This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shinozaki, K. Articles by Harano, Y. Search for Related Content PubMed PubMed Citation Articles by Shinozaki, K. Articles by Harano, Y.

(Stroke. 1996;27:37-43.)
© 1996 American Heart Association, Inc.

Articles

Role of Insulin Resistance Associated With Compensatory Hyperinsulinemia in Ischemic Stroke

Kazuya Shinozaki, MD; Hiroaki Naritomi, MD; Takao Shimizu, MD; Masaaki Suzuki, MD; Motoyoshi Ikebuchi, MD; Tohru Sawada, MD Yutaka Harano, MD

From the Division of Atherosclerosis, Metabolism, and Clinical Nutrition (K.S., M.S., M.I., Y.H.) and the Division of Cerebrovascular Disease (H.N., T. Shimizu, T. Sawada), Department of Medicine, National Cardiovascular Center, Osaka, Japan.

Correspondence to Kazuya Shinozaki, MD, Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565, Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Although insulin resistance and hyperinsulinemia play a crucial role in the pathogenesis of atherosclerosis, little is known about their roles in ischemic stroke. The purpose of this study was to clarify whether insulin resistance and hyperinsulinemia are causative factors in the pathogenesis of ischemic stroke.

Methods Thirty-four consecutive patients with ischemic stroke, who were normotensive, nondiabetic, and not obese, were classified into three groups—atherothrombotic infarction (n=16), lacunar infarction (n=10), and cardioembolic infarction (n=8)—based on clinical findings, brain imaging, and cerebral angiography. Both oral glucose tolerance tests and lipid analyses were performed. Insulin sensitivity was determined by the steady state plasma glucose method with the use of octreotide acetate. Data were compared with those of healthy control subjects (n=15).

Results Steady state plasma glucose levels were significantly higher in the atherothrombotic infarction group compared with control subjects and the other two stroke groups, indicating the presence of insulin resistance in patients with atherothrombotic infarction. In the atherothrombotic infarction group, the 2-hour insulin area (area under the plasma insulin concentration curve) during a 75-g oral glucose tolerance test was significantly increased and dyslipidemic changes (increased triglyceride and apolipoprotein B, decreased high-density lipoprotein) were observed, whereas these changes were not found in the lacunar infarction and cardioembolic stroke groups.

Conclusions Insulin resistance in association with compensatory hyperinsulinemia and dyslipidemia may be an important pathogenetic factor underlying the development of atherothrombotic infarction.

Key Words: atherosclerosis • cerebral ischemia • insulin • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Identification of risk factors for stroke and awareness of their interactions yield important clues for understanding the pathogenesis of ischemic stroke. Recently, several lines of evidence have related insulin resistance and hyperinsulinemia to coronary atherosclerosis^{1 2 3 4} ; however, little attention has been paid to their role in cerebrovascular atherosclerosis.⁵ In 1969, Stout and Vallance-Owen⁶ raised the possibility that chronic hyperinsulinemia may contribute to the development of atherosclerosis by a direct effect on the artery. Harano et al⁷ demonstrated the presence of atheromatous changes in chronic insulinopenic diabetic monkeys, although whether this is a reflection of insulin resistance or a causal factor for atheroma has not been elucidated. Hypertension,⁸ obesity,⁹ and diabetes¹⁰ have been found to be associated with insulin resistance. Moreover, insulin resistance in association with hyperinsulinemia accelerates hypertension, decreases HDL cholesterol levels, and increases triglyceride levels.¹¹ Based on these observations, it is necessary to evaluate insulin sensitivity only in normotensive, nondiabetic, and nonobese subjects. The presence of pathological heterogeneity^{12 13 14 15} in the penetrating arteries of stroke subjects implies that the stenosis of penetrating arteries (ie, small arteries) may be based on a pathogenesis different from that of basal cerebral arteries (ie, large arteries). The relationships among insulin resistance, plasma insulin level, and risk of each type of ischemic stroke remain unclear, and to date no studies have addressed this question directly.

The purposes of our study were to determine insulin sensitivity in consecutively admitted normotensive, nondiabetic, and nonobese patients with brain infarcts and to evaluate the degree of insulin resistance among the different manifestations of stroke types.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Subjects
Sixteen patients with atherothrombotic infarction, 10 with lacunar infarction, 8 with cardioembolic infarction, and 15 control subjects, all of whom were younger than 65 years, were recruited into this study. All stroke subjects had been admitted to our hospital between May 1990 and July 1994 and were chosen sequentially. Since diabetes mellitus, high blood pressure, and obesity are known to produce insulin resistance, only nonobese, nondiabetic subjects with normotension were chosen to participate in the study.

The diagnosis was based on clinical features and other laboratory methods such as brain CT, MRI, echocardiography, and duplex imaging of extracranial arteries. The definitions of stroke subtypes were based on the classification of subtypes of acute ischemic stroke by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) investigators¹⁶ and classified as follows: (1) atherothrombotic infarction (large-artery atherosclerosis) (n=16); (2) lacunar infarction (small-artery occlusion) (n=10); and (3) cardioembolism (n=8).

CT examinations were performed on the first hospital day in all stroke subjects and were repeated two or more times during the observation period. MRI was also undertaken in 31 of 34 patients to identify small ischemic lesions that were not detected by CT. Intra-arterial digital subtraction arteriography was performed in all stroke subjects. Both the anteroposterior and the left oblique views of the angiograms were evaluated. In the determination of atherosclerosis, all visible atherosclerotic lesions in both projections of the angiograms were taken into account.

