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Introduction: It has been suggested that atherosclerotic vascular disease is a chronic inflammatory process. The aim of this study was to investigate the importance of C-reactive protein (CRP) as a cardiovascular risk marker and predictor of death, as well as its relation to other factors of the metabolic syndrome in a cohort of type 2 diabetic patients at high risk of severe macrovascular complications., Material and Methods: 592 patients, aged 55 to 74 years (311 men, 281 women), with signs and symptoms of circulation deficits were examined by duplex ultrasound for suspected cerebrovascular and peripheral arterial disease and followed over a period of 5 years. At baseline, 292 patients of the total group had type 2 diabetes (49.3%). Ischemic heart disease was present in 40.2%, internal carotid stenosis in 21.9% and peripheral arterial disease in 39.7% of the subjects., Results: During the observation period, 104 patients had died, 72 (69.2%) due to cardiovascular causes. Non-fatal myocardial infarction occurred in 39 patients (7.4%), non-fatal stroke in 70 patients (13.3%) and amputations because of gangrene were unavoidable in 24 patients (4.6%). In Cox regression analysis, CRP was the strongest predictor of death and cardiovascular death in the total cohort (RR 3.7 [95% CI 1.86-7.50] and 5.4 [2.13-13.76]), as well as in the type 2 diabetic subgroup (RR 3.3 [1.27-8.70] and 5.4 [1.44-20.0]). In contrast neither the traditional cardiovascular risk factors nor the data of diabetic metabolic control were able to improve prediction. CRP was correlated positively with plasma levels of triglycerides (r=0.19, p=0.002), C-peptide (r=0.21, p=0.004), postprandial glucose (r=0.17, p=0.009), albuminuria (r=0.16, p=0.020), and inversely with HDL cholesterol (r=-0.20, p=0.002) in type 2 diabetic patients., Conclusions: CRP seems to be a better predictor of death and cardiovascular events than traditional risk factors or parameters of metabolic control in type 2 diabetic patients at high risk for cardiovascular endpoints. Additionally, CRP is associated with several facets of the metabolic syndrome.

Non-insulin-dependent diabetes mellitus is a major health problem in developed countries. The descriptive epidemiology of this disease and its cardiovascular complications are reviewed, and insulin resistance is identified as a common risk factor for both of them. The requirements for cost-effective programs to modify insulin resistance to prevent this disorder and its cardiovascular complications are discussed.

Numerous surveys have shown that in industrial countries diabetic subjects develop hypertension more frequently than non-diabetic persons. In fact, three typical hypertension forms in these patients can be discerned: essential, renal, and isolated systolic hypertension. In type 2-diabetes (NIDDM) hypertension can be seen in close association with obesity, glucose intolerance, lipid changes, and insulin resistance within the framework of the metabolic syndrome. The increased incidence of hypertension in type 1-diabetes (IDDM) is a result of development of diabetic nephropathy. In the elderly type 2-diabetics particularly frequently isolated systolic hypertension is present which reflects increased arterial stiffness and loss of vascular distensibility. In hypertension progression of both macrovascular disease and microangiopathy is increased whereby interaction of hyperglycemia and hypertension seems to be the main risk factor. In most hypertensive diabetic patients drugs will be necessary to lower blood pressure in a therapeutical range. There are several effective substances available which should be prescribed individually according to the needs and accompanying conditions in these patients.

Clinical and epidemiological findings over the last few years are increasingly pointing to a metabolic syndrome comprising major cardiovascular risk factors, which frequently characterizes type II diabetes and its preliminary stages. More recent studies have shown that insulin resistance is genetically determined and can be detected in a pre-diabetic stage long before diabetes mellitus becomes manifest. It is thus not surprising that a large percentage of patients with type II diabetes already have clear signs of arteriosclerosis at the time the diagnosis is made. The results of the Schwabing study II indicate a "point of no return" for the development of cardiovascular disease, which makes early and vigorous intervention involving all facets of the metabolic syndrome a matter of urgency.

