Pathophysiological Links Between Diabetes and Blood Pressure

Accepted Manuscript Pathophysiological Links between Diabetes and Blood Pressure Renata Libianto, MD, Duygu Batu, MD, Richard J. MacIsaac, MD, PhD, Mark E. Cooper, MD, PhD, Elif I. Ekinci, MD, PhD PII:

S0828-282X(18)30013-8

DOI:

10.1016/j.cjca.2018.01.010

Reference:

CJCA 2708

To appear in:

Canadian Journal of Cardiology

Received Date: 1 November 2017 Revised Date:

8 January 2018

Accepted Date: 8 January 2018

Please cite this article as: Libianto R, Batu D, MacIsaac RJ, Cooper ME, Ekinci EI, Pathophysiological Links between Diabetes and Blood Pressure, Canadian Journal of Cardiology (2018), doi: 10.1016/ j.cjca.2018.01.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Title: Pathophysiological Links between Diabetes and Blood Pressure

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Short Title: Diabetes and Blood Pressure

Authors: Renata Libianto, MD1,2, Duygu Batu, MD2, Richard J MacIsaac, MD,

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PhD1,3, Mark E Cooper, MD, PhD4, Elif I Ekinci, MD, PhD1,2

Affiliations: 1Department of Medicine, The University of Melbourne 2Department of

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Endocrinology, Austin Health 3Department of Endocrinology & Diabetes, St Vincent’s Hospital Melbourne 4Department of Medicine, Monash University. All institutions are in Melbourne, Australia.

Dr Elif I Ekinci

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Corresponding Author:

Department of Endocrinology

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Level 2 Boronia Building

Heidelberg Repatriation Hospital

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300 Waterdale Rd, Ivanhoe, VIC 3079, Australia [email protected]

Word count: 4,926 (including references: 8,599)

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ACCEPTED MANUSCRIPT Brief Summary: Diabetes and hypertension frequently co-exist, and an understanding of their pathophysiology is important to guide treatment. This article discusses the pathogenesis of hypertension in diabetes, including i) how sodium is regulated in diabetes; ii) the influence of the renin-angiotensin-aldosterone system; iii) the role of

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the autonomic nervous system; iv) mechanisms responsible for diabetic kidney disease and how endothelial dysfunction leads to hypertension; and v) how obesity

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leads to hypertension and diabetes.

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ACCEPTED MANUSCRIPT Abstract: Hypertension is highly prevalent amongst people with diabetes, and the presence of diabetes amongst those with hypertension portends an increase in cardiovascular risk. This review aims to explore the pathophysiological links between diabetes and hypertension. Renal sodium handling differs in diabetes as there is an upregulation

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of sodium transporters in the kidneys. The renin-angiotensin-aldosterone system (RAAS) may be upregulated in diabetes, leading to hypertension through a direct effect mediated by angiotensin II, as well as indirectly through upregulation of sympathetic activity. RAAS blockade is a mainstay therapy for hypertension, and

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evidence suggests that it may also reduce the incidence of diabetes. People with diabetes frequently have autonomic dysfunction, which could contribute to

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hypertension through increased sympathetic tone and through stimulation of renin production in the juxtaglomerular apparatus. Furthermore, people with diabetes also frequently demonstrate an abnormality in their circadian blood pressure pattern. Another important link between hypertension and diabetes is both the development and progression of diabetic kidney disease, the pathophysiology of which is mediated through several pathways including endothelial dysfunction and advanced

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glycation end products. Finally, obesity and the metabolic syndrome, through their effects on various hormones and inflammation, may also contribute to the

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pathogenesis of hypertension and diabetes.

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ACCEPTED MANUSCRIPT Introduction The prevalence of diabetes mellitus is increasing worldwide and it is now the eighth leading cause of death [1]. It is projected that diabetes will affect 366 million people by 2030 [2]. Meanwhile, hypertension is an important comorbidity, being present in more than 50% of people with diabetes [3]. Conversely, amongst people with

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hypertension, about 50% demonstrate insulin resistance [4]. The co-existence of diabetes and hypertension significantly increases the risk of cardiovascular disease

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and mortality by two to three fold [5, 6].

