Insulin-dependent Glucose Transport Research Articles

Hepatocellular Ballooning is Due to Highly Pronounced Glycogenosis Potentially Associated with Steatosis and Metabolic Reprogramming.

Hepatocellular ballooning is a common finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degeneration but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are damaged cells on the path to death or rather viable cells, possibly involved in neoplastic development. Using specimens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme- and immunohistochemical approaches with serial paraffin and cryostat sections. BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen storage of (glycogenosis) and/or lipids (steatosis) were characteristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunoreactivity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulated along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis. BH are hallmarked by particularly pronounced glycogenosis with facultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepatocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogramming, indicative of a preneoplastic nature.

Abstract 059: (Pro)renin Receptor Ablation In Tyrosine Hydroxylase Neurons In The Paraventricular Nucleus Of The Hypothalamus Improves Insulin Sensitivity In Mice Fed A High-fat Diet

We recently reported that neuron-specific (pro)renin receptor (PRR) deletion reduces blood pressure (BP), fasting blood glucose (BG) and improves glucose tolerance in high-fat diet (HFD)-treated mice. To investigate underlying mechanisms, we focused on tyrosine hydroxylase (TH) neurons in the hypothalamic paraventricular nucleus (TH PVN neurons), a largely GABAergic population that expresses PRR and projects to autonomic centers important for BP and BG regulation. The PRR was ablated specifically in the TH-positive neurons in the PVN using Cre-LoxP approach. Radio telemetric BP recording, fasting blood glucose (FBG) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed following 6-week HFD (60% calories from fat). HFD induced elevation of BP within the first week ( p < 0.05) and maintained elevated during 6-week protocol; however, there was no difference in BP between TH PVN PRRKO and WT control mice in both sexes following HFD. In male mice, the controls had higher FBG when compared with the TH PVN PRRKO mice (144.1 ± 5.74 vs. 121.9 ± 4.34 mg/dl, p < 0.05) at the end of the 6-week HFD treatment. Interestingly, PRR ablation in the TH PVN neurons did not reduce FBG in female mice. The TH PVN PRRKO mice showed improved glucose handling during FSIVGTT (AUC: 3481 ± 247.5 vs. 4263 ± 153.9, p < 0.05), while there was no difference in insulin secretion (AUC: 1782 ± 339.2 vs. 2324 ± 495.6, p > 0.05) between the two groups suggesting that TH PVN PRR ablation attenuates HFD-induced glucose intolerance through either an increase in insulin sensitivity or an insulin-independent pathway. Detected by western blot, the glucose transporter 4, an insulin-dependent glucose transporter, was higher on the plasma membrane of skeletal muscle in the TH PVN PRRKO mice (1.9 ± 0.2 vs. 1.0 ± 0.1, p < 0.05) compared with the controls. The hepatic mRNA expression of glucose-6-phosphatase, a gluconeogenic gene transcriptional negative-regulated by insulin, was lower in the TH PVN PRRKO (0.60 ± 0.07 vs. 0.95 ± 0.10, p < 0.05) compared with the control mice, suggesting improvement of insulin sensitivity in the TH PVN PRRKO mice. In conclusion, PRR ablation in TH PVN neurons attenuates FBG and glucose tolerance through improvement of insulin sensitivity without impacting BP.

Nocturnal melatonin increases glucose uptake via insulin-independent action in the goldfish brain.

Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.

Alzheimer's disease: Is there a relationship between brain renin-angiotensin system, estradiol and glucose transporter-4 (GLUT-4)?

<abstract> <p>One of the diseases more related to the continuous aging of the population is Alzheimer's disease, which is a type of dementia currently without either effective diagnosis biomarkers or treatments. Its higher prevalence in women makes it necessary to study pathways/systems that could participate and/or be involved in its development, as well as those that could be affected by hormonal factors, which, in this case, are estradiol levels. In this sense, one of the systems under study that is gaining special relevance in the scientific community is the brain renin-angiotensin system and its regulatory proteolytic enzymes. This system is strongly modulated by estrogens, and it is also connected with the cerebral glucose metabolism through the angiotensin IV receptor, also recognized as the insulin-regulated aminopeptidase (IRAP). Due to the fact that the cerebral glucose metabolism is highly compromised in patients with Alzheimer's disease, it is necessary to know the elements of the systems and their functions in this process, namely, the cerebral renin-angiotensin system, estradiol and IRAP, an enzyme and receptor co-localized in brain tissue with the insulin-dependent glucose transporter 4 (GLUT4). Knowledge of the connection between them could shed light on the molecular mechanisms of this disease and also provide new diagnostic and therapeutic targets.</p> </abstract>

MYH10 Governs Adipocyte Function and Adipogenesis through Its Interaction with GLUT4.

