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Diabetes Care 29:1856-1859, 2006
DOI: 10.2337/dc06-0182
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

Impaired Exercise-Induced Blood Volume in Type 2 Diabetes With or Without Peripheral Arterial Disease Measured by Continuous-Wave Near-Infrared Spectroscopy

Emile R. Mohler, III, MD1, Gwen Lech, RN, MSNC2, Gregory E. Supple, MD1, Hao Wang, MS3 and Britton Chance, PHD2

1 Cardiovascular Division, Vascular Medicine Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2 Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
3 Center for Clinical Epidemiology and Biostatistics, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Emile R. Mohler, III, MD, University of Pennsylvania School of Medicine, 4 Penn Tower, 3400 Spruce St., Philadelphia, PA 19104. E-mail: mohlere{at}uphs.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—Diabetes is a significant risk factor for peripheral arterial disease (PAD) and is associated with accelerated atherosclerosis and limb loss. However, the pathophysiology involved in PAD is unclear. This study was conducted to evaluate the hemodynamic response to exercise of patients with and without diabetes and PAD.

RESEARCH DESIGN AND METHODS—The hemodynamic response in calf muscles of patients with diabetes, PAD, or both was determined using near-infrared spectroscopy (NIRS). Patients performed both a plantar-flexion and treadmill-walking exercise regimen.

RESULTS—Skeletal muscle capillary blood volume expansion during exercise, as measured by NIRS, was significantly impaired in the lower extremities of diabetic patients with a normal ankle-brachial index. The relative deoxygenation and oxygenation recovery times measured by NIRS correlates significantly with the presence of PAD.

CONCLUSIONS—Patients with diabetes have reduced capillary volume expansion even without PAD. This is likely due to impaired vasodilation secondary to endothelial dysfunction. Further studies are needed to determine whether pharmaceutical intervention improves the blood volume expansion in the diabetic state.

Abbreviations: ABI, ankle-brachial index • NIRS, near-infrared spectroscopy • PAD, peripheral arterial disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis and present in at least 25% of individuals over the age of 70 years (1,2). Diabetes, a well-recognized risk factor for PAD, may accelerate atherosclerosis and portends a pattern of infrapopliteal artery occlusive disease (3). Other tissue-damaging effects of hyperglycemia include those of capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, and neurons and Schwann cells in peripheral nerves. The pathophysiology of diabetic vascular disease in the extremities is complex, affecting large conduit vessels, microvessels, and skeletal muscle (4).

Near-infrared spectroscopy (NIRS) provides real-time measurement of the levels of oxygenated and deoxygenated hemoglobin/myoglobin in tissues (5). Prior studies have demonstrated that several NIRS measurements (such as deoxygenation and recovery times) significantly correlate with ankle-brachial index (ABI), a measure of limb pressure (6). One study indicates that NIRS correlates better with severity of exercise-induced pain than ABI in patients with PAD (7). Although several studies have evaluated NIRS in patients with PAD, there are no reports evaluating NIRS parameters in patients with diabetes and no evidence for hemodynamically significant PAD.

The purpose of this study was to determine whether NIRS hemodynamic measurements are perturbed in patients with diabetes before development of hemodynamically significant PAD as measured with the ABI.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Subjects were recruited through the vascular laboratory at the University of Pennsylvania and from community exercise programs. The study was approved by the University of Pennsylvania Institutional Review Board. After signing informed consent, a total of 74 volunteers over the age of 50 years were recruited into four groups: 1) healthy control subjects (n = 25, 60% female), 2) diabetes only (n = 17, 18% female), 3) PAD only (n = 13, 23% female), and 4) diabetes and PAD (n = 19, 16% female). The diabetes-only group was defined as those patients diagnosed with type 2 diabetes by a physician and an ABI of >0.9 and who had no claudication symptoms. The PAD-alone group was defined as those patients with an ABI of ≤0.9 and symptoms of claudication. The patients with PAD and diabetes were those with an ABI of ≤0.9 and symptoms of claudication, as well as a previous diagnosis of type 2 diabetes.

ABI measurement
The ABI was measured after the subjects were supine on an examination table for 15 min. Subjects refrained from any significant physical activity for at least an hour before the test. Standard blood pressure cuffs were placed on both arms and both ankles, and systolic pressure was measured with a handheld continuous-wave Doppler machine (Imex Elite; Nicolet Vascular, Conshohocken, PA). The ABI is calculated as a ratio of the ankle-to-arm measurement of systolic pressure as previously published (8). The higher of the arm pressures is used as the denominator and the higher of the ankle pressures is used as the numerator for each respective right and left ABI.

NIRS measurements
The NIRS measurements were made using a continuous light source, dual-wave-length spectrophotometer (Runman) as previously published (9). The NIRS probe was placed on the belly of the medial gastrocnemious. For those with PAD, the probe was placed on the most symptomatic leg, and if bilateral claudication was present, the probe was placed on the leg with the most severely reduced ABI. After application of the probe, continuous measurements were obtained at baseline and during exercise. Subjects initially performed a 30–plantar-flexion exercise over 1 min. After resting for 10 min, subjects walked on a treadmill according to the Gardner protocol (10). The subjects continued to the point of maximum claudication or up until 10 min of exercise. Of note, all hemodynamic parameters were allowed to return to normal before the next exercise phase of the study.

