Hepatic Glucose Uptake Research Articles

Males Require Estrogen Signaling Too: Sexual Dimorphism in the Regulation of Glucose Homeostasis by Nuclear ERα.

Females are more protected against insulin resistance and cardiovascular disease compared with males of the same age or BMI, and this relative protection is diminished in postmenopausal women, attributable to a loss in estrogen signaling (1–4). Evidence from genetic animal models further points to the beneficial effects of estrogen signaling via estrogen receptor-α (ERα) in regard to glucose homeostasis in health and metabolic diseases (5). Mice harboring whole-body deletion of ERα (ERαKO) reveal that estrogen signaling through this receptor regulates glucose homeostasis in part by modulating hepatic insulin sensitivity (6) and glucose uptake in the skeletal muscle and adipose tissue (7). Moreover, ERα signaling has been demonstrated to promote pancreatic insulin-producing β-cell function, survival, and proliferation, as well as protection from development of diabetes in mice of both sexes (8–10). Thus, estrogen is generally thought to positively regulate glucose homeostasis primarily through ERα, which is expressed in both male and female tissues, but the respective importance of nuclear and membrane ERα pools in the regulation of glucose homeostasis is not clear. ERα is predominantly characterized as a nuclear receptor and thus noted for exclusively regulating transcription of target genes. However, extranuclear ERα action or membrane compartment–initiated estrogen signaling is now widely accepted to activate different pathways occurring in the cytoplasm and nucleus. For example, membrane localization of ERα (which accounts for ∼5–10% of the ERα pool depending on cell type) facilitates membrane-initiated signaling events important for reproduction and vascular physiology (11) as well as β-cell function and survival (12). Although it is clear that ERα positively regulates glucose homeostasis, the distinct and overlapping contributions of the extranuclear and nuclear pool of ERα remain unknown. Therefore, mouse models specifically engineered to have only nuclear or membrane ERα action are necessary to delineate specific ERα functions related to …

First person – Andrea Raposo López-Pastor

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Andrea Raposo López-Pastor is first author on ‘Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity’, published in DMM. Andrea is a PhD student in the lab of Manuel Benito at Complutense University of Madrid, Madrid, Spain, investigating mechanisms implicated in progression of fatty liver and its relation with other metabolic pathologies.

Ex Vivo Method to Simultaneously Evaluate Glucose Utilization, Uptake, and Production in Rat Liver.

A novel ex vivo method to simultaneously evaluate hepatic glucose utilization, uptake, and production was developed in rats. The right lateral lobe of the liver was perfused with Krebs-Henseleit bicarbonate buffer containing 5 mmol/L uniformly labeled 13C-glucose ([U-13C]-glucose). The whole glucose concentration in the perfusate was measured by colorimetric assay, and the concentrations of [U-12C]-glucose (natural isotope) or [U-13C]-glucose were estimated on the basis of the abundance ratio of [U-12C]-glucose or [U-13C]-glucose, which were measured by GC-MS. The difference in whole glucose and [U-13C]-glucose concentrations between the baseline and effluent perfusate represents hepatic glucose utilization and glucose uptake, respectively. The [U-12C]-glucose concentration in the effluent perfusate corresponds to hepatic glucose production. With this method, we clarified the precise mechanism that underlies the hepatic impairment of diabetic animals and pharmacological effects of anti-diabetic agents. Thus, this method is useful for the pathophysiological and pharmacological research of type 2 diabetes.

Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity.

ABSTRACTAmong the main complications associated with obesity are insulin resistance and altered glucose and lipid metabolism within the liver. It has previously been described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes compared with isoform B (IRB), improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high-fat-diet-induced obesity. We addressed the role of insulin receptor isoforms in glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAVs) in a mouse model of diet-induced insulin resistance and obesity. IRA, but not IRB, expression induced increased glucose uptake in the liver and muscle, improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1 expression. Taken together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB at favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease associated with obesity.This article has an associated First Person interview with the first author of the paper.

