Can glycaemia affect blood pressure?

The strong association between diabetes and hypertension has been recognized for 80 years [1]. The incidence and prevalence of hypertension are increased in patients with diabetes and impaired glucose tolerance (IGT) [2–4]. In these subjects, systolic blood pressure correlates significantly with both fasting plasma glucose (FPG) and glucose levels measured 2 h after an oral glucose ingestion (2-h PG), even after adjustment for age and obesity [3]. Furthermore, lean men with impaired fasting glucose (IFG, 6.1–6.9 mmol/l) had a double multivariate-adjusted risk of hypertension compared to those with normal FPG [5]. On the other hand, more than one-third of subjects with hypertension have type 2 diabetes [6,7]. Recently, a prospective study examined the relationship between high–normal blood pressure or hypertension and the development of type 2 diabetes during a 5–16-year observation period in a cohort of 7594 Japanese non-diabetic men aged 35–60 years with FPG < 110 mg/dl. This study demonstrated that both high–normal blood pressure and hypertension were associated with a higher risk of developing type 2 diabetes, after adjustment for age, body mass index (BMI), physical activity and parenteral history of diabetes. The association was also present in lean subjects who had a double risk of type 2 diabetes compared to normotensive individuals [8]. The cause of the association between hypertension and hyperglycaemia is still a matter of debate because it is not clear if high levels of blood glucose alone or other factors often associated with hyperglycaemia, such as insulin resistance, dyslipidemia and obesity, are responsible for the progressive development of hypertension. Blood pressure and insulin resistance The Insulin Resistance Atherosclerosis Study Group suggested that insulin resistance is independently associated with atherosclerotic diseases [9], and recent evidence suggests that postprandial hyperinsulinemia is independently associated with coronary artery disease, irrespective of fasting and postprandial glucose in non-diabetic women [10]. Many epidemiological studies have demonstrated a correlation between blood pressure and insulin resistance [11]. Hyperinsulinemia may raise blood pressure through different mechanisms: (i) activation of sympathetic nervous system; (ii) stimulation of the renin–angiotensin system; (iii) promotion of vascular smooth muscle cell proliferation and (iv) release of prothrombotic factors [12,13]. Seventy percent of lean non-diabetic subjects with essential hypertension had a resistance to the metabolic effects of insulin with compensatory hyperinsulinemia [14]. However, long-term studies conducted in humans are not completely convincing with regard to an independent association between insulin levels and blood pressure. Instead, this appears to be determined by the presence of other variables, such as obesity, sedentarism, dyslipidemia and hyperglycaemia, which often cluster with hyperinsulinemia [11,15]. Blood pressure and hyperglycaemia High–normal glucose levels and mild hyperglycaemia are frequently observed in insulin resistant subjects, as well as in hypertensive patients [15]. Hyperglycaemia damages blood vessel endothelial cells by complex mechanisms, including activation of protein kinase C, increased expression of adhesion molecules, adhesion and uptake of leukocytes, production of proliferative substances, proliferation of endothelial cells, synthesis of collagen IV and fibronectin, and decreased production of the atheroprotective nitric oxide [16]. Hyperglycaemia may also raise blood pressure by inducing renal sodium retention and extravascular shift of fluid and sodium [17]. Interestingly, sodium retention may in turn favour the development of insulin resistance because it has been shown that a high salt intake may induce hyperinsulinemia and worsen insulin-mediated glucose disposal in salt-sensitive patients [15]. The relevance of hyperglycaemia in hypertensive patients was recently demonstrated in a longitudinal study conducted in 113 hypertensive men with normal FPG which demonstrated a significant positive and independent association between 2-h PG and cardiovascular disease (CVD) leading to death during a 6-year follow-up [18]. Furthermore, a prospective study conducted in 1860 non-diabetic men aged 50 years recently demonstrated that subjects who developed myocardial infarction after the age of 60 years had a significantly larger increase in FPG compared to those who did not develop myocardial infarction. In particular, in patients who were treated for hypertension at age 60 years, an increase of 10% in FPG was associated with a 21.7% higher risk of myocardial infarction, independently of lipids, BMI and blood pressure [19]. The presence of high–normal glucose has been shown to be associated with increases in CVD mortality. Many epidemiological studies have reported that IGT is a strong predictor for subsequent diabetes and a risk factor for CVD, but several reports suggest that even lower degrees of dysglycaemia than those defined by IGT are associated with a higher risk of CVD [20]. For example, in the British Heart Study conducted in 7177 men followed for 9 years, subjects with FPG > 6.1 mmol/l had a significantly increased rate of coronary heart diseases compared to those with lower levels [21]. Blood pressure and high-normal glycaemia An analysis of a 20-year mortality in non-diabetic men recruited in three European cohorts, the Whitehall Study, the Paris Prospective Study and the Helsinki Policemen Study, demonstrated that individuals in the upper 20% of distribution of 2-h PG and those in the upper 2.5% of FPG had a significantly higher risk of all-cause mortality compared to men in the lower 80% of these distributions. Interestingly, this mostly referred to normotolerant subjects because less than one-third of these individuals had diabetes or IGT or IFG [22,23]. In this context, a 22-year follow-up study conducted by Bjornholt et al. [24] in healthy white men, aged 40–59 years, demonstrated that an FPG of 4.7–6.1 mmol/l was associated with a 53% increase in CVD mortality, suggesting that even an FPG in the upper normal range may be an important independent predictor of CVD leading to death [24]. In this issue of the journal, Bjornholt et al. [25] investigated whether variations of FPG in non-diabetic non-hypertensive men are associated with variations in systolic blood pressure at rest and during exercise. All the 1947 men included in their study had a FPG ≤ 6.0 mmol/l and were submitted at baseline to an intravenous glucose tolerance test in order to calculate the glucose disappearance rate (KG), which is an index of glucose intolerance. Ninety-one percent of men who were still alive were included in the follow-up study. The authors report that, in baseline conditions, systolic blood pressure, heart rate, triglycerides, BMI and physical fitness follow significantly increasing and decreasing trends, respectively, across the four quartiles of FPG and KG. In particular, systolic blood pressure and heart rate at rest and during exercise were significantly higher in the IV quartile (4.8–6.0 mmol/l) than in I quartile (2.9–4.1 mmol/l) of FPG. Interestingly, the pattern of blood pressure across FPG quartiles was identical when subjects were divided in quartiles of physical fitness. The multivariate analysis confirmed that FPG was positively and independently associated with systolic blood pressure. After a mean 7.4-year follow-up, it was observed that subjects who could not have participated in the study due to death or illness, or who were more frequently treated for hypertension or CVD diseases, belonged to the upper quartile of FPG. Even in a normal range, FPG is revealed to be a strong independent predictor of the development of hypertension, to the point where men with 4.8–6.0 mmol/l FPG values had a 1.17-higher relative risk of hypertension compared to those with 2.9–4.1 mmol/l FPG values. The study by Bjornholt et al. [25] adds new information on the role of glycaemia in promoting one of the most important CVD risk factors. As previously mentioned, modest rises in FPG or 2-h PG, mostly in the range of hyperglycaemia (IFG/IGT), have been shown to increase the risk of cardiovascular disease or coronary heart diseases or death [18–21]. However, it was never previously demonstrated that FPG in itself influences the development of hypertension, even in the absence of glucose intolerance. The provided associations between FPG, on the one hand, and systolic blood pressure and heart rate, on the other, are noteworthy because the authors, apart from the influence of dyslipidemia and BMI, also took into account physical fitness. The relevance of physical fitness is due to low fitness being an independent predictor of all-cause mortality; unfit men have a three times greater risk of overall and CVD-related death and being fit reduces the hazard of obesity [26,27]. The association found by the authors between FPG and heart rate at rest and during exercise further corroborates the influence of even small increases in glycaemia on the cardiovascular system. In agreement with these observations, it was recently reported that FPG is strongly and independently related to the abnormal heart rate recovery after exercise in glucose intolerant, as well as in normotolerant, subjects [28]. Some further points raised in the study by Bjornholt et al. [25] are worthy of discussion. First, in basal conditions, a proportion of the subjects studied might have had an IGT, which is known to be associated with significantly higher values of systolic and diastolic blood pressure compared to those of subjects with normal glucose tolerance [29]. Indeed, the index used by the authors (KG) is a combined measure of insulin secretion and action and this is not diagnostic for IGT, and FPG alone does not allow the exclusion of the presence of IGT. More than 70% of the subjects with IGT have an FPG < 6.1 mmol/l. Furthermore, it has been shown that an FPG level of 5.5 mmol/l is the optimal cut-off for predicting IGT [29], while an FPG of 6.1–6.9 mmol/l has a low sensitivity (28%) for the presence of IGT [20]. Second, at baseline, there is the possibility that elevated plasma insulin levels could have influenced systolic blood pressure values as this topic was not analysed due to the few insulin measurements available in this cohort. Third, the lack of data on FPG values at follow-up do not reveal whether eventual increases in FPG were responsible for the recorded blood pressure rises. The demonstration that small increases in FPG levels, inside a normal range, lead to parallel increases in systolic blood pressure and heart rate values, independently of the changes in tryglicerides, BMI and physical activity, remains remarkable. Attention must be paid to high–normal values of FPG in newly diagnosed hypertensives, and administration of antihypertensive compounds that are known to worsen glycaemic control should possibly be avoided or deferred in these subjects.