In order to effectively manage diabetes and hypertension, an understanding of their underlying pathophysiology is important. Given that these two conditions commonly

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co-exist, it is postulated that they share similar pathogenetic mechanisms. This review, therefore, aims to explore the pathophysiological links between diabetes and hypertension, with a focus on the role of sodium, the renin angiotensin aldosterone system (RAAS), autonomic nervous system, diabetic kidney disease and various mediators of the metabolic syndrome. We will also discuss how pharmacotherapy

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used in the treatment of diabetes or hypertension may contribute to our

Sodium

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understanding of the underlying pathophysiology.

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Dietary Sodium Intake

The modern Western diet contains high sodium and low potassium. The lack of renal adaptation in excreting the excess sodium leads to increased extracellular-fluid volume, resulting in increased peripheral vascular resistance and hypertension [7]. Interventional studies have demonstrated the importance of sodium reduction for the treatment of hypertension in those subjects with and without diabetes [8]. However, results from epidemiological studies which examined the association between sodium intake and blood pressure (BP) in different populations have been controversial. The Prospective Urban Rural Epidemiology (PURE) study, in which 8% of the participants had diabetes, reported a positive association between

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ACCEPTED MANUSCRIPT morning spot urinary sodium and office BP [9]. Interestingly, the International Study of Salt and Blood Pressure (INTERSALT) study found a significant association between 24h urinary sodium excretion with clinic BP of individuals in only 15 of the 52 centres, which were mostly from Western countries [10]. The FinnDiane study which involved patients with type 1 diabetes also reported no significant association

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between clinic BP and urinary sodium excretion after adjustments were made for age and sex [11].

The American Diabetes Association recommends a daily intake of sodium of less However, we have

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than 100mmol (2,300mg) per day for reduction of BP [12].

demonstrated that in an Australian cohort of people with type 2 diabetes attending a tertiary hospital, the majority (more than 80%) exceeded the recommended intake

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[13]. In people with type 2 diabetes, a low sodium diet of less than 100mmol/24h, which is difficult to achieve, has been shown to potentiate the antihypertensive effect of the angiotensin II receptor antagonist losartan, resulting in a BP reduction of a similar magnitude to that which would be expected with the addition of a second antihypertensive agent [14]. Furthermore, sodium supplementation attenuates the

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antihypertensive effect of telmisartan in patients with type 2 diabetes [15] but at the same time blunted the telmisartan-associated increase in plasma renin activity [16].

Separate from the effect of sodium reduction on BP, its effect on cardiovascular

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outcome and mortality is controversial [17]. We have previously reported that a lower 24h urinary sodium excretion, as a reflection of dietary sodium intake, was

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associated with higher all-cause and cardiovascular mortality in patients with type 2 diabetes [18] and others have demonstrated a U-shaped relationship between sodium excretion and mortality [19]. One possible explanation for this may be stimulation of the RAAS with low dietary sodium intake [20].

Ratio of Sodium to Potassium Intake Potassium has gained increasing recognition as a determinant of BP. In INTERSALT and PURE, higher urinary potassium excretion was associated with lower systolic BP [9, 10]. Interestingly, randomised trials have also shown that not only does potassium supplementation reduce BP, but that it can also blunt the effect of 5

ACCEPTED MANUSCRIPT increased sodium on BP [21]. PURE and INTERSALT study investigators reported a stronger association between clinic BP and the urinary sodium-to-potassium ratio compared with urinary sodium or potassium excretion separately [9, 10]. Similarly, a stronger association was found between cardiovascular disease and the urinary sodium-to-potassium ratio in the Trials of Hypertension Prevention (TOHP) trial

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compared with sodium or potassium alone [22]. In patients with diabetes, we have demonstrated that the 24h urinary sodium-to-potassium ratio, but not sodium or potassium individually, predicted 24h ambulatory BP [23]. In this study, the contribution of the 24h urinary sodium-to-potassium ratio to ambulatory BP was

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rather small, and factors such as age and circadian BP pattern played bigger roles

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[23].