Rapid altering light cycles promotes increased hepatic glucose uptake and de novo lipogenesis

Rapid altering light cycles promotes increased hepatic glucose uptake and de novo lipogenesis

Developmental exposure to DEHP alters hepatic glucose uptake and transcriptional regulation of GLUT2 in rat male offspring

Type-2-diabetes (T2D) is a long term metabolic disorder characterized by high blood glucose and insulin resistance. It has become an alarming issue globally due to tremendous increase in number of new subjects every year. Apart from the classical factors, there are few non-classical factors such as environmental pollutants, endocrine disrupting chemicals (EDCs) which also play a major role in pathogenesis of T2D. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer which is an endocrine disrupting chemical. It is used in the plastic industry to give flexibility and durability. Its widespread use resulted in constant presence in the environment and human are under high risk of exposure to this compound. There are literature available stating that DEHP has an impact on glucose homeostasis. Glucose transporter 2 (GLUT2) is a principal transporter of glucose in liver and it is a bi-directional transporter. We investigated whether DEHP exposure during gestation and lactation alters transcriptional regulation of GLUT2 and epigenetics changes in the rat F1 male offspring at adulthood. Pregnant rats were divided into three groups and administered with DEHP (10 and 100 mg /kg /day) or olive oil from gestational day (GD) 9– to postnatal day (PND) 21 through oral gavage. DEHP treated rats showed decreased glucose uptake and oxidation, decreased mRNA levels of insulin receptor (IR), GLUT2 and reduced GLUT2 protein in cytosol but unaltered level in plasma membrane. There are three main transcription factors (SREBP1c, HNF3β and HNF1α) involved in the regulation of GLUT2 gene and all these proteins were reduced in DEHP exposed groups. A weak interaction of the transcription factors (SREBP1c & HNF1α) with GLUT2 gene promoter was observed in DEHP-treated groups. Hyper- methylation of IR and GLUT2 gene promoter was observed in both the DEHP-exposed groups compared to control. The present study reveals that DEHP exposure alters transcriptional regulation of GLUT2 and imposes epigenetic alteration in IR and GLUT2 gene promoters which plays a significant role in the development of metabolic abnormality in F1 male offspring at adulthood.

Peripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain.

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic β-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of β-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of HGU through increased hepatic glucokinase activity.

Contribution of pancreatic α-cell function to insulin sensitivity and glycemic variability in patients with type1 diabetes.

Aims/IntroductionTo evaluate the contribution of pancreatic α‐cell function to the dawn phenomenon, insulin sensitivity, hepatic glucose uptake and glycemic variability in patients with type 1 diabetes.Materials and MethodsIn 40 patients with type 1 diabetes, arginine stimulation tests were carried out, and the area under the curve (AUC) of glucagon was measured using radioimmunoassays (AUC glc RIA) and enzyme‐linked immunosorbent assays (AUC glc ELISA). The ratio of the insulin dose delivered by an artificial pancreas to maintain euglycemia between 04.00 and 08.00 hours or between 00.00 and 04.00 hours was measured as the dawn index. The glucose infusion rate and hepatic glucose uptake were measured using hyperinsulinemic euglycemic clamp and clamp oral glucose loading tests. Glycemic variability in 96 h was measured by continuous glucose monitoring.ResultsThe median dawn index (1.7, interquartile range 1.0–2.8) was not correlated with AUC glc RIA (R 2 = 0.03, P = 0.39) or AUC glc ELISA (R 2 = 0.04, P = 0.32). The median glucose infusion rate (7.3 mg/kg/min, interquartile range 6.4–9.2 mg/kg/min) was significantly correlated with AUC glc RIA (R 2 = 0.20, P = 0.02) and AUC glc ELISA (R 2 = 0.21, P = 0.02). The median hepatic glucose uptake (65.3%, interquartile range 40.0–87.3%) was not correlated with AUC glc RIA (R 2 = 0.07, P = 0.26) or AUC glc ELISA (R 2 = 0.26, P = 0.79). The standard deviation of glucose levels measured by continuous glucose monitoring was significantly correlated with AUC glc RIA (R 2 = 0.11, P = 0.049), but not with AUC glc ELISA (R 2 = 0.01, P = 0.75).ConclusionsPancreatic α‐cell function contributed to insulin sensitivity in patients with type 1 diabetes.