Adipogenesis is dependent on cytoskeletal remodeling that determines and maintains cellular shape and function. Cytoskeletal proteins contribute to the filament-based network responsible for controlling the shape of adipocytes and promoting the intracellular trafficking of cellular components. Currently, the understanding of these mechanisms and their effect on differentiation and adipocyte function remains incomplete. In this study, we identified the non-muscle myosin 10 (MYH10) as a novel regulator of adipogenesis and adipocyte function through its interaction with the insulin-dependent glucose transporter 4 (GLUT4). MYH10 depletion in preadipocytes resulted in impaired adipogenesis, with knockdown cells exhibiting an absence of morphological alteration and molecular signals. MYH10 was shown in a complex with GLUT4 in adipocytes, an interaction regulated by insulin induction. The missing adipogenic capacity of MYH10 knockdown cells was restored when the cells took up GLUT4 vesicles from neighbor wildtype cells in a co-culture system. This signaling cascade is regulated by the protein kinase C ζ (PKCζ), which interacts with MYH10 to modify the localization and interaction of both GLUT4 and MYH10 in adipocytes. Overall, our study establishes MYH10 as an essential regulator of GLUT4 translocation, affecting both adipogenesis and adipocyte function, highlighting its importance in future cytoskeleton-based studies in adipocytes.

Antidiabetic effects of nerolidol through promoting insulin receptor signaling in high-fat diet and low dose streptozotocin-induced type 2 diabetic rats.

The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4weeks and administering a single intraperitoneal dose of streptozotocin (35mg/kg body weight). Diabetic rats were treated with nerolidol (25mg/kg BW) for 28days. Results showed that nerolidol treatment significantly reduced (p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved (p < 0.05) the body weight and insulin level. Nerolidol also considerably improved (p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered (p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing (p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering (p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring (p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.

NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.

The SGLT2 inhibitor ertugliflozin causes a switch of cardiac substrate utilization leading to reduced cardiac mTOR-signaling, unfolded protein response and apoptosis

Abstract Introduction SGLT2 inhibitors reduce hospitalization for heart failure in patients with and without diabetes. The underlying mechanisms remain incompletely understood but might relate to the induction of a fasting like response with low blood glucose and insulin levels and increased ketone bodies. The study aimed to investigate underlying signaling pathways. Methods and results Cardiac hypertrophy was induced by transverse aortic constriction (TAC) surgery in 20-week-old C57Bl/6J mice. Mice were treated with the SGLT2 inhibitor ertugliflozin (225 mg/kg chow diet) or vehicle for a period of 10 weeks. Ertugliflozin significantly improved left ventricular systolic and diastolic function (dp/dtmax: TAC ctrl.: 8900±3362 mmHg/s vs. TAC ertu.: 12051±1604 mmHg/s (p&amp;lt;0.001) and dp/dtmin: TAC ctrl.: −7653±2770 mmHg/s vs. TAC ertu.: −10199±2463 mmHg/s (p&amp;lt;0.01); by millar catheter with dobutamine stress) and reduced myocardial fibrosis (p=0.17) and hypertrophy (p=0.09). This was paralleled by the expected fasting like response with lower glucose and insulin levels (HOMA-IR p&amp;lt;0.05) and increased ketone body concentrations (p&amp;lt;0.05). As a consequence cardiac insulin signaling (AKT-phosphorylation at Thr(308), 0.39-fold (p&amp;lt;0.01)) was reduced by ertugliflozin with less insulin-dependent glucose transporter GLUT4 expression (0.64-fold (p&amp;lt;0.05)) while fatty acid transporter CD36 (2.12-fold (p&amp;lt;0.001)) and the ketone body catabolizing key enzyme beta-hydroxybutyrate dehydrogenase BDH-1 were increased (1.59-fold (p&amp;lt;0.01)) in addition to AMPK-signaling (AMPK-phosphorylation at Thr(172), 1.62-fold (p&amp;lt;0.01)). This led to downstream inhibition of the mTOR pathway with reduced phosphorylation of p70S6K, 4E-BP1 and ULK1 (p70S6K-phosphorylation at Thr(389) (0.57-fold (p&amp;lt;0.05)), 4E-BP1-phosphorylation at Ser(65) (0.74-fold (p&amp;lt;0.05)) and ULK1-phosphorylation at Ser(757) (0.56-fold (p&amp;lt;0.01))). MTOR signaling critically mediates cardiac hypertrophy, endoplasmic reticulum stress, unfolded protein response (UPR) and adverse cardiac remodeling. Consistently, we found ertugliflozin to reduce ATF6 (0.69-fold (p&amp;lt;0.05)) and elf2α-phosphorylation at Ser(51) (0.66-fold (p=0.0611)) as well as downstream signaling (ATF4 0.58-fold (p&amp;lt;0.01); CHOP 0.36-fold (p&amp;lt;0.001)). This let to reduced caspase 3 (0.74-fold (p&amp;lt;0.05)), collagen I (0.60-fold (p&amp;lt;0.01)) and IL-1β (0.46-fold (p&amp;lt;0.01)) expression indicating less apoptosis, fibrosis and left ventricular remodeling with consequential reduction of BNP expression (0.60-fold (p&amp;lt;0.001)) in response to SGLT2 inhibition. Conclusion The SGLT2 inhibitor ertugliflozin improves left ventricular function in a murine model of cardiac hypertrophy. Mechanistically, this was associated with a metabolic switch of cardiac substrate utilization with reduced cardiac insulin- and increased cardiac AMPK-signaling leading to reduced cardiac mTOR-signaling, unfolded protein response and apoptosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): MSD

A novel phenolic formulation for treating hepatic and peripheral insulin resistance by regulating GLUT4-mediated glucose uptake

Chronic insulin resistance suppresses muscle and liver response to insulin, which is partially due to impaired vesicle trafficking. We report here that a formula consisting of resveratrol, ferulic acid and epigallocatechin-3-O-gallate is more effective in ameliorating muscle and hepatic insulin resistance than the anti-diabetic drugs, metformin and AICAR. The formula enhanced glucose transporter-4 (GLUT4) translocation to the plasma membrane in the insulin-resistant muscle cells by regulating both insulin-independent (calcium and AMPK) and insulin-dependent (PI3K) signaling molecules. Particularly, it regulated the subcellular location of GLUT4 through endosomes to increase glucose uptake under insulin-resistant condition. Meanwhile, this phytochemicals combination increased glycogen synthesis and decreased glucose production in the insulin-resistant liver cells. On the other hand, this formula also showed anti-diabetic potential by the reduction of lipid content in the myotubes, hepatocytes, and adipocytes. This study demonstrated that the three phenolic compounds in the formula could work in distinct mechanisms and enhance both insulin-dependent and independent vesicles trafficking and glucose transport mechanisms to improve carbohydrate and lipid metabolism.

SHORT-TERM CRIZOTINIB TREATMENT REVERSES GLUT4 GLUCOSE TRANSPORTER DOWNREGULATION IN DIABETIC RAT HEART

Objective: Crizotinib is a multitarget ALK/c-MET/ROS1/RON inhibitor that can potentially inhibit non-intended receptor tyrosine kinases (RTKs) which play a role in cardiac development, function and/or metabolism. Tyrosine kinase inhibitors (TKIs) studies in diabetic patients showed antidiabetic effects of some TKIs and several potential mechanisms were suggested including mechanisms via RTKs. We examined RTKs after short-term crizotinib treatment in diabetic heart. Design and method: To induce diabetes, male Wistar rats were injected with streptozotocin (STZ; 80 mg/kg, i.p.), controls received vehicle (CON). After 3 days, diabetic rats were treated with crizotinib in a dose 25 mg/kg/day p.o. (STZ+CRI) or vehicle p.o. for 7 days (STZ). mRNA expression of selected RTKs were assessed by RT-qPCR method in rat left ventricle samples. Blood glucose, c-peptide and glucagon in plasma samples and expression of cardiac glucose transporters Glut1 and Glut4 were assessed to determine impact on glucose homeostasis. Results: Intriguingly, crizotinib had a hypoglycaemic effect in diabetic animals (plasma glucose in STZ: 19.2 mmol/L vs. STZ+CRI: 14.5 mmol/L., P&lt;0.05). STZ animals had lower c-peptide and unaltered glucagon plasma levels. However, plasma levels of c-peptide and glucagon were not changed after crizotinib treatment suggesting altered glucose utilization in tissues. In STZ rats, we detected downregulation of insulin dependent glucose transporter Glut4 (by 40% as compared to CON, P &lt; 0.05). Interestingly, crizotinib prevented this downregulation. Insulin non-dependent Glut1 glucose transporter remained stable across all groups. Diabetes upregulated cardiac insulin receptor and Igf-1 receptor without significant crizotinib impact. Regarding RTKs, we observed unaltered c-Met, Flt1 and Erbb2 expressions in diabetic hearts without influence of crizotinib. Conclusions: Crizotinib had a hypoglycaemic effect in diabetic animals after short-term treatment. This was independent of insulin and glucagon levels. Crizotinib prevented cardiac insulin-dependent Glut4 decrease. Downregulation of cardiac insulin receptor family RTKs expression remains stable under crizotinib suggesting modulation of alternative pathways responsible for crizotinib action in diabetic rat heart.

The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes.

Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80mg·kg-1, i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25mg·kg-1 per day p.o.) or vehicle was administered for 7days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P< 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

An Evolutionary Remedy for an Abominable Physiological Mystery: Benign Hyperglycemia in Birds.

Relative to other vertebrates, birds have unusually high blood glucose levels. In humans, the hyperglycemia observed in birds would be associated with diabetes mellitus and the non-enzymatic glycation of proteins, which leads to the accumulation of advanced glycation products and to a plethora of microvascular pathologies. How do birds avoid the negative effects of hyperglycemia? Anthony-Regnitz et al. (J Mol Evol 88: 653-661, 2020) discovered that birds might have evolved glycation-resistant proteins. Serum albumin is an important multifunctional protein susceptible to glycation. Anthony-Regnitz et al. (J Mol Evol 88: 653-661, 2020) found that chicken albumin is resistant to glycation relative to bovine serum albumin. Protein glycation takes place primarily in lysine residues, which are less abundant in chicken than in bovine serum albumin. A multispecies comparison of serum albumin sequences revealed lower numbers of lysine residues in birds than in mammals. Benign hyperglycemia is a shared derived trait of birds and glycation resistance mechanisms appear to have accompanied its evolution. The evolution of benign hyperglycemia in birds coincided with a genomic upheaval that included the loss of important genes, including the one that codes for GLUT4, the transporter responsible for insulin-dependent glucose transport in other vertebrates' insulin-sensitive cells. This loss seems to have resulted in the remodeling of the insulin-signaling pathway in bird tissues. Avian hyperglycemia has been considered a mystery for a long time. Although we remain ignorant of its origins and its repercussions for the physiology of birds, the discovery of resistance to glycation in bird serum albumin offers a path forward to solve this mystery.

Functional characterization and tissue localization of the facilitative glucose transporter GLUT12.

Facilitative glucose transporters (GLUTs) play crucial roles in glucose utilization and homeostasis. GLUT12 was initially isolated as a novel GLUT4-like transporter involved in insulin-dependent glucose transport. However, tissue distribution and biochemical properties of GLUT12 are not well understood. In this study, we investigated the basic kinetic properties and tissue distribution of GLUT12. Human GLUT12 and GLUT1 were overexpressed and purified using Ni-NTA column chromatography. Reconstituted proteoliposomes showed time-dependent d-glucose transport activity, which was inhibited by phloretin and dehydroascorbate. Dose dependence of glucose transport revealed a KM and Vmax values of 6.4 mM and 1.2 μmol/mg/min, respectively, indicating that GLUT12 is a high-affinity type GLUT. Glucose transport by GLUT12 was inhibited by ATP and glucose-1-phosphate, glucose-6-phosphate and disaccharides (properties similar to those of GLUT1). Indirect immunohistochemistry revealed the distribution of mouse GLUT12 in the apical region of distal tubules and collecting ducts in the kidney and epithelial cells of the jejunum. In addition to these cells, GLUT12 was present in chromaffin cells in the adrenal medulla, the anterior pituitary lobe, as well as the thyroid and pyloric glands. These tissue distributions suggest a unique function of GLUT12, besides that of an insulin-dependent glucose transport.

METABOLIC CONTROL OF HIGH-FREQUENCY GAMMA OSCILLATIONS IN THE BRAIN

A high-frequency electrical activity across the range of 30–100 Hz, known as gamma rhythms, is observed in many regions of the brain. This phenomenon serves to synchronize the activity of various neural networks intended to process, transmit, store and receive information. Gamma rhythms play a key role in such processes of higher nervous activity as attention, sensory perception and memory formation. Impairment of gamma rhythms is a common symptom of diseases associated with cognitive impairment, including Alzheimer’s disease, epilepsy and schizophrenia. Recent studies have shown that a particular population of GABAergic-inhibiting neurons, i.e. parvalbumin-positive (PV+) interneurons, is the source of high-frequency oscillations. Maintenance of gamma rhythms is an extremely energy-intensive process that relies on a high rate of oxidative phosphorylation in the mitochondria of neurons and is limited by the presence of glucose. Insulin may be involved in the metabolic control of gamma oscillations, since PV+ interneurons selectively express the insulin-dependent glucose transporter GLUT4, which can provide an additional glucose influx under near-limit functioning conditions as in the case of high-frequency gamma oscillations. This review generalized available literature data on the relationship between metabolism and a high-frequency electrical brain activity, with an emphasis on the possible contribution of central insulin resistance to disturbances of gamma rhythms in the brain.

Unappreciated role of low‐density lipoprotein receptor‐related protein 1 in pancreatic β cells: Multiple roles of low‐density lipoprotein receptor‐related protein 1 in glucose and lipid metabolism

Unappreciated role of low‐density lipoprotein receptor‐related protein 1 in pancreatic β cells: Multiple roles of low‐density lipoprotein receptor‐related protein 1 in glucose and lipid metabolism

Insulin Acts in Ventromedial Hypothalamus to Regulate the Sympathoadrenal Response to Hypoglycemia in Rats

We tested the hypothesis that the correction of ventromedial hypothalamus (VMH) insulin deficiency was sufficient to restore the impaired sympathoadrenal response to hypoglycemia in diabetic rats. Sprague-Dawley rats were injected with either vehicle (nondiabetic controls; CON) or streptozotocin (STZ; 65 mg/kg IP). STZ diabetic rats received osmotic mini-pumps to infuse either artificial cerebrospinal fluid (DIAB) or insulin (3mU/day; DIAB+InsVMH) into the VMH bilaterally. Two weeks later, all three groups underwent hyperinsulinemic (50 mU.kg-1.min-1) hypoglycemic (∼50 mg/dl) clamps. As expected, STZ-diabetic rats showed blunted epinephrine response to hypoglycemia as compared to nondiabetic controls. Chronic infusion of insulin into VMH of diabetic rats normalized the epinephrine response to hypoglycemia and lowered the glucose infusion rate required to maintain hypoglycemia. Examining brain insulin action, it was noted that STZ diabetic rats had decreased Akt phosphorylation and decreased expression of insulin dependent glucose transporter 4 (GLUT4) in VMH by 44 and 40% respectively as compared to the nondiabetic controls. Notably, chronic infusion of insulin to the VMH normalized Akt phosphorylation and GLUT4 expression. In summary, insulin acts chronically in the VMH to preserve the sympathoadrenal response to hypoglycemia, possibly by regulating GLUT4 expression. Disclosure R. Agrawal: None. A. Vieira de Abreu: None. G.T. Durupt: None. S.J. Fisher: None.

Increased Insulin Resistance and Glucagon Levels in Mild/Inactive Systemic Lupus Erythematosus Patients Despite Normal Glucose Tolerance.

To assess insulin sensitivity in patients with systemic lupus erythematosus (SLE) in response to a meal tolerance test (MTT). In this cross-sectional study, 33 adult females with mild/inactive SLE (SLE group) and 16 age- and body mass index-matched female healthy controls (CTRL group) underwent an MTT and were assessed for insulin sensitivity and beta cell function. Skeletal muscle protein expressions of total and membrane insulin-dependent glucose transporter 4 (GLUT-4) were also evaluated (SLE group: n = 10, CTRL group: n = 5); muscle biopsies were performed after MTT. Further measurements included inflammatory cytokines, adipocytokines, physical activity level, body composition, and food intake. SLE and CTRL groups showed similar fasting glucose, glucose response, and skeletal muscle GLUT-4 translocation after MTT. However, the SLE group demonstrated higher fasting insulin levels (P = 0.01; effect size [ES] 1.2), homeostatic model assessment insulin resistance (IR) (P = 0.03; ES 1.1), insulin-to-glucose ratio response to MTT (P = 0.02; ES 1.2), fasting glucagon levels (P = 0.002; ES 2.7), glucagon response to MTT (P = 0.0001; ES 2.6), and a tendency toward lower Matsuda index of whole-body insulin sensitivity (P = 0.06; ES -0.5) when compared with the CTRL group. Fasting proinsulin-to-insulin ratio and proinsulin-to-insulin ratio response to MTT were similar between groups (P > 0.05), while the SLE group showed a higher insulinogenic index when compared with the CTRL group (P = 0.02; ES = 0.9). We have identified that SLE patients had a bi-hormone metabolic abnormality characterized by increased IR and hyperglucagonemia despite normal glucose tolerance and preserved beta cell function and skeletal muscle GLUT-4 translocation. Strategies capable of ameliorating insulin sensitivity to reduce the risk of type 2 diabetes mellitus and cardiovascular disease in SLE may require more than targeting IR alone.

Oxyresveratrol Supplementation to C57bl/6 Mice Fed with a High-Fat Diet Ameliorates Obesity-Associated Symptoms.

Oxyresveratrol has been proven effective in inhibiting adipogenesis in a 3T3-L1 cell model. We investigated the preventive effect of oxyresveratrol supplementation on obesity development in high-fat diet-fed mice. Male C57bl/6 mice were randomly subjected to control (5% fat by weight, LF), high-fat (30% fat by weight, HF), and high-fat supplemented with 0.25% and 0.5% oxyresveratrol (OXY1 and OXY2, respectively) diet groups for eight weeks. Oxyresveratrol supplementation effectively alleviated obesity-associated symptoms such as insulin resistance, hyperglycemia, and hepatic steatosis in high-fat diet-fed mice. Compared to the high-fat diet group, oxyresveratrol supplementation suppressed expression of glucose-6-phosphatase, sterol regulatory element-binding proteins 1, fatty acid synthase and CCAAT/Enhancer-binding proteins α, and elevated AMP-activated protein kinase (α2-catalytic subunit) level in liver, upregulated insulin-dependent glucose transporter type 4 level in adipose tissue, and increased expression of insulin receptor substrate 1, insulin-dependent glucose transporter type 4, AMP-activated protein kinase α, peroxisome proliferator-activated receptor γ coactivator-1α, and sirtuin 1 in muscle to regulate lipid and glucose homeostasis in these tissues. This study demonstrated that oxyresveratrol supplementation effectively ameliorated obesity-associated symptoms in high-fat diet-fed mice, presumably attributed to mediating critical regulators involved in lipid and glucose homeostasis in liver, visceral fat, and muscle.

NK cell count and glucotransporter 4 (GLUT4) expression in subjects with type 2 diabetes and colon cancer.

BackgroundType 2 diabetes (T2D) and colon cancer (CC) are numbered among the most common diseases in the world. The decreased activity of natural killer (NK) cells previously revealed in both mentioned pathological states may be correlated with impaired expression of GLUT4 as the major insulin-dependent glucose transporter in these cells.MethodsThe aim of this study was to evaluate GLUT4 expression and NK cells number in subjects with T2D and/or CC in comparison with control group. We evaluated 78 individuals divided into four groups: (1) patients with CC and T2DM, (2) patients with CC, (3) patients with T2DM (4) healthy control. GLUT4 expression on the surface of NK cells was measured using flow cytometry and phenotyping of NK cell was performed by immunofluorescent method.ResultsSubjects with diabetes had the highest GLUT4 expression (21.35 ± 7.2 %) in comparison with other groups (P < 0.01). The mean values of GLUT4 expression in group with CC and in patients with both T2D and CC were similar (1.4 ± 0.4 % vs 1.5 ± 1.0 %; respectively). These values were significantly lower than in control group (12.6 ± 2.9 %; P < 0.01). In patients with T2D and CC the number of NK cells (20.15 ± 6.6 %) was significantly higher than in other groups, i.e. in group with T2D (14.08 ± 5.7 %), in group with CC (9.21 ± 3.6 %) and in control group (9.48 ± 4.7 %), respectively (P < 0.01).ConclusionsIt seems that there is a need to pay more attention to the high incidence of colon cancer among patients with type 2 diabetes. Decreased GLUT4 expression observed on NK cells in patients with colon cancer may be responsible for dysfunction of these cells and the higher carcinogenic risk in type 2 diabetic subjects.

Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel.

Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3−∕−) results in “Super-smeller” mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3−∕− mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3−∕− male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3−∕− mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3−∕− mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.