K. Pyörälä

Predictors of Stroke in Middle-Aged Patients With Non–Insulin-Dependent Diabetes

BACKGROUND AND PURPOSE The risk of stroke is known to be markedly elevated in patients with non-insulin-dependent diabetes mellitus (NIDDM), but the information on risk factors predicting stroke events in middle-aged NIDDM patients is limited. Therefore, we evaluated the significance of different cardiovascular risk factors with respect to the incidence of stroke in middle-aged NIDDM patients. METHODS Levels of cardiovascular risk factors were determined at baseline in 1059 NIDDM patients (581 men, 478 women) and 1373 nondiabetic control subjects (638 men, 735 women), aged from 45 to 64 years, in eastern and western Finland. These patients were followed up for 7 years with respect to stroke events. RESULTS Altogether, 34 NIDDM patients (13 men, 21 women) and 5 nondiabetic subjects (4 men, 1 woman) died from stroke, and 125 NIDDM patients (61 men, 64 women) and 30 (18 men, 12 women) nondiabetic subjects had a fatal or nonfatal stroke. The risk of stroke in NIDDM men was about threefold and in NIDDM women fivefold higher than that in corresponding nondiabetic subjects. Previous history of stroke increased the risk of a new stroke event by threefold. Patients with hyperglycemia (plasma glucose > 13.4 mmol/L) and high hemoglobin A1 (> 10.7%) had about a twofold higher risk of stroke than patients with better glycemic control. Low levels of high-density lipoprotein cholesterol (< 0.90 mmol/L), high levels of total triglyceride (> 2.30 mmol/L), and the presence of hypertension were associated with a twofold increase in the risk of stroke mortality or morbidity. CONCLUSIONS Our prospective population-based study gives evidence that previous history of stroke, hypertension, hyperglycemia, and dyslipidemia are strong predictors of stroke in middle-aged patients with NIDDM.

Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects.

Background and Purpose Non-insulin-dependent diabetes mellitus (NIDDM) is a major risk factor for stroke in the middle-aged population, but few prospective population-based studies are available in the elderly. Moreover, the importance of metabolic control and the duration of diabetes in diabetic subjects has remained controversial. There are no previous studies on association of insulin with the risk of stroke. The present study examined whether NIDDM, its metabolic control and duration, and insulin level predict stroke. Methods We measured cardiovascular risk factors including glucose tolerance, plasma insulin, and glycosylated hemoglobin Alc in a Finnish cohort of 1298 subjects aged 65 to 74 years and investigated the impact of these risk factors on the incidence of both fatal and nonfatal stroke during 3.5 years of follow-up. Results Of 1298 subjects participating in the baseline study, 1069 did not have diabetes and 229 had NIDDM. During the 3.5-year follow-up, 3.4% (n=36) of nondiabetic subjects and 6.1% (n = 14) of NIDDM subjects had a nonfatal or fatal stroke. The incidence of stroke was significantly higher in diabetic women compared with nondiabetic women (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.65 to 3.06). In contrast, the risk of stroke was not significantly higher in diabetic men than in nondiabetic men (OR, 1.36; 95% CI, 0.44 to 4.18). In multivariate logistic regression analyses including all study subjects, fasting and 2-hour glucose (P<.01 and P<.05, respectively), glycosylated hemoglobin Alc (P<.01), atrial fibrillation (P<.05), hypertension (P<.05), and previous stroke (P<.01) predicted stroke events. In diabetic subjects, fasting and 2-hour glucose (P<.01 and P<.05, respectively), glycosylated hemoglobin Alc (P<.O5), the duration of diabetes (P<.05), and atrial fibrillation (P<.05) were the baseline variables predicting stroke events. Finally, fasting insulin (P<.05), hypertension (P<.05), and previous stroke (p<.01) were associated with stroke incidence in nondiabetic subjects. Conclusions Our 3.5-year follow-up study provides evidence that NIDDM, its metabolic control, and the duration of diabetes are important predictors of stroke in elderly subjects, particularly in women. Moreover, fasting insulin level appears to be a risk factor for stroke in elderly nondiabetic subjects.

Cardiovascular disease risk factors as predictors of Type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects

SummaryRisk factors measured in a cross-sectional study in subjects aged 65–74 years living in eastern Finland were correlated with the risk of developing diabetes 3.5 years later. Sixty-nine of 892 initially non-diabetic subjects developed diabetes during the follow-up. Subjects who subsequently developed diabetes had multiple adverse changes in risk factor levels before the diagnosis of diabetes. Subjects who developed diabetes had higher body mass index and waist-hip ratio as well as higher levels of fasting and 2-h plasma glucose and insulin and higher prevalence of family history of diabetes than those who remained healthy. Furthermore, prevalence of hypertension and levels of diastolic blood pressure and total triglycerides were higher and HDL cholesterol lower among subjects who developed diabetes than among those who remained healthy. The highest risk of developing diabetes was associated with impaired glucose tolerance (World Health Organisation criteria) (odds ratio = 9.8,95% confidence interval = 6.1–5.8). The risk of developing diabetes was 3.7 (3.2–6.1) among subjects in the highest quartile of 2-h insulin distribution, 3.5 (2.0–6.1) in those with triglycerides greater than 2.5 mmol/l,2.7 (1.5–4.6) in those with waist-hip ratio greater than 1.0,2.5 (1.5–4.4) in those with HDL cholesterol less than 1.0 mmol/l, 2.1 (1.2–3.6) in those with body mass index greater than 30 kg/m2, 1.9 (1.1–3.3) among those in the highest quartile of fasting insulin distribution, 1.8 (1.0–3.1) in those having hypertension, and 1.7 (1.0–2.9) in those with a family history of diabetes. The risk of diabetes increased by clustering of risk factors related to insulin resistance (impaired glucose tolerance, triglycerides >2.5 mmol/l, HDL cholesterol <1.0, hypertension) so that the risk was 3.6-fold in those having one risk factor and 59-fold in those having all four risk factors compared to subjects having no risk factors. In conclusion, cardiovascular risk factors related to insulin resistance are predictors of diabetes in the elderly.

Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with Type II diabetes

Aims/hypothesis. Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with Type II (non-insulin-dependent) diabetes is limited and controversial. Therefore, we carried out a prospective study to examine the predictive value of fasting plasma insulin and “hyperinsulinaemia cluster” with regard to the risk of CHD mortality.¶Methods. At baseline risk factors for CHD were determined in 902 patients aged 45 to 64 years with Type II diabetes not treated by insulin (499 men and 403 women). These patients were followed up to 7 years for CHD mortality.¶Results. Coronary heart disease mortality (16.2 % in men, 9.2 % in women) increased significantly in men with increasing plasma insulin tertiles (p = 0.006) and in both sexes combined (p = 0.010) but not in women (p = 0.090). The predictive value of hyperinsulinaemia with regard to death from CHD was independent of conventional cardiovascular risk factors but not of risk factors clustering with hyperinsulinaemia. By applying factor analysis and principal component analysis we showed that “hyperinsulinaemia cluster” (a factor having high positive loadings for body mass index, triglycerides and insulin; and a high negative loading for high-density lipoprotein cholesterol) was predictive of death from CHD in patients with Type II diabetes (hazard ratio with 95 % confidence intervals 1.43 (1.18, 1.73), p < 0.001).¶Conclusion/interpretation. Our results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in patients with Type II diabetes not treated with insulin. [Diabetologia (2000) 43: 148–155]

Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed type 2 (non-insulin-dependent) diabetic patients