NIRS analysis
The total hemoglobin/myoglobin content (correspondent to blood volume in the vascular territory of the underlying muscle) and relative oxyhemoglobin amount (compared with resting baseline) was measured and graphed continuously during the exercise protocol. The blood volume expansion was calculated as the increase in measured volume over time (slope) during treadmill walking after the initial decrease due to muscle contraction. This calculation reflects the expansion of capillary blood volume. The blood deoxygenation was calculated as a percent change from baseline of measured oxyhemoglobin/myoglobin during exercise. The oxygen recovery time (T50) was calculated as the time it takes for oxygenation to return to half baseline after termination of exercise.

Statistical analysis
Linear models were used to evaluate difference among groups for each outcome of blood volume expansion, oxygen recovery time, and percent deoxygenation after plantar flexion or treadmill exercise. Since patients were not randomized to the four groups, group comparisons for NIRS measurements were adjusted with respect to potential confounding factors, including age, race, sex, BMI, smoking status, and hypertension. P values <0.05 were considered statistically significant. All analyses were carried out using SAS statistical software (version 9.1).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
The demographics of the study population are listed in Table 1. Of those enrolled in the study, there were more men than women with diabetes and PAD. The mean ABI was not significantly different between the PAD-alone and PAD with diabetes group (P = 0.44).


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  		Table 1— Demographics of study population

 
Blood volume expansion
A representative NIRS tracing is depicted in Fig. 1. The slopes of the mean values for blood volume expansion were calculated for all groups (Table 2). Group comparisons were adjusted for BMI and smoking status. Compared with healthy control subjects, the diabetes-only group did not show a significant difference in the change in blood volume during treadmill exercise. Their slope difference is –0.0002 (95% CI –0.0027 to 0.0023). The presence of PAD without diabetes was associated with a significant increase in the volume compared with control subjects (P = 0.039), and the difference between them in terms of the rate of blood volume expansion was 0.0032 (0.0002–0.0062). However, diabetic patients with PAD had an attenuated blood volume response compared with PAD-only patients (P = 0.04). The rate of blood volume expansion for diabetes with PAD patients was 0.0031 units smaller than for PAD-only patients (with 95% CI –0.0064 to –0.0001). The use of vasoactive medications (ß-blockers, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers) had no significant effect on blood volume (data not shown). The blood volume was not measured during plantar-flexion due to the brief period of exercise (1 min), which does not allow adequate time for responses unconfounded by blood volume changes from onset and cessation of exercise.


Figure 1
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  		Figure 1— Representative example of NIRS measurement of deoxygenation and blood volume during treadmill walking in a healthy control subject compared with a subject with both diabetes and PAD. The arrow with T50 points to the line that is used to calculate the time it takes for oxygenation to return to half baseline (T50) after exercise. There was little change in blood volume during exercise in this patient as evidence from relatively flat slope. —, PAD/diabetes deoxygenation; {diamondsuit}, PAD/diabetes blood volume.

 

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  		Table 2— NIRS measurements

 
T50
The mean values for T50 were calculated for all four groups to determine the relative oxygenation recovery time (Table 2). While diabetes had no effect (the ratio of T50 for diabetes patients relative to healthy controls was 0.9 [95% CI 0.61–1.4]), the presence of PAD significantly increased the T50. Compared with healthy control subjects, oxygen recovery time was 2.6 (1.6–4.1) and 2.4 (1.6–3.6) times longer in PAD-only patients and patients with both PAD and diabetes, respectively. After adjusting for smoking status, race, and personal history of coronary artery disease, these comparisons remained significant.

Deoxygenation
The mean values for deoxygenation were calculated in all four groups to determine the relative amount of desaturation of hemoglobin/myoglobin in the tissue (Table 2). The presence of claudication was associated with a significant increase in deoxygenation during both treadmill walking (P = 0.03) and plantar-flexion (P = 0.02) compared with healthy control subjects (P = 0.03). There was no significant increase in deoxygenation for the group with only diabetes during treadmill exercise or plantar-flexion compared with healthy control subjects (P = NS).


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
This is the first report of impaired blood volume expansion with exercise in patients with diabetes despite a normal ABI and relatively normal parameters of deoxygenation and recovery times. The impaired blood volume expansion likely reflects a decrease in the vasodilatation capacity of capillaries in the skeletal muscle of the lower extremity during physical activity. Patients with diabetes are known to have endothelial dysfunction (11,12), and it is likely that microvascular dysfunction contributes to the impaired blood volume expansion seen in this study. Our study results also show that patients with PAD, but without diabetes, have increased blood volume during exercise compared with healthy control subjects, likely reflecting a greater local hypoxemia, causing a vasodilatation response. The hypoxemia may cause release of vasodilating factors such as lactate, CO2, and adenosine. The data indicate that patients with PAD and diabetes lose this ability to increase blood volume, indicating a severely blunted microvascular vasodilator response. Similar to a previously published study (6), the deoxygenation and recovery times were abnormal in patients with PAD.

Tissue oxygenation, defined as relative saturation of oxyhemoglobin and myoglobin, depends on the balance between oxygen delivery, as reflected by the product of blood flow and oxygen content and metabolic rate or oxygen consumption. The normal response during exercise is a gradual decline in tissue oxygen saturation with increasing metabolic demand, and the initial response depends on exercise intensity. Our study results show that percent deoxygenation of hemoglobin and myoglobin occurs rapidly in both normal control subjects and those with PAD alone or with diabetes. The plateau level for percent deoxygenation is lower in the control group than in the patients with PAD, whereas the plateau for patients with diabetes and no PAD was not significantly different from healthy control subjects. The T50, a measure of oxygen recovery, is longer in patients with PAD compared with control patients, whereas the blood volume expansion is higher in PAD than control subjects and significantly lower in those with diabetes.

The pathologic influences resulting from the hyperglycemic state and resulting in endothelial dysfunction are multifactorial and include advanced glycation end products, increased formation of oxygen-derived free radicals, and activation of protein C (13). The presence of PAD results in reduced endothelium-derived vasodilator prostanoids and nitric oxide (4). The current study results indicate that a unique aspect of the diabetic state is impairment of blood volume during exercise that does not appear evident in patients without diabetes and hemodynamically significant lower extremity atherosclerosis. Our results are consistent with those of Kingwell et al. (14), who found that limb blood flow response to acetylcholine and exercise were significantly attenuated in patients with diabetes compared with healthy control subjects. Also, others have shown that impaired limb blood flow response to exercise may limit exercise capacity in patients with type 2 diabetes (15–17).

In conclusion, our study results indicate that the impaired blood flow response occurs early in diabetic vasculopathy and may occur before hemodynamically significant PAD. These findings may partly explain the accelerated atherosclerosis observed in patients with diabetes. Further studies are needed to determine whether impaired blood volume expansion in the diabetic state portends increased risk of developing PAD.


   Acknowledgments
 
We thank Elizabeth Medenilla for her assistance with treadmill testing.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication January 24, 2006. Accepted for publication April 24, 2006.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D: The prevalence of peripheral arterial disease in a defined population. Circ 71:510–515, 1985[Abstract/Free Full Text]
  2. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR: Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 286:1317–1324, 2001[Abstract/Free Full Text]
  3. Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581, 2002[Abstract/Free Full Text]
  4. Creager MA, Luscher TF, Cosentino F, Beckman JA: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circ 108:1527–1532, 2003[Free Full Text]
  5. Breit GA, Gross JH, Watenpaugh DE, Chance B, Hargens AR: Near-infrared spectroscopy for monitoring of tissue oxygenation of exercising skeletal muscle in a chronic compartment syndrome model. J Bone Joint Surg Am 79:838–843, 1997[Abstract/Free Full Text]
  6. McCully KK, Halber C, Posner JD: Exercise-induced changes in oxygen saturation in the calf muscles of elderly subjects with peripheral vascular disease. J Gerontol 49:B128–B134, 1994[Medline]
  7. Komiyama T, Shigematsu H, Yasuhara H, Muto T: Near-infrared spectroscopy grades the severity of intermittent claudication in diabetics more accurately than ankle pressure measurement. Br J Surg 87:459–466, 2000[Medline]
  8. Mohler ER III: Peripheral arterial disease: identification and implications. Arch Intern Med 163:2306–2314, 2003[Abstract/Free Full Text]
  9. Chance B, Dait MT, Zhang C, Hamaoka T, Hagerman F: Recovery from exercise-induced desaturation in the quadriceps muscles of elite competitive rowers. Am J Physiol 262:C766–C775, 1992
  10. Gardner AW, Skinner JS, Cantwell BW, Smith LK: Progressive vs single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc 23:402–408, 1991[Medline]
  11. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA: Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circ 88:2510–2516, 1993[Abstract/Free Full Text]
  12. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA: Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27:567–574, 1996[Abstract]
  13. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA: Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circ 97:1695–1701, 1998[Abstract/Free Full Text]
  14. Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK: Type 2 diabetic individuals have impaired leg blood flow responses to exercise: role of endothelium-dependent vasodilation. Diabetes Care 26:899–904, 2003[Abstract/Free Full Text]
  15. Estacio RO, Wolfel EE, Regensteiner JG, Jeffers B, Havranek EP, Savage S, Schrier RW: Effect of risk factors on exercise capacity in NIDDM. Diabetes 45:79–85, 1996[Abstract]
  16. Estacio RO, Regensteiner JG, Wolfel EE, Jeffers B, Dickenson M, Schrier RW: The association between diabetic complications and exercise capacity in NIDDM patients. Diabetes Care 21:291–295, 1998[Abstract]
  17. Katoh J, Hara Y, Kurusu M, Miyaji J, Narutaki K: Cardiorespiratory function as assessed by exercise testing in patients with non-insulin-dependent diabetes mellitus. J Int Med Res 24:209–213, 1996[Medline]

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