The appropriate whole body metric for calculating standardised uptake value and the influence of sex.

AimTo compare weight, lean body mass and body surface area for calculation of standardised uptake value (SUV) in fluorine-18-fluorodeoxyglucose PET/computed tomography, taking sex into account.Patients and methodsThis was a retrospective study of 161 (97 men) patients. Maximum standardised uptake value (SUVmax) and mean standardised uptake value (SUVmean) were obtained from a 3-cm region of interest over the right lobe of the liver and scaled to weight, scaled to lean body mass (SUL) and scaled to body surface area (SUA). Mean hepatic computed tomography density was used to adjust SUVmean for hepatic fat (SUVFA). Hepatic SUV indices were divided by SUV from left ventricular cavity, thereby, eliminating whole body metric, to obtain a surrogate of blood fluorine-18-fluorodeoxyglucose clearance into liver, and multiplied by blood glucose to give a surrogate of hepatic glucose uptake rate (mSUV).ResultsSULmax, SUAmax and all scaled to weight indices correlated strongly with weight. SULmean, SULFA, SUAmean and SUAFA, however, correlated weakly or not at all with weight, nor with their corresponding whole body metric in men or women, but correlated strongly when the sexes were combined into one group. This was the result of sex differences in SUL (greater in men) and SUA (greater in women). There was, however, no sex difference in mSUV.ConclusionWeight is unsuitable for calculating SUV. SUL and SUA are also inappropriate as maxima but appropriate as mean and fat-adjusted values. However, SUL is recommended for both sexes because SUA is influenced by both body fat and weight. Sex differences in SUL and SUA give rise to misleading correlations when sexes are combined into one group.

Aptamer-based search for correlates of plasma and serum water T2: implications for early metabolic dysregulation and metabolic syndrome

BackgroundMetabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T2 was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T2 and thus, metabolic health.MethodsWater T2 measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T2. The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking.ResultsThe multi-step analysis unveiled five new proteins most predictive of water T2: hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T2 have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T2 that would not have been identified in a hypothesis-driven biomarker search.ConclusionsThe identification of new proteins associated with water T2 demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T2 and the pathophysiology of metabolic syndrome.

Glucose lowering and vascular protective effects of cycloset added to GLP-1 receptor agonists in patients with type 2 diabetes.

SummaryObjectiveTo determine the glucose‐lowering mechanism of action and the effects of a quick‐release bromocriptine‐QR, a D2‐dopamine agonist (Cycloset) on vascular function in patients with type 2 diabetes (T2D).Study design and methodsFifteen poorly controlled T2D treated with metformin plus glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) were studied after 4 months of Cycloset, 3.2 mg/d. Subjects received a 5‐hour double‐tracer (iv 3‐3H‐glucose and oral 14C‐glucose) mixed meal test (MMT) to quantitate rates of endogenous glucose production (EGP), oral glucose appearance (RaO) and disappearance (Rd) pre‐ and post‐Cycloset. Vascular assessments included 2‐day continuous BP monitoring, reactive hyperaemia index (RHI) and arterial stiffness (AS).ResultsHbA1c decreased from 8.3 ± 0.3% to 7.7 ± 0.2% (P < 0.05), fasting plasma glucose did not change (143 ± 4 vs 147 ± 5) and mean plasma glucose during MTT decreased from 223 ± 3 to 210 ± 4 mg/dL (P < 0.05) after Cycloset. Basal EGP (2.2 ± 0.2 vs 2.1 ± 0.2 mg/kg min) was unchanged, but there was greater MMT suppression (1.1 ± 0.1 vs 0.7 ± 0.1, P < 0.05). After Cycloset, RaO declined from 2.0 ± 0.1 to 1.7 ± 0.2 mg/kg min and peripheral oral glucose appearance from 53.1 ± 3.2 to 44.4 ± 3.1 g (P < 0.01). There were no changes in plasma insulin or glucagon concentration. Systolic (134 ± 4 vs 126 ± 6), diastolic (78 ± 3 vs 73 ± 4), mean BP (97 ± 5 vs 90 ± 4) and pulse pressure (54 ± 2 vs 51 ± 2 mm Hg) were reduced; RHI increased from 1.4 ± 0.1 to 1.9 ± 0.3 au and AS decreased modestly (19.8 ± 4.1 to 16.2 ± 3.7 au, P = NS).ConclusionsAddition of Cycloset to GLP‐1 RA improved vascular indices and postprandial hyperglycaemia in T2DM primarily by lowering oral glucose appearance, suggesting that hepatic glucose uptake was enhanced. Improved vascular indices may explain the reduction in cardiovascular events observed with Cycloset therapy in patients with T2DM.

