March 2016
Volume 57, Issue 3
Open Access
Retina  |   March 2016
Effects of Habitual Cigarette Smoking on Retinal Circulation in Patients With Type 2 Diabetes
Author Affiliations & Notes
  • Tsuneaki Omae
    Department of Ophthalmology Asahikawa Medical University, Asahikawa, Japan
  • Taiji Nagaoka
    Department of Ophthalmology Asahikawa Medical University, Asahikawa, Japan
  • Akitoshi Yoshida
    Department of Ophthalmology Asahikawa Medical University, Asahikawa, Japan
  • Correspondence: Tsuneaki Omae, Department of Ophthalmology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan;
Investigative Ophthalmology & Visual Science March 2016, Vol.57, 1345-1351. doi:10.1167/iovs.15-18813
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Tsuneaki Omae, Taiji Nagaoka, Akitoshi Yoshida; Effects of Habitual Cigarette Smoking on Retinal Circulation in Patients With Type 2 Diabetes. Invest. Ophthalmol. Vis. Sci. 2016;57(3):1345-1351. doi: 10.1167/iovs.15-18813.

      Download citation file:

      © ARVO (1962-2015); The Authors (2016-present)

  • Supplements

Purpose: To examine the long-term effects of cigarette smoking on retinal circulation in patients with type 2 diabetes.

Methods: Seventy-four patients with type 2 diabetes mellitus and minimal (no or mild nonproliferative) diabetic retinopathy (DR) were evaluated. These patients with type 2 diabetes were divided into three groups based on their smoking history: current smokers (n = 19), past smokers (n = 20), and never smoked (n = 35). The retinal circulatory parameters were measured with laser Doppler velocimetry and were compared among the groups.

Results: There were significant decreases in the retinal blood flow (RBF; 8.9 ± 2.9 vs. 11.6 ± 3.1 μL/min, P = 0.009) with decreased blood velocity (V; 29.6 ± 6.8 vs. 37.8 ± 9.0 mm/s, P = 0.003) but no difference in the vessel diameter (D; 112.0 ± 11.9 vs. 113.7 ± 8.6 μm, P = 0.57) in the current smokers compared with those who never smoked. There were no differences in the RBF, blood V, and vessel D in the past smokers compared with those who never smoked and current smokers. Multiple regression analysis showed that the creatinine level was correlated negatively with the RBF and that current smoking was significantly and independent correlated with decreased RBF.

Conclusions: Our results indicated that the blood V and RBF in the retinal arterioles may decrease in patients with type 2 diabetes who are chronic smokers, suggesting that chronic smoking may be associated with decreased RBF, probably via lower blood V in the retinal arterioles in early-phase DR.

Cigarette smoking has been identified as a major risk factor for atherosclerotic complications in the coronary, aortic, and cerebral circulatory systems.1 Further, several previous reports have indicated that cigarette smoking is a significant and independent risk factor for cardiovascular diseases in patients with diabetes.24 Thus, these observations indicate that cigarette smoking may be involved in development of vascular disorders in diabetes mellitus via a deleterious effect on the circulation. 
Most previous studies have investigated the effects of cigarette smoking on ocular blood flow parameters in nondiabetic smokers.510 In addition to basal ocular blood flow, retinal vascular reactivity to flicker stimuli,11,12 and gas provocation10,1315 was shown to decrease in chronic smokers. Thus, most data regarding effects of regular smoking on the ocular circulation and retinal vascular reactivity in smokers without diabetes are available. However, few studies have examined the effects of long-term smoking on the ocular circulation in patients with diabetes. 
The relationship between chronic smoking per se and the retinal circulation in patients with diabetes is unclear. Using a retinal laser Doppler velocimetry (LDV) system, we reported that the retinal blood flow (RBF) decreases in patients with type 2 diabetes without retinopathy and with mild retinopathy.16 Although the role of smoking in diabetic microangiopathy, particular retinopathy, has not been clearly established,1723 impaired retinal microcirculation caused by cigarette smoking may be implicated in the pathogenesis of diabetic retinopathy (DR). Herein, we examined the effects of chronic smoking on the retinal microcirculation in patients with type 2 diabetes with early-stage of retinopathy. 