The risk profile and the macro-vascular complications of patients with type II diabetes mellitus (NIDDM) was investigated in general practice patients for the first time in the FRG. It was the aim of the study to evaluate the efficacy of the therapy and possible improvements after detailed instructions in a random sample of well defined NIDDM in the greater Munich area. 290 NIDDM (187 female, 103 male) out of a total of 1500 patients treated by 22 general practitioners were randomly recruited for the study. First results indicated an excess morbidity of the NIDDM, e.g. 43.5% with HbA1c greater than 8%, hypertension in 73.8%, hypertriglyceridemia in 75%, hypercholesterolemia in 36.3% adipositas in 78%, and a micro/macro-albuminuria in 44.5%. A similar risk profile could be determined in cases with recently diagnosed NIDDM. The remarkable risk profile documents itself in the incidence of macro-vascular complications: 40.8% of the male and 43.2% of the female showed a peripheral arterial disease (pAVD), in 8% of all patients a carotid artery stenoses could be detected by means of doppler ultrasound technique; 46.6% of the male and 59.3% of the female patients showed symptoms of CHD. With the exception of the incidence of CHD in patients less than 64 years the duration of NIDDM had no influence on the macro-vascular complications as demonstrated in previous studies. The age however always had a significant influence on all three vascular regions examined. Albuminuria correlated as such with a number of risk factors showed a significant correlation with the incidence of pAVD and occurred more often in males with carotid artery stenoses. Other correlations established were: Hypercholesterolemia and FVIII ass. Ag respectively, and the incidence of carotid artery stenoses; blood pressure, F VIII ass. Ag and pAVD. In the female a negative correlation could be seen between the pAVD and the HDL-level. In patients with CHD sex specific correlations could be determined to blood pressure, HbA1c, c-peptide and triglyceride levels.

The incidence of macrovascular morbidity and mortality in diabetics is high. At the end of a five-year observation period in the Schwabing Study 138 (26.5%) out of 542 reexamined diabetics suffered from a cardiovascular death, gangrene or myocardial infarction. Univariate and multiple logistic analysis revealed age, systolic blood pressure, and serum triglycerides as significant predictors. Duration of diabetes was only significant in type I-diabetics. Sex differences exist. In conclusion, a basis for preventive measures of major macrovascular complications in diabetes is given. Atherosclerosis represents the major cause of morbidity and mortality in the diabetic patient. Particularly overt and borderline diabetics are afflicted who constitute 10-15% of the population in the western industrial countries. Due to high incidence and rapid progression of atherosclerosis in diabetes mellitus cardiovascular diseases and their causes can be studied in these patients at best. An excess morbidity in diabetics due to cardiovascular disease has been noted in several epidemiologic studies, although the number of patients are rather small in some studies. In the Bedford Study, for instance, 111 overt diabetics, in the Framingham Study less than 250 diabetic were included. Furthermore, subjects were examined at a relatively young age (35-55 years) where only a low incidence of vascular diseases at diagnosed by noninvasive methods can be expected. Accordingly, inconsistant data have been obtained. The Schwabing Study for Macrovascular Disease in Diabetes Mellitus is a longitudinal study of more than 600 diabetic outpatients by all ages. The results of 5-year incidence of major macrovascular complications and its relationship to a number of cardiovascular risk factors will be given in this communication.

EKG-findings of 186 non-selected diabetic outpatients and 52 control subjects of the age group of 50 to 79 years have been examined in relation to cardiovascular risk factors as well as to peripheral vascular disease (PVD) and carotid artery stenosis (CS). The Whitehall-Criteria of the Minnesota-Code were seen in diabetics (D) approximately twice as frequently as in non-diabetics (C): Minnesota-Code I: D 7% vs C 4%; IV 27% vs 13%; V 25% vs 15%; VII1 2% vs 0%. Beside higher levels of blood glucose and HbAI, diabetics differed from controls mainly by higher systolic blood pressure (p less than 0.001). Furthermore, they showed more signs of PVD and CS. Only in 27% of diabetics normal EKG-findings were seen. In comparison to age-adjusted diabetics with EKG-abnormalities, these patients showed signs of PVD and CS only to a minor degree and lower values were found for systolic (p less than 0,01) and diastolic (p less than 0.05) blood pressure, weight (p less than 0.05), serum triglycerides (p less than 0.02), and markedly higher values for HDL-cholesterol (p less than 0.01). These data show that in diabetics more frequently abnormal EKG-findings are seen and that a normal EKG in diabetics older than 50 years indicates low cardiovascular morbidity and a favorable risk factor profile.