Exclusion criteria applied in the selection of the patients were as follows: (1) patients who were taking lipid-lowering drugs, ß-adrenergic blocking drugs, or diuretics, which may have adverse effects on carbohydrate and lipid metabolism^{17 18} ; (2) stroke subjects who did not undergo cerebral angiography; (3) subjects with acute stroke of other known etiology (eg, hypercoagulable states, nonatherosclerotic vasculopathies, or hematologic disorders) and undetermined etiology; (4) those with a history of former stroke and other macrovascular diseases (eg, myocardial infarction, angina pectoris, peripheral vascular disease); (5) the association of diabetes mellitus; hypertension (use of antihypertensive drugs or systolic and diastolic blood pressures >160/95 mm Hg); obesity (BMI >26.0 kg/m²); familial hypercholesterolemia; and hepatic, renal, and endocrine dysfunction; (6) physically extremely inactive subjects (Frenchay Activities Index <27); and (7) any subjects with polycythemia or rheumatic and inflammatory diseases. All subjects gave their informed consent, and the study protocol was approved by the Ethical Committee of the National Cardiovascular Center.

Baseline Study
The mean interval between the cerebral angiography and metabolic evaluation (blood sampling) was 5.4 months (range, 3 to 10 months). Venous blood samples were drawn from each subject after an overnight fast for measurement of plasma glucose, insulin, total cholesterol, triglyceride, HDL cholesterol, and apolipoproteins A-I and B. LDL cholesterol levels were calculated according to the Friedewald equation¹⁹ : LDL cholesterol (millimolar)=total cholesterol-HDL cholesterol-triglyceride/2.2. Hyperlipoproteinemias were defined according to the World Health Organization classification.²⁰ The cutoff points were 6.0 mmol/L for total cholesterol, 1.7 mmol/L for triglyceride, and 1.03 mmol/L for HDL cholesterol. A 75-g load of glucose (Trelan G 75, Shimizu Co) was administered, and blood samples (glucose and insulin) were drawn at 30, 60, and 120 minutes. Plasma glucose and insulin responses to glucose ingestion were evaluated by calculation of the glucose and insulin areas throughout the 120 minutes of the test period. The classification of glucose tolerance was based on a 2-hour oral glucose tolerance test according to World Health Organization criteria.²¹ Glucose was determined by the glucose oxidase method²² and insulin by radioimmunoassay with the use of a double antibody.²³ Total cholesterol,²⁴ triglyceride,²⁵ HDL cholesterol,²⁶ and apolipoproteins A-I and B²⁷ levels were determined as described previously. After a 15-minute rest, a mercury sphygmomanometer was used to obtain systolic and diastolic (phase V Korotkoff sound) blood pressures, and the averages of the two blood pressure values were used for data analyses. Study subjects were classified as nonsmokers if they had never smoked or stopped smoking at least 1 year before cerebral catheterization. All the other subjects were classified as smokers. The number of cigarette-years was used as a cumulative estimate of tobacco consumption (pieces per day times years). BMI was calculated from the formula BMI=weight (kilograms)/height (meters)². The Frenchay Activities Index was used to measure physical activity and handicap after the stroke.²⁸

Insulin Sensitivity Test
Insulin sensitivity tests were performed in all study subjects. Insulin sensitivity was estimated by the SSPG method²⁹ with the use of octreotide acetate (Sandostatin; Sandoz) originally described by Harano et al.³⁰ An adequate dose of octreotide acetate was used to suppress endogenous insulin secretion.³¹ After an overnight fast, glucose (6 mg/kg per minute), KCl (0.5 µEq/kg per minute), Novolin R40 insulin (7.5 mU/kg in a bolus, followed by a constant infusion at a rate of 0.77 mU/kg per minute), and octreotide acetate (150 µg/2 h) were infused simultaneously for 2 hours at a rate of 3 mL/kg per hour through an antecubital vein by a constant infusion pump. Blood samples were obtained at 0, 30, and 120 minutes for the determination of plasma glucose and insulin. SSPG and SSPI concentrations were obtained at 120 minutes. Under these steady state conditions, plasma glucose levels are inversely correlated with the rate of insulin-mediated glucose disposal and are inversely proportional to insulin sensitivity.²⁹ Plasma catecholamine (epinephrine and norepinephrine) levels were determined with the use of high-performance liquid chromatography with spectrofluorometric detection.³²

Statistical Analysis
Data are expressed as mean±SEM. Statistical analysis was performed with the SAS computer program (SAS Institute). Student's t test (continuous variables) was used to test the significance of the differences between two groups. Group differences of categorical data were tested by ² analysis with Yates' correction. SSPG and SSPI levels in the four groups during the oral glucose tolerance test, blood pressure, and lipid and lipoprotein concentrations were compared with one-way ANOVA. Pearson's correlation coefficients were calculated to determine the relationship between SSPG and lipid variables. Differences with values of P<.05 were considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of the Study Subjects
The clinical characteristics of the study subjects are shown in Table 1. No statistical differences were observed between control subjects and the three groups of stroke patients in terms of age, sex, BMI, or blood pressure. All four groups showed similar proportions of subjects with impaired glucose tolerance and smokers. The Frenchay Activities Index was significantly lower in stroke patients compared with control subjects (P<.05). However, there were no significant differences among the three stroke groups in the levels of the activity index. Analysis of phenotypes for dyslipoproteinemia showed a significantly increased prevalence of phenotype IV in patients with atherothrombotic infarction.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Study Subjects