Renal Sodium Handling

Renal sodium handling differs in people with diabetes compared to those without. People with diabetes may have increased exchangeable sodium compared to those without diabetes. Furthermore, those individuals with both hypertension and diabetes

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may have even higher exchangeable sodium, which correlates with systolic BP [24, 25]. In addition to having elevated exchangeable sodium levels, people with diabetes are more sensitive to the effects of sodium than are controls. Indeed, some studies have demonstrated that people with diabetes had a higher increment in BP following

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a high sodium diet [26, 27].

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Insulin can increase sodium reabsorption throughout the different parts of the renal tubule [28]. In a landmark study where participants were infused with insulin, there was a reduction in urinary sodium excretion without an associated change in the filtered load of glucose or glomerular filtration rate [29]. However, the effect of insulin infusion in humans has demonstrated inconsistent BP responses, with increase [30], decrease [31], or no change [32] in BP reported.

Renal Sodium Transporters The presence of diabetes also influences the regulation of various renal sodium transporters. The epithelial sodium channel (ENaC) plays a critical role in sodium 6

ACCEPTED MANUSCRIPT balance and hypertension [33]. Mutations such as those involving the beta subunit of ENaC occur more frequently in people with hypertension, and these mutations may result in increased renal tubular sodium reabsorption, contributing to the development of hypertension [34]. Animal models of Zucker rats that were obese were found to have increased renal expression of ENaC, which possibly contributes

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to sodium retention and obesity-associated hypertension [35]. Insulin has also been shown to increase the activity of ENaC [28]. In Sprague-Dawley rats with streptozotocin-induced diabetes, there was an increase in the abundance of ENaC in the kidneys within a few days of the onset of diabetes [36]. Furthermore, there was a

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positive correlation between the blood glucose level and the density of certain ENaC subunits.

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Another important class of carrier proteins in the kidney is the sodium-glucose cotransporters (SGLTs) which co-transport glucose and sodium across the luminal epithelial surface in the proximal tubule [37]. SGLT2 is uniquely expressed in the kidney and its inhibitors are widely used in the treatment of type 2 diabetes, in part due to the results of two large cardiovascular outcomes studies – the Empagliflozin

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Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPAREG OUTCOME [38]) and the Canagliflozin Cardiovascular Assessment Study (CANVAS [39]) trials. Other than their glucose-lowering effect, SGLT2 inhibitors also lower BP and reduce weight. In the EMPA-REG BP trial, assessing blood pressure in

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825 subjects with type 2 diabetes, treatment with empagliflozin for 12 weeks resulted in up to 4mmHg reduction in ambulatory systolic BP and a 1.5mmHg reduction in

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ambulatory diastolic BP [40]. A similar reduction in blood pressure was reported with canagliflozin in the CANVAS trial [39], although this trial was not designed to assess the blood pressure outcome specifically. Dapagliflozin also resulted in a reduction in blood pressure, even in patients who were already receiving RAAS blockade [41]. Unlike its effect on glycaemia, the reduction in BP seen with SGLT-2 inhibitors was preserved even in the setting of chronic kidney disease [42]. The mechanisms by which SGLT-2 inhibitors reduce BP may include improved glycaemic control, weight loss, osmotic diuresis, and improved arterial stiffness [43]. Furthermore, the BP reduction with SGLT-2 inhibitors is not accompanied by an increase in heart rate, suggesting that SGLT-2 inhibition might also affect sympathetic activity [44].

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ACCEPTED MANUSCRIPT In summary, renal sodium handling differs in people with diabetes and there is an upregulation of sodium transporters. Whilst excess sodium intake has been shown to contribute to hypertension, the effect of sodium restriction on cardiovascular

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outcome amongst people with diabetes is controversial.

Renin Angiotensin Aldosterone System (RAAS)

The RAAS plays an important role in the pathophysiology of both hypertension and

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diabetes. Angiotensin II binds to the angiotensin type 1 (AT1) receptor causing vasoconstriction, increased sodium reabsorption, and stimulation of aldosterone

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release from the adrenal cortex which further stimulates sodium reabsorption [45], resulting in increased BP. In animal studies, AT1 receptor knock-out mice had lower BP compared to wild-type mice, and the BP interestingly remained unchanged and did not increase following induction of diabetes with streptozotocin [46]. Furthermore, in a trial involving people with diabetes subjected to high and low sodium diet, the infusion of angiotensin II resulted in a similar augmentation of BP [27]. Whereas

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controls had a lesser increase in BP following angiotensin II infusion on low-sodium diet, these vascular responses were not decreased in people with diabetes on lowsodium diet, thus suggesting that the interaction between RAAS, sodium, and blood

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pressure may differ in those with and without diabetes [27].

