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Several clinical studies have shown the benefits of renin-angiotensin system (RAS) blockade in the development of diabetes, and a local RAS has been identified in pancreatic islets. Angiotensin I-converting enzyme (ACE)2, a new component of the RAS, has been identified in the pancreas, but its role in β-cell function remains unknown. Using 8- and 16-week-old obese db/db mice, we examined the ability of ACE2 to alter pancreatic β-cell function and thereby modulate hyperglycemia. Both db/db and nondiabetic lean control (db/m) mice were infected with an adenovirus expressing human ACE2 (Ad-hACE2-eGFP) or the control virus (Ad-eGFP) via injection into the pancreas. Glycemia and β-cell function were assessed 1 week later at the peak of viral expression. In 8-week-old db/db mice, Ad-hACE2-eGFP significantly improved fasting glycemia, enhanced intraperitoneal glucose tolerance, increased islet insulin content and β-cell proliferation, and reduced β-cell apoptosis compared with Ad-eGFP. ACE2 overexpression had no effect on insulin sensitivity in comparison with Ad-eGFP treatment in diabetic mice. Angiotensin-(1-7) receptor blockade by D-Ala(7)-Ang-(1-7) prevented the ACE2-mediated improvements in intraperitoneal glucose tolerance, glycemia, and islet function and also impaired insulin sensitivity in both Ad-hACE2-eGFP- and Ad-eGFP-treated db/db mice. D-Ala(7)-Ang-(1-7) had no effect on db/m mice. In 16-week-old diabetic mice, Ad-hACE2-eGFP treatment improved fasting blood glucose but had no effect on any of the other parameters. These findings identify ACE2 as a novel target for the prevention of β-cell dysfunction and apoptosis occurring in type 2 diabetes.

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2(-/y)) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y). Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y), although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y) mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y) mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y) mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.

The nutritional dietary supplement chromium picolinate, [Cr(pic)3], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic)3] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic)3] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster. [Cr(pic)3], but not CrCl3, at levels of 260 μg Cr/kg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility.

Angiotensin Coverting Enzyme (ACE) 2, a recently discovered ACE homologue, counter-balances the renin-angiotensin system (RAS) activity by cleaving Angiotensin (Ang) II to generate Ang-(1-7). Recently, loss of ACE2 was found to cause pancreatic β-cell dysfunction. Ang-(1-7) was shown to improve insulin signaling and prevent fructose-induced insulin resistance. Therefore, we hypothesized that ACE2 would ameliorate glycemic control in diabetic mice. Adenovirus coding for human ACE2 (Ad-hACE2-eGFP) or a control virus coding for GFP (Ad-GFP) was administered via direct injection to the pancreas (5x107 particle forming units (pfu) in a total volume of 100 μ1-11 of 0.9% w/v saline) of leptin receptor deficient diabetic mice (db/db) and non-diabetic controls (db/m). To assess glycemic homeostasis, glucose tolerance, insulin tolerance and firstphase insulin secretion were assessed. In both 8 and 16 week old mice, ACE2 over-expression improved fasting blood glucose, glucose tolerance and firstphase insulin secretion in db/db mice in comparison to Ad-eGFP treated db/db mice, but had no effect on insulin sensitivity. ACE2 over-expression had no effect on fasting blood glucose, insulin sensitivity or first phase insulin secretion in db/m mice. Ad-hACE2-eGFP expression also enhanced islet insulin content. Infusion with D-Ala7-Ang-(1-7) (600 ng/kg/min, 7 days sc), a MAS receptor antagonist in 8 week old mice prevented ACE2 mediated changes in fasting blood glucose, but had no effect on Ad-GFP diabetic mice. D-Ala7-Ang-(1-7) infusion also prevented ACE2 mediated improvements in glucose tolerance but did not affect Ad-GFP treated mice. To determine the effect of ACE2 over-expression on islet function, we measured islet insulin content, proliferation and apoptosis. ACE2 overexpression increased islet insulin content, and pancreatic β-cell proliferation and decreased apoptosis in 8 week old db/db mice in comparison to Ad-GFP treated controls, but had no effect on 16-week old db/db mice. D-Aia7-Ang-(1-7) infusion prevented ACE2-mediated improvements in insulin content and islet apoptosis and proliferation. ACE2 over-expression reduced islet TGF-13 expression, but had no effect on islet fibrosis in 8 week old db/db mice. ACE2 had no effect on TGF-13 expression or islet fibrosis of 16 week old db/db mice. These data indicate that ACE2 may improve glucose homeostasis through Ang-(1-7) mediated improvement in pancreatic 13-cell function.

The nutritional dietary supplement chromium picolinate, [Cr(pic) 3 ], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic) 3 ] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic) 3 ] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster . [Cr(pic) 3 ], but not CrCl 3 , at levels of 260 μg Cr/kg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility.