The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBβ, mice lacking this isoform were generated. Both male and female Akt2/PKBβ-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBβ-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBβ-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic β cell failure. In contrast, female Akt2/PKBβ-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBβ-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBα, indicating that both Akt2/PKBβ and Akt1/PKBα participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic β cells and adipose tissue in Akt2/PKBβ-deficient mice suggest that Akt2/PKBβ plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM.MethodsPatients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52).ResultsHbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (–0.85%, –1.06%, and –0.13%; p < 0.001); these reductions were maintained at week 52 (–0.74%, –0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo.ConclusionsCanagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.

Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocataly-

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Background-Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results-We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (nϭ10) or vehicle (nϭ8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1Ϯ0.

Differentiation of human placental villous trophoblast includes syncytial fusion of cytotrophoblast forming syncytiotrophoblast. Early stages of the apoptosis cascade were described to be involved in this differentiation process. We investigated the role of the initiator caspase 8 in syncytial fusion in vitro, cultivating placental villous explants with or without caspase 8 antisense oligonucleotides or peptide inhibitors for up to 120 h. Trophoblast fusion and differentiation were assessed by confocal microscopy, immunohistochemistry and Western blot analysis. Culture with caspase 8 antisense oligonucleotides or peptide inhibitors reduced the fusion of cytotrophoblast with the syncytiotrophoblast, and resulted in multilayered cytotrophoblast. Caspase 8 expression was suppressed by antisense oligonucleotides and caspase 8 activities were reduced by peptide inhibitors. The organic anion-transporter hOAT-4 normally expressed in the cytotrophoblast and transferred into the syncytiotrophoblast by syncytial fusion was retained in the cytotrophoblast due to lack of fusion. We conclude that expression and activity of caspase 8 is a prerequisite for differentiation and syncytial fusion of cytotrophoblast cells.

The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBβ, mice lacking this isoform were generated. Both male and female Akt2/PKBβ-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBβ-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBβ-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic β cell failure. In contrast, female Akt2/PKBβ-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBβ-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBα, indicating that both Akt2/PKBβ and Akt1/PKBα participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic β cells and adipose tissue in Akt2/PKBβ-deficient mice suggest that Akt2/PKBβ plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.