Gurushankar Govindarajan University of Missouri, Columbia , James R Sowers University of Missouri, Columbia , Craig S Stump University of Missouri, Columbia, and Harry S Truman Memorial VA Hospital

There has been an increase in the prevalence of diabetes mellitus over the past 40 years, both in the US and worldwide. The worldwide prevalence of diabetes in 2000 was approximately 2.8% and is estimated to grow to 4.4% by 2030. This translates to a projected rise of diabetes from 171 million in 2000 to well over 350 million in 2030. The epidemic of diabetes will continue to rise as there is growing prevalence of obesity in children, which predisposes to diabetes. There is considerable evidence for an increased prevalence of hypertension in diabetic persons. In a large prospective cohort study that included 12,550 adults, the development of type 2 diabetes was almost 2.5 times as likely in persons with hypertension than in their normotensive counterparts. Similarly, evidence points to increased prevalence of hypertension in diabetic persons. Moreover, each pathophysiological disease entity serves to exacerbate the other. Both hypertension and diabetes predisposes to the development of cardiovascular disease (CVD) and renal disease. Subjects with diabetes are at about 60% increased risk of early mortality. The age-adjusted relative risk of death due to cardiovascular events in persons with type 2 diabetes is three-fold higher than in the general population. The presence of hypertension in diabetic patients substantially increases the risks of coronary heart disease, stroke, nephropathy and retinopathy. Indeed, when hypertension coexists with diabetes, the risk of CVD is increased by 75%, which further contributes to the overall morbidity and mortality of an already high-risk population. Generally, hypertension in type 2 diabetic persons clusters with other CVD risk factors such as microalbuminuria, central obesity, insulin resistance, dyslipidaemia, hypercoagulation, increased inflammation and left ventricular hypertrophy. This clustering risk factor in diabetic patients ultimately results in the development of CVD, which is the major cause of premature mortality in patients with type 2 diabetes.

Pathophysiology of Hypertension in the Diabetic Patient

Epidemiologic studies provide evidence for co-existence of hypertension and diabetes and
possibly point towards a common genetic and environmental factor promoting both diabetes and hypertension. Similarly, clustering of hypertension, insulin resistance or frank type 2 diabetes, hyperlipidaemia and central obesity have been documented in several populations. Insulin resistance, increased tissue inflammation and reactive oxygen species (ROS) production resulting in endothelial dysfunction, increased tissue renin–angiotensin– aldosterone system (RAAS) and increased sympathetic nervous system (SNS) activity have all been implicated in this complex pathophysiology of diabetes and hypertension.

Diabetes, Insulin Resistance and Hypertension – A Complex Interrelated Process and the Crucial Role of RAAS

It is estimated that about 25–47% of persons with hypertension have insulin resistance or impaired glucose tolerance. With insulin resistance there are impaired biological and physiological tissue responses to insulin. The relationship of insulin resistance, diabetes and hypertension is complex and interrelated. Untreated patients with essential hypertension have higher fasting and postprandial insulin levels than age- and sex-matched normotensive persons, regardless of body mass; a direct correlation between plasma insulin levels and blood pressure (BP) exists. Interestingly, the relationship between hyperinsulinaemia and hypertension is not seen in secondary hypertension. This indicates that insulin resistance and hyperinsulinaemia are not consequences of hypertension, but rather a genetic predisposition that acts as a fertile soil for both diseases. This notion is supported by the observation that there is abnormal glucose metabolism in the offspring of hypertensive parents. Thus, there is a strong association between hypertension, diabetes and insulin resistance. There is also a strong association between upregulation of RAAS, hypertension and diabetes. This upregulation of RAAS results in enhanced generation of ROS and may explain impaired glucose utilisation as well as hypertension associated with insulin resistance and type 2 diabetes. It has been proposed that increased autocrine/paracrine activity of angiotensin II (ANG II) results in diminished action of insulin and insulin growth factor-1 (IGF-1) signalling through the PI3K/Akt pathway, resulting in inhibition of mechanisms involved in the vasodilator and glucose transport properties of insulin and IGF-1 (see Figure 1 and 2). Insulin activates the PI3K/Akt system in skeletal muscle, adipose, and myocardial tissues and initiates translocation of the GLUT4 glucose receptor to the cell membrane. The unregulated ANG II acts through its receptor (AT1R) and results in formation of ROS and the activation of lowmolecular- weight G proteins such as Rho A. Activation of these small G proteins and consequent enhancement of the generation of ROS inhibits insulin/IGF-1 actions mediated through PI3K/Akt signalling including activation of endothelial nitric oxide (NO) synthase (eNOS) activity, Na+ pump activation, and Ca2+-myosin light chain (MLC) desensitisation.