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Upregulation of the RAAS in diabetes Although diabetes is usually associated with a hyporeninaemic state at the systemic level, a study comparing people with and without diabetes revealed an upregulation of angiotensin converting enzyme (ACE) gene expression in the renal tissue of those with diabetes [47]. Furthermore, in obese hypertensive individuals, renin, ACE and AT1 receptor genes were upregulated in the subcutaneous abdominal adipocytes [48]. The RAAS plays a role in adipocyte differentiation, adipocyte sensitivity to insulin, and possibly in body fat accumulation [49]. We have also demonstrated increased pancreatic islet cell expression of various components of the RAAS, including the angiotensin I receptor and ACE, in Zucker diabetic fatty rats compared

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ACCEPTED MANUSCRIPT to lean rats [50]. Thus, the presence of diabetes is associated with increased RAAS expression in various organs.

Renal and Cardiovascular Outcome in Diabetes with RAAS Blockade

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The importance of the RAAS in the pathophysiology of diabetic nephropathy has been well described [49, 51], and RAAS blockade remains a first-line treatment for hypertension in people with diabetes [12]. In the Heart Outcomes Prevention Evaluation (HOPE) trial, in which 38% of the participants had diabetes, ramipril

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significantly reduced mortality and cardiovascular outcomes over a follow up of five years [52]. RAAS blockade also has a reno-protective effect, as demonstrated in numerous trials including the Irbesartan Diabetic Nephropathy Trial (IDNT) which

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randomised 1715 hypertensive patients with nephropathy secondary to type 2 diabetes, to irbesartan, amlodipine, or placebo [53]. Following a follow-up of 2.6 years, treatment with irbesartan reduced the risk of progression of nephropathy. This benefit was not found in the amlodipine group, nor was it explained by differences in BP that was achieved. Similarly, losartan conferred a reno-protective effect

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independent of its effect on BP amongst people with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

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(RENAAL) study [54].

Anti-hyperglycaemic Effects of RAAS Blockade

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RAAS blockade may also reduce the incidence of new onset type 2 diabetes. In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients with hypertension who were treated with valsartan had a significantly lower rate of newonset diabetes over a mean follow up of 4 years, compared to those treated with amlodipine [55]. Similarly, the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) trial reported a lower rate of new-onset diabetes in heart failure patients treated with candesartan compared to placebo [56].

RAAS blockade may have antihyperglycaemic effects by improving insulin and glucose delivery to peripheral skeletal muscle, as well as by directly affecting glucose transport and insulin signalling pathways [57]. There is also evidence to 9

ACCEPTED MANUSCRIPT suggest that the RAAS plays an important role in the pancreas, and RAAS blockade reduces the adverse effects of angiotensin II on inflammation, fibrosis, apaptosis and beta-cell death in the pancreas, thereby delaying the development of insulin resistance and diabetes [50]. Thus, the RAAS is upregulated in diabetes, and RAAS

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blockade may help delay or prevent the development of diabetes.

Thus, the RAAS is upregulated in diabetes, and RAAS blockade may help delay or

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prevent the development of diabetes.

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The Autonomic Nervous System

RAAS and the Sympathetic Nervous System

The interaction between the RAAS and the sympathetic nervous system has been extensively characterised. In vivo experiments have demonstrated that infusion of angiotensin II increased the release of noradrenaline in the heart [58]. Meanwhile, animal studies have shown that the administration of ACE inhibitors increased the

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neuronal uptake of catecholamine in the heart [59, 60]. The improved neuronal noradrenaline uptake is thought to restore sympathetic balance and could be the mechanism whereby an which ACE inhibitor exerts its antihypertensive and

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cardioprotective effects [59].

The sympathetic nervous system is also known to affect the RAAS by directly

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stimulating β-1 receptors on the juxtaglomerular apparatus resulting in increased renin release [61]. One week of therapy with a β-blocker in normo- and hypertensive subjects resulted in a reduction in plasma angiotensin II levels and a reduction in plasma renin activity [62].

Hyperinsulinism and Sympathetic Activation Apart from the RAAS, the association between hypertension and diabetes may be explained by the interaction between the sympathetic nervous system and hyperinsulinaemia [63]. This relationship was explored by studies using the

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ACCEPTED MANUSCRIPT hyperinsulinaemic euglycaemic clamp and various measurements of nerve activity. In healthy humans, hyperinsulinaemia resulted in an elevation of skeletal muscle sympathetic neural outflow and vasodilation, but an overall neutral effect on arterial pressure [64]. In obese individuals, there was a higher basal rate of muscle sympathetic nerve activity, and the effect of hyperinsulinism on vasodilation was

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attenuated [65]. The greatest muscle sympathetic nerve activity was found in hypertensive patients with diabetes [66]. Increased sympathetic tone could also cause insulin resistance by several mechanisms including skeletal muscle vasoconstriction, altered composition of muscle fibres and decreased skeletal

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Renal Sympathetic Denervation

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muscle small blood vessels [63].

The importance of sympathetic nervous system in the pathophysiology of diabetes and hypertension is further demonstrated through studies on renal denervation. This catheter-based abolishment of renal sympathetic nerves was shown to downregulate hepatic gluconeogenesis and normalised hepatic insulin sensitivity in obese animals,

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with no alteration in kidney function [67, 68]. Animals exposed to either unilateral of bilateral renal denervation also had lower blood pressure than those exposed to sham operation [68]. Importantly, renal denervation in high fat diet-fed rats lowered plasma, hepatic and renal catecholamine contents, suggesting a reduction in

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sympathetic nervous system activity [68]. In a human study, hypertensive patients who underwent renal denervation had up to 30mmHg reduction in systolic blood

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pressure within 3 months without changes in their antihypertensive treatment [69]. Renal denervation also resulted in reduction in fasting glucose level, insulin resistance as assessed using the Homeostasis Model Assessment (HOMA) index, and 2hour glucose level during oral glucose tolerance test [69]. Despite the improvement seen in blood pressure and insulin resistance, it is unclear whether renal denervation improve cardiovascular and renal outcome [70], and further studies are needed before it can be recommended for routine practice.

Circadian Blood Pressure Pattern and Diabetes

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ACCEPTED MANUSCRIPT In healthy subjects, BP decrease (“dip”) during night time sleep by about 10%. However, 60% of patients with diabetes exhibit a lack of nocturnal BP dipping [23] and lack of nocturnal BP dipping is an independent predictor of mortality in people with diabetes [71, 72]. An increase in nocturnal systolic BP also predicted the development of microalbuminuria amongst people with type 1 diabetes [73]. The

neuropathy

with

sympathetic

overdrive

due

to

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abnormal dipping pattern found in people with diabetes reflects autonomic impaired

parasympathetic

cardiovascular innervations [63] and indeed may lead to excess cardiovascular events due to the stress imposed on the vascular system over the 24h period.

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Furthermore, people with diabetes have increased BP variability and increased heart rate throughout a 24hr period, which may reflect sympathovagal imbalance or baroreflex dysfunction [74]. A Cochrane review reported the benefit on 24h BP with

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evening dosing of antihypertensive medication (reduction in systolic BP by 1.71mmHg and diastolic BP by 1.38mmHg) [75]. In one randomised trial involving patients with hypertension and type 2 diabetes, nocturnal administration of antihypertensive agents resulted in reduced cardiovascular death, myocardial infarct and stroke [76]. Thus, nocturnal administration of antihypertensive drugs could be

validate these findings.

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considered in people with diabetes [12], although further studies are needed to

To summarise, people with diabetes frequently have autonomic dysfunction, which

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could contribute to hypertension through increased sympathetic tone and through

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stimulation of renin production in the juxtaglomerular apparatus. Furthermore, people with diabetes also frequently demonstrate an abnormality in their circadian blood pressure pattern.

