organ damage
Hubacek et al 2004	Rotiglitazone	NIDDM	+EDVD
Pistrosch et al 2004
Tack et al 1998
Manzella et al 2005)	repaglinide (1 mg BID) for 4/12	16 pt. NIDDM	improves brachial reactivity and ↓ oxidative stress indexes.
Bengel et al 2005	nateglinide 120 mg t.i.d. 16 wks	47 pt. NIDDM	No effect myocardial blood flow
De Mattia et al 2003	Gliclazide for 12 wk	15 pt NIDDM	improves both antioxidant status and NO-mediated vasodilation
Katakam et al 2000	Metformin	NIDDM	+EDVD
Mather et al 2001

Table 2B Role of various modalities of therapy on endothelial dysfunction

Reference	Treatment	Patient	Result on endothelial function
	Role of statin and other lipid lowering agent
Fegan et al 2005	cerivastatin	11 pt. NIDDM	improvement in microvascular endothelial function
Beishuizen et al 2005	0.4 mg cerivastatin	250 pt. NIDDM	no effect on FMD in type 2 diabetes
Joyce et al 2004	Pravastatin, 40 mg per day /1/12	9 pt. IDDM	Improve (FMD)
Dalla Nora et al 2003	Atorvastatin for 1 year	25 pt. NIDDM	Improve (FMD)
van Venrooij et al 2002	30 wks’ Tx of atorvastatin 10 mg & 80 mg	133 pt. NIDDM	Did not reverse endothelial dysfunction.
van Etten et al 2002	4 weeks of 80 mg atorvastatin daily	23 pt. NIDDM	no effect on NO availability in forearm resistance arteries
Tan, Chow, Tam et al 2002	atorvastatin (10 mg daily for 3/12 followed by 20 mg daily for 312)	80 pt. NIDDM	+EDVD,(significant)
van de Ree et al 2001	6-week Tx with simvastatin 40 mg/daily	17 pt. NIDDM	No effect
Dumont et al 2001	Pravastatin (20 mg/kg/day) for 2 wks	Experimental rats	restores endothelial function
Tsunekawa et al 2001	cerivastatin (0.15 mg/d) for 3 days	27 elderly NIDDM	improved impaired endothelial function without affecting lipid profiles
Avogaro et al 2001	Gemfibrozil 600 mg b.i.d, for 12 wks	10 pt. NIDDM	improves both insulin action and FMD
Evans et al 2000	Ciprofibrate 3/12	NIDDM	improves fasting and postprandial endothelial function
	Role of insulin
Vehkavaara et al 2000, ^Citation2004	insulin glargine and metformin	49 in vivo endothelial function tests in 11 pt. NIDDM	+EDVD and endothelium-independent vasodilatation
Gaenzer et al 2002	insulin and metformin	21 poorly controlled NIDDM	beneficial effects on vascular function, resulting in enhanced EDD
Evans et al 2003	6 weeks of insulin lispro (0.2 Iu kg-1) and vitamin C 1-g daily	20 pt. NIDDM	Improve endothelial dysfunction

Table 2C Role of various modalities of therapy on endothelial dysfunction

Reference	Treatment	Patient	Result on endothelial function
	Role of L-arginine
Sahach et al 2005 Kabat et al 2006	L-arginine	Porcine endothelialaortic cells (experimental)	Prevent endothelial dysfunction
De Cobelli et al 2004	L-arginine	uremic IDDM pt.	induced vasodilatation of renal vls
Regensteiner et al 2003	1-week Tx of oral L-arginine (9 g daily) or vitamins E (1800 mg) and C (1000 mg)	10 premenopausal women with NIDDM function	improved measures of endothelial
	Role of antioxidants
Qian et al 2006	Injection of IL-2 (5000 and 50,000 U/ kg/ d s.c.) for 5 wks	diabetic rats	significantly ameliorated the endothelial dysfunction induced by hyperglycemia
Shemyakin et al 2006	A 60 minute intraarterial infusion of the ET(A) receptor antagonist BQ123 (10 nmol/min) combined with the ET(B) receptor antagonist BQ788 (5 nmol/min	12 individuals with insulin resistance resistance with no any history of diabetes	enhances EDV in subjects with insulin resistance
Zoukourian et al 1996	iloprost	Diabetic erythrocyte-endothelium	Alter endothelial dysfunction
Clemens et al 1999	200 microg octreotide/day for 6/12	27 patients (IDDM).	Reduce endothelial dysfunction
Chowienczyk et al 2000	raxofelast (600 mg twice daily) for 1 wk.	10 pt. NIDDM	↓ oxidative stress improves endothelial function
Bilsborough et al 2002	pentoxifylline 400 mg tid for 8 wks	13 pt. NIDDM	No effect on endothelial dysfunction
	Role of vitamins
MacKenzie et al 2006	folate (5 mg daily) & vitamin B6 (100 mg daily)	124 children, IDDM	+EDVD in children with IDDM.
McSorley et al 2005	vitamin E	14 pt. NIDDM	no effect
Pena et al 2004	oral folic acid (5 mg/d) and	36 subjects IDDM	improves endothelial function
Dhein et al 2003	8 wks vitamin E	Diabetic rat	prevent partially hyperglycemia-induced endothelial dysfunction
Skyrme-Jones et al 2000	Vit E	NIDDM	+EDVD
Darko et al 2002	vitamin C 1.5 g daily in 3 doses for 3 wks	35 pt. NIDDM	No effect
Skyrme-Jones et al 2001	1000 IU vitamin E for 3/12	IDDM	No effect VCAM-1 and P-selectin
Heitzer et al 2000	tetrahydrobiopterin (500 microg/min)	23 pt, NIDDM	improves endothelial function
Skyrme-Jones et al 2001	vitamin E supplement (1,000 IU for 3/12)	IDDM	Improves (EVF)
Pinkney et al 1999	vitamin E 500 U/day 3/12	46 pt. IDDM	enhance FMD
	Others
Pieper et al 1997	50 mg/kg hydroxyethyl starch conjugated-deferoxamine for a total of 8 wks.	Diabetic rat	prevent diabetes-induced defects in endothelium-dependent relaxation.
Fuchsjager-Mayrl et al 2002	aerobic exercise training	26 pt. IDDM	improve endothelial function in different vascular bed
Pieper et al 1996	Pancreatic cell transplantation	Diabetic rat	+EDVD
Maiorana et al 2001	combined aerobic & resistance exercise	16 pt. NIDDM	Improves endothelial vasodilator function
Shai et al 2004	Moderate alcohol intake	726 pt.NIDDM (Health Professionals Follow-up Study)	↓inflammation markers and endothelial dysfunction

Abbreviations: NIDDM, non insulin dependent diabetes mellitus; IDDM, insulin dependant diabetes mellitus; FMD, flow mediated dilatation; EDVD, endothelial dependant vasodilatation; ACEI, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers, FMD, flow mediated dilatation; ET(A), endothelin(A), endothelial vasodilator function (EVF).

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