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      The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

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          Abstract

          Background

          Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.

          Methods

          DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.

          Results

          HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P ≤ 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P ≤ 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P ≤ 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.

          Conclusions

          Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

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          Most cited references 38

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          Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004.

          Detection of hypertension and blood pressure control are critically important for reducing the risk of heart attacks and strokes. We analyzed the trends in the prevalence, awareness, treatment, and control of hypertension in the United States in the period 1999-2004. We used the National Health and Nutrition Examination Survey 1999-2004 database. Blood pressure information on 14 653 individuals (4749 in 1999-2000, 5032 in 2001-2002, and 4872 in 2003-2004) aged >or=18 years was used. Hypertension was defined as blood pressure >or=140/90 mm Hg or taking antihypertensive medications. The prevalence of hypertension in 2003-2004 was 7.3+/-0.9%, 32.6+/-2.0%, and 66.3+/-1.8% in the 18 to 39, 40 to 59, and >or=60 age groups, respectively. The overall prevalence was 29.3%. When compared with 1999-2000, there were nonsignificant increases in the overall prevalence, awareness, and treatment rates of hypertension. The blood pressure control rate was 29.2+/-2.3% in 1999-2000 and 36.8+/-2.3% in 2003-2004. The age-adjusted increase in control rate was 8.1% (95% CI: 2.4 to 13.8%; P=0.006). The control rates increased significantly in both sexes, non-Hispanic blacks, and Mexican Americans. Among the >or=60 age group, the awareness, treatment, and control rates of hypertension had all increased significantly (P
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            Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.

            Glucose-insulin-potassium infusions are beneficial in uncomplicated patients with acute myocardial infarction (AMI) but are of unproven efficacy in AMI with left ventricular (LV) dysfunction because of volume requirements associated with glucose infusion. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties that stimulate glucose uptake without the requirements for concomitant glucose infusion. We investigated the safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF) 1.63+/-0.09, P 2.02+/-0.11, P<0.01) compared with control subjects. The benefits of GLP-1 were independent of AMI location or history of diabetes. GLP-1 was well tolerated, with only transient gastrointestinal effects. When added to standard therapy, GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty.
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              The role of gut hormones in glucose homeostasis.

              The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients. Furthermore, signals from the gastrointestinal tract are important regulators of gut motility and satiety, both of which have implications for the long-term control of body weight. Among the specialized cell types in the gastrointestinal mucosa, enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. This article reviews the biological actions of gut hormones regulating glucose homeostasis, with an emphasis on mechanisms of action and the emerging therapeutic roles of gut hormones for the treatment of type 2 diabetes mellitus.
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                Author and article information

                Journal
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central
                1475-2840
                2010
                3 August 2010
                : 9
                : 32
                Affiliations
                [1 ]Amylin Pharmaceuticals, Inc., San Diego, CA, USA
                Article
                1475-2840-9-32
                10.1186/1475-2840-9-32
                2922097
                20678234
                Copyright ©2010 Liu et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Original Investigation

                Endocrinology & Diabetes

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