Tucum-do-cerrado (Bactris setosa Mart.) may enhance hepatic glucose response by suppressing gluconeogenesis and upregulating Slc2a2 via AMPK pathway, even in a moderate iron supplementation condition

Dietary phytochemicals may improve glucose metabolism while iron excess seems to be associated to impaired glucose homeostasis and insulin responses. This study investigated the effect of tucum-do-cerrado (Bactris setosa Mart.) consumption on the carbohydrate metabolism and redox response in rats supplemented or not with dietary iron. Male wistar rats were treated with one of the following diets: CT: control diet (AIN- 93G); +Fe: iron-enriched diet; Tuc: control diet +15% tucum-do-cerrado or Tuc + Fe: iron-enriched diet +15% tucum-do-cerrado. Iron supplementation increased muscle lipid and protein oxidation, hepatic glucokinase (GK) and phosphofrutokinase 1 (PFK1) activities and decreased hepatic glucose-6-phosphatase (G6Pase), intestinal Scl2a2 and muscle Slc2a4 and Prkaa2α mRNA levels compared to CT group. Tucum-do-cerrado consumption (Tuc) increased hepatic Slc2a2, Prkaa1α, Prkaa2α and intestinal Slc5a1 mRNA levels, also decreased hepatic G6Pase activity, muscle Slc2a4 and Prkaa2α in relation to CT group. The association of tucum-do-cerrado with iron-enriched diet increased hepatic Prkaa1 and Pck1 compared to the CT and + Fe groups, intestinal Slc2a2 mRNA levels compared to the +Fe group, while decreased hepatic G6Pase activity in relation to the CT, +Fe and Tuc + Fe groups and muscle Slc2a4 and Prkaa2α compared to CT group. These results suggest that tucum-do-cerrado consumption might induce Prkaa1α and Prkaa2α expression, which may inhibit gluconeogenic rate limiting enzyme, G6Pase, and upregulates GLUT2 hepatic glucose uptake. In addition, moderate iron supplementation improves intracellular hepatic glucose response, stimulating the glycolytic rate limiting enzymes GK and PFK1 while inhibiting gluconeogenic enzyme G6Pase.

Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing in vitro insulin secretion and hepatic glucose uptake.

The objective of this study was to evaluate the ability of anthocyanins (ANC) present in purple corn to enhance insulin secretion and hepatic glucose uptake in pancreatic cells and hepatocytes, through activation of the free fatty acid receptor-1 (FFAR1) and glucokinase (GK), respectively. Using a dual-layer cell culture with Caco-2 cells, INS-1E or HepG2 cells were treated with an anthocyanin-rich extract from the pericarp of purple corn (PCW), as well as pure ANC cyanidin-3-O-glucoside (C3G), peonidin-3-O-glucoside, pelargonidin-3-O-glucoside. Delphinidin-3-O-glucoside (D3G) was used for comparative purposes. Semipurified C3G (C3G-P) and condensed forms (CF-P) isolated from PCW were also used. At 100 μM, the pure ANC enhanced glucose-stimulated insulin secretion (GSIS) in INS-1E cells ranging from 18% to 40% (p<0.05) compared to untreated cells. PCW increased GSIS by 51%. D3G was the most effective anthocyanin activating FFAR1 (EC50: 196.6 μM). PCW had activating potential on FFAR1 (EC50: 77 μg/mL). PCW, as well as C3G and D3G increased the expression of FFAR1, PLC, and phosphorylation of PKD, related to the FFAR1-dependent insulin secretory pathway. The treatment with 100 μM of P3G and C3G increased (p<0.05) glucose uptake in HepG2 cells by 19% and 31%. PCW increased the glucose uptake in HepG2 cells by 48%. It was determined that CF-P was the most effective for activating GK (EC50: 39.9 μM) and the PCW extracts had an efficacy of EC50: 44 μg/mL. The ANC in purple corn also reduced AMPK phosphorylation and PEPCK expression in HepG2 cells, known to be related to reduction in gluconeogenesis. It is demonstrated for the first time that dietary ANC can enhance the activity of novel biomarkers FFAR1 and GK and potentially ameliorate type-2 diabetes comorbidities.