Diabetic Kidney Disease

Advanced Glycation End Products

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ACCEPTED MANUSCRIPT The pathogenesis of diabetic kidney disease has been well described in the literature [77, 78]. One mechanism whereby hyperglycaemia contributes to renal damage is through the increased production of advanced glycation end products and activation of their receptor (RAGE), which triggers increases in protein kinase C, nuclear factorkappa B, transforming growth factor-β and connective tissue growth factor [79]. activation

induces

glomerular

matrix

and

mitochondrial

superoxide

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RAGE

production, resulting in increased oxidative stress [80]. Current data suggest that RAGE-mediated mitochondrial dysfunction and oxidative stress may precede the development of albuminuria and diabetic kidney disease [81], although clinical trials

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have failed to demonstrate reno-protection with treatment which target oxidative

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stress or inflammation [79]. However, more trials are currently underway.

Endothelial Dysfunction

Normal endothelial function requires a balance between vasoconstrictors such as endothelin-1 (ET-1), and vasodilators such as nitric oxide. In states of insulin resistance, this balance is disrupted [82]. In animal studies, induction of diabetes

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using pharmacologic means resulted in increased ET-1 gene expression and increased urinary ET-1 peptide [83]. Plasma ET-1 concentrations were found to be significantly higher in patients with diabetes compared with healthy subjects [84] and in patients with uraemia compared to non-uraemic controls [85]. In randomised trials,

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the endothelin antagonists avosentan and atrasentan were shown to reduce albuminuria and BP in patients with diabetic nephropathy, but there were more

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adverse events in the treatment group [86, 87]. Despite this, interest in the potential use of endothelin receptor antagonist for the treatment of diabetic nephropathy persists, with more trials such as Study of Diabetic Nephropoathy with Atrasentan (SONAR, ClinicalTrials.gov Identifier: NCT01858532) currently underway.

Endothelial nitric oxide synthase (eNOS) is involved in the production of nitric oxide. In bovine endothelial cells, hyperglycaemia inhibited eNOS activity by almost 70% [88], and diabetic eNOS knockout mice developed hypertension, albuminuria and renal insufficiency [89]. Furthermore, while insulin enhances eNOS gene expression, activation of protein kinase C in insulin resistance and diabetes may inhibit eNOS 13

ACCEPTED MANUSCRIPT expression leading to endothelial dysfunction [90]. Meanwhile, the concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS, was found to be significantly higher in people with type 2 diabetes [91] and end stage kidney disease [92], and it is a strong and independent predictor of mortality and cardiovascular outcome in this population [93]. In healthy humans, infusion of ADMA

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increased mean BP by 6mmHg [94], suggesting roles for ADMA and nitric oxide in the development of hypertension associated with diabetic kidney disease.

Hence, diabetic kidney disease is an important link between diabetes and

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hypertension, and its pathophysiology is mediated through several pathways including those linked to endothelial dysfunction and advanced glycation end products. Aside from kidney disease, vascular dysfunction may also explain other

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shared complications of diabetes and hypertension such as cardiovascular disease and retinopathy. We have previously shown that increasing vascular resistance of the intra-renal arteries, as estimated by the intra-renal vascular resistance index, is highly correlated with markers of left ventricular diastolic dysfunction which are

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surrogate markers of ventricular compliance [95].

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Obesity and the Metabolic Syndrome

In 1999, the World Health Organisation published a definition of the metabolic syndrome. The main underlying pathophysiology of the metabolic syndrome is

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believed to be insulin resistance, which is contributed to by the increased amount of free fatty acids (FFA) levels in people with excess adipose tissue [96]. This section will explore the various mediators and hormones involved in the metabolic syndrome and how they contribute to the pathophysiology of diabetes and hypertension.

Insulin In normal people, insulin induces vasodilation of skeletal muscle vasculature, an effect that is mediated by endothelium-derived nitric oxide [97]. However, in the presence of insulin resistance, this vasodilatory action is diminished [98].

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ACCEPTED MANUSCRIPT Furthermore, insulin increases sodium reabsorption in the kidneys [29], an effect which is preserved even in the presence of insulin resistance [99]. Thus, impaired vasodilation and increased sodium reabsorption may contribute to hypertension in

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individuals with metabolic syndrome and hyperinsulinism.

Amylin

Amylin, also known as islet-associated amyloid polypeptide (IAPP), is co-secreted in a ratio of 1 to 100 with insulin by the pancreatic β cell [100]. Pramlintide, a derivative

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of amylin, is a relatively new glucose lowering treatment in type 2 diabetes, albeit not widely used [101]. Animal studies have shown effects of this peptide on proximal tubule sodium reabsorption and plasma renin activity (PRA) [102, 103]. This effect

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on PRA has been confirmed in man [104]. However, if these effects are relevant to diabetes associated hypertension is not known.

Leptin

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The circulating level of leptin, an adipocyte-derived hormone, is proportional to the percentage of body fat [105]. Animals deficient in leptin develop insulin resistance and diabetes, and administration of leptin ameliorates the insulin resistance and diabetes, independently of changes in weight [106]. Despite this, randomised trials in

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humans have not demonstrated a consistent effect of leptin treatment on insulin

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sensitivity or glycaemic control [107, 108].

Leptin may also be an important link between obesity and hypertension. In animal studies, diet-induced obesity drives an increase in leptin levels and BP, but the BP effect was not seen in animals deficient in leptin or leptin receptors [109]. Furthermore, humans with homozygous complete loss-of-function mutations in the gene encoding leptin were obese, but had lower BP than equally obese controls with normal leptin level [109]. The effect of leptin on BP could be mediated by neuronal circuits in the dorsomedial hypothalamus, as administration of leptin receptor antagonist directly into this area resulted in a rapid reduction of BP in mice, independent of changes in weight [109]. Leptin may also increase BP by affecting nitric oxide production and increasing the sympathetic activity [110]. 15

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Glucagon-like peptide-1 (GLP-1) GLP-1 is released from the gut in response to food intake, and functions as a satiety signal as well as stimulator of insulin release from the pancreas [111]. GLP-1

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agonists such as exenatide, liraglutide and semaglutide are used in the treatment for type 2 diabetes and there is strong evidence that they improve cardiovascular outcome [112, 113]. The GLP-1 agonists also cause a reduction in systolic and diastolic blood pressure by 0.5-5 mmHg [114, 115]. The mechanism of BP reduction

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with GLP-1 agonist is not clearly understood, but may involve RAAS inhibition, increased urinary sodium excretion, and increased insulin production leading to vasodilatation [114]. Unlike SGLT-2 inhibitors, the BP reduction with GLP-1 agonist

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is accompanied by an increase in heart rate [115], suggesting that sympathetic inhibition is probably not the mechanism by which it exerts an antihypertensive effect. The secretion of GLP-1 is inhibited by an elevated circulating free fatty acid levels found in obesity [116], and this may provide another link between diabetes

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and hypertension.

Peroxisome proliferator-activated receptors (PPARs) Another important element in the metabolic syndrome is the PPARs. PPARs are

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ligand-activated transcription factors involved in various metabolic regulations in the body, including glucose, lipids, and blood pressure [117]. PPARγ levels are elevated

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in adipocytes [118] and they are thought to play an important role in adipocyte differentiation. PPARα agonists such as fenofibrate are used in the treatment of dyslipidaemia, and PPARγ agonists such as thiazolidinediones, which act as insulin sensitisers, are used to treat type 2 diabetes. PPARγ also plays a role in the vascular smooth muscle, and individuals who are lacking in PPARγ receptors developed not only insulin resistance and type 2 diabetes, but also hypertension at an unusually early age [119]. Treatment of patients with type 2 diabetes with thiazolidinediones reduced HbA1c as well as blood pressure by approximately 10mmHg [120, 121], although this degree of BP reduction is not a universal finding.

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ACCEPTED MANUSCRIPT Inflammation The metabolic and immune systems are closely tied, and obesity is associated with a state of chronic, low grade inflammation [122]. With the development of obesity and the metabolic syndrome, adipocytes showed higher expression of proinflammatory

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molecules [123] which has cardiovascular implications [124]. In large prospective studies, an elevated level of C-reactive protein (CRP) independently predicted development of incident hypertension [125] as well as future cardiovascular outcomes in an additive manner with hypertension [126]. The incidence of type 2

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diabetes was also predicted by higher levels of CRP and interleukin 6 [127]. In a randomised trial, weight loss, as the mainstay treatment for the metabolic syndrome, has been shown to reduce CRP, interleukin 6 and interleukin 8 [128]. A recent

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cardiovascular outcome study demonstrated reduction in cardiovascular events with canakinumab, an anti-inflammatory therapy targeting the interleukin-1β innate immune pathway [129]. In this trial, 80% of the participants had hypertension and 40% had diabetes. They were recruited into the trial if they had a history of myocardial infarction and a blood level of high-sensitivity CRP of 2mg or more per

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liter. This study highlights the importance of inflammation in cardiovascular complications associated with diabetes and hypertension.

