Approved LXR agonists exert unspecific effects on pancreatic β-cell function.

Novel agonists of the nuclear liver-X-receptor (LXR) are designed to treat metabolic disorders or cancer. The rationale to develop these new drugs is based on promising results with established LXR agonist like T0901317 and GW3965. LXRα and LXRβ are expressed in β-cells, and expression is increased by T0901317.

PET/MRI enables simultaneous quantification of β-cell mass and function.

Non-invasive imaging of β-cells represents a desirable preclinical and clinical tool to monitor the change of β-cell mass and the loss of function during pre-diabetic stages. Although it is widely accepted that manganese (Mn) ions are actively gated by voltage-dependent calcium channels (VDCC) in response to glucose metabolism, little is known on its specificity for quantification of islet β-cell function using Mn and magnetic resonance imaging (MRI). On the other hand, glucagon-like-peptide-1 receptor (GLP-1R) represents a validated target for the estimation of β-cell mass using radiolabeled exendin-4 (Ex4) and positron emission tomography (PET).

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway.

The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in β-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine β-cell function by TGR5 activation.

The LXR Ligand T0901317 Acutely Inhibits Insulin Secretion by Affecting Mitochondrial Metabolism.

The role of liver X receptor (LXR) in pancreatic β-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in β-cells induces lipotoxicity, a key step in the development of β-cell dysfunction, which accompanies type 2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the micromolar range to study the significance of LXR activation.

The Angiotensin-(1-7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo.

The angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas underlying mechanisms are mostly unknown. Here we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined.

Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo.

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.