Stimulation Of Glucose Transport Research Articles

Comparison Between SGLT2 Inhibitors and Lactation: Implications for Cardiometabolic Health in Parous Women.

Sodium-glucose cotransporter-2 (SGLT2) inhibition and lactation result in the excretion of large amounts of glucose in urine or milk and are associated with a lower risk of cardiovascular events. The respective mechanisms behind this association with cardiovascular protection are not clear. This review compares the contribution of noninsulin-mediated glucose transport during pharmacologic inhibition of SGLT2 with noninsulin-mediated glucose transport during lactation in terms of the implications for the cardiometabolic health of parous women. The search topics used to obtain information on SGLT2 inhibitors included mechanisms of action, atherosclerosis, and heart failure. The search topics used to obtain information on lactation included cardiovascular health and milk composition. Subsequent reference searches of retrieved articles were also used. Active treatment with SGLT2 inhibitors affects glucose and sodium transport in the kidneys and predominantly protects against hospitalization for heart failure soon after the onset of therapy. Active lactation stimulates glucose transport into the mammary gland and improves subclinical and clinical atherosclerotic vascular disease years after delivery. Both SGLT2 inhibitors and lactation have effects on a variety of glucose transporters. Several mechanisms have been proposed to explain the cardiometabolic benefits of SGLT2 inhibition and lactation. Learning from the similarities and differences between both processes will advance our understanding of cardiometabolic health for all people.

Comment on, "Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat".

Wu et al. (2021) investigated the neuroprotective effects of hypoxia preconditioning (HPC) in a rat model of traumatic brain injury (TBI). The study demonstrated that HPC enhances brain resilience to TBI by upregulating glucose transporters GLUT1 and GLUT3 through the HIF-1α signaling pathway. Comprehensive molecular and histological analyses confirmed increased expression of these transporters, correlating with reduced neuronal apoptosis and cerebral edema. The robust methodology, including rigorous statistical validation and time-course assessments, underscores HPC's potential therapeutic role in mitigating neuronal loss and improving glucose transport post-injury. However, the study could be strengthened by incorporating additional preconditioning controls, comparative analyses with other neuroprotective strategies, and exploring downstream metabolic effects in greater detail. Furthermore, expanding the research to include diverse animal models and examining sex-dependent responses would enhance the generalizability and translational relevance of the findings. Future studies should also integrate metabolic flux analysis and advanced imaging techniques to further elucidate HPC's mechanisms of action.

Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium.

The kidney proximal tubule is uniquely responsible for reabsorption of filtered glucose and gluconeogenesis (GNG). Insulin stimulates glucose transport and suppresses GNG in the proximal tubule, however, the signaling mechanisms and coordinated regulation of these processes remain poorly understood. The kinase complex mTORC2 is critical for regulation of growth, metabolism, solute transport, and electrolyte homeostasis in response to a wide array of inputs. Here we examined its role in the regulation of renal glucose reabsorption and GNG. Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule specific Rictor knockout (TRKO) mice. These animals were subjected to fasting, refeeding, and variation in dietary K + . Metabolic parameters including glucose homeostasis and renal function were assessed in balance cages. Kidneys and livers were also harvested for molecular analysis of gluconeogenic enzymes, mTORC2-regulated targets, and plasma membrane glucose transporters. On a normal chow diet, TRKO mice had marked glycosuria despite indistinguishable blood glucose relative to WT controls. Kidney plasma membrane showed lower SGLT2 and SGLT1 in the fed state, supporting reduced renal glucose reabsorption. Additional metabolic testing provided evidence for renal insulin resistance with elevated fasting insulin, impaired pyruvate tolerance, elevated hemoglobin A1c, and increased renal gluconeogenic enzymes in the fasted and fed states. These effects were correlated with reduced downstream phosphorylation of Akt and the transcription factor FOXO4, identifying a novel role of FOXO4 in the kidney. Interestingly, high dietary K + prevented glycosuria and excessive GNG in TRKO mice, despite persistent reduction in mTORC2 substrate phosphorylation. Renal tubule mTORC2 is critical for coordinated regulation of sodium-glucose cotransport by SGLT2 and SGLT1 as well as renal GNG. Dietary K + promotes glucose reabsorption and suppresses GNG independently of insulin signaling and mTORC2, potentially providing an alternative signaling mechanism in states of insulin resistance. The kidney contributes to regulation of blood glucose through reabsorption of filtered glucose and gluconeogenesis. This study shows that mTORC2 and dietary potassium coordinate the regulation of sodium-glucose cotransport and glucose production in the kidney via independent mechanisms. New insights into the regulation of these processes in the kidney offer promising implications for diabetes mellitus management and treatment.

Imaging of extracellular and intracellular ATP in pancreatic beta cells reveals correlation between glucose metabolism and purinergic signalling

Adenosine triphosphate (ATP) is a universal energy molecule and yet cells release it and extracellular ATP is an important signalling molecule between cells. Monitoring of ATP levels outside of cells is important for our understanding of physiological and pathophysiological processes in cells/tissues. Here, we focus on pancreatic beta cells (INS-1E) and test the hypothesis that there is an association between intra- and extracellular ATP levels which depends on glucose provision. We imaged real-time changes in extracellular ATP in pancreatic beta cells using two sensors tethered to extracellular aspects of the plasma membrane (eATeam3.10, iATPSnFR1.0). Increase in glucose induced fast micromolar ATP release to the cell surface, depending on glucose concentrations. Chronic pre-treatment with glucose increased the basal ATP signal. In addition, we co-expressed intracellular ATP sensors (ATeam1.30, PercevalHR) in the same cultures and showed that glucose induced fast increases in extracellular and intracellular ATP. Glucose and extracellular ATP stimulated glucose transport monitored by the glucose sensor (FLII12Pglu-700uDelta6). In conclusion, we propose that in beta cells there is a dynamic relation between intra- and extracellular ATP that depends on glucose transport and metabolism and these processes may be tuned by purinergic signalling. Future development of ATP sensors for imaging may aid development of novel approaches to target extracellular ATP in, for example, type 2 diabetes mellitus therapy.

Phosphorylation of Syntaxin 4 by the Insulin Receptor Drives Exocytic SNARE Complex Formation to Deliver GLUT4 to the Cell Surface.

A major consequence of insulin binding its receptor on fat and muscle cells is the stimulation of glucose transport into these tissues. This is achieved through an increase in the exocytic trafficking rate of the facilitative glucose transporter GLUT4 from intracellular stores to the cell surface. Delivery of GLUT4 to the cell surface requires the formation of functional SNARE complexes containing Syntaxin 4, SNAP23, and VAMP2. Insulin stimulates the formation of these complexes and concomitantly causes phosphorylation of Syntaxin 4. Here, we use a combination of biochemistry and cell biological approaches to provide a mechanistic link between these observations. We present data to support the hypothesis that Tyr-115 and Tyr-251 of Syntaxin 4 are direct substrates of activated insulin receptors, and that these residues modulate the protein's conformation and thus regulate the rate at which Syntaxin 4 forms SNARE complexes that deliver GLUT4 to the cell surface. This report provides molecular details on how the cell regulates SNARE-mediated membrane traffic in response to an external stimulus.

Association of polymorphic variants of the gene BDNF in human adaptation to extreme environmental conditions and life expectancy

BDNF is a member of the neurotrophin protein family, which plays an important role in the development, maintenance and plasticity of the central and peripheral nervous system. BDNF is expressed in neurons of the developing and adult mammalian nervous system, where it is produced in relatively small amounts, but has high activity, causing biological reactions at picomolar concentrations. It promotes the differentiation of neurons from stem cells, enhances neurite growth and synaptogenesis, and can prevent programmed cell death (apoptosis). The role of BDNF in the regulation of energy homeostasis is also great: by stimulating glucose transport and mitochondrial biogenesis, BDNF enhances cell bioenergetics and protects neurons from damage and neurodegenerative diseases. It is BDNF that controls nutrition patterns (regulating appetite) and types of physical activity, modulates glucose metabolism in peripheral tissues and mediates the positive effect of exercise and fasting on cognitive functions, mood, cardiovascular function and peripheral metabolism. This article presents a mini-review of the data accumulated to date on the role of polymorphic variants of the BDNF gene in the processes of active physiological and psychological adaptation and their comparison with the data obtained by the authors in the study of psychological adaptation to working conditions in the Arctic region of the Russian Federation. The given materials allow us to conclude that optimal adaptation to extreme external conditions is most likely provided genetically by the presence of the Val/Val genotype of the BDNF gene (also associated, in turn, with the probable extension of the individual survival period), and psychologically by the increased use of creative ability.

Hyperglycemia increases SCO-spondin and Wnt5a secretion into the cerebrospinal fluid to regulate ependymal cell beating and glucose sensing.

Hyperglycemia increases glucose concentrations in the cerebrospinal fluid (CSF), activating glucose-sensing mechanisms and feeding behavior in the hypothalamus. Here, we discuss how hyperglycemia temporarily modifies ependymal cell ciliary beating to increase hypothalamic glucose sensing. A high level of glucose in the rat CSF stimulates glucose transporter 2 (GLUT2)-positive subcommissural organ (SCO) cells to release SCO-spondin into the dorsal third ventricle. Genetic inactivation of mice GLUT2 decreases hyperglycemia-induced SCO-spondin secretion. In addition, SCO cells secrete Wnt5a-positive vesicles; thus, Wnt5a and SCO-spondin are found at the apex of dorsal ependymal cilia to regulate ciliary beating. Frizzled-2 and ROR2 receptors, as well as specific proteoglycans, such as glypican/testican (essential for the interaction of Wnt5a with its receptors) and Cx43 coupling, were also analyzed in ependymal cells. Finally, we propose that the SCO-spondin/Wnt5a/Frizzled-2/Cx43 axis in ependymal cells regulates ciliary beating, a cyclic and adaptive signaling mechanism to control glucose sensing.

Abstract P2016: Extracellular Stiffness Induces Glucose Dysregulation Via Microtubule-dependent Mechanism

Previous studies have reported profound changes in metabolic fuel utilization pathways during the development of heart failure, including changes in glucose uptake, glucose transporter mislocalization and/or Insulin-resistance. insulin stimulates glucose transport in muscle cells by triggering redistribution of the GLUT4 glucose transporter from an intracellular perinuclear location to the cell surface. Multiple reports have shown that the microtubules in adipocytes and muscle cells play an important role in the insulin-stimulated glucose transport process. We recently demonstrated, using a tunable stiffness substrate mimicking disease myocardium, that we could induces early, cell-autonomous remodeling of adult cardiomyocytes that is dependent on detyrosination of α-tubulin. We therefore employed this culture substrate to define how adult isolated rat cardiomyocytes glucose uptake response is to Insulin when cultured on stiff vs. soft. At the same time, we studied the localization and expression of Glut4 transporter. We found that 48h on stiff substrate was sufficient to induce a loss of insulin sensitivity in our isolated cardiomyocytes. Immunofluorescence reveals a decrease of Glut4 at the Intercalated disc (ID) but show increase of aggregates of the Glut4 transporter at the cell surface. Western Blot analyses shows no change in the total expression of the transporter. Finally, knowing the importance of microtubules network in the trafficking of Glut4, we overexpressed of tubulin tyrosine ligase (TTL) to prevent the detyrosination of microtubules. Surprisingly, TTL not only restored Glut4 at the ID and decreased the number of aggregates, but it also significantly increased glucose uptake as well as the total amount of Glut4 by more than 2-fold compared to soft control. In conclusion, we demonstrated the importance of microtubule dynamics in cardiomyocytes for the Insulin-dependent trafficking of Glut4 to the membrane.

Phosphorylation of the N-terminus of Syntaxin-16 controls interaction with mVps45 and GLUT4 trafficking in adipocytes.

The ability of insulin to stimulate glucose transport in muscle and fat cells is mediated by the regulated delivery of intracellular vesicles containing glucose transporter-4 (GLUT4) to the plasma membrane, a process known to be defective in disease such as Type 2 diabetes. In the absence of insulin, GLUT4 is sequestered in tubules and vesicles within the cytosol, collectively known as the GLUT4 storage compartment. A subset of these vesicles, known as the 'insulin responsive vesicles' are selectively delivered to the cell surface in response to insulin. We have previously identified Syntaxin16 (Sx16) and its cognate Sec1/Munc18 protein family member mVps45 as key regulatory proteins involved in the delivery of GLUT4 into insulin responsive vesicles. Here we show that mutation of a key residue within the Sx16 N-terminus involved in mVps45 binding, and the mutation of the Sx16 binding site in mVps45 both perturb GLUT4 sorting, consistent with an important role of the interaction of these two proteins in GLUT4 trafficking. We identify Threonine-7 (T7) as a site of phosphorylation of Sx16 in vitro. Mutation of T7 to D impairs Sx16 binding to mVps45 in vitro and overexpression of T7D significantly impaired insulin-stimulated glucose transport in adipocytes. We show that both AMP-activated protein kinase (AMPK) and its relative SIK2 phosphorylate this site. Our data suggest that Sx16 T7 is a potentially important regulatory site for GLUT4 trafficking in adipocytes.

Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with β-Thalassemia Major: Causality or Potential Link?

Insulin-like growth factor-1 (IGF-1) has been shown to lower blood glucose through stimulating glucose transport to fat and muscle and inhibiting hepatic glucose output. Although previous cross-sectional reports reported an association between low circulating concentrations of IGF-1 and glucose dysregulation (GD), its role is still debated. The present retrospective study was designed to assess the circulating IGF-1 levels in β-thalassemia major (β -TM) patients with normal oral glucose tolerance test (NGT-OGTT) and (GD) referred for an endocrine evaluation to explore the potential link between low IGF-1 and GD. Our study included 34 young adult patients with β-TM; 12 patients with NGT after OGTT, 7 with impaired glucose tolerance (IGT), 9 with impaired fasting glucose (IFG) plus IGT, and 6 patients with β-TM-related diabetes mellitus (β-TM- DM). Twenty-two β-TM patients with GD or β-TM- DM and 1 patient with NGT had IGF-1 levels below the 2.5th percentile. Correlation of IGF-1 with fasting plasma glucose, HOMA-IR (homeostatic model assessment for insulin resistance) and OGIS (oral glucose insulin sensitivity) was found. Moreover, a negative correlation was documented between ALT and the Insulinogenic Index (IGI) and a positive correlation between serum ferritin and PG 2-h after OGTT. This study reports for the first time an association between low levels of IGF-1 and GD in β-TM patients. Despite some limitations, our study can serve to generate proposals for more convenient and efficient methods to identify and treat early GD in patients with β-TM, and to conduct more extensive studies. www.actabiomedica.it).

Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects

Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.

Stimulation of Akt Phosphorylation and Glucose Transport by Metalloporphyrins with Peroxynitrite Decomposition Catalytic Activity.

Iron porphyrin molecules such as hemin and iron(III) 4,4',4″,4‴-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (FeTBAP) have previously been shown to influence insulin signaling and glucose metabolism. We undertook this study to determine whether a catalytic action of iron porphyrin compounds would be related to their stimulation of insulin signaling and glucose uptake in C2C12 myotubes. FeTBAP did not display nitrite reductase activity or alter protein S-nitrosylation in myotubes, eliminating this as a candidate mode by which FeTBAP could act. FeTBAP displayed peroxynitrite decomposition catalytic activity in vitro. Additionally, in myotubes FeTBAP decreased protein nitration. The peroxynitrite decomposition catalyst Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride (FeTPPS) also decreased protein nitration in myotubes, but the iron porphyrin Fe(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachlorideporphyrin pentachloride (FeTMPyP) did not. FeTBAP and FeTPPS, but not FeTMPyP, showed in vitro peroxidase activity. Further, FeTBAP and FeTPPs, but not FeTMPyP, increased Akt phosphorylation and stimulated glucose uptake in myotubes. These findings suggest that iron porphyrin compounds with both peroxynitrite decomposition activity and peroxidase activity can stimulate insulin signaling and glucose transport in skeletal muscle cells.

Multiple Direct Effects of the Dietary Protoalkaloid N-Methyltyramine in Human Adipocytes.

Dietary amines have been the subject of a novel interest in nutrition since the discovery of trace amine-associated receptors (TAARs), especially TAAR-1, which recognizes tyramine, phenethylamine, tryptamine, octopamine, N-methyltyramine (NMT), synephrine, amphetamine and related derivatives. Alongside the psychostimulant properties of TAAR-1 ligands, it is their ephedrine-like action on weight loss that drives their current consumption via dietary supplements advertised for ‘fat-burning’ properties. Among these trace amines, tyramine has recently been described, at high doses, to exhibit an antilipolytic action and activation of glucose transport in human adipocytes, i.e., effects that are facilitating lipid storage rather than mobilization. Because of its close structural similarity to tyramine, NMT actions on human adipocytes therefore must to be reevaluated. To this aim, we studied the lipolytic and antilipolytic properties of NMT together with its interplay with insulin stimulation of glucose transport along with amine oxidase activities in adipose cells obtained from women undergoing abdominal surgery. NMT activated 2-deoxyglucose uptake when incubated with freshly isolated adipocytes at 0.01–1 mM, reaching one-third of the maximal stimulation by insulin. However, when combined with insulin, NMT limited by half the action of the lipogenic hormone on glucose transport. The NMT-induced stimulation of hexose uptake was sensitive to inhibitors of monoamine oxidases (MAO) and of semicarbazide-sensitive amine oxidase (SSAO), as was the case for tyramine and benzylamine. All three amines inhibited isoprenaline-induced lipolysis to a greater extent than insulin, while they were poorly lipolytic on their own. All three amines—but not isoprenaline—interacted with MAO or SSAO. Due to these multiple effects on human adipocytes, NMT cannot be considered as a direct lipolytic agent, potentially able to improve lipid mobilization and fat oxidation in consumers of NMT-containing dietary supplements.

EFR3 and phosphatidylinositol 4-kinase IIIα regulate insulin-stimulated glucose transport and GLUT4 dispersal in 3T3-L1 adipocytes.

Insulin stimulates glucose transport in muscle and adipocytes. This is achieved by regulated delivery of intracellular glucose transporter (GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, resulting in increased cell surface GLUT4 levels. Recent work identified a potential further regulatory step, in which insulin increases the dispersal of GLUT4 in the plasma membrane away from the sites of vesicle fusion. EFR3 is a scaffold protein that facilitates localization of phosphatidylinositol 4-kinase type IIIα to the cell surface. Here we show that knockdown of EFR3 or phosphatidylinositol 4-kinase type IIIα impairs insulin-stimulated glucose transport in adipocytes. Using direct stochastic reconstruction microscopy, we also show that EFR3 knockdown impairs insulin stimulated GLUT4 dispersal in the plasma membrane. We propose that EFR3 plays a previously unidentified role in controlling insulin-stimulated glucose transport by facilitating dispersal of GLUT4 within the plasma membrane.

Acetylation of α-tubulin on Lys40, a new way to modulate cardiac glucose transport

Cardiovascular disease remains the leading cause of death in the diabetic population. Diabetic patients develop a specific heart condition called diabetic cardiomyopathy that can evolve to heart failure and that is characterized by altered metabolism in the early stages of the disease. Our group previously demonstrated that overfueling the heart with branched-chain amino acids, ketone bodies or fatty acids, substrates that are upregulated in diabetes, inhibits glucose entry in cardiomyocytes through a global rise in protein acetylation that interferes with glucose transporter 4 (GLUT4) translocation to the plasma membrane. However, the acetylated proteins involved in this process were not yet identified. We investigated the role of α-tubulin, an important cytoskeleton element responsible for GLUT4 translocation, that is known to be acetylable on Lys40 (K40). Acetylation level of α-tubulin on K40 was evaluated in a mouse model of diabetes (high-fat diet, 4 months) and in primary cultured adult rat cardiomyocytes. Its acetylation level was modulated by using a pharmacological inhibitor of its deacetylase (tubacin 10 μM, 5 hrs) and by overexpressing a non-acetylable form of α-tubulin (mCherry α-tubulin K40A). GLUT4 translocation was assessed by fluorescent immunostaining in cells expressing the fusion protein HA-GLUT4-GFP. Glucose transport was measured by following the detritiation rate of 2-3H-glucose in insulin-sensitive and insulin-resistant cardiomyocytes. Acetylation of α-tubulin on K40 was significantly enhanced in the heart of diet-induced diabetic mice. Experimentally increasing its acetylation level in cardiomyocytes with tubacin impaired GLUT4 translocation to the plasma membrane and reduced both basal and insulin-dependent glucose uptake. On the other hand, decreasing α-tubulin K40 acetylation via the overexpression of the K40A form of α-tubulin stimulated glucose transport. Interestingly, reducing α-tubulin K40 acetylation similarly promoted glucose entry in insulin-resistant conditions. Cardiac glucose transport can be regulated by modulation of α-tubulin K40 acetylation, which may lead to new therapeutic strategies preventing the metabolic changes occurring during the development of diabetic cardiomyopathy.

Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKα activation

We found compound 12 N - p -trifluoromethylbenzenesulfonyl matrinane ( 1 ) was a potent anti-diabetic agent. Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes, taking 1 as the lead. In high-fat diet (HFD) and STZ induced diabetic mice, 9a significantly lowers blood glucose, improves glucose tolerance, and especially alleviates diabetic nephropathy and islet damage. Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio, as well as liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase (CaMKK), which synergistically activates AMPK α and then stimulates glucose transporter 4 (GLUT4) membrane translocation and 2-deoxyglucose (2-DG) uptake to exert anti-diabetic efficacy. Therefore, compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism, worthy of further investigation. Tricyclic matrinic derivative 9a exerts good anti-diabetic effects, and alleviates diabetic nephropathy and islet damage in vivo by activating AMPK α and stimulating GLUT4 membrane translocation and 2-DG uptake.

PTEN-induced kinase 1 deficiency alters albumin permeability and insulin signaling in podocytes.

Alterations of insulin signaling in diabetes are associated with podocyte injury, proteinuria, and renal failure. Insulin stimulates glucose transport to cells and regulates other intracellular processes that are linked to cellular bioenergetics, such as autophagy, gluconeogenesis, fatty acid metabolism, and mitochondrial homeostasis. The dysfunction of mitochondrial dynamics, including mitochondrial fusion, fission, and mitophagy, has been observed in high glucose-treated podocytes and renal cells from patients with diabetes. Previous studies showed that prolonged hyperglycemia is associated with the development of insulin resistance in podocytes, and high glucose-treated podocytes exhibit an increase in mitochondrial fission and decrease in markers of mitophagy. In the present study, we found that deficiency of the main mitophagy protein PTEN-induced kinase 1 (PINK1) significantly increased albumin permeability and hampered glucose uptake to podocytes. We suggest that PINK1 inhibition impairs the insulin signaling pathway, in which lower levels of phosphorylated Akt and membrane fractions of the insulin receptor and glucose transporter-4 were observed. Moreover, PINK1-depleted podocytes exhibited lower podocin and nephrin expression, thus identifying a potential mechanism whereby albumin leakage increases under hyperglycemic conditions when mitophagy is inhibited. In conclusion, we found that PINK1 plays an essential role in insulin signaling and the maintenance of proper permeability in podocytes. Therefore, PINK1 may be a potential therapeutic target for the treatment or prevention of diabetic nephropathy.

Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats.

BACKGROUNDDespite overt insulin resistance, adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIMTo investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide, since it is produced by monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in adipocytes.METHODS 3H-2-deoxyglucose uptake (2-DG) was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine. 14C-tyramine oxidation and binding of imidazolinic radioligands [3H-Idazoxan, 3H-(2-benzofuranyl)-2-imidazoline] were studied in adipocytes, the liver, and muscle. The influence of in vivo administration of tyramine + vanadium on glucose handling was assessed in lean and obese rats.RESULTS2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats, when compared to their lean littermates. Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited, while MAO was increased and SSAO decreased. These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat, when compared to the lean. In vitro, tyramine precluded the binding to I2 sites, while in vivo, its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese rats. CONCLUSIONThe adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number. However, probably as a consequence of SSAO down-regulation, the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes. The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.

High doses of tyramine stimulate glucose transport in human fat cells.

Among the dietary amines present in foods and beverages, tyramine has been widely studied since its excessive ingestion can cause catecholamine release and hypertensive crisis. However, tyramine exerts other actions than depleting nerve endings: it activates subtypes of trace amine associated receptors (TAARs) and is oxidized by monoamine oxidases (MAO). Although we have recently described that tyramine is antilipolytic in human adipocytes, no clear evidence has been reported about its effects on glucose transport in the same cell model, while tyramine mimics various insulin-like effects in rodent fat cells, such as activation of glucose transport, lipogenesis, and adipogenesis. Our aim was therefore to characterize the effects of tyramine on glucose transport in human adipocytes. The uptake of the non-metabolizable analogue 2-deoxyglucose (2-DG) was explored in adipocytes from human subcutaneous abdominal adipose tissue obtained from women undergoing reconstructive surgery. Human insulin used as reference agent multiplied by three times the basal 2-DG uptake. Tyramine was ineffective from 0.01 to 10µM and stimulatory at 100µM-1mM, without reaching the maximal effect of insulin. This partial insulin-like effect was not improved by vanadium and was impaired by MAO-A and MAO-B inhibitors. Contrarily to benzylamine, mainly oxidized by semicarbazide-sensitive amine oxidase (SSAO), tyramine activation of glucose transport was not inhibited by semicarbazide. Tyramine effect was not dependent on the Gi-coupled receptor activation but was impaired by antioxidants and reproduced by hydrogen peroxide. In all, the oxidation of high doses of tyramine, already reported to inhibit lipolysis in human fat cells, also partially mimic another effect of insulin in these cells, the glucose uptake activation. Thus, other MAO substrates are potentially able to modulate carbohydrate metabolism.

A Review on Metformin: Clinical Significance and Side Effects

Metformin is a biguanide that has been used extensively worldwide for the treatment of type II diabetes mellitus. It improves glycaemic control by enhancing insulin sensitivity in liver and muscle. An advantage of metformin treatment is the tendency of weight reduction and the absence of significant hypoglycaemia; blood glucose levels are reduced only to normal as it does not stimulate insulin secretion. Metformin also has a beneficial effect on several cardiovascular risk factors including dyslipidemia, elevated plasminogen activator inhibitor 1 levels, other fibrinolytic abnormalities, hyperinsulinemia, and insulin resistance. Metformin enhances muscle and adipocyte insulin receptor number and/or affinity, increases insulin receptor tyrosine kinase activity, stimulates glucose transport and glycogen synthesis, and reduces both hepatic gluconeogenesis and glycogenolysis. The disadvantages are confined to the gastro-intestinal side effects and the potential risk of vitamin B 12 and folic acid deficiency during long-term use. These side effects can be minimized by slow titration and consumption with meals. The under lying mechanism for gastrointestinal intolerance are proposed to be stimulation of intestinal secretion of serotonin, alteration in incretin and metabolism of glucose, and malabsorption of bile salts. Lactic acidosis is rare contraindication associated with metformin. Most reported cases of lactic acidosis occur in patients with contraindications, particularly impaired renal function. Metformin has a good safety profile, efficacy and comparatively reduced cost. Its ability to improve insulin sensitivity and the cardiovascular risk profile of type II diabetic patients has enhanced its clinical use as first-line therapy.