Platelet aggregation, beta-thromboglobulin levels and the platelet adenylate cyclase activity (expressed as increase of cAMP levels) were determined in blood samples from healthy control subjects and from diabetic patients with and without microangiopathy. Patients with diabetic microangiography showed significantly higher beta-thromboglobulin levels, an increased tendency to platelet aggregation, and higher cAMP levels in platelet-rich plasma after incubation with PGI2. The findings were interrupted by the assumption of an increased turn-over of platelets which might be a consequence of the microvascular disease.

623 non-selected diabetic outpatients were screened by the Doppler-ultrasonic-method for peripheral vascular disease. Additional angiologic work up was performed to define the location of stenosis and obliteration. 15.9% of the diabetics were shown to have peripheral vascular disease and 57% of those denied claudication. 9% of the patients had signs of mediasclerosis. The predilection of peripheral vascular disease in diabetics for the arteries below the knee (peripheral type) was confirmed in our study. Patients with a pelvic or femoropopliteal type of peripheral vascular disease showed a high frequency of cardiovascular risk factors. An influence of the duration of diabetes on peripheral vascular disease was not evident. In contrast to this, a significant correlation (p less than 0.001) of the peripheral type of peripheral vascular disease-as well as of mediasclerosis--could be demonstrated with the diabetes of long duration. In patients with the peripheral type of peripheral vascular disease significantly more often higher blood sugar volues were found. Thus the quality of metabolic control seems to be of some importance for this form of diabetic macroangiopathy.

In the longitudinal Schwabing study, unselected insulin-treated diabetic patients were followed for major vascular complication (MVC) (stroke, myocardial infarction, gangrene) and asymptomatic, early detectable peripheral vascular disease (PVD). In the group of insulin-treated NIDDM multiple logistic regression analysis revealed the number of daily injected insulin units as a significant predictor for MVC and PVD (t = 1.98; p less than 0.04; x +/- S.D.: PVD yes 57.6 +/- 21.4 U/d; PVD no 44.3 +/- 17.7; age-adjusted univariate p less than 0.001). Daily insulin dose correlated highly significantly with serum triglycerides (r = 0.40, p less than 0.001) as well as with blood glucose (r = 0.33, p less than 0.001). These data suggest that insulin resistance is characteristic for atherosclerotic disease in NIDDM and the hyperinsulinemia-hypertriglyceridemia-syndrome might be a powerful cardiovascular risk factor in diabetes mellitus.

Increased platelet reactivity has been suggested in the pathogenesis of both arteriosclerosis and diabetic microangiopathy. Therefore, platelet function and platelet enzyme activities were assessed in a large group of 357 diabetics (256 patients with IDDM, aged 16-49 and 101 patients with NIDDM, aged 50-78) and 163 matched controls, and related to photographically documented retinopathy (Rd) and to peripheral vascular disease (PVD) as well as to plasma levels of von Willebrand factor (VIII R:Ag) as an indicator of endothelial damage. Patients with IDDM had increased platelet aggregation (PA, expressed as microM ADP threshold concentration) before Rd was detectable in comparison to control subjects (P less than 0.01). PA was further increased in patients with advanced Rd (P less than 0.01), whereas 20 newly diagnosed diabetics with IDDM exhibited normal PA. Patients with minimal Rd did not differ from patients without Rd. Plasma beta-thromboglobulin (reflecting platelet consumption in vivo) was enhanced significantly in patients with Rd only (P less than 0.05), as was malondialdehyde (MDA) production of platelets (as a measure of platelet endoperoxide formation). Factor VIII-related antigen in plasma was already increased in patients without Rd (P less than 0.05), yet more so in patients with Rd (P less than 0.01). Prostacyclin-stimulated adenylate cyclase activity (ACA) of platelets (as an antiaggregatory enzyme system) was twice as high in diabetics with advanced Rd compared with patients without Rd and with controls (P less than 0.01). Significant correlations were found between PA and plasma F VIII R: Hg, MDA production, and ACA of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)