All study subjects had a hemispheric infarction except for 2 patients with lacunar infarction in the pons. Of 10 patients with lacunar infarction, 3 had a small deep infarct in the basal ganglia, 5 in the internal capsule, and the remainder in the pons. Of 16 patients with atherothrombotic infarction, 8 had atherothrombotic stenosis (stenosis >50%) in the extracranial internal carotid artery, 6 had stenosis in the trunk of the middle cerebral artery, and the remaining 2 had stenosis in the basilar artery. All 10 patients with lacunar infarction and 6 with cardioembolic infarction had no stenotic lesions (<25% stenosis of the luminal diameter) in both large intracranial and extracranial arteries. The other 2 patients with cardioembolic infarction had embolic shadow. Carotid or vertebrobasilar dissection and fibromuscular dysplasia were excluded by means of cerebral angiography.

Plasma Lipid, Lipoprotein, and Apolipoprotein Levels
Plasma concentrations of lipid, lipoprotein, and apolipoprotein are shown in Table 2. Compared with the control subjects and the other two stroke groups, triglyceride and apolipoprotein B levels were significantly elevated in patients with atherothrombotic infarction. HDL cholesterol level was markedly decreased in those with atherothrombotic infarction compared with the other three groups. Although the apolipoprotein A-I level showed a tendency toward reduction in those with atherothrombotic infarction, none of the differences reached statistical significance. The four groups had no significant difference in the levels of total cholesterol and LDL cholesterol. Plasma catecholamine levels were comparable among the groups.

View this table: [in this window] [in a new window]   Table 2. Plasma Concentrations of Lipids and Apolipoprotein B in Study Subjects

Plasma Glucose and Insulin Levels
Plasma glucose and insulin responses in the four study groups during a 75-g oral glucose tolerance test are shown in Figs 1 and 2. The plasma glucose responses (Fig 1) and 2-hour glucose areas (Fig 2) in the four groups were the same. On the other hand, the insulin responses were significantly higher at 30, 60, and 120 minutes in patients with atherothrombotic infarction compared with the control subjects and the other two stroke groups (Fig 1). While patients with cardioembolism and those with lacunar infarction (527.9±78.6, 478.4±46.9 pmol/Lxh, respectively) had 2-hour insulin areas nearly identical to that in control subjects (501.2±59.2 pmol/Lxh), patients with atherothrombotic infarction (1123.5±152.0 pmol/Lxh) had a significantly greater 2-hour insulin area compared with the control group and the other two stroke groups (Fig 2).

View larger version (18K): [in this window] [in a new window]   Figure 1. Line graphs show plasma glucose (top) and insulin (bottom) responses to a 75-g oral glucose load. Symbols represent control subjects (n=15), patients with cardioembolic infarction (n=8), patients with lacunar infarction (n=10), and patients with atherothrombotic infarction (n=16). *P<.05, §P<.01, patients with cardioembolic infarction and lacunar infarction significantly different from control subjects (ANOVA). Values are mean±SEM.

View larger version (33K): [in this window] [in a new window]   Figure 2. Bar graphs show plasma glucose (top) and insulin (bottom) areas during 75-g oral glucose load. *P<.001, §P<.01, significantly different from patients with atherothrombotic infarction (ANOVA). Values are mean±SEM.

Results of Insulin Sensitivity Test
SSPG levels of the four groups are plotted in Fig 3. The mean SSPG levels were significantly (P<.001) higher in patients with atherothrombotic infarction (10.6±0.6 mmol/L) compared with the control subjects, patients with cardioembolism, and patients with lacunar infarction (5.3±0.4, 4.3±0.5, and 5.1±0.6 mmol/L, respectively). No elevation of SSPG levels was observed in patients with cardioembolic infarction and those with lacunar infarction. SSPI levels showed no significant difference among the four groups. These results clearly indicate the presence of an insulin resistance for glucose utilization in those with atherothrombotic infarction and its absence in those with lacunar infarction or cardioembolic infarction. The group with atherothrombosis was divided into two subgroups: large-artery thrombosis with evidence of occlusive lesions in the intracranial cerebral artery (n=8) and the extracranial cerebral artery (n=8). However, no differences were found with respect to mean SSPG and SSPI levels (Fig 4) and concentrations of plasma lipids and lipoproteins (data not shown). In patients with atherothrombotic infarction, SSPG levels were positively correlated with triglyceride (r=.58, P<.01) and apolipoprotein B (r=.44, P<.05) levels and inversely correlated with HDL cholesterol levels (r=-.62, P<.01). Similar results were obtained when the analyses were repeated after adjustment for sex.

View larger version (17K): [in this window] [in a new window]   Figure 3. Plots show SSPG (left) and SSPI (right) levels during insulin sensitivity tests in control subjects and patients with cardioembolic infarction, lacunar infarction, and atherothrombotic infarction.

View larger version (14K): [in this window] [in a new window]   Figure 4. Plots show SSPG (left) and SSPI (right) levels during insulin sensitivity tests in atherothrombotic patients with stenotic lesions in intracranial or extracranial cerebral arteries.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study is the first to demonstrate severe insulin resistance and compensatory hyperinsulinemia in patients with atherothrombotic infarction, which was found to be absent in patients with lacunar and cardioembolic infarctions. Insulin resistance was correlated positively with triglyceride and apolipoprotein B levels and inversely with HDL cholesterol levels. These results suggest that insulin resistance in association with compensatory hyperinsulinemia may contribute to the pathogenesis of large–cerebral artery atherosclerosis.

Regardless of differences in study designs and populations, there is growing evidence for a strong association between hyperinsulinemia and coronary atherosclerosis.^{1 2 3 4} We recently reported that insulin resistance and compensatory hyperinsulinemia were strongly associated with occlusive coronary artery disease³³ as well as vasospastic angina.³⁴ However, much less is known about the association of insulin resistance and ischemic stroke. Gertler et al⁵ found that abnormally high insulin responses during oral glucose tolerance tests were present in ischemic thrombotic cerebrovascular disease. In a prospective study including 1069 nondiabetic subjects with a mean 3.5-year follow-up, there was clear evidence of a relationship between fasting insulin level and incidence of stroke.³⁵ However, no separate analyses were performed on patients with atherothrombotic infarction (ie, large-vessel disease) or lacunar infarction (ie, small-vessel disease).

To exclude the possibility that patients with lacunar infarction may have relevant stenosis of a large parent artery,³⁶ we selected subjects with lacunar infarction who showed no definitive major-artery stenosis on angiography. Therefore, it is conceivable that a specific type of lacunar infarction may have been selected. The present results provide an important clue for elucidating the differences in the atherosclerotic process between large-artery and small-artery disease. Because there is strong evidence that insulin insensitivity is directly related to BMI⁹ and blood pressure,⁸ we carefully screened nonobese normotensive patients for the subjects in the present study. Insulin resistance is known to be associated with physical inactivity³⁷ and alterations in sympathetic nervous activity.³⁸ Physically inactive persons were therefore excluded from the study. In the present study daily activity was significantly decreased in stroke patients compared with control subjects. However, there were no significant differences among the three groups of stroke patients in the levels of activity index. Patients with lacunar infarction and cardioembolic infarction showed no statistically significant elevation in SSPG levels compared with control subjects. Therefore, it is unlikely that the observed insulin resistance in patients with atherothrombotic infarction was attributable to reduction of physical activity. Moreover, there were no differences among the four groups in terms of plasma catecholamine levels. Since we did not perform CT, MRI, or cerebral angiography in control subjects, we cannot completely rule out the possibility that some control subjects might have silent brain infarction or intracranial/extracranial atherosclerotic lesions. Since age and hypertension are known to be strongly and independently correlated with the occurrence of silent brain infarction,^{39 40} we selected patients younger than 65 years and normotensive subjects. Previous studies have demonstrated that acute stroke affects the plasma lipid levels in the acute phase, especially within the 48 hours after stroke.^{41 42} Therefore, we collected the blood samples for analyses at least 3 months after ischemic events.

Laakso et al,⁴³ using the euglycemic insulin clamp technique, first demonstrated the presence of insulin resistance in patients with asymptomatic atherosclerosis in the femoral or carotid arteries. In their study subjects with atherosclerosis in the femoral or carotid arteries showed a 20% reduction in whole-body glucose uptake. However, plasma insulin levels during an oral glucose tolerance test were maintained at normal levels in these subjects. In the present study patients with atherothrombotic infarction showed twofold higher values in 2-hour insulin area by oral glucose tolerance test and SSPG levels. The patients in the present study had more advanced atherosclerotic lesions in the carotid arteries and intracranial cerebral arteries compared with those in the study of Laakso et al. Therefore, the discrepancy of the results may be in part attributable to such differences in the stage of atherosclerosis.

It remains unclear whether the decrease of insulin sensitivity in patients with atherothrombotic infarction is essential for the development of cerebral artery atherosclerosis or simply reflects coincidental association. Hyperinsulinemia is often associated with insulin resistance in patients with non–insulin-dependent diabetes mellitus, obese subjects, or hypertensive subjects. In our patients with atherothrombotic infarction, insulin resistance and compensatory hyperinsulinemia were observed despite the absence of these conditions. Studies on the cell biology of the arterial wall and experimental pathology indicate that hyperinsulinemia can exert a direct effect on atherogenesis.^{44 45 46} Other studies have demonstrated that insulin stimulates arterial smooth muscle cell proliferation,^{47 48} cholesterol synthesis,⁴⁹ and LDL binding in arterial smooth muscle cells and macrophages.⁵⁰