Contribution of Pancreatic Alpha-Cell Function to Insulin Sensitivity and Glucose Variability in Type 1 Diabetes Patients

In type 1 diabetes (T1D) patients, relationships between pancreatic alpha cell function and glucose metabolism remain elusive. Therefore, we aimed to reveal the contribution of alpha cell function to insulin sensitivity, hepatic glucose uptake (HGU), and glucose variability, including the dawn phenomenon, in T1D patients. We recruited forty Japanese T1D patients with a median (interquartile range) BMI of 21.0 (19.3-22.7) kg/m2, diabetes duration of 2.6 (0.1-10.3) years, and HbA1c level of 8.2 (7.4-10.3) %. We measured the arginine-stimulated glucagon secretion using RIA and double-sandwich ELISA and subsequently assessed the dawn phenomenon using an artificial pancreas (STG-55®, Nikkiso, Japan) and performed a hyperinsulinemic-euglycemic clamp followed by oral glucose loading to evaluate insulin sensitivity and HGU. Glycemic variability was analyzed with continuous glucose monitoring (CGM). The median areas under the curve of glucagon measured by RIA (AUCglcRIA) and ELISA (AUCglcELISA) were 3.7 (2.6-4.6) × 104 and 1.9 (0.8-4.3) × 103 pg/mL × min, respectively. The glucose infusion rate (GIR) during the euglycemic clamp was inversely correlated with AUCglcRIA and AUCglcELISA (R2 = 0.21 and 0.44, P = 0.033 and 0.038, respectively, adjusted for age, sex, and BMI). In addition, the median GIR was significantly lower in the high glucagon response group than in the low glucagon response group [7.3 (5.1-8.4) vs. 9.2 (7.0-11.7), P = 0.049]. The dawn index (ratio of insulin requirements between 4:00-8:00 and 0:00-04:00) and HGU did not correlate AUCglcRIA and AUCglcELISA. The standard deviation of glucose levels determined by CGM significantly correlated with AUCglcRIA (R2 = 0.28, P = 0.015) but not with AUCglcELISA (R2 = 0.01, P = 0.62). In conslusion, alpha cell function may contribute to insulin sensitivity in T1D, and its relationship with glycemic variability may be affected by the procedure of the glucagon assay used. Disclosure N. Takahashi: None. D. Chujo: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Kyowa Hakko Kirin Co., Ltd.. H. Kajio: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc..