The study adhered to the tenets of the Declaration of Helsinki and the guidelines approved by the ethics committee of our institution. All participants provided written informed consent. The current study included 74 consecutive native Japanese patients (42 men, 32 women; age, mean ± SD, 59.0 ± 10.2 years) with type 2 diabetes mellitus diagnosed according to the criteria of the American Diabetes Association.24 Patients were considered to have diabetes if they were treated with insulin or oral hypoglycemic agents, or if the fasting blood glucose value exceeded 140 mg/dL. Patients were considered to have hypertension if the blood pressure (BP) exceeded 140/90 mm Hg or they used antihypertensive drugs.25 Dyslipidemia was diagnosed in patients with low-density lipoprotein (LDL) cholesterol of 140 mg/dL or higher and/or high-density lipoprotein (HDL) cholesterol below 40 mg/dL, and/or triglyceride values of 140 mg/dL or higher in subjects with a history of cholesterol-lowering therapy.26 
The urinary albumin excretion is presented as the albumin-to-creatinine ratio (ACR) (mg/g creatinine). Diabetic nephropathy was staged based on analysis of spot urine samples: stage I (normoalbuminuria ACR, <30 mg/g creatinine; stage II [microalbuminuria]), 30 less than ACR less than 300 mg/g creatinine; stage III (macroalbuminuria), ACR greater than 300 mg/g creatinine (or dipstick urinalysis showing 2+, 3+, or 4+), and an estimated glomerular filtration rate (eGFR), less than 30 mL/min/1.73 m2. The serum creatinine was measured within 4 hours of fasting venous blood collection using a Hitachi 747 biochemistry analyzer (Hitachi High-Technologies Corporation, Tokyo, Japan). Renal function also was evaluated based on the eGFR, which was calculated using a previously reported formula.27 The chronic kidney disease (CKD) stages were based on the National Kidney Foundation Disease Outcomes Quality Initiative clinical practice guidelines.28 
In the current study, we recruited patients with type 2 diabetes, no or mild DR, and no or microalbuminuria. Because impaired renal function may be associated with decreased RBF in early-phase DR,29 patients with stage 3 CKD, macroalbuminuria, or proteinuria and those undergoing hemodialysis were excluded. In addition, patients with poorly control diabetes (hemoglobin [Hb] A1 >10.0%) uncontrolled hypertension (BP >140/90 mm Hg), acute renal failure, chronic glomerulonephritis, and interstitial nephritis, were excluded as were those with cardiovascular diseases, such as coronary artery diseases, congestive heart failure, peripheral vascular disease, and ischemic stroke. The specialists in our institution diagnosed and were masked to the information from the ocular examination. 
All patients underwent a baseline ophthalmologic evaluation before the RBF measurement. All patients had a visual acuity exceeding 20/20 and IOP below 20 mm Hg. After the pupils were dilated with a 0.5% tropicamide eye drop, a well-trained ophthalmologist, masked to the RBF status, assessed the DR at every visit. For each eye, the maximal grade in any of the seven standard photographic fields was determined for each lesion and used to define the DR levels.30 The severity of the DR was determined once when the patients entered the study and categorized as none (level 10), mild nonproliferative DR (NPDR; levels 21–37), moderate-to-severe NPDR (levels 43–53), or proliferative DR (levels 60–65).31 Patients with moderate-to-severe NPDR and PDR and clinically relevant macular edema were excluded. The ophthalmologic exclusion criteria included a previous intraocular surgery, history of laser photocoagulation, moderate-to-severe cataract, and moderate-to-high refractive error (> ±3.0 diopters). The eye with the worse DR that met the inclusion criteria was included; if both eyes were equal, one eye was chosen randomly. 
These patients were divided into three groups: the never smoked group, the past-smoker group, and the current-smoker group. The current smoker was defined as a patient currently smoking cigarettes every day. Smokers were defined as those who smoked more than 10 cigarettes daily for more than 10 years. The past smoker was defined as a patient who had smoked regularly but had ceased for at least 1 year before entrance into the study.32 
RBF Measurements
The RBF was measured after the ocular examination. The subjects abstained from coffee for at least 12 hours before the measurement. A retinal LDV system (Canon Laser Blood Flowmeter, model CLBF 100; Canon, Tokyo, Japan) estimated the blood flow in the superior branch of the first-order major temporal retinal artery. The detailed system methodology was described previously.33 
Briefly, the retinal LDV system allows noninvasive measurement of the absolute values of the red blood cells flowing in the centerline of the vessel, based on bidirectional LDV.33 The mean retinal blood velocity (Vmean) was defined as the V of the averaged maximal speed during one cardiac cycle. Computer analysis of the signal produced by the arterial image on the array sensor using the half height of the transmittance profile to define the vessel edge automatically determined the retinal artery diameter (D).33 The patients with diabetes mellitus had not changed any medications for at least 6 months before the RBF measurements. 
