(Stroke. 1996;27:219-223.)
© 1996 American Heart Association, Inc.
Articles |
From the Department of Neurology, University of Münster (Germany).
Correspondence to Peter Zunker, MD, Department of Neurology, University of Münster, Albert-Schweitzer-Str 33, D-48129 Münster, Germany.
| Abstract |
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Methods One hundred ninety-four consecutive patients presenting with symptomatic cerebrovascular disease were assigned to three subgroups that were differentiated by clinical presentations, brain imaging studies, and extracranial as well as transcranial vascular ultrasound findings: (1) patients with lacunes (n=20), (2) patients with subcortical arteriosclerotic encephalopathy (n=35), and (3) patients with strokes due to large-vessel disease (n=99). Patients who had suffered a cryptogenic (n=9) or cardioembolic (n=16) stroke or who showed characteristics of the microangiopathy and macroangiopathy groups (n=15) were not further evaluated. Thirty patients without manifestations of cerebrovascular disease were also examined. Fasting blood glucose, insulin, and C-peptide levels were determined in all subjects.
Results There were no significant differences in age or sex among the three groups and control patients. Insulin levels were significantly higher in the lacunar group compared with the subcortical arteriosclerotic encephalopathy group, the macroangiopathy group, and the control patients (median [interquartile range]: 103.8 [198.6], 72.0 [103.2], 66.0 [57.0], and 52.2 [57.0] pmol/L, respectively; all P<.05, Mann-Whitney test). There was a statistically significant difference in insulin concentrations between the microangiopathy group (subcortical arteriosclerotic encephalopathy and lacunes) and the macroangiopathy and control groups (81.0 [110.4], 66.0 [57.0], and 55.2 [57.0] pmol/L, respectively; all P<.05, Mann-Whitney). The same was true for the distribution of C-peptide levels and to a minor extent blood glucose values, but these differences failed to reach statistical significance.
Conclusions Elevated insulin levels potentially represent a pathogenetic factor in the development of cerebral small-vessel disease, predominantly in patients presenting with lacunes. Whether this is due solely to atherosclerotic changes of the small penetrating arteries or whether changes in hemorheology are operative as well remains to be evaluated.
Key Words: atherosclerosis small vessel disease lacunar infarction insulin
| Introduction |
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On the basis of these experimental data and postmortem findings, we investigated whether elevated insulin levels in humans are associated with symptomatic cerebral microangiopathy compared with stroke due to large-vessel disease of the brain-supplying arteries.21 22 23 24 25 26 27
| Subjects and Methods |
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Blood was drawn for determination of levels of fasting insulin, fasting capillary blood glucose, and C peptide (Coat-A-Count Insulin RIA and Double Antibody C-Peptide, Diagnostic Product Corporation).
Diagnosis of hypertension was based either on the presence of antihypertensive treatment on admission or on three blood pressure values exceeding 160 mm Hg (systolic value) and/or 95 mm Hg (diastolic value) at least 3 days after an acute event.
Diagnosis of DM was assigned for patients either already receiving antidiabetic therapy on admission or with pathological oral glucose tolerance tests. Evaluation of the fasting glucose levels was used as a screening test in all cases, followed by a tolerance test if the level exceeded 6.38 mmol/L. A detailed history concerning actual and former smoking behavior was obtained from all patients.
The following patients were excluded from this study: (1) patients with potential cardioembolic sources of stroke (n=16; atrial fibrillation [n=10], atrial thrombus [n=2], infective endocarditis [n=1], and hypokinetic region of the left ventricle after anterior myocardial infarction [n=3]), (2) patients with cryptogenic stroke (n=9), and (3) patients with a combined macroangiopathy and microangiopathy (n=15). On the basis of the results of these investigations, the patients were divided into three etiologic subgroups.
The lacunar group (group 1) included all patients who fulfilled the following criteria: (1) normal findings on vascular ultrasound examination; (2) small deep infarctions of <1.5 cm in diameter including the deep white matter, basal ganglia, internal capsule, thalamus, and brain stem23 on brain imaging studies; and (3) clinical symptoms compatible with lacunar syndrome (pure motor, sensory stroke, ataxic hemiparesis, sensorimotor stroke, and dysarthria clumsy hand syndrome).
Group 2 consisted of patients suffering from SAE. This diagnosis was based on the following criteria: (1) diffuse periventricular and subcortical hypodensity on CT scan or hyperintensity of the same areas on T2-weighted MRI scans, (2) normal findings on vascular ultrasound examination, and (3) at least two typical clinical symptoms (eg, disorders of memory and cognition, psychiatric disturbances [disorientation, confusion, irritability, depression], long tract signs, and deterioration of gait and sphincter control). All these patients were free of a family history of strokelike episodes, dementia, and psychiatric disorders suggesting CADASIL disease.31
Group 3 consisted of patients with occlusive disease of the cerebral arteries. This was defined as a >50% stenosis detectable by extracranial or transcranial Doppler examination and/or as a local reduction in diameter >30% visible in the duplex scan of the carotid, subclavian, and vertebral arteries (V0, V1, and V2). This limit clearly exceeds normal age-related atherosclerotic changes.
Thirty patients from the neurological ward who had muscle contraction headache (n=12), herniated disks (n=8), or Parkinson's disease (n=10) underwent the same examinations and served as the control group. Thirteen patients from this group underwent MRI and 9 underwent CT scan of the skull.
Statistical analysis was performed using the two-sample
t test for normally distributed data, and the Mann-Whitney
test was used for data that were not normally distributed. Distribution
of frequency was evaluated with the
2 test.
Significance was declared at a level of P<.05.
| Results |
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There were no significant differences in age distribution among the
three groups and the normal control subjects (68±10, 67±10,
63±12,
and 67±9 years [P>.05, paired t test];
men/women distribution: 13/7, 24/11, 66/33, and 16/14
[P>.05,
2 test], groups 1, 2, 3,
and normal control subjects, respectively). The prevalence of
hypertension, DM type II, and smoking behavior is shown in Table
1
.
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The lacunar group contained the most patients with DM. None of the
examined patients suffered from type I DM. All patients with
cerebrovascular disease showed a statistically higher prevalence of
hypertension and nicotine abuse compared with the control group.
Insulin levels were significantly higher in patients with lacunar
stroke (group 1) compared with the patients with SAE, with
macroangiopathy, and the normal control subjects (median
[interquartile range]: 103.8 [198.6], 72.0
[103.2], 66.0
[57.9], 55.2 [57.0] pmol/L, respectively; all
P<.05,
Mann-Whitney test; Table 2
). The lacunar group also
showed statistically higher C-peptide levels compared with the control
patients (1.1 [0.97] and 0.73 [0.43] nmol/L, respectively;
P<.05, Mann-Whitney; Table 2
).
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Insulin and C-peptide levels did not correlate with glucose levels. Nine patients (45%) of the lacunar group, 16 (45%) of the SAE group, and 25 (25%) of the macroangiopathy group had normal blood glucose levels, whereas their insulin and/or C-peptide levels were elevated. Ten patients (18%) with cerebral microangiopathy and long-standing type II DM (lacunar group, n=6 [30%]; SAE, n=4 [11.4%]) and 15 of 99 patients (15%) of the macroangiopathy group had elevated blood glucose but normal or even low insulin and C-peptide values.
The prevalence of arterial hypertension in patients with hyperinsulinism was 76% (25 of 33) in the microangiopathy group (n=55), 68% (22 of 32) in the macroangiopathy group (n=99), and 25% (2 of 8) in the control group (n=30).
| Discussion |
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In accordance with previous studies, we also found an association between hyperinsulinism and hypertension.4 Still, this finding does not argue against the pathogenetic role of hyperinsulinemia in the development of cerebral microangiopathy. Furthermore, it cannot be the sole explanation for our results, since arterial hypertension was only diagnosed in 25 (76%) of the 33 patients with hyperinsulinemia in the microangiopathy group (lacunes and SAE).
Elevated insulin levels obviously do not play a role in the development of macroangiopathy of the brain-supplying neck arteries. Serum insulin and C-peptide values in these patients were in the same range as those in the control group. Similar results were reported on the relationship between hyperinsulinism and coronary heart disease.8 9 This could potentially be explained by the higher susceptibility of the cerebral microvascular endothelium to the mitogenic and metabolic effects of insulin compared with endothelium from other vessel territories.
High insulin and C-peptide levels are not necessarily equivalent to high blood glucose levels, as was demonstrated by the elevated insulin and/or C-peptide levels but normal blood glucose concentrations of 25 patients from the microangiopathy group. Although the same finding was recently published by Kuusisto et al,14 who identified high fasting insulin levels as an independent risk factor for stroke in nondiabetic patients, these authors provided no information concerning various stroke subtypes.
The large interquartile ranges of the insulin and C-peptide concentrations found in our microangiopathy groups were due to 10 patients with long-standing type II DM who had low insulin and C-peptide levels but high blood glucose concentrations. According to the current understanding of the temporal development of type II DM, this finding must be interpreted as an exhaustion of the insulin production after a preceding stage of hyperinsulinism.32 33 34 35
Small-vessel disease is characterized by a thickening of the basement membrane, proliferation of the endothelium, and the development of microatheroma with a high content of foam cells.21 36 Insulin can promote such changes in various ways. First, its metabolic and mitogenic effects on cerebral small-vessel endothelium may contribute to its "primary injury." Subsequent dysfunction of the endothelial cells leads to the adhesion of monocytes and platelets.14 15 16 17 19 37 38 39 Second, the capability of insulin to increase the 3-hydroxy-3-methylglutarylcoenzyme A reductase activity in monocytes and to stimulate low-density lipoprotein binding to their cell membrane may cause the formation of foam cells.40 41 This has been shown to correspond to the lipid content of arterial lesions and wall thickening in experimental animal models after long-term treatment with insulin.42 43 Third, insulin stimulates migration and proliferation of smooth muscle cells16 17 43 and enhances their cholesterol synthesis in cell cultures.44
Insulin also influences fibrinolysis. Vague et al45 reported that the changes in insulin plasma levels even within the physiological range modulate the fibrinolytic system at the PAI-1 level. Schneider and Sobel46 demonstrated increased synthesis of PAI-1 when cultured hepatocytes (hepg2) were stimulated by insulin and insulinlike growth factor. Even proinsulin augments the activity of PAI-1 in endothelial cells.47 In human atherosclerotic arteries, the expression of the PAI-1 gene is predominantly localized in the mesenchymal-appearing neointimal cells, suggesting that the expression of this gene is linked to the cellular proliferative response.48 Thus, injured endothelium can lead to increased mitogenic activity and attract and stimulate neighboring smooth muscle cells. A reduction of the fibrinolytic activity by an insulin-induced increased PAI-1 synthesis has also been postulated.45 47 These pathophysiological mechanisms based on the high susceptibility of cerebral small-vessel endothelium to the mitogenic and metabolic effects of insulin are in line with our findings in patients with cerebral small-vessel disease, which suggest that insulin does not significantly contribute to the development of macroangiopathy of the brain-supplying arteries. Hypertension and smoking are the most relevant risk factors for cerebral large-vessel disease.49 50
In conclusion, our findings of high insulin and C-peptide levels in patients with cerebral microangiopathy, and especially in those with lacunes, as opposed to patients with large-vessel disease and control subjects are in agreement with previous studies reporting a strong metabolic and mitogenic influence of insulin on small-vessel endothelium. Whether elevated insulin acts solely by stimulating the atherosclerotic process of the small penetrating arteries as such, or whether the suppression of the endogenous fibrinolysis is another crucial pathogenetic mechanism for the manifestation of cerebral microangiopathy, remains unclear. Our results suggest that hypertension and smoking, but not elevated insulin and C-peptide levels, stimulate atherosclerosis of the supra-aortic large brain arteries.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received July 10, 1995; revision received October 9, 1995; accepted October 27, 1995.
| References |
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