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Insulin Resistance and CKD

CKD and insulin resistance have a bidirectional interaction. In the non-diabetic Asian

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population, insulin resistance was associated with prevalent CKD and a rapid decline in renal function [130]. In the Atherosclerosis Risk in Communities study involving more than 10,000 participants without diabetes or CKD at baseline, those at the highest quintile of insulin resistance (assessed using HOMA index) had a 70% increased risk for development of CKD over 9 years [131]. Insulin resistance is thought to promote CKD through mechanisms such as sympathetic nervous system activation, inflammation, and glomerular hyperfiltration which result in impaired renal haemodynamics [132].

Conversely, the presence of CKD is a risk factor for the development of insulin resistance. In 1981, DeFronzo et al found evidence of insulin resistance amongst 17

ACCEPTED MANUSCRIPT patients with CKD using the euglycaemic hyperinsulinaemic clamp technique [133]. Patients with hypertension-related CKD had lower insulin sensitivity compared to hypertensive patients without CKD [134]. The pathophysiology of insulin resistance in CKD is multifactorial, and may include chronic inflammation, oxidative stress, deranged adipokine regulation and an altered gut microbiome [135]. Thus,

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hypertensive CKD is associated with insulin resistance, and conversely insulin resistance is associated with incident CKD which may lead to hypertension.

Therefore, obesity and the metabolic syndrome, through their effects on various

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hormones and inflammation, may also contribute to the pathogenesis of

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hypertension and diabetes.

Conclusion

Hypertension and diabetes are highly prevalent and confer a greatly increased risk of cardiovascular disease. They share many common pathophysiological mechanisms

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involving complex interactions among sodium, the RAAS, the autonomic nervous system, kidney disease and obesity. A holistic management of hypertension and diabetes require all of these aspects be taken into consideration. Two classes of

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glucose lowering medications are now available which also have favourable effects on blood pressure. The SGLT2 inhibitors lower blood pressure, induce a natriuresis and diuresis but do not increase pulse rate.

The GLP-1 receptor agonists also

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decrease blood pressure, induce a natriuresis but increase pulse rates. Unravelling mechanisms responsible for the blood pressure lowering effects of these two classes of medications may help to better define the pathophysiological factors responsible for link between diabetes and hypertension. Other areas of interest include the effect of renal denervation on cardiovascular outcome, and the potential of targeting inflammatory mediators and hormones such as leptin and amylin for the management diabetes and hypertension.

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ACCEPTED MANUSCRIPT Disclosures EIE is supported by a Viertel Clinical Investigatorship, RACP Fellowship, Sir Edward Weary Dunlop Medical Research Foundation and Diabetes Australia Research Program research grants.

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honoraria from B1, A2, Lilly, MSD and Novartis.

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MEC is a NHMRC Senior Principal Research Fellow. MEC received grants and

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ACCEPTED MANUSCRIPT Figure Legend Randomised studies have shown that high dietary sodium intake is associated with hypertension in diabetes. People with diabetes demonstrate a differential renal sodium handling and an upregulation of sodium transporters in the kidneys. The RAAS is also upregulated in diabetes, which in turn leads to hypertension through a

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direct effect mediated by angiotensin II, as well as indirectly through upregulation of sympathtetic activity. RAAS blockade is a mainstay therapy for hypertension, and it may also reduce the incidence of diabetes. People with diabetes frequently have autonomic dysfunction, which could contribute to hypertension through increased

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sympathetic tone and through stimulation of renin. People with diabetes may demonstrate abnormality in circadian blood pressure pattern. Furthermore, diabetic kidney disease, mediated by endothelial dysfunction and advanced glycation end

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