The RBF was calculated as RBF = Vmean × area, where Vmean is calculated as Vmean = V of the averaged maximal speed/2, and area is the cross-sectional area of the retinal artery at the LDV measurement site.33 The mean arterial BP (MABP) was determined by the formula: diastolic BP + (systolic BP − diastolic BP)/3.33 Ocular perfusion pressure (OPP) was determined by the formula OPP = 2/3(MABP) − IOP.16 Retinal arterial vascular resistance (RVR) was determined using the formula RVR = OPP/RBF.34 The wall shear rate (WSR) was not measured directly in this model but was calculated with a Poiseuillean parabolic model of V distribution across the arterial lumen according to the formula: WSR = 8 × Vmean/D.33 
Statistical Analysis
All values are expressed as the mean ± SD. Comparisons between groups were made using 1-way ANOVA (for continuous variables) and the χ2 test (for categorical variables). One-way ANOVA was followed by a post hoc comparison with the Tukey-Kramer procedure. Standardized regression coefficients from multiple regression analysis of the retinal circulatory parameters in relation to various factors including smoking status were analyzed. For this analysis, based on our previous studies,16,35 clinically important variables were entered: age, HbA1C, diabetes duration, plasma glucose, body mass index (BMI), BP, heart rate, IOP, OPP, LDL, creatinine (CRE), eGFR, and smoking (current or otherwise). Second, the variables with a P value below 0.2 from Pearson's analysis were included in the final multiple regression analysis.36 To avoid multicollinearity, if there was a significant correlation (r > 0.7) between two variables, only one variable was selected and entered into the model. P less than 0.05 was considered significant. 
Male ratio in sex distribution and the plasma glucose value in the current- and past-smoker group were significantly higher compared with never-smoked group. Although the group-average triglyceride values were significantly lower and the group-average CRE values were significantly higher in the past-smoker group compared with the other groups, there were no significantly differences in age, HbA1c, diabetes duration, BMI, systemic and diastolic BP, mean BP, heart rate, IOP, total cholesterol, HDL, LDL, blood urea nitrogen, or eGFR among the groups (Table 1). We found significant decreases in the blood V (P = 0.003), RBF (P = 0.009), and WSR (P = 0.01) in the current-smoker group compared with the group that never smoked; however, there were no differences in the vessel D among the groups. We found no significant differences in blood V, RBF, and WSR in the past-smoker group compared with the group that never smoked and current-smoker group. Moreover, our results showed a modest, but not significant, elevation of RVR in the current-smoker group compared with the never-smoked group (Table 2). In univariate analysis, the CRE remained negatively correlated with the RBF (Table 3). Multiple regression analysis was performed to determine whether smoking was an independent variable related to the RBF in patients with type 2 diabetes, based on our previous findings. Variables with a P value lower than 0.20 in univariate analysis were the diastolic BP, mean BP, and CRE (Table 3). Because of the high correlation between the mean BP and diastolic BP (r = 0.896; data not shown), the mean BP was selected instead of the diastolic BP. In addition to smoking status, the CRE and mean BP were included in the multiple regression analysis. The multiple regression analysis showed that current smoking was a significant and independent variable associated with the RBF in these patients in addition to the serum CRE (Table 4). 
Table 1
Characteristics of Patients With Type 2 Diabetes With Early-Stage Retinopathy
Table 1
Characteristics of Patients With Type 2 Diabetes With Early-Stage Retinopathy
Table 2
Retinal Circulatory Parameters in the Study Groups
Table 2
Retinal Circulatory Parameters in the Study Groups
Table 3
Characteristics of Patients With Type 2 Diabetes With Early-Stage DR and Correlations Between RBF and Systemic and Ocular Parameters
Table 3
Characteristics of Patients With Type 2 Diabetes With Early-Stage DR and Correlations Between RBF and Systemic and Ocular Parameters
Table 4
Multiple Regression Analysis of RBF in 74 Patients With Type 2 Diabetes
Table 4
Multiple Regression Analysis of RBF in 74 Patients With Type 2 Diabetes
The current study found, for the first time, that the blood V and RBF in the retinal arterioles decreased in current smokers with type 2 diabetes, suggesting that chronic smoking may be associated with decreased retinal circulation in early-stage DR in type 2 diabetes. Indeed, some previous studies of diabetes have reported abnormalities in the retinal vessel parameters.3740 Moreover, we previously reported that the RBF with decreased blood V was significantly lower in patients with type 2 diabetes with early-phase DR compared with in nondiabetic control subjects.16 Taken together, we speculated that alterations in the retinal microcirculation caused by chronic smoking may be implicated in the pathogenesis of DR. 
Several previous studies have focused on determining the effect of chronic smoking on the ocular blood flow. Acute smoking increases the tissue blood V in the optic nerve and choroid of habitual smokers.6 In keeping with that, a study using the blue-field entoptic technique showed increased leukocyte V in the perimacular region in chronic smokers.5 These results have been confirmed by another report showing increased blood flow V in the ophthalmic artery and lateral posterior ciliary artery in smokers compared with nonsmoking subjects.7 In contrast, the blood V in the ophthalmic artery,8 central retinal artery, and posterior ciliary artery9 has been reported to be lower in smokers than in nonsmokers. Moreover, Morgado et al.10 reported that acute smoking reduced the RBF in habitual smokers. Not only the basal ocular blood flow but also the retinal vascular reactivity to flicker-light stimulation11,12 and gas provocation10,1315 were shown previously to be reduced in chronic smokers. Although the reason for these contradicting results is unknown, these findings suggested alterations in ocular perfusion in chronic smokers without diabetes. 