SummaryWe studied the relationship of slight albuminuria (microalbuminuria) to serum lipid and lipoproteins in a representative group of middle-aged Type 2 (non-insulin-dependent) diabetic patients. A random sample of non-diabetic control subjects was also examined. Diabetic patients had both at diagnosis and after five years higher total, LDL- and VLDL-triglyceride levels and higher VLDL-cholesterol, but lower HDL-cholesterol levels than non-diabetic subjects. No consistent difference was found in LDL-cholesterol levels between diabetic and non-diabetic subjects. The prevalence of microalbuminuria (>35 mg/24 h) remained about the same in diabetic patients at both examinations (19–20%). The diabetic patients with persistent microalbuminuria were slightly hyperglycaemic and they tended to have lower creatinine clearance at the 5-year examination than those without persistent microalbuminuria. There were no differences in the blood pressure levels or the occurrence of hypertension between the diabetic groups with and without microalbuminuria. At the baseline examination, no differences were seen in serum lipids and lipoproteins between diabetic patients with and without microalbuminuria. In patients with persistent microalbuminuria. a statistically significant increase in VLDL-cholesterol (p<0.05) and VLDL- and LDL-triglyceride levels (p<0.05) and a decrease in HDL-cholesterol level (p<0.05) was seen at the 5-year follow-up. These changes could not be explained by age, sex, body mass index or HbA1. In conclusion, persistent microalbuminuria predicts and aggravates abnormalities in lipoprotein composition and a decrease in HDL-cholesterol in patients with Type 2 diabetes mellitus. The excess cardiovascular morbidity and mortality in diabetic patients with increased albuminuria may, in part, be explained by these lipoprotein abnormalities.

High fasting plasma insulin is an indicator of coronary heart disease in non-insulin-dependent diabetic patients and nondiabetic subjects.

The association between fasting plasma insulin level and coronary heart disease (CHD) was studied in 909 non-insulin-dependent diabetic (NIDDM) patients, aged 45-64 years, and in 1,373 nondiabetic control subjects. Both diabetic and nondiabetic subjects with various manifestations of CHD had higher plasma insulin levels than did subjects free of CHD. By plasma insulin quintiles formed according to values in nondiabetic subjects, the age-adjusted prevalence of CHD defined by symptoms and/or electrocardiographic changes in diabetic men was 48.2% in quintiles I + II (lowest), 54.8% in quintiles III + IV, and 65.7% in quintile V (highest) (p = 0.006). The respective prevalences in diabetic women were 53.5%, 59.1%, and 73.3% (p = 0.004); in nondiabetic men, 28.1%, 33.7%, and 43.3%, respectively (p = 0.016); and in nondiabetic women, 28.1%, 34.9%, and 44.3%, respectively (p = 0.007). An essentially similar association was observed between plasma insulin level and definite or possible myocardial infarction (MI). In diabetic subjects, a positive association between plasma insulin level and CHD manifestations was also found when insulin strata were formed using quintile cutoff points determined separately from diabetic subjects. The association between plasma insulin level and the prevalence of CHD or MI disappeared or was weaker, especially in men, when adjustment was made for body mass index, hypertension, and triglyceride or high density lipoprotein (HDL) cholesterol level. The association between high plasma insulin level and CHD was significant in diabetic subjects with a body mass index greater than 27 kg/m2 but not in those diabetics with a body mass index less than or equal to 27 kg/m2. A significant clustering of hypertension, high triglyceride values, and low HDL cholesterol levels was observed in diabetic subjects in the highest insulin quintiles. The results suggest that hyperinsulinemia is an indicator of CHD in both NIDDM patients and nondiabetic subjects. Hyperinsulinemia may be directly atherogenic, but it is more probable that hyperinsulinemia reflects insulin resistance, which may be a factor enhancing atherogenesis by causing adverse changes in many CHD risk factors.

Impairment of diastolic function in middle-aged Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients free of cardiovascular disease

SummaryLeft ventricular systolic and diastolic function was studied using systolic time intervals and echocardiography in 19 male and 17 female patients with Type 1 (insulin-dependent) diabetes, 24 male and 15 female patients with Type 2 (non-insulin-dependent) diabetes and 24 male and 24 female control subjects. The subjects for the present study were selected from a population based study in which 117 Type 1 and 510 Type 2 diabetic patients and 649 non-diabetic subjects were originally examined. After exclusions, none of the subjects had any evidence of coronary heart disease, hypertension or other diseases known to affect left ventricular function. There were no consistent differences in systolic time intervals or echocardiographic variables of systolic function between patients with Type 1 diabetes and non-diabetic control subjects; but patients with Type 2 diabetes showed an increased fractional shortening. Female patients with Type 2 diabetes showed an increased left ventricular mass not explicable by hypertension. Isovolumic relaxation period was longer in male (86±3 ms; mean±SEM) and female patients (84±6 ms) with Type 2 diabetes than in male (76±3 ms; p<0.05) and female (71±3 ms; p<0.05) control subjects. Peak diastolic filling rate was lower in female patients with Type 1 diabetes (12.8±0.8 cm/s, p<0.05) and in male (11.5±0.8 cm/s; p<0.01) and female patients (11.5±0.6 cm/s; p<0.001) with Type 2 diabetes as compared to male (14.4±0.7 cm/s) and female (14.9±0.5 cm/s) control subjects. In male patients with Type 1 diabetes the respective value (12.7±0.6 cm/s) did not differ significantly from that in male control subjects. Altogether 14 diabetic patients (26%) showed an abnormal low peak diastolic filling rate. The impaired diastolic filling among diabetic patients did not show any relationship to the duration and metabolic control of diabetes or the presence of microangiopathy, but a weak correlation was found between the peak diastolic filling rate and the diminution of heart rate variation suggestive of the presence of diabetic autonomic neuropathy.

Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects

SummaryInsulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ratio to the risk of developing NIDDM 3.5 years later in 65–74-year-old non-diabetic Finnish subjects participating in a populationbased study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range; 123 (77–154), 108 (74–143), 118 (83–145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32,33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8–9.0) vs 7.3 (4.8–10.0) pmol/l, p=0.005; 7.3 (4.5–13.0) vs 10.4 (7.1–18.0) pmol/l, p=0.002; 0.073 (0.057–0.110) vs 0.097 (0.060–0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0–7.7) vs 7.3 (4.8–10.0) pmol/l, p=0.019; 0.048 (0.035–0.071) vs 0.064 (0.045–0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.

Myocardial infarct size and mortality in patients with non-insulin-dependent diabetes mellitus.

Abstract. Objectives. To study the infarct size and mortality in patients with non‐insulin‐dependent diabetes mellitus (NIDDM) and in non‐diabetic subjects with their first acute myocardial infarction.

Lipid and lipoprotein abnormalities associated with coronary heart disease in patients with insulin-dependent diabetes mellitus.

We measured serum lipid and lipoprotein levels in 63 insulin-dependent diabetic (IDD) patients (32 men, 31 women) and in 63 nondiabetic control subjects (32 men, 31 women) without coronary heart disease (CHD) and in 19 IDD patients (11 men, 8 women) and in 18 nondiabetic subjects (8 men, 10 women) with CHD. All diabetic patients had postglucagon C-peptide levels of less than 0.60 mmol/liter and none had signs of renal failure. Male IDD patients with CHD had higher levels of total cholesterol, low density lipoprotein (LDL) cholesterol, total triglycerides, very low density lipoprotein (VLDL) triglycerides and lower level of high density lipoprotein (HDL) cholesterol than male IDD patients without CHD. In female IDD patients, similar lipid and lipoprotein abnormalities were observed between the groups of diabetics with and without CHD except for total cholesterol, which was the same in both groups. A comparison between IDD patients without CHD and nondiabetic control subjects without CHD showed no difference in lipid and lipoprotein levels in males; female IDD patients without CHD showed even higher levels of HDL and HDL2 cholesterol and lower levels of VLDL triglycerides than nondiabetic controls. Our results indicate that in IDD patients without nephropathy and CHD, the lipid and lipoprotein levels do not differ from nondiabetic controls, but in IDD patients with CHD the lipid and lipoprotein pattern is similar to that known to be characteristic for nondiabetic patients with CHD.