Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells.

Background: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (KATP). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac KATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells.

Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt.

Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This "Warburg effect" represents a standard to diagnose and monitor tumor aggressiveness with (18)F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption.

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane.

IGF1 regulates PKM2 function through Akt phosphorylation.

Pyruvate kinase M2 (PKM2) acts at the crossroad of growth and metabolism pathways in cells. PKM2 regulation by growth factors can redirect glycolytic intermediates into key biosynthetic pathway. Here we show that IGF1 can regulate glycolysis rate, stimulate PKM2 Ser/Thr phosphorylation and decrease cellular pyruvate kinase activity.

Metformin, cancer and glucose metabolism.

Metformin is the first-line treatment for type 2 diabetes. Results from several clinical studies have indicated that type 2 diabetic patients treated with metformin might have a lower cancer risk. One of the primary metabolic changes observed in malignant cell transformation is an increased catabolic glucose metabolism.

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer.

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates.

Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II.

The anti-hyperglycaemic drug metformin has important anticancer properties as shown by the direct inhibition of cancer cells proliferation. Tumor cells avidly use glucose as a source for energy production and cell building blocks. Critical to this phenotype is the production of glucose-6-phosphate (G6P), catalysed by hexokinases (HK) I and II, whose role in glucose retention and metabolism is highly advantageous for cell survival and proliferation.

Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice.

Unlabelled: In the course of metformin treatment, staging abdominal cancer lesions with (18)F-FDG PET images is often hindered by the presence of a high bowel radioactivity. The present study aimed to verify the mechanism underlying this phenomenon.

Methods: Fifty-three mice were submitted to dynamic acquisitions of (18)F-FDG kinetics under fasting conditions.

Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells.

Metformin causes an AMP/ATP ratio increase and AMP-activated protein kinase (AMPK) activation. Since caveolin-1 (Cav-1) plays a role in AMPK activation and energy balance, we investigated whether Cav-1 could participate in metformin's inhibitory effect on IGF1 signaling. The effect of metformin was studied in two non-small-cell lung cancer (NSCLC) cell lines, Calu-1 and Calu-6, expressing higher and lower amounts of Cav-1, respectively.

High frequency of development of B cell lymphoproliferation and diffuse large B cell lymphoma in Dbl knock-in mice.

Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho, Rac, and Cdc42 and to induce a transformed phenotype in murine fibroblasts. We previously reported that Dbl-null mice are viable and fertile but display defective dendrite elongation of distinct subpopulations of cortical neurons, suggesting a role of Dbl in controlling dendritic growth.

IGF-IR internalizes with Caveolin-1 and PTRF/Cavin in HaCat cells.

Background: Insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. IGF-IR interacts directly with Caveolin-1 (Cav-1), the most relevant protein of caveolae.

Beta-cell function improvement after biliopancreatic diversion in subjects with type 2 diabetes and morbid obesity.

In subjects with obesity and type 2 diabetes mellitus (T2DM), biliopancreatic diversion (BPD) improves glucose stimulated insulin secretion, whereas the effects on other secretion mechanisms are still unknown. Our objective was to evaluate the early effects of BPD on nonglucose-stimulated insulin secretion. In 16 morbid obese subjects (9 with T2DM and 7 with normal fasting glucose (NFG)), we measured insulin secretion after glucose-dependent arginine stimulation test and after intravenous glucose tolerance test (IVGTT) before and 1 month after BPD.

Cell-cell bond modulates vascular smooth muscle cell responsiveness to Angiotensin II.

Cell attachment is provided by cell-matrix and cell-cell bonds, and acts as a regulator of vascular smooth muscle cell (VSMC) survival, activity and homeostasis, as well as of VSMCs response to pathogenic stimuli. In this work we elicited an exclusive cell-cell contact by culturing A7r5 VSMCs on agarose-coated wells to form floating cell clusters, and we demonstrated that a steady state with a reduced response to the vasoactive peptide Angiotensin II (ATII) was induced. We found that clustered VSMCs showed subcortical stabilization of beta-catenin and Caveolin 1 (Cav1), unlike adherent confluent counterparts.

Insulin analogues: fears, facts and fantasies.

IGF-I and insulin, acting through both IGF-I and insulin receptors, have been studied widely to evaluate their oncogenic and teratogenic properties. These two properties need to be studied for each new insulin analogue, in addition to measurements of their metabolic and pharmacodynamic features. This editorial critiques a study in this issue of the journal of several insulin analogues in their action in vitro on several cancer-related cell lines.

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion.

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.

Caveolin-1 down-regulation inhibits insulin-like growth factor-I receptor signal transduction in H9C2 rat cardiomyoblasts.

Caveolin (Cav)-1, the major caveolar protein, directly interacts with IGF-I receptor (IGF-IR) and its intracellular substrates. To determine the role of Cav-1 in IGF-IR signaling, we transfected H9C2 cells with small interfering RNA specific for Cav-1-siRNA. The selective down-regulation of Cav-1 (90%) was associated with a smaller reduction of Cav-2, whereas Cav-3 expression was unaffected.

High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects.

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high-molecular weight (HMW) multimers and low-molecular weight (LMW) trimers.

Insulin and IGF-I phosphorylate eNOS in HUVECs by a caveolin-1 dependent mechanism.

Caveolae are plasmamembrane regions which take part in the regulation of intracellular trafficking and signaling of tyrosine kinase receptors. Insulin and IGF-I receptors and their intracellular substrates localize in caveolae. Also eNOS is targeted to caveolae and caveolin-1, the major caveolar protein, acts as a regulator of eNOS activity.

Glimepiride activates eNOS with a mechanism Akt but not caveolin-1 dependent.

Insulin stimulates caveolin-1 and eNOS phosphorylation. The sulfonylurea glimepiride mimics several insulin actions by mechanisms that are poorly understood. Glimepiride induces caveolin-1 phosphorylation and activates PI3K and Akt in rat adipocytes.

The signature motif in human glucose-6-phosphate transporter is essential for microsomal transport of glucose-6-phosphate.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Sequence alignments identify a signature motif shared by G6PT and a family of transporters of phosphorylated metabolites. Two null signature motif mutations have been identified in the G6PT gene of GSD-Ib patients.

Regulation of proto-Dbl by intracellular membrane targeting and protein stability.

The pleckstrin homology (PH) domain of onco-Dbl, a guanine nucleotide exchange factor (GEF) for Cdc42 and RhoA GTPases, interacts with phosphoinositides (PIPs). This interaction modulates both the GEF activity and the targeting to the plasma membrane of onco-Dbl. Conversely, we have previously shown that in proto-Dbl an intramolecular interaction between the N-terminal domain and the PH domain imposes a negative regulation on both the DH and PH functions, suppressing its transforming activity.