In the current study, the decreased RBF resulted primarily from decreased V, because the vessel D did not change in current smoker patients compared with nonsmoker patients with type 2 diabetes (Table 2). It is likely that the decreased in blood V without a change in vessel D indicates vasoconstriction of the smaller arterioles that are located downstream from the measured point (first branch retinal artery). Most clinical and experimental investigations have reported that chronic cigarette smoking impaired endothelial dependent vasodilation, which may be related to decreased endothelial production or increased degradation of nitric oxide (NO),41 in various vessels.4244 The immunohistochemical expression of endothelial NO synthase (eNOS) in the pulmonary arterial endothelium and the eNOS protein in lung tissue were lower in smokers than nonsmokers.45 Because NO is a well-known powerful vasodilator in the retinal vessels,34 the reduced NO production caused by chronic smoking can evoke decreased upstream blood flow V followed by increased resistance elements with vasoconstriction of the distal retinal arterioles and/or capillaries. Moreover, this was supported by our observation that the RVR increased modestly but not significantly in the current smoker patients compared with nonsmoker patients with type 2 diabetes (Table 2). Indeed, conscious rats exposed to high-nicotine cigarette smoke showed an enhanced and significant increase in total peripheral resistance.46 We speculate that chronic smoking may reduce the RBF via vasoconstriction of the resistance vessels, which are smaller than the measured large artery (first branch), in patients with type 2 diabetes. 
The current study showed that RBF and WSR, indices of shear stress, were lower in current smoker patients than in nonsmoker patients with type 2 diabetes (Table 2). Our recent in vitro study reported that low shear stress upregulated mRNA expression of molecular adhesion such as vascular cellular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, which leads to leukocyte adhesion to the endothelium in the retinal vasculature in the diabetic retina,47 in human retinal microvascular endothelial cells.48 Experimentally reduced blood flow by surgical manipulation, which decreased shear stress, also increased monocytic adhesion to the surface endothelium of the common carotid arteries in rabbits.49 Thus, we speculate that the RBF may be regulated by interaction of low shear stress with molecular adhesion to the endothelium in the retinal microcirculation in type 2 diabetic patients with smoking habits. In addition, serum VCAM-1 and ICAM-1 concentrations were elevated in smoking hypertensive patients compared with nonsmoking hypertensive patients.50 Overall, although we did not measure the serum level of adhesion molecules, the results indicated that reduced RBF and WSR may be attributed to increased expression of adhesion molecules on the endothelium in the retinal vessels. 
Several reports have implicated endothelin-1 (ET-1), a potent retinal vasoconstrictor, activation in the control of vascular tone as a result of cigarette smoking. Plasma ET-1 levels in patients undergoing coronary angiography who were smokers and in rats exposed to cigarette smoke for 16 weeks were higher than those of nonsmoking patients51 and nonsmoking rats,52 respectively. However, two studies of human volunteers reported that within the first 10 minutes of active smoking there is a rise in plasma ET-1 level, which is followed by a decline over time.53,54 Similarly, acute cigarette smoke exposure (30 minutes) increased ET-1 mRNA expression in rat hearts and lungs, while chronic exposure (6 months) did not alter ET-1 mRNA expression.55 Moreover, ET-1 production by human umbilical endothelial cells treated with serum from nonsmokers, light smokers, and heavy smokers did not differ between the three groups.56 Thus, the effect of chronic smoking on plasma ET-1 levels is inconclusive. Recently, the expressions of mRNA and protein for endothelin type A (ETA) and endothelin type B (ETB) receptors in the coronary arteries of smoked-exposed rats were higher than that of animals exposed to fresh air.57 It also has been reported that blockade of ETA and ETB receptors attenuates augmented vascular contractility to phenylephrine in aortas and carotid arteries of rats exposed to cigarette smoke.52 Indeed, a previous study showed the expression of ETA and ETB receptor mRNA and protein in the retinal arterioles.58 Although we did not measure the serum level of ET-1, the ET system can contribute to the retinal circulatory changes caused by chronic smoking in type 2 diabetes. 
Our observation that chronic smoking reduced retinal blood V and RBF in patients with type 2 diabetes with early-phase DR is inconsistent with the previous finding that no significant difference was observed in the retinal circulatory parameters between nondiabetic smokers and healthy nonsmoking subjects.13 However, acute cigarette smoking induced a marked decrease in RBF, more pronounced in diabetics than in healthy controls.10 Moreover, insulin upregulates the ETA receptor in cultured rat aortic smooth muscle cells.59 Thus, the ET receptor can be upregulated in patients with type 2 diabetes, characterized by a state of hyperinsulinemia. Therefore, the deleterious effect of chronic cigarette smoking on retinal vascular reactivity in type 2 diabetes can be attributed to increased sensitivity to cigarette smoking. 
Cigarette smoke contains high concentrations of free radicals and oxidants.60 Indeed, a short exposure (30 minutes) of bovine pulmonary artery endothelial cells to cigarette smoke extracts resulted in a large increase in superoxide anion production.61 In diabetic patients, the antioxidant capacity is decreased,62 finally resulting in an increased susceptibility to oxidative stress. Therefore, it seems that the difference between diabetic and nondiabetic subjects can be attributed to the sensitivity of the retinal vasculature to oxidative stress caused by cigarette smoke. 
The RBF in past-smoker patients was decreased but not significantly compared with nonsmoking patients with type 2 diabetes (Table 2), suggesting that smoking cessation can improve retinal circulation impaired by chronic cigarette smoking in patients with type 2 diabetes. Significant improvement of flow-mediated dilation, which is a well-established and widely used method of evaluating the vascular endothelial function, of the branchial artery in current smokers 1 year after cessation has been reported.63 Indeed, reduction in resting cerebral blood flow caused by chronic exposure to smoking improved within 1 year after smoking cessation,64 and several years following smoking cessation are required for improvement of the decreased cerebral blood flow in long-term smokers.65 Although further investigations of whether smoking cessation can improve impaired RBF caused by chronic smoking are required, chronic cigarette smoking may be associated with potentially reversible impairment of the retinal microcirculation in patients with type 2 diabetes. 
In the current study, the multivariate regression model included serum CRE and MABP (Table 3). In addition to current smoking, our multivariate regression analysis showed a negative correlation between serum CRE and RBF in patients with type 2 diabetes (Table 4), suggesting that the serum CRE and current smoking are independent risk factors for RBF in our patients. 
Our multivariate regression analysis showed a negative correlation between serum CRE and RBF in patients with type 2 diabetes, suggesting that impaired renal function may be associated with reduced RBF in patients with type 2 diabetes. Indeed, NO production decreases in renal disease due to impaired endothelial function and renal NO production.66 Moreover, we recently reported that RBF decreased in patients with type 2 diabetes with stage 3 CKD.29 Thus, impaired renal function may be associated with decreased RBF in early-phase DR. 
The current study had some limitations. First, we could not determine the specific components of cigarette smoke responsible for reduced RBF. Nicotine has been one of the most widely studied among the more than 4000 chemicals in cigarettes. Nicotine significantly attenuated endothelial-dependent vasodilation in the canine basilar artery and NO synthesis in cultured human endothelial cells,67 suggesting that nicotine may play a critical role in altered vasoreactivity. Although nicotine tested in a glaucoma group showed significant changes in blood V in the ophthalmic artery compared with the placebo-tested group,68 it is uncertain whether nicotine can affect retinal vasomotion in patients with type 2 diabetes. Additional investigations are needed to clarify the molecular mechanisms underlying the deleterious effect of cigarette smoking on the retinal circulation. Second, it remains unclear whether there is a linear dose effect of smoking on the retinal circulatory parameters. In the current study, no significant association was seen between the RBF and pack-years in the current-smoker patients with type 2 diabetes (Pearson's coefficient of correlation, r = −0.13, P = 0.60; data not shown). Indeed, an experimental study showed that incubation of isolated rabbit aortas with cigarette smoke extract inhibited endothelial-dependent relaxation in a dose-dependent manner.69 In contrast, the clinical data regarding the dose-dependent effects of smoking on endothelial-dependent vasodilation are inconclusive. Celermajer et al.70 reported a dose-dependent reduction of endothelial-dependent vasodilation related to pack-years of active smoke exposure, but another study reported that both the active light (with smoking ≤ 1 pack/week) and heavy (with smoking ≥ 1 pack/day) smokers had a similar reduction in branchial artery endothelial-dependent vasodilation compared with nonsmokers.56 Because of variations in the amount of nicotine per cigarette, the number of cigarettes consumed daily, and the amount of smoke actually inhaled, it may be difficult to examine in detail the dose-dependent effect of smoking on the retinal circulatory parameters in a clinical investigation. Third, there was a significant difference in sex among the three study groups. Because generally, more men than women smoke,71 the current distribution of male patients was greater than that of female patients with type 2 diabetes in the past and current smoker groups. However, similar results were obtained in male-only patients (data not shown). In contrast, the number of female smoking patients with type 2 diabetes was uneven and the differences in the retinal circulatory parameters among the three groups were not significant (data not shown). Further study of the effects of sex differences on the retinal circulation affected by smoking is required. Fourth, we could not evaluate the effect of changes in the systemic BP caused by smoking on the retinal vessel parameters. Acute smoking caused a significant increase in the systemic BP in habitual smokers.72 Furthermore, our previous report indicated that increased systemic BP constricts the retinal arterioles to maintain the RBF in healthy subjects.73 Although we found no differences in the systemic BP among the groups (Table 1), a future study should examine the effect of changes in the systemic BP caused by smoking on the retinal vessel parameters. 
