Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

Olsen, Michael Hecht; Fossum, Eigil; Høieggen, Aud; Wachtell, Kristian; Hjerkinn, Elsa M.; Nesbitt, Shawna D.; Andersen, Ulrik B.; Phillips, Robert A.; Gaboury, Cynthia L.; Ibsen, Hans; Kjeldsen, Sverre E.; Julius, Stevo

doi:10.1097/01.hjh.0000163160.60234.15

Cited by 54 publications

(50 citation statements)

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“…In a study in 70 hypertensive patients, losartan also reduced vascular rarefaction and hypertrophy and improved insulin sensitivity after 3 years of treatment, compared with the b-blocker atenolol. 101 In line, in SHR, the angiotensin II type 1 receptor blocker olmesartan improved insulin signalling and prevented microvascular rarefaction in the skeletal muscle; 102 thus, theoretically, restored insulin signalling may also contribute to vascular proliferation and angiogenesis.…”

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confidence: 97%

Angiogenesis and hypertension: an update

2009

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The purpose of this review is to provide a basic understanding of the important relationship between microvascular remodelling, angiogenesis and hypertension, that is, provide an overview of recent experimental and clinical evidence from anti-hypertensive and pro-and anti-angiogenic therapy with respect to hypertension and microvascular structure. Microvascular rarefaction, that is, a loss of terminal arterioles and capillaries, is found in most forms of human and experimental arterial hypertension. This further increases peripheral resistance, and aggravates hypertension and hypertension-induced target organ damage. In some cases with a genetic predisposition, hypertension is preceded by a loss of microvessels. Therefore, new therapies aimed at reversing microvascular rarefaction potentially represent candidate treatments of hypertension. The microvasculature is formed by the continuous balance between de novo angiogenesis and microvascular regression. Imbalanced angiogenesis, in addition to functional shut-off of blood flow, contributes to microvascular rarefaction. Numerous clinical trials assessing anti-angiogenic agents in cancer patients show that this therapy leads to microvascular rarefaction and causes or aggravates hypertension. The development of specific pro-angiogenic treatment to correct hypertension or ischaemic disorders, however, it is still in its infancy. On the other hand, long-term treatment by classic anti-hypertensive therapies that present vasodilator activity can correct for hypertension-associated rarefaction in man.

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confidence: 97%

Angiogenesis and hypertension: an update

2009

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“…Our observation in db/db mice that islet AT1R may become upregulated and thus gain an increased importance in regulating islet functions that is detrimental for glucose-induced insulin release and (pro)insulin biosynthesis, suggests an alternative explanation for the clinical findings. Although AT1R blockers could improve insulin sensitivity (36,37), their effects in this aspect remain controversial and varied (12,38,39). Meanwhile, losartan has been reported to abolish the insulin sensitivity-enhancing effects of angiotensin II in vitro and in vivo (39).…”

Section: At1r Blockade In Type 2 Diabetesmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Blockade Improves β-Cell Function and Glucose Tolerance in a Mouse Model of Type 2 Diabetes

et al. 2006

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We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to ␤-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves ␤-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined. Diabetes 55:367-374, 2006 T he prevalence of obesity is rising in North America, where 61% of adults are now overweight or obese, a trend mirrored worldwide (1). The accompanying epidemic of type 2 diabetes and its cardiovascular complications are evident in the Western world (2,3) and also in Asia (4). Therapies aimed at increasing insulin sensitivity offer only partial solutions, since ␤-cell dysfunction and ␤-cell loss may also contribute to disease progression. In this regard, the mechanisms that underlie islet failure have yet to be elucidated. A recently identified local renin-angiotensin system (RAS) may play an important role in pancreatic physiology and pathophysiology (5,6). While the acinar RAS regulates exocrine function (7) and pancreatitis (8), a local islet RAS also exists. The RAS constituents angiotensinogen, ACE, and angiotensin II types 1 and 2 receptors (AT1R and AT2R) have been demonstrated to be present in pancreatic islets, with the AT1R localized specifically to the ␤-cells (9). This local pancreatic islet RAS has the potential to regulate insulin release, in that AT1R activation may inhibit insulin release in response to glucose loading. This action is mediated, at least in part, through alterations in islet (pro)insulin synthesis and islet blood flow engendered by angiotensin II biosynthesis (9,10).The clinically observed benefits of RAS blockade in persons at risk for developing type 2 diabetes, namely a reduced incidence of developing diabetes (11,12), have been hard to explain. A better understanding of the protective effects of RAS inhibition on type 2 diabetes is of profound importance...

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“…They increase the number of small insulin-sensitive adipocytes [27]. They may increase the percentage of type I skeletal muscle fibers [141], enhance skeletal muscle blood flow [153,154], and improve skeletal muscle glucose uptake [21]. Losartan increases serum levels of free insulin-like growth-factor I, which may decrease IR [155].…”

Section: Mechanismsmentioning

confidence: 99%

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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Hypertension, a multifactorial-polygenic disease, interacts with multiple environmental stressors and results in functional and structural changes in numerous end organs, including the cardiovascular system. This can result in coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, end-stage renal disease, insulin resistance, and damage to the pancreatic islet. Hypertension is the most important modifiable risk factor for major health problems encountered in clinical practice. Whereas hypertension was once thought to be a medical condition based on discrete blood pressure readings, a new concept has emerged defining hypertension as part of a complex and progressive metabolic and cardiovascular disease, an important part of a cardiometabolic syndrome. The central role of insulin resistance, oxidative stress, endothelial dysfunction, metabolic signaling defects within tissues, and the role of enhanced tissue renin-angiotensin-aldosterone system activity as it relates to hypertension and type 2 diabetes mellitus is emphasized. Additionally, this review focuses on the effect of hypertension on functional and structural changes associated with the vulnerable pancreatic islet. Various classes of antihypertensive drugs are reviewed, especially their roles in delaying or preventing damage to the vulnerable pancreatic islet, and thus delaying the development of type 2 diabetes mellitus.

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Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

Cited by 54 publications

References 47 publications

Angiogenesis and hypertension: an update

Angiogenesis and hypertension: an update

Angiotensin II Type 1 Receptor Blockade Improves β-Cell Function and Glucose Tolerance in a Mouse Model of Type 2 Diabetes

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

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