Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes: The LEAD (Liraglutide Effect and Action in Diabetes)-2 study

OBJECTIVE—The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy

GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy

Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD

The inner kernel theorem for a certain Segal algebra

The Segal algebra $\mathbf{S}_{0}(G)$ is well defined for arbitrary locally compact Abelian Hausdorff (LCA) groups $G$. It is a Banach space that exhibits a kernel theorem similar to the well-known Schwartz kernel theorem. Specifically, we call this characterization of the continuous linear operators from $\mathbf{S}_{0}(G_{1})$ to $\mathbf{S}'_{0}(G_{2})$ by generalized functions in $\mathbf{S}'_{0}(G_{1} \times G_{2})$ the 'outer kernel theorem'. The main subject of this paper is to formulate what we call the 'inner kernel theorem'. This is the characterization of those linear operators that have kernels in $\mathbf{S}_{0}(G_{1} \times G_{2})$. Such operators are regularizing -- in the sense that they map $\mathbf{S}'_{0}(G_{1})$ into $\mathbf{S}_{0}(G_{2})$ in a $w^{*}$ to norm continuous manner. A detailed functional analytic treatment of these operators is given and applied to the case of general LCA groups. This is done without the use of Wilson bases, which have previously been employed for the case of elementary LCA groups. We apply our approach to describe natural laws of composition for operators that imitate those of linear mappings via matrix multiplications. Furthermore, we detail how these operators approximate general operators (in a weak form). As a concrete example, we derive the widespread statement of engineers and physicists that pure frequencies 'integrate' to a Dirac delta distribution in a mathematically justifiable way