A separate question is whether the effects of insulin resistance on cerebrovascular atherosclerosis are mediated through risk factors such as lipid disturbances. Lipid or lipoprotein abnormalities have been shown to affect mainly the large cerebral arteries in quite a few reports,⁵¹ whereas the effect of hypertension appears to primarily affect the small intracranial vessels.^{51 52} Few reports have identified the risk factors for atherosclerosis of intracranial and extracranial cerebral arteries.^{53 54} Since there appears to be some difference in the atherosclerotic process between intracranial and extracranial arteries, the risk factors for them should be analyzed separately. We found no statistical differences between intracranial and extracranial arteries in regard to SSPG levels and 2-hour insulin area. Reaven et al⁵⁵ demonstrated that insulin resistance has been associated with small, dense LDL particles, which are known to be atherogenic. In the present study the patients with atherothrombotic infarction had high levels of triglyceride and apolipoprotein B and low HDL cholesterol levels, and their SSPG levels were correlated positively with triglyceride and apolipoprotein B and inversely with HDL cholesterol levels. The aforementioned dyslipidemic changes of lipids and lipoproteins in the presence of insulin resistance and compensatory hyperinsulinemia likely accelerate the progression of atheromatous lesions. Hyperinsulinemia may enhance very-low-density lipoprotein production in the liver, contributing to the dyslipidemic alterations.⁵⁶

Our results suggest that no relationship exists between insulin resistance and lacunar infarction. However, only the patients with lacunar infarction who had no major-artery lesion were examined for comparison with those with major-artery disease. In this context, our cases of lacunar infarction are specific. The present results, therefore, may not be directly applicable to the more common type of lacunar infarction, which may be associated with major-artery disease.

In conclusion, these data suggest that insulin resistance in association with compensatory hyperinsulinemia and dyslipidemia may be an important pathogenetic factor underlying the development of atherothrombotic infarction.

	Selected Abbreviations and Acronyms

 

BMI = body mass index HDL = high-density lipoprotein LDL = low-density lipoprotein SSPG = steady state plasma glucose SSPI = steady state plasma insulin

	Acknowledgments

 
This study was supported by Special Coordination Funds for Promoting Science and Technology (Encouragement System of Center of Excellence) from the Science and Technology Agency of Japan. We wish to express our gratitude to Dr Yasushi Hara of the Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Dr Wataru Kakuda, Dr Seiji Kazui, Dr Koutaro Miyashita, and Dr Kazuyuki Nagatsuka of the Division of Cerebrovascular Disease for helpful guidance and suggestions.

Received July 10, 1995; revision received September 29, 1995; accepted September 29, 1995.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
1. Pyörälä K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care. 1979;2:131-141. [Abstract]

2. Welborn TA, Werarne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentration. Diabetes. 1979;2:154-160.

3. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia. 1980;19:205-210. [Medline] [Order article via Infotrieve]

4. Rönnemaa T, Laakso M, Pyörälä K, Kallio V, Puukka P. High fasting plasma insulin is an indicator of coronary heart disease in non–insulin-dependent diabetic patients and nondiabetic subjects. Arterioscler Thromb.. 1991;11:80-90. [Abstract/Free Full Text]

5. Gertler MM, Leetma HE, Koutrouby RJ, Johnson ED. The assessment of insulin, glucose and lipids in ischemic thrombotic cerebrovascular disease. Stroke. 1975;6:77-84. [Abstract/Free Full Text]

6. Stout RW, Vallance-Owen J. Insulin and atheroma. Lancet. 1969;1:1078-1080. [Medline] [Order article via Infotrieve]

7. Harano Y, Kojima H, Kosugi K, Suzuki M, Harada M, Nakao T, Hidaka H, Kashiwagi A, Torii R, Taniguchi Y, Nishimori T, Yasuda Y, Shigeta Y. Hyperlipidemia and atherosclerosis in experimental insulinopenic diabetic monkeys. Diabetes Res Clin Pract. 1992;16:163-173. [Medline] [Order article via Infotrieve]

8. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357. [Abstract]

9. Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J Clin Endocrinol Metab. 1990;70:1114-1118. [Abstract/Free Full Text]

10. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for qualifying insulin secretion and resistance. Am J Physiol. 1979;273:E214-E223.

11. Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med. 1992;231:25-30. [Medline] [Order article via Infotrieve]

12. Ooneda G. Pathology of stroke. Jpn Circ J. 1986;50:1224-1234. [Medline] [Order article via Infotrieve]

13. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke. 1988;19:1083-1092. [Abstract/Free Full Text]

14. Challa VR, Bell MA, Moody DM. A combined hematoxylin-eosin, alkakine phosphatase and high-resolution microradiographic study of lacunes. Clin Neuropathol. 1990;9:196-204. [Medline] [Order article via Infotrieve]

15. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol (Berl).. 1969;12:1-15.

16. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Lobe BB, Gordon DL, Marsh EE, and the TOAST Investigators. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke. 1993;24:35-41. [Abstract/Free Full Text]

17. Fishman WH. Beta-adrenergic receptor blockers: adverse effects and drug interactions. Hypertension. 1988;11(suppl II):II-21-II-29.

18. Weinberger MH. Diuretics and their side effects: dilemma in the treatment of hypertension. Hypertension. 1988;11(suppl II):II-16-II-20.

19. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifugation. Clin Chem. 1972;18:499-502. [Abstract]

20. Beaumont JL, Carlson LA, Cooper GR, Fejfar Z, Fredrickson DS, Strasser T. Memorandum on classification of hyperlipidemias and hyperlipoproteinemias. Bull World Health Organ.. 1970;43:891-898. [Medline] [Order article via Infotrieve]

21. World Health Organization. Definition, Diagnosis, and Classification: Diabetes Mellitus: Report of a WHO Study Group. Geneva, Switzerland: World Health Organization; 1985:9-25. Technical Report Series 727.