In conclusion, the current findings showed that the RBF decreased in current smoker patients with type 2 diabetes, suggesting that chronic cigarette smoking may affect the RBF in early-phase DR. These results indicated that impaired retinal microcirculation resulting from chronic smoking may be implicated in the pathogenesis of DR. 
Supported by a Grant-in-Aid for Young Scientists (B) 24791828 (TO) and Young Scientists (B) 26861428 (TO) from the Ministry of Education, Science, and Culture (Tokyo, Japan). 
Disclosure: T. Omae, None; T. Nagaoka, None; A. Yoshida, None 
Fielding JE. Smoking: health effects and control (1). N Engl J Med. 1985; 313: 491–498.
Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998; 316: 823–828.
Kothari V, Stevens RJ, Adler AI, et al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke. 2002; 33: 1776–1781.
Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS, 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. 2002; 25: 894–899.
Robinson F, Petrig BL, Riva CE. The acute effect of cigarette smoking on macular capillary blood flow in humans. Invest Ophthalmol Vis Sci. 1985; 26: 609–613.
Tamaki Y, Araie M, Nagahara M, Tomita K. Acute effects of cigarette smoking on tissue circulation in human optic nerve head and choroid-retina. Ophthalmology. 1999; 106: 564–569.
Kaiser HJ, Schoetzau A, Flammer J. Blood flow velocity in the extraocular vessels in chronic smokers. Br J Ophthalmol. 1997; 81: 133–135.
Williamson TH, Lowe GD, Baxter GM. Influence of age systemic blood pressure, smoking, and blood viscosity on orbital blood velocities. Br J Ophthalmol. 1995; 79: 17–22.
Steigerwalt RD,Jr, Laurora G, Incandela L, Cesarone MR, Belcaro GV, De Sanctis MT. Ocular and orbital blood flow in cigarette smokers. Retina. 2000; 20: 394–397.
Morgado PB, Chen HC, Patel V, Herbert L, Kohner EM. The acute effect of smoking on retinal blood flow in subjects with and without diabetes. Ophthalmology. 1994; 101: 1220–1226.
Garhofer G, Resch H, Sacu S, et al. Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects. Microvasc Res. 2011; 82: 351–355.
Heitmar R, Blann AD, Cubbidge RP, Lip GY, Gherghel D. Continuous retinal vessel diameter measurements: the future in retinal vessel assessment? Invest Ophthalmol Vis Sci. 2010; 51: 5833–5839.
Wimpissinger B, Resch H, Berisha F, Weigert G, Schmetterer L, Polak K. Response of retinal blood flow to systemic hyperoxia in smokers and nonsmokers. Graefes Arch Clin Exp Ophthalmol. 2005; 243: 646–652.
Langhans M, Michelson G, Groh MJ. Effect of breathing 100% oxygen on retinal and optic nerve head capillary blood flow in smokers and non-smokers. Br J Ophthalmol. 1997; 81: 365–369.
Rose K, Flanagan JG, Patel SR, Cheng R, Hudson C. Retinal blood flow and vascular reactivity in chronic smokers. Invest Ophthalmol Vis Sci. 2014; 55: 4266–4276.
Nagaoka T, Sato E, Takahashi A, Yokota H, Sogawa K, Yoshida A. Impaired retinal circulation in patients with type 2 diabetes mellitus: retinal laser Doppler velocimetry study. Invest Ophthalmol Vis Sci. 2010; 51: 6729–6734.
Paetkau ME, Boyd TA, Winship B, Grace M. Cigarette smoking and diabetic retinopathy. Diabetes. 1977; 26: 46–49.
Nielsen MM, Hjollund E. Smoking and diabetic microangiopathy. Lancet. 1978; 2: 533–534.
Walker JM, Cove DH, Beevers DG, et al. Cigarette smoking, blood pressure and the control of blood glucose in the development of diabetic retinopathy. Diabetes Res. 1985; 2: 183–186.
Muhlhauser I, Sawicki P, Berger M. Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in type 1 (insulin-dependent) diabetes. Diabetologia. 1986; 29: 500–502.
Marshall G, Garg SK, Jackson WE, Holmes DL, Chase HP. Factors influencing the onset and progression of diabetic retinopathy in subjects with insulin-dependent diabetes mellitus. Ophthalmology. 1993; 100: 1133–1139.
Ballard DJ, Melton LJ,III, Dwyer MS, et al. Risk factors for diabetic retinopathy: a population-based study in Rochester, Minnesota. Diabetes Care. 1986; 9: 334–342.
Moss SE, Klein R, Klein BE. Association of cigarette smoking with diabetic retinopathy. Diabetes Care. 1991; 14: 119–126.
Expert Committee on the D, Classification of Diabetes M. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003; 26 (suppl 1): S5–S20.
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.
Teramoto T, Sasaki J, Ueshima H, et al. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb. 2007; 14: 45–50.
Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009; 53: 982–992.
Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005; 67: 2089–2100.
Nagaoka T, Yoshida A. Relationship between retinal blood flow and renal function in patients with type 2 diabetes and chronic kidney disease. Diabetes Care. 2013; 36: 957–961.
Klein BE, Davis MD, Segal P, et al. Diabetic retinopathy. Assessment of severity and progression. Ophthalmology. 1984; 91: 10–17.
Grading diabetic retinopathy from stereoscopic color fundus photographs–an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991; 98: 786–806.
Li L, Psoter WJ, Buxo CJ, Elias A, Cuadrado L, Morse DE. Smoking and drinking in relation to oral potentially malignant disorders in Puerto Rico: a case-control study. BMC Cancer. 2011; 11: 324.
Nagaoka T, Yoshida A. Noninvasive evaluation of wall shear stress on retinal microcirculation in humans. Invest Ophthalmol Vis Sci. 2006; 47: 1113–1119.
Nagaoka T, Sakamoto T, Mori F, Sato E, Yoshida A. The effect of nitric oxide on retinal blood flow during hypoxia in cats. Invest Ophthalmol Vis Sci. 2002; 43: 3037–3044.
Nagaoka T, Sato E, Takahashi A, Sogawa K, Yokota H, Yoshida A. Effect of aging on retinal circulation in normotensive healthy subjects. Exp Eye Res. 2009; 89: 887–891.
Lee JY, Lee HK, Lee DC, Lee JW. Serum carcinoembryonic antigen is associated with abdominal visceral fat accumulation in female Korean nonsmokers. PLoS One. 2012; 7: e43518.
Bursell SE, Clermont AC, Kinsley BT, Simonson DC, Aiello LM, Wolpert HA. Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy. Invest Ophthalmol Vis Sci. 1996; 37: 886–897.
Clermont AC, Aiello LP, Mori F, Aiello LM, Bursell SE. Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy. Am J Ophthalmol. 1997; 124: 433–446.
Patel V, Rassam S, Newsom R, Wiek J, Kohner E. Retinal blood flow in diabetic retinopathy. BMJ. 1992; 305: 678–683.
Burgansky-Eliash Z, Barak A, Barash H, et al. Increased retinal blood flow velocity in patients with early diabetes mellitus. Retina. 2012; 32: 112–119.
Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol. 1997; 30: 325–333.
Zeiher AM, Schachinger V, Minners J. Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation. 1995; 92: 1094–1100.
Tanriverdi H, Evrengul H, Kuru O, et al. Cigarette smoking induced oxidative stress may impair endothelial function and coronary blood flow in angiographically normal coronary arteries. Circulation J. 2006; 70: 593–599.
Freischlag JA, Johnson D, Farooq MM, et al. Cigarette smoke impairs endothelium-dependent relaxation in rabbit superficial femoral veins. J Surg Res. 1999; 81: 77–80.
Barbera JA, Peinado VI, Santos S, Ramirez J, Roca J, Rodriguez-Roisin R. Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers. Am J Respir Crit Care Med. 2001; 164: 709–713.
Houdi AA, Dowell RT, Diana JN. Cardiovascular responses to cigarette smoke exposure in restrained conscious rats. J Pharmacol Exp Ther. 1995; 275: 646–653.
Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A. 1999; 96: 10836–10841.
Ishibazawa A, Nagaoka T, Yokota H, Ono S, Yoshida A. Low shear stress up-regulation of proinflammatory gene expression in human retinal microvascular endothelial cells. Exp Eye Res. 2013; 116: 308–311.
Walpola PL, Gotlieb AI, Langille BL. Monocyte adhesion and changes in endothelial cell number morphology, and F-actin distribution elicited by low shear stress in vivo. Am J Pathol. 1993; 142: 1392–1400.
Mazzone A, Cusa C, Mazzucchelli I, et al. Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. Clin Chem Lab Med. 2001; 39: 822–826.
Orem A, Orem C, Alioglu Y, Vanizor B, Erdol C. Effect of coronary angiography on plasma endothelin-1 and nitric oxide concentrations. Angiology. 2001; 52: 231–235.
Rahman MM, Elmi S, Chang TK, et al. Increased vascular contractility in isolated vessels from cigarette smoking rats is mediated by basal endothelin release. Vasc Pharmacol. 2007; 46: 35–42.
Haak T, Jungmann E, Raab C, Usadel KH. Elevated endothelin-1 levels after cigarette smoking. Metab Clin Exper. 1994; 43: 267–269.
Goerre S, Staehli C, Shaw S, Luscher TF. Effect of cigarette smoking and nicotine on plasma endothelin-1 levels. J Cardiovasc Pharmacol. 1995; 26 (suppl 3): S236–S238.
Adachi C, Naruse M, Ishihara Y, et al. Effects of acute and chronic cigarette smoking on the expression of endothelin-1 mRNA of the cardiovascular tissues in rats. J Cardiovasc Pharmacol. 2000; 36 (5 suppl 1): S198–S200.
Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC. Heavy and light cigarette smokers have similar dysfunction of endothelial vasoregulatory activity: an in vivo and in vitro correlation. J Am Coll Cardiol. 2002; 39: 1758–1763.
Cao L, Zhang Y, Cao YX, Edvinsson L, Xu CB. Cigarette smoke upregulates rat coronary artery endothelin receptors in vivo. PLoS One. 2012; 7: e33008.
Hein TW, Ren Y, Yuan Z, et al. Functional and molecular characterization of the endothelin system in retinal arterioles. Invest Ophthalmol Vis Sci. 2009; 50: 3329–3336.
Hopfner RL, Hasnadka RV, Wilson TW, McNeill JR, Gopalakrishnan V. Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells. Diabetes. 1998; 47: 937–944.
Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Persp. 1985; 64: 111–126.
Jaimes EA, DeMaster EG, Tian RX, Raij L. Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler Thromb Vasc Biol. 2004; 24: 1031–1036.
Maxwell SR, Thomason H, Sandler D, et al. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1997; 27: 484–490.
Johnson HM, Gossett LK, Piper ME, et al. Effects of smoking and smoking cessation on endothelial function: 1-year outcomes from a randomized clinical trial. J Am Coll Cardiol. 2010; 55: 1988–1995.
Rogers RL, Meyer JS, Judd BW, Mortel KF. Abstention from cigarette smoking improves cerebral perfusion among elderly chronic smokers. JAMA. 1985; 253: 2970–2974.
Yamashita K, Kobayashi S, Yamaguchi S. Cerebral blood flow and cessation of cigarette smoking in healthy volunteers. Internal Medicine (Tokyo Japan). 2000; 39: 891–893.
Baylis C. Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol. 2008; 294: F1–F9.
Koide M, Nishizawa S, Yamamoto S, Yamaguchi M, Namba H, Terakawa S. Nicotine exposure, mimicked smoking, directly and indirectly enhanced protein kinase C activity in isolated canine basilar artery, resulting in enhancement of arterial contraction. J Cereb Blood Flow Metab. 2005; 25: 292–301.
Rojanapongpun P, Drance SM. The effects of nicotine on the blood flow of the ophthalmic artery and the finger circulation. Graefes Arch Clin Exper Ophthalmol. 1993; 231: 371–374.
Ota Y, Kugiyama K, Sugiyama S, et al. Impairment of endothelium-dependent relaxation of rabbit aortas by cigarette smoke extract–role of free radicals and attenuation by captopril. Atherosclerosis. 1997; 131: 195–202.
Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993; 88: 2149–2155.
Rudatsikira E, Abdo A, Muula AS. Prevalence and determinants of adolescent tobacco smoking in Addis Ababa Ethiopia. MC Public Health. 2007; 7: 176.
Kool MJ, Hoeks AP, Struijker Boudier HA, Reneman RS, Van Bortel LM. Short- and long-term effects of smoking on arterial wall properties in habitual smokers. J Am Coll Cardiol. 1993; 22: 1881–1886.
Nagaoka T, Mori F, Yoshida A. Retinal artery response to acute systemic blood pressure increase during cold pressor test in humans. Invest Ophthalmol Vis Sci. 2002; 43: 1941–1945.
Table 1
Characteristics of Patients With Type 2 Diabetes With Early-Stage Retinopathy
Table 1
Characteristics of Patients With Type 2 Diabetes With Early-Stage Retinopathy
Table 2
Retinal Circulatory Parameters in the Study Groups
Table 2
Retinal Circulatory Parameters in the Study Groups
Table 3
Characteristics of Patients With Type 2 Diabetes With Early-Stage DR and Correlations Between RBF and Systemic and Ocular Parameters
Table 3
Characteristics of Patients With Type 2 Diabetes With Early-Stage DR and Correlations Between RBF and Systemic and Ocular Parameters
Table 4
Multiple Regression Analysis of RBF in 74 Patients With Type 2 Diabetes
Table 4
Multiple Regression Analysis of RBF in 74 Patients With Type 2 Diabetes

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.