Regulation of Pancreatic β Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein β Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-ϐ-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein ϐ (C/EBPϐ) expression levels. The effect of C/EBPϐ phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBPϐ transgenic mice to investigate the relationship between C/EBPϐ expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBPϐ lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBPϐ expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBPϐ transgenic mice decreased C/EBPϐ expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBPϐ expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure

Inwardly rectifying potassium channels (KIR) in GtoPdb v.2021.3

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3)

Inwardly rectifying potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3)

A Novel Function of Noc2 in Agonist-Induced Intracellular Ca2+ Increase during Zymogen-Granule Exocytosis in Pancreatic Acinar Cells

Noc2, a putative Rab effector, contributes to secretory-granule exocytosis in neuroendocrine and exocrine cells. Here, using two-photon excitation live-cell imaging, we investigated its role in Ca2+-dependent zymogen granule (ZG) exocytosis in pancreatic acinar cells from wild-type (WT) and Noc2-knockout (KO) mice. Imaging of a KO acinar cell revealed an expanded granular area, indicating ZG accumulation. In our spatiotemporal analysis of the ZG exocytosis induced by agonist (cholecystokinin or acetylcholine) stimulation, the location and rate of progress of ZG exocytosis did not differ significantly between the two strains. ZG exocytosis from KO acinar cells was seldom observed at physiological concentrations of agonists, but was normal (vs. WT) at high concentrations. Flash photolysis of a caged calcium compound confirmed the integrity of the fusion step of ZG exocytosis in KO acinar cells. The decreased ZG exocytosis present at physiological concentrations of agonists raised the possibility of impaired elicitation of calcium spikes. When calcium spikes were evoked in KO acinar cells by a high agonist concentration: (a) they always started at the apical portion and traveled to the basal portion, and (b) calcium oscillations over the 10 µM level were observed, as in WT acinar cells. At physiological concentrations of agonists, however, sufficient calcium spikes were not observed, suggesting an impaired [Ca2+]i-increase mechanism in KO acinar cells. We propose that in pancreatic acinar cells, Noc2 is not indispensable for the membrane fusion of ZG per se, but instead performs a novel function favoring agonist-induced physiological [Ca2+]i increases

Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells

Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study

Aims To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol = 2.59 to = 100 to = 2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy

Cellular expression of Noc2, a Rab effector protein, in endocrine and exocrine tissues in the mouse.

Noc2 is a Rab effector which participates in regulated exocytosis. It is expressed abundantly in endocrine cells but at low levels in exocrine tissues. Noc2-deficient mice, however, exhibit marked accumulation of secretory granules in exocrine cells rather than endocrine cells. In the present study, we investigated localization of Noc2 immunohistochemically in various endocrine and exocrine tissues in normal mice. Western blotting detected a Noc2-immunoreactive band of 38 kDa in isolated pancreatic islets, the adrenal gland, pituitary gland, and thyroid gland. Immunostaining for Noc2 labeled endocrine cells in the adrenal medulla and adenohypophysis, pancreatic islet cells, thyroid parafollicular cells, and gut endocrine cells, supporting the notion that Noc2 is a Rab effector protein shared by amine/peptide-secreting endocrine cells. Besides endocrine tissues, granular ducts in salivary glands contained Noc2. Although immunostaining failed to detect Noc2 in acinar cells of all exocrine glands examined, reverse transcriptase-polymerase chain reaction analysis detected the mRNA expression in exocrine pancreas. Ultrastructurally, Noc2 immunoreactivity was associated with the limiting membrane of granules in both pancreatic endocrine and salivary duct exocrine cells. The cellular and subcellular localizations of Noc2 should yield key information on its functional significance as well as account for the phenotype in Noc2-deficient mice