22. Hoffman WS. A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem. 1937;120:52-55.

23. Hale CN, Randle PJ. Immunoassay of insulin with insulin-antibody precipitate. Biochem J. 1963;88:137-146. [Medline] [Order article via Infotrieve]

24. Richmond W. Preparation and properties of a cholesterol oxidase from Nacardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem. 1973;19:1350-1356. [Abstract]

25. Fletcher MJ. A colorimetric method for estimating serum triglycerides. Clin Chim Acta. 1968;22:393-397. [Medline] [Order article via Infotrieve]

26. Didez LI. Separation and quantitation of subclasses of human plasma high density lipoproteins by a single precipitation procedure. J Lipid Res. 1982;23:1206-1223. [Abstract]

27. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Int J Immunochem. 1965;2:235-240.

28. Schuling J, Haan D, Limburg M, Groenier KH. The Frenchay Activities Index: assessment of functional status in stroke patients. Stroke. 1993;24:1173-1177. [Abstract/Free Full Text]

29. Harano Y, Hidaka H, Takatsuki K, Ohgaku S, Haneda M, Motoi S, Shigeta Y, Abe H. Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo. Metabolism. 1978;27(suppl I):1449-1452.

30. Harano Y, Kageyama A, Hirose J, Asakura Y, Yokota C, Ikebuchi M, Suzuki M, Omae T. Improvement of insulin sensitivity for glucose metabolism with long-acting Ca channel blocker, amlodipine in essential hypertensive subjects. Metabolism. 1995;44:315-319. [Medline] [Order article via Infotrieve]

31. Ikebuchi M, Suzuki M, Kageyama A, Hirose J, Yokota C, Ikeda K, Shinozaki K, Harano Y. Modified method using Sandostatin to assess in vivo insulin sensitivity. Endocr J. In press.

32. Nohta H, Mitsui A, Ohkura Y. Spectrofluorometric determination of catecholamines with 1,2-diphenylethylenediamine. Anal Chim Acta.. 1984;165:171-176.

33. Shinozaki K, Suzuki M, Ikebuchi M, Hara Y, Harano Y. Demonstration of insulin resistance in coronary artery disease documented with angiography. Diabetes Care. In press.

34. Shinozaki K, Suzuki M, Ikebuchi M, Takaki H, Hara Y, Tsushima M, Harano Y. Insulin resistance associated with compensatory hyperinsulinemia as an independent risk factor for vasospastic angina. Circulation. 1995;92:1749-1757. [Abstract/Free Full Text]

35. Kuusisto J, Mykkänen L, Pyörälä K, Laakso M. Non–insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke. 1994;25:1157-1164. [Abstract]

36. Bogousslavsky J, Regli F, Maeder P. Intracranial large-artery disease and `lacunar' infarction. Cerebrovasc Dis. 1991;1:154-159.

37. Regensteiner JG, Mayer EJ, Shetterly SM, Eckel RH, Haskell WL, Marshall JA, Baxter J, Hamman RF. Relationship between habitual physical activity and insulin levels among nondiabetic men and women: San Luis Valley Diabetes Study. Diabetes Care. 1991;14:1066-1074. [Abstract]

38. Lager I, Atvall S, Eriksson M, von Schenk H, Smith U. Studies on the insulin-antagonistic effect of catecholamines in normal man. Diabetologia. 1986;29:409-416. [Medline] [Order article via Infotrieve]

39. Herderschee D, Hijdra A, Algra A, Koudstaal PJ, Kappelle LJ, van Gijn J. Silent stroke in patients with transient ischemic attack or minor ischemic stroke. Stroke. 1992;23:1220-1224. [Abstract/Free Full Text]

40. Ricci S, Celani MG, La Rosa F, Righetti E, Duca E, Caputo N. Silent infarction in patients with first-ever stroke: a community-based study in Umbria, Italy. Stroke. 1993;24:647-651. [Abstract/Free Full Text]

41. Mendez I, Hachinski V, Wolfe B. Serum lipids after stroke. Neurology. 1987;37:507-511. [Abstract/Free Full Text]

42. Woo J, Lam CWK, Kay R, Wong HY, Teoh R, Nicholls MG. Acute and long-term changes in serum lipids after acute stroke. Stroke. 1990;21:1407-1441. [Abstract/Free Full Text]

43. Laakso M, Sarlund H, Salonen R, Suhonen M, Pyörälä K, Salonen JT, Karhapää P. Asymptomatic atherosclerosis and insulin resistance. Arterioscler Thromb. 1991;11:1068-1076. [Abstract/Free Full Text]

44. Marquie G. Effect of insulin in the induction and regression of experimental cholesterol atherosclerosis in the rabbit. Postgrad Med. 1978;54:80-85. [Abstract/Free Full Text]

45. Cruz AB Jr, Amatuzio DS, Grande F, Hay LJ. Effect of intraarterial insulin on tissue cholesterol and fatty acids in alloxan-diabetic dogs. Circ Res. 1961;9:38-43.

46. Sato Y, Shiraishi S, Oshida Y, Ishiguro, Sakamoto N. Experimental atherosclerosis-like lesions induced by hyperinsulinism in Wistar rats. Diabetes. 1989;38:91-96. [Abstract]

47. Stout RW. Development of vascular lesions in insulin-treated animals fed a normal diet. Br Med J. 1970;3:685-687.

48. Pfeifle B, Ditschuneit H. Two separate receptors for insulin and insulin-like growth factors on arterial smooth muscle cells. Diabetologia. 1981;20:155-158. [Medline] [Order article via Infotrieve]

49. Stout RW. The effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells. Atherosclerosis. 1977;27:271-278. [Medline] [Order article via Infotrieve]

50. Oppenheimer MJ, Sundquist K, Bierman EL. Downregulation of high-density lipoprotein receptor in human fibroblasts by insulin and IGF-I. Diabetes. 1989;38:117-122. [Abstract]

51. Solberg LA, McGarry PA. Cerebral atherosclerosis in Negroes and Caucasians. Atherosclerosis. 1972;16:141-154. [Medline] [Order article via Infotrieve]

52. Mathew NT, Davis D, Meyer JS, Chander K. Hyperlipoproteinemia in occlusive cerebrovascular disease. JAMA. 1975;232:262-266. [Abstract/Free Full Text]

53. Harrison MJG, Wilson LA. Effect of blood pressure on prevalence of carotid atheroma. Stroke. 1983;14:550-551. [Abstract/Free Full Text]

54. Crouse JR, Toole JF, McKinney WM, Dignan MB, Howard G, Kahl FR, McMahan MR, Harpold GH. Risk factors for extracranial carotid artery atherosclerosis. Stroke. 1987;18:990-996. [Abstract/Free Full Text]

55. Reaven GM, Chen YDI, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J Clin Invest.. 1993;92:141-146.

56. Harano Y, Nakao Y, Kageyama A, Suzuki M, Hirose J, Asakura Y, Sato A, Komatsu R, Tsushima M, Yamamoto A. Contribution of hyperinsulinemia and hyperglycemia to lipoprotein disorder in obesity. In: Oomura Y, Tarui S, Inoue S, Shimazu T, eds. Progress in Obesity Research. London, UK: John Libbey & Co Ltd; 1990:299-302.

This article has been cited by other articles:

				T. Urabe, H. Watada, Y. Okuma, R. Tanaka, Y. Ueno, N. Miyamoto, Y. Tanaka, N. Hattori, and R. Kawamori Prevalence of Abnormal Glucose Metabolism and Insulin Resistance Among Subtypes of Ischemic Stroke in Japanese Patients Stroke, April 1, 2009; 40(4): 1289 - 1295. [Abstract] [Full Text] [PDF]

				W T. Cade Diabetes-Related Microvascular and Macrovascular Diseases in the Physical Therapy Setting Physical Therapy, November 1, 2008; 88(11): 1322 - 1335. [Abstract] [Full Text] [PDF]

				N. Asfandiyarova, N. Kolcheva, I. Ryazantsev, and V. Ryazantsev Risk factors for stroke in type 2 diabetes mellitus Diabetes and Vascular Disease Research, May 1, 2006; 3(1): 57 - 60. [Abstract] [PDF]

				B. Erdos, J. A. Snipes, C. D. Tulbert, P. Katakam, A. W. Miller, and D. W. Busija Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1264 - H1270. [Abstract] [Full Text] [PDF]

				H. J. Milionis, E. Rizos, J. Goudevenos, K. Seferiadis, D. P. Mikhailidis, and M. S. Elisaf Components of the Metabolic Syndrome and Risk for First-Ever Acute Ischemic Nonembolic Stroke in Elderly Subjects Stroke, July 1, 2005; 36(7): 1372 - 1376. [Abstract] [Full Text] [PDF]

				B. Erdos, J. A. Snipes, B. Kis, A. W. Miller, and D. W. Busija Vasoconstrictor mechanisms in the cerebral circulation are unaffected by insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1456 - R1461. [Abstract] [Full Text] [PDF]

				B. Erdos, J. A. Snipes, A. W. Miller, and D. W. Busija Cerebrovascular Dysfunction in Zucker Obese Rats Is Mediated by Oxidative Stress and Protein Kinase C Diabetes, May 1, 2004; 53(5): 1352 - 1359. [Abstract] [Full Text] [PDF]

				G.E. Schuitemaker, G.J. Dinant, G.A. Van Der Pol, A.F.M. Verhelst, and A. Appels Vital Exhaustion as a Risk Indicator for First Stroke Psychosomatics, April 1, 2004; 45(2): 114 - 118. [Abstract] [Full Text] [PDF]

				B. Erdos, S. A. Simandle, J. A. Snipes, A. W. Miller, and D. W. Busija Potassium Channel Dysfunction in Cerebral Arteries of Insulin-Resistant Rats Is Mediated by Reactive Oxygen Species Stroke, April 1, 2004; 35(4): 964 - 969. [Abstract] [Full Text] [PDF]

				W. N. Kernan, S. E. Inzucchi, C. M. Viscoli, L. M. Brass, D. M. Bravata, G. I. Shulman, J. C. McVeety, and R. I. Horwitz Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke Neurology, May 13, 2003; 60(9): 1447 - 1451. [Abstract] [Full Text] [PDF]

				M. G. Wulffele, A. Kooy, P. Lehert, D. Bets, J. C. Ogterop, B. Borger van der Burg, A. J.M. Donker, and C. D.A. Stehouwer Combination of Insulin and Metformin in the Treatment of Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2133 - 2140. [Abstract] [Full Text] [PDF]

				B. Erdos, A. W. Miller, and D. W. Busija Alterations in KATP and KCa channel function in cerebral arteries of insulin-resistant rats Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2472 - H2477. [Abstract] [Full Text] [PDF]

				A. H. FRIEDLANDER, N. R. GARRETT, and D. C. NORMAN The prevalence of calcified carotid artery atheromas on the panoramic radiographs of patients with type 2 diabetes mellitus J Am Dent Assoc, November 1, 2002; 133(11): 1516 - 1523. [Abstract] [Full Text] [PDF]

				W. N. Kernan, S. E. Inzucchi, C. M. Viscoli, L. M. Brass, D. M. Bravata, and R. I. Horwitz Insulin resistance and risk for stroke Neurology, September 24, 2002; 59(6): 809 - 815. [Abstract] [Full Text] [PDF]

				E. Rizos and D. P Mikhailidis Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res, November 1, 2001; 52(2): 199 - 207. [Abstract] [Full Text] [PDF]

				K. Kain, A. J. Catto, J. Young, J. Bamford, J. Bavington, and P. J. Grant Insulin Resistance and Elevated Levels of Tissue Plasminogen Activator in First-Degree Relatives of South Asian Patients With Ischemic Cerebrovascular Disease Stroke, May 1, 2001; 32(5): 1069 - 1073. [Abstract] [Full Text] [PDF]

				K. Kario, T. Matsuo, H. Kobayashi, S. Hoshide, and K. Shimada Hyperinsulinemia and hemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects J. Am. Coll. Cardiol., March 1, 2001; 37(3): 871 - 877. [Abstract] [Full Text] [PDF]

				S. I. McFarlane, M. Banerji, and J. R. Sowers Insulin Resistance and Cardiovascular Disease J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 713 - 718. [Full Text]

				T. J. Tegos, E. Kalodiki, S.-S. Daskalopoulou, and A. N. Nicolaides Stroke: Epidemiology, Clinical Picture, and Risk Factors: Part I of III Angiology, October 1, 2000; 51(10): 793 - 808. [Abstract] [PDF]

				K. Shinozaki, Y. Nishio, T. Okamura, Y. Yoshida, H. Maegawa, H. Kojima, M. Masada, N. Toda, R. Kikkawa, and A. Kashiwagi Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats Circ. Res., September 29, 2000; 87(7): 566 - 573. [Abstract] [Full Text] [PDF]

				H.-M. Lakka, T. A. Lakka, J. Tuomilehto, J. Sivenius, and J. T. Salonen Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study Arch Intern Med, April 24, 2000; 160(8): 1160 - 1168. [Abstract] [Full Text] [PDF]

				S. Soderberg, B. Ahren, B. Stegmayr, O. Johnson, P.-G. Wiklund, L. Weinehall, G. Hallmans, and T. Olsson Leptin Is a Risk Marker for First-Ever Hemorrhagic Stroke in a Population-Based Cohort Stroke, February 1, 1999; 30(2): 328 - 337. [Abstract] [Full Text] [PDF]

				M. L. Goalstone, R. Natarajan, P. R. Standley, M. F. Walsh, J. W. Leitner, K. Carel, S. Scott, J. Nadler, J. R. Sowers, and B. Draznin Insulin Potentiates Platelet-Derived Growth Factor Action in Vascular Smooth Muscle Cells Endocrinology, October 1, 1998; 139(10): 4067 - 4072. [Abstract] [Full Text] [PDF]

				J. R. Sowers Obesity and cardiovascular disease Clin. Chem., August 1, 1998; 44(8): 1821 - 1825. [Abstract] [Full Text] [PDF]

				C. M. Burchfiel, D. S. Sharp, J. D. Curb, B. L. Rodriguez, R. D. Abbott, R. Arakaki, and K. Yano Hyperinsulinemia and Cardiovascular Disease in Elderly Men : The Honolulu Heart Program Arterioscler. Thromb. Vasc. Biol., March 1, 1998; 18(3): 450 - 457. [Abstract] [Full Text] [PDF]

				K. Shinozaki, Y. Hattori, M. Suzuki, Y. Hara, A. Kanazawa, H. Takaki, M. Tsushima, and Y. Harano Insulin Resistance as an Independent Risk Factor for Carotid Artery Wall Intima Media Thickening in Vasospastic Angina Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 3302 - 3310. [Abstract] [Full Text]

				R. L. Sacco, E. J. Benjamin, J. P. Broderick, M. Dyken, J. D. Easton, W. M. Feinberg, L. B. Goldstein, P. B. Gorelick, G. Howard, S. J. Kittner, et al. Risk Factors Stroke, July 1, 1997; 28(7): 1507 - 1517. [Full Text]

				J. R. Sowers Insulin and Insulin-Like Growth Factor in Normal and Pathological Cardiovascular Physiology Hypertension, March 1, 1997; 29(3): 691 - 699. [Full Text]

				M. Suzuki, K. Shinozaki, A. Kanazawa, Y. Hara, Y. Hattori, M. Tsushima, and Y. Harano Insulin Resistance as an Independent Risk Factor for Carotid Wall Thickening Hypertension, October 1, 1996; 28(4): 593 - 598. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shinozaki, K. Articles by Harano, Y. Search for Related Content PubMed PubMed Citation Articles by Shinozaki, K. Articles by Harano, Y.