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Mimicking gastric bypass glucotonic effect: the role of atypical PKC activation and GLUT1

ABSTRACT: Bariatric surgery has demonstrated a significant therapeutic impact in reducing obesity and achieving euglycemia in diabetic patientspatients with diabetes. We previously demonstrated that iIntestinal glucotonic transformation, defined as increased intestinal serum glucose uptake and secretion into the lumen, has anplays a vital important role in bypass surgeryies. Altered transcriptomes were evaluated in variable intestinal glucotonic models and big-data artificial intelligence AI-based drug discovery systems. We found noted that protein kinase C (PKC) activation mimics the intestinal transcriptome changes alterations observed in during intestinal glucotonic transformation. Among PKC subfamilies, atypical PKC promotes GLUT1- mediated intestinal glucotonic transformation without inducing oncogenic proliferation. Intestinal aPKC activation through via the transposon expression vector induces serum glucose uptake into intestinal tissue and excretion into the lumeinal space. . Prostratin, a non-tumorigenic phorbol ester, was found observed to activate aPKC and induce a similar glucotonic effect. Taken together, our study results highlightCollectively, we identified a a new chemical compound and target molecular pathways that may provide a distinct and effective approach to to treating diabetes .

ORGANISM(S): Mus musculus

PROVIDER: GSE240754 | GEO | 2025/08/13

REPOSITORIES: GEO

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Mimicking gastric bypass glucotonic effect: the role of atypical PKC activation and GLUT1

Project description:Bariatric surgery has demonstrated a significant therapeutic impact in reducing obesity and achieving euglycemia in diabetic patientspatients with diabetes. We previously demonstrated that iIntestinal glucotonic transformation, defined as increased intestinal serum glucose uptake and secretion into the lumen, has anplays a vital important role in bypass surgeryies. Altered transcriptomes were evaluated in variable intestinal glucotonic models and big-data artificial intelligence AI-based drug discovery systems. We found noted that protein kinase C (PKC) activation mimics the intestinal transcriptome changes alterations observed in during intestinal glucotonic transformation. Among PKC subfamilies, atypical PKC promotes GLUT1- mediated intestinal glucotonic transformation without inducing oncogenic proliferation. Intestinal aPKC activation through via the transposon expression vector induces serum glucose uptake into intestinal tissue and excretion into the lumeinal space. . Prostratin, a non-tumorigenic phorbol ester, was found observed to activate aPKC and induce a similar glucotonic effect. Taken together, our study results highlightCollectively, we identified a a new chemical compound and target molecular pathways that may provide a distinct and effective approach to to treating diabetes .

2025-07-23 | GSE239399 | GEO

Expression data from TGFbeta-treated control or aPKC silenced A549 cells

Project description:Aberrant TGFbeta signalling is a hallmark of epithelial derived tumours. Signalling patterns can depend on the membrane trafficking and internalization of the TGFbeta receptors. Protein kinase C (PKC), particularly the atypical PKC isoforms, alter the trafficking of TGFbeta receptors and can alter TGFbeta induced gene expression. We used microarrays to detail the programme of gene expression underlying TGFbeta induction between control or aPKC silenced A549 cells. Control or aPKC silenced A549 cells were serum starved and treated with TGFbeta for 1 hour. Total RNA was extracted from untreated or TGFbeta treated cells after 8 and 24 hours and analyzed using Affymetrix microarrays. We sought to assess TGFbeta gene expression in aPKC silenced lung cancer cells, as we found that knockdown of aPKC extends TGFbeta signalling as assessed by phospho Smad2 levels. Furthermore, increased expression and oncogenic activity of aPKC (PKCiota) has been reported in lung cancer cells.

2011-01-29 | E-GEOD-26241 | biostudies-arrayexpress

Otsuka Long-Evans Tokushima fatty rats with Roux-en-Y gastric bypass surgery

Project description:Objective: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We previously observed temporal migrations in small intestinal glycolysis, suggesting that glucose excretion may contribute to glucose homeostasis. This study aimed to evaluate the mechanisms underlying serum glucose excretion and its contribution to glucose homeostasis by using 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography. Design: FDG distribution in reconstructed intestinal limbs of sham- or RYGB-operated obese rats was identified. RNA sequencing was performed in areas of high or low FDG uptake.

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Insulin-Independent Regulation of Type 1 Diabetes via Large Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2

Project description:Current treatments for type 1 diabetes (T1D) focus on optimizing insulin replacement. We demonstrate the therapeutic potential of the large secreted protein fraction from brown adipose tissue (BAT), independent of insulin. This secreted fraction mediates insulin receptor-dependent recovery of euglycemia in diabetic nonobese diabetic (NOD) mice by suppressing glucagon secretion. It also promotes white adipocyte differentiation and browning, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. From this fraction, we identify nidogen-2 as a brown adipocyte-secreted factor that reverses hyperglycemia in T1D NOD, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the secreted fraction. These findings provide proof of principle that the pleiotropic effects of BAT-derived peptides represent a novel approach to diabetes management.

2025-03-13 | PXD051972 | Pride

Young and undamaged recombinant albumin alleviates T2DM by improving hepatic glycolysis through EGFR and protecting islet β cells in mice

Project description:Type 2 Diabetes Mellitus (T2DM) is a severe disease that has reached epidemic proportions. In this study, treatment of T2DM mice with young, undamaged, and ultrapure recombinant mouse serum albumin (rMSA) increased their serum albumin levels, which resulted in a reversal of the disease including reduced fasting blood glucose levels, improved glucose tolerance, increased glucose-stimulated insulin secretion, and alleviated islet atrophy. At the cellular level, rMSA improved glucose uptake and glycolysis in hepatocytes. Mechanistically, rMSA reduced the binding between CAV1 and EGFR to increase EGFR activation leading to PI3K-AKT activation. Furthermore, rMSA extracellularly reduced the rate of fatty acid uptake by islet β-cells, which relieved the accumulation of intracellular ceramide, endoplasmic reticulum stress, and apoptosis. This study provided the first clear demonstration that injections of young, undamaged, and ultrapure recombinant serum albumin can alleviate T2DM in mice.

2023-11-11 | GSE217975 | GEO

WNK1-specific phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1

Project description:Glucose uptake by mammalian cells is a key mechanism to maintain cell and tissue homeostasis and relies mostly on plasma membrane-localized glucose transporter proteins (GLUTs). Two main cellular mechanisms regulate GLUT proteins in the cell: first, expression of GLUT genes is under dynamic transcriptional control and is used by cancer cells to increase glucose availability. Second, GLUT proteins are regulated by membrane traffic from storage vesicles to the plasma membrane (PM). This latter process is triggered by signaling mechanisms and well-studied in case of insulin-responsive cells, which activate protein kinase AKT to phosphorylate TBC1D4, a RAB-GAP involved in membrane traffic regulation. Previously, we identified protein kinase WNK1 as another kinase able to phosphorylate TBC1D4 and regulate the surface expression of the constitutive glucose transporter GLUT1. Here we describe that downregulation of WNK1 through RNA interference in HEK293 cells led to a 2-fold decrease in PM GLUT1 expression, concomitant with a 60% decrease in glucose uptake. By mass spectrometry, we identified serine (S) 704 in TBC1D4 as a WNK1-specific phosphorylation site, and also S565 in the paralogue TBC1D1. Transfection of the respective phosphomimetic or unphosphorylatable TBC1D mutants into cells revealed that both affected the cell surface abundance of GLUT1. The results reinforce a regulatory role for WNK1 in cell metabolism and have potential impact for the understanding of cancer cell metabolism or therapeutic options in type 2 diabetes.

2021-11-03 | PXD016218 | Pride

Expression data from TGFbeta-treated control or aPKC silenced A549 cells

2011-01-29 | GSE26241 | GEO

Gene expression profiles in cardiac specific overexpression of Glut1 transgenic mice

Project description:Cardiac-specific Glut1 transgenic (Glut1-TG) mice exhibited higher glucose uptake and utilization compared with wild type mice. Cardiac pathological hypertrophy is accompanied by a switch of substrate metabolism from fatty acid oxidation to glucose use, resulting in a fetal like metabolic profile. However, the role of increasing glucose utilization in regulating cardiomyocyte growth is poorly understood. In order to identify novel pathways that is regulated by glucose, we performed microarray analyses using hearts from Glut1-TG and WT mice. The microarray analyses revealed that many genes that are involved in branched-chain amino acids (BCAAs) were downregulated in Glut1-TG mice.

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Cell polarity proteins promote macropinocytosis in response to metabolic stress

Project description:Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKC and PKCas novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for cell polarity proteins in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

2024-10-22 | GSE276007 | GEO

Effects of astrocytic absence of glucose transporter 1 (GLUT1) on the cortical astrocytic translatome

Project description:Brain activities rely on a steady supply of blood glucose, which is shuttled into the brain by glucose transporters and used to fuel metabolic pathways and energy demands in all neural cells. Astrocytes express glucose transporter 1 (GLUT1), which is considered the key glucose uptake route for glycolytic astrocytes to ensure their metabolic support functions to neurons and other glial cells in vivo. GLUT1 deficiency causes severe developmental impairments, however, the role of GLUT1 in astroglial glucose metabolism and brain function is poorly understood. Here we examine the effect of astrocytic GLUT1 deletion on the active translatome of astrocytes in the the mouse cortex.

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