Basal Oral Insulin Analog I338 Enhances Meal-Related Hepatic Glucose Disposal

Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3-3H glucose was given. After 90 min of equilibration and 30 min of basal sampling, a clamp was conducted (0-300 min), with somatostatin to inhibit pancreatic secretion and basal glucagon replacement. In the LOW dogs (n=5) I338 (pmol/kg/min) was infused either Po at 40 (0-45 min to mimic oral absorption) or IV at 1 (0-300 min to mimic subcutaneous [SC] delivery), approximately an equivalent daily dose (1800 vs. 1440 pmol/kg, Po vs. IV). High dose dogs (HI; n=4) received I338 at 50 (Po) or 5 (IV) pmol/kg/min. A Po glucose infusion mimicking meal absorption was given via computer algorithm from 30-252 min. All dogs were studied twice, 2 weeks apart in random order, receiving both Po and IV I338. Po vs. IV, respectively, resulted in: 1) lower glycemic levels (peak glucose LOW 6.2±0.3 and 10.3±0.6,* HI 4.5±0.3, and 7.8±0.8* mM); 2) increased net hepatic glucose uptake (AUC30-240 min Low 218.4±151.8 and -852.0±371.4,* HI 732.6±338.5 and -58.5±578.4* µmol/kg); 3) enhanced glucose clearance (AUC30-240 min LOW 481.9±29.7 and 359.4±33.7,* HI 874.3±99.8 and 495.3±25.9* mL/kg) and 4) greater peak hepatic fractional glucose extraction (LOW 0.05±0.02 and -0.01±0.01,* HI 0.10±0.and 0.04±0.02*)(*P&amp;lt;0.vs. corresponding Po treatment). In short, Po basal I338 delivery produced superior glucose lowering and hepatic glucose disposal during a morning “meal” compared to SC-like delivery. Thus basal oral I338 can improve the glycemic response to the first meal after dosing, potentially improving glucose disposal at subsequent meals via the 2nd meal effect. Disclosure M.C. Moore: None. E. Nishimura: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. C.L. Brand: Other Relationship; Self; Novo Nordisk A/S. T. Kjeldsen: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. P. Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H.H. Refsgaard: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. K. Wassermann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. S. Gram-Nielsen: Employee; Self; Novo Nordisk A/S. M.S. Smith: None. L. Moore: None. B. Farmer: None. J.R. Hastings: None. P.E. Williams: None. A.D. Cherrington: Advisory Panel; Self; Biocon. Consultant; Self; Boston Scientific Corporation. Research Support; Self; Boston Scientific Corporation. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Consultant; Self; Galvani Bioelectronics Limited. Research Support; Self; Galvani Bioelectronics Limited. Consultant; Self; MedImmune. Advisory Panel; Self; Metavention. Stock/Shareholder; Self; Metavention. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; NuSirt Biopharma, Inc., Sensulin Labs, LLC.. Other Relationship; Self; Sensulin Labs, LLC.. Consultant; Self; Silver Lake. Research Support; Self; Silver Lake. Consultant; Self; Thermalin Diabetes, LLC., Thetis Pharmaceuticals LLC.. Stock/Shareholder; Self; Thetis Pharmaceuticals LLC.. Advisory Panel; Self; VTV Therapeutics. Consultant; Self; VTV Therapeutics. Advisory Panel; Self; Zafgen. Research Support; Self; Zafgen. Stock/Shareholder; Self; Zafgen. Consultant; Self; Abvance. Other Relationship; Self; Abvance. Consultant; Self; California Institute for Biomedical Research (Calibr). Advisory Panel; Self; These Three Medical, Inc (T3M).

Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen Storage Later in the Day.

We observed that a 4-h morning (AM) duodenal infusion of glucose versus saline doubled hepatic glucose uptake (HGU) and storage during a hyperinsulinemic-hyperglycemic (HIHG) clamp that afternoon (PM). To separate the effects of AM hyperglycemia versus AM hyperinsulinemia on the PM response, we used hepatic balance and tracer ([3-3H]glucose) techniques in conscious dogs. From 0 to 240 min, dogs underwent a euinsulinemic-hyperglycemic (GLC; n = 7) or hyperinsulinemic-euglycemic (INS; n = 8) clamp. Tracer equilibration and basal sampling occurred from 240 to 360 min, followed by an HIHG clamp (360-600 min; four times basal insulin, two times basal glycemia) with portal glucose infusion (4 mg ⋅ kg-1 ⋅ min-1). In the HIHG clamp, HGU (5.8 ± 0.9 vs. 3.3 ± 0.3 mg ⋅ kg-1 ⋅ min-1) and net glycogen storage (6.0 ± 0.8 vs. 2.9 ± 0.5 mg ⋅ kg-1 ⋅ min-1) were approximately twofold greater in INS than in GLC. PM hepatic glycogen content (1.9 ± 0.2 vs. 1.3 ± 0.2 g/kg body weight) and glycogen synthase (GS) activity were also greater in INS versus GLC, whereas glycogen phosphorylase (GP) activity was reduced. Thus AM hyperinsulinemia, but not AM hyperglycemia, enhanced the HGU response to a PM HIHG clamp by augmenting GS and reducing GP activity. AM hyperinsulinemia can prime the liver to extract and store glucose more effectively during subsequent same-day meals, potentially providing a tool to improve glucose control.

Murine remote preconditioning increases glucose uptake and suppresses gluconeogenesis in hepatocytes via a brain-liver neurocircuit, leading to counteracting glucose intolerance

AimsOur previous study revealed that cyclic hindlimb ischaemia–reperfusion (IR) activates cardiac acetylcholine (ACh) synthesis through the cholinergic nervous system and cell-derived ACh accelerates glucose uptake. However, the mechanisms regulating glucose metabolism in vivo remain unknown. We investigated the effects and mechanisms of IR in mice under pathophysiological conditions. MethodsUsing IR-subjected male C57BL/6J mice, the effects of IR on blood sugar (BS), glucose uptake, central parasympathetic nervous system (PNS) activity, hepatic gluconeogenic enzyme expression and those of ACh on hepatocellular glucose uptake were assessed. ResultsIR decreased BS levels by 20% and increased c-fos immunoreactivity in the center of the PNS (the solitary tract and the dorsal motor vagal nucleus). IR specifically downregulated hepatic gluconeogenic enzyme expression and activities (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) and accelerated hepatic glucose uptake. Transection of a hepatic vagus nerve branch decreased this uptake and reversed BS decrease. Suppressed gluconeogenic enzyme expression was reversed by intra-cerebroventricular administration of a choline acetyltransferase inhibitor. Moreover, IR significantly attenuated hyperglycaemia in murine model of type I and II diabetes mellitus. ConclusionsIR provides another insight into a therapeutic modality for diabetes mellitus due to regulating gluconeogenesis and glucose-uptake and advocates an adjunctive mode rectifying disturbed glucose metabolism.

Effect of titanium dioxide nanoparticles on glucose homeostasis after oral administration.

As food additives, titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various products that are usually simultaneously consumed with a high content of sugar, thus necessitating research on the effect of TiO2 NPs on glucose homeostasis. We conducted an animal study to explore the effect of orally administrated TiO2 NPs on glucose absorption and metabolism in rats at 0, 2, 10 and 50mg kg-1 body weight day-1 for 30 and 90days. The results showed that oral exposure to TiO2 NPs caused a slight and temporary hypoglycemic effect in rats at 30days post-exposure but recovered at 90days post-exposure. Decreased levels of intestinal glucose absorption and increased levels of hepatic glucose metabolism may be responsible for the hypoglycemic effect. Remodeling of the villi in the small intestine that decreased the surface area available for glucose absorption and increased levels of hepatic glucose uptake, utilization and storage related to hepatocellular injury are supposed to be the mechanisms. Our results demonstrated that dietary intake of TiO2 NPs as food additives could affect the absorption and metabolism of glucose.

Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein

Impaired hepatic glucose uptake (HGU) causes postprandial hyperglycemia in type 2 diabetes. Here, we show that diminished hepatic Sirt2 activity impairs HGU in obese diabetic mice. Hepatic Sirt2 overexpression increases HGU in high-fat diet (HFD)-fed obese diabetic mice and mitigates their impaired glucose tolerance. Hepatic Sirt2 knockdown in non-diabetic mice reduces HGU and causes impaired glucose tolerance. Sirt2 promotes glucose-dependent HGU by deacetylating K126 of glucokinase regulatory protein (GKRP). Glucokinase and GKRP glucose-dependent dissociation is necessary for HGU but is inhibited in hepatocytes derived from obese diabetic mice, depleted of Sirt2 or transfected with GKRP acetylation-mimicking mutants. GKRP deacetylation-mimicking mutants dissociate from glucokinase in a glucose concentration-dependent manner in obese diabetic mouse-derived hepatocytes and increase HGU and glucose tolerance in HFD-induced or db/db obese diabetic mice. We demonstrate that Sirt2-dependent GKRP deacetylation improves impaired HGU and suggest that it may be a therapeutic target for type 2 diabetes.

Natural products, an important resource for discovery of &lt;br /&gt;multitarget drugs and functional food for regulation of hepatic glucose metabolism

Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound–multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs.