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(Stroke. 1996;27:219-223.)
© 1996 American Heart Association, Inc.

Articles

Hyperinsulinism and Cerebral Microangiopathy

Peter Zunker, MD; Achim Schick; Hans-Christian Buschmann; Dimitrios Georgiadis, MD; Darius G. Nabavi, MD; Michael Edelmann, MD E. Bernd Ringelstein, MD

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose High insulin levels are a recognized risk factor for atherosclerosis. Microvascular endothelium is more susceptible to metabolic and mitogenic effects of insulin than large-vessel endothelium. Besides their atherogenic effect, high insulin levels impair fibrinolysis by enhancing plasminogen activator inhibitor–1. We undertook this study to evaluate the hypothesis that elevated serum insulin and C-peptide levels are related to cerebral small-vessel disease rather than large-vessel pathology.

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Atherosclerosis is the main cause of myocardial and cerebral infarction.¹ While the causative role of hyperinsulinism in the development of coronary heart disease is still a matter of discussion,^{2 3 4 5 6 7 8 9 10} several studies have demonstrated increased insulin responses and elevated glucose levels after oral glucose stimulation^{11 12 13} or elevated fasting insulin levels¹⁴ in patients with cerebrovascular events. Experimental data showed a great difference in the biological response to insulin between small- and large-vessel endothelium.¹⁵ King et al¹⁶ found an increased insulin-induced [C¹⁴]glucose incorporation into glycogen of bovine retinal endothelium and pericytes but not into aortic endothelial cells. Mouse brain microvessels showed greater uptake of aminoisobutyric acid than bovine aortic endothelium in response to identical insulin levels.¹⁷ A pronounced insulin-induced stimulation of DNA synthesis was observed in microvascular endothelium of various species, such as bovine retinal capillary endothelial cells,¹⁸ mouse brain microvessel endothelium,¹⁹ and human cerebral microvessel endothelium.²⁰ This mitogenic effect, however, was not seen in bovine aortic endothelial cells.¹⁸ Small-vessel disease of diabetic patients is characterized by a thickening of the basement membrane and by proliferation of the endothelium.²¹

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
One hundred ninety-four consecutive patients (125 men and 69 women, age 66±6 years) presenting with an acute ischemic stroke were examined in this study according to a standard protocol entailing clinical examination, imaging studies of the brain, ultrasound evaluation of the heart and the extracranial and intracranial arteries, electrocardiography, and endocrinologic and hematologic parameters. Patients with an intracranial hemorrhage on the initial CT examination were not evaluated further. Studies of the brain entailed CT and/or MRI, the results of which were evaluated by an experienced neuroradiologist. Transthoracic echocardiography (Sonos 1000, Hewlett-Packard), continuous-wave Doppler, transcranial Doppler, and extracranial color duplex studies (Multidop X, DWL, and Sonos 1000, Hewlett-Packard, respectively) were performed on all subjects. Evaluation of the extracranial arteries (carotid, subclavian, and extracranial portion of the vertebral arteries) was performed according to standard criteria.^{28 29} Stenoses of the intracranial arteries were diagnosed on the basis of the criteria published by Ley-Pozo and Ringelstein.³⁰ All patients with intracranial stenoses (n=24) or high-grade carotid stenosis referred for carotid surgery (n=40) underwent selective intra-arterial cerebral angiography (n=46) and/or MR angiography (n=29).

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
After exclusion of 40 patients (21%), 154 patients (79%) were evaluated in this study. Twenty (13%) of the 154 evaluated patients were in group 1 (lacunar stroke). Brain imaging studies of these patients revealed a single lacunar lesion in 8 cases (40%), two to five separate lesions in 9 cases (45%), and more than five lesions in the remaining 3 cases (15%). A subcortical arteriosclerotic encephalopathy was diagnosed in 35 patients (23%) (group 2). Lacunar infarctions were viewed in 22 (63%) of these cases (one lacunar lesion in 9 cases, two to four lesions in the remaining 13 cases). Macroangiopathic lesions of the arteries supplying the symptomatic territory were diagnosed in 99 patients (64%) (group 3). These consisted of >70% stenosis or occlusion of the ICA in 65 cases (66%) (29 with 70% to 80% ICA stenosis [5 with bilateral ICA stenosis], 11 with 80% to 99% ICA stenosis [3 with bilateral ICA stenosis], 25 with ICA occlusion [10 with contralateral ICA stenosis, 1 with bilateral ICA occlusion]), high-grade stenosis of the carotid siphon (n=3, 3%) and the middle cerebral artery (n=14, 14%; 2 with bilateral middle cerebral artery stenosis, 1 with additional anterior cerebral artery stenosis), and a high-grade stenosis of the basilar artery (n=4, 4%). Six (6%) patients had high-grade vertebral artery stenoses (3 extracranial and 3 intracranial), and 7 (7%) suffered an occlusion of a vertebral artery (n=3 proximal and n=4 distal artery occlusion). Additional asymptomatic macroangiopathic vascular lesions were viewed in 16 of these patients (n=14 with stenosis of the subclavian artery, n=2 with occlusion of the subclavian artery).

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.

View this table: [in this window] [in a new window]   Table 1. Prevalence of Risk Factors in Subgroups of Cerebrovascular Disease

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).

View this table: [in this window] [in a new window]   Table 2. Glucose, Insulin, and C-Peptide Levels in Different Patient Subgroups

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The hypothesis that significantly elevated insulin levels correlate with the prevalence of cerebral small-vessel disease is supported by the finding of higher serum insulin and C-peptide concentrations in the microangiopathy group (lacunes and SAE) compared with both normal control subjects and patients with large-vessel disease. This finding is particularly striking in the lacunar group.

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-methylglutaryl–coenzyme 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 cells^{16 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

 

DM = diabetes mellitus ICA = internal carotid artery PAI-1 = plasminogen activator inhibitor–1 SAE = subcortical arteriosclerotic encephalopathy

	Acknowledgments

 
The authors wish to thank Dr P. Cleef (Medizinische Klinik A, Klinikum Ludwigshafen [Germany]) for his valuable comments concerning this work.

Received July 10, 1995; revision received October 9, 1995; accepted October 27, 1995.

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