Glucose homeostasis in rainbow trout fed a high-carbohydrate diet: metformin and insulin interact in a tissue-dependent manner

2011 ◽  
Vol 300 (1) ◽  
pp. R166-R174 ◽  
Author(s):  
S. Polakof ◽  
T. W. Moon ◽  
P. Aguirre ◽  
S. Skiba-Cassy ◽  
S. Panserat
Keyword(s):  
Skeletal Muscle ◽  
Rainbow Trout ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Combined Treatment ◽  
Hypoglycemic Agents ◽  
Dependent Manner ◽  
Metformin Treatment ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Glucose Output

Carnivorous fish species such as the rainbow trout ( Oncorhynchus mykiss ) are considered to be “glucose intolerant” because of the prolonged hyperglycemia experienced after intake of a carbohydrate-enriched meal. In the present study, we use this species to study glucose homeostasis in fish chronically infused with the hypoglycemic agents, insulin, and metformin, and fed with a high proportion of carbohydrates (30%). We analyzed liver, skeletal muscle, and white adipose tissue (WAT), which are insulin- and metformin-specific targets at both the biochemical and molecular levels. Trout infused with the combination of insulin and metformin can effectively utilize dietary glucose at the liver, resulting in lowered glycemia, increased insulin sensitivity, and glucose storage capacity, combined with reduced glucose output. However, in both WAT and skeletal muscle, we observed decreased insulin sensitivity with the combined insulin + metformin treatment, resulting in the absence of changes at the metabolic level in the skeletal muscle and an increased potential for glucose uptake and storage in the WAT. Thus, the poor utilization by rainbow trout of a diet with a high proportion of carbohydrate can at least be partially improved by a combined treatment with insulin and metformin, and the glucose intolerance observed in this species could be, in part, due to some of the downstream components of the insulin and metformin signaling pathways. However, the predominant effects of metformin treatment on the action of insulin in these three tissues thought to be involved in glucose homeostasis remain exclusive in this species.

Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. E28-E37 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Heidi S. Camp ◽  
Liyun Ding ◽  
Todd Leff
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Muscle Tissue ◽  
Glucose Homeostasis ◽  
Muscle Cells ◽  
Whole Body ◽  
Fiber Types ◽  
Dependent Manner

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARγ plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARγ activation in muscle cells. We found that pharmacological activation of PPARγ in primary cultured myocytes, and genetic activation of muscle PPARγ in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARγ activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARγ activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARγ-dependent manner. We propose that activation of PPARγ in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.

Uptake of taurocholic acid and cholic acid in isolated hepatocytes from rainbow trout

1994 ◽  
Vol 267 (3) ◽  
pp. G380-G386 ◽  
Author(s):  
C. M. Rabergh ◽  
K. Ziegler ◽  
B. Isomaa ◽  
M. M. Lipsky ◽  
J. E. Eriksson
Keyword(s):  
Rainbow Trout ◽  
Bile Acids ◽  
Low Temperatures ◽  
High Efficiency ◽  
Isolated Hepatocytes ◽  
Metabolic Inhibitors ◽  
Dependent Manner ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Transport Component ◽  
Efficient Uptake

The uptake of the bile acids cholate (CHA) and taurocholate (TCHA) was studied in isolated hepatocytes from rainbow trout (Oncorhynchus mykiss). Both CHA and TCHA were taken up in a concentration- and temperature-dependent manner with optimum temperature at 15 degrees C and a strikingly efficient uptake even at low temperatures (0-5 degrees C). The total uptake was a combination of a saturable [Michaelis-Menten constant (Km) for CHA, 20 microM; Km for TCHA, 19 microM] and a nonsaturable component. The maximal uptake rate of the saturable component was 416 and 805 pmol.mg protein-1.min-1 for CHA and TCHA, respectively. The uptake of both bile acids was shown to be energy dependent, since it was inhibited by the metabolic inhibitors antimycin A, oligomycin and carbonyl cyanide m-chlorophenylhydrazone. The uptake was clearly Na+ independent, since isosmotic replacement of extracellular Na+ by Li+, choline, or K+ did not inhibit the uptake. Furthermore, it seemed to be independent of the presence of extracellular Cl-, since it was not inhibited by replacement of Cl- with sodium gluconate. On the whole, our results show that the hepatocellular uptake of bile acids in rainbow trout is mediated by a Na(+)-independent carrier system, with characteristics resembling the corresponding transport component in mammalian hepatocytes, but with high efficiency even at low temperatures.

Regulation of glucose production in rainbow trout: role of epinephrine in vivo and in isolated hepatocytes

2000 ◽  
Vol 278 (4) ◽  
pp. R956-R963 ◽  
Author(s):  
Jean-Michel Weber ◽  
Deena S. Shanghavi
Keyword(s):  
Rainbow Trout ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Isolated Hepatocytes ◽  
Relative Increase ◽  
Dependent Manner ◽  
Rainbow Trout Oncorhynchus Mykiss

The rate of hepatic glucose production (Ra glucose) of rainbow trout ( Oncorhynchus mykiss) was measured in vivo by continuous infusion of [6-3H]glucose and in vitro on isolated hepatocytes to examine the role of epinephrine (Epi) in its regulation. By elevating Epi concentration and/or blocking β-adrenoreceptors with propranolol (Prop), our goals were to investigate the mechanism for Epi-induced hyperglycemia to determine the possible role played by basal Epi concentration in maintaining resting Ra glucose and to assess indirect effects of Epi in the intact animal. In vivo infusion of Epi caused hyperglycemia (3.75 ± 0.16 to 8.75 ± 0.54 mM) and a twofold increase in Ra glucose (6.57 ± 0.79 to 13.30 ± 1.78 μmol ⋅ kg− 1 ⋅ min− 1, n = 7), whereas Prop infusion decreased Ra from 7.65 ± 0.92 to 4.10 ± 0.56 μmol ⋅ kg− 1 ⋅ min− 1( n = 10). Isolated hepatocytes increased glucose production when treated with Epi, and this response was abolished in the presence of Prop. We conclude that Epi-induced trout hyperglycemia is entirely caused by an increase in Ra glucose, because the decrease in the rate of glucose disappearance normally seen in mammals does not occur in trout. Basal circulating levels of Epi are involved in maintaining resting Ra glucose. Epi stimulates in vitro glucose production in a dose-dependent manner, and its effects are mainly mediated by β-adrenoreceptors. Isolated trout hepatocytes produce glucose at one-half the basal rate measured in vivo, even when diet, temperature, and body size are standardized, and basal circulating Epi is responsible for part of this discrepancy. The relative increase in Ra glucose after Epi stimulation is similar in vivo and in vitro, suggesting that indirect in vivo effects of Epi, such as changes in hepatic blood flow or in other circulating hormones, do not play an important role in the regulation of glucose production in trout.

Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue

2009 ◽  
Vol 297 (1) ◽  
pp. E124-E133 ◽  
Author(s):  
Rodrigo P. A. Barros ◽  
Chiara Gabbi ◽  
Andrea Morani ◽  
Margaret Warner ◽  
Jan-Åke Gustafsson
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Wild Type ◽  
Glut4 Expression ◽  
Glucose Challenge ◽  
Fasting Hypoglycemia

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.

scholarly journals Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

2013 ◽  
Vol 219 (2) ◽  
pp. 173-182 ◽  
Author(s):  
P Brandimarti ◽  
J M Costa-Júnior ◽  
S M Ferreira ◽  
A O Protzek ◽  
G J Santos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Alternative Splicing ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Cafeteria Diet ◽  
Mrna Levels ◽  
Insulin Degrading Enzyme ◽  
Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

scholarly journals Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

2018 ◽  
Vol 47 (3) ◽  
pp. 1042-1050 ◽  
Author(s):  
Chen Juan Gu ◽  
Hua Hua Yi ◽  
Jing Feng ◽  
Zhi Guo Zhang ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Intermittent Hypoxia ◽  
Quantitative Polymerase Chain Reaction ◽  
Liver Cells ◽  
Dependent Manner ◽  
Independent Manner ◽  
Obstructive Sleep ◽  
Gsk 3Β ◽  
Glucose Output

Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH2-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG2 cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O2 for 60 s followed by 21% O2 for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.

scholarly journals Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3

2006 ◽  
Vol 26 (22) ◽  
pp. 8217-8227 ◽  
Author(s):  
Ho-Jin Koh ◽  
David E. Arnolds ◽  
Nobuharu Fujii ◽  
Thien T. Tran ◽  
Marc J. Rogers ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Glucose Utilization ◽  
Cell Metabolism ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Energy Sensing

ABSTRACT LKB1 is a tumor suppressor that may also be fundamental to cell metabolism, since LKB1 phosphorylates and activates the energy sensing enzyme AMPK. We generated muscle-specific LKB1 knockout (MLKB1KO) mice, and surprisingly, found that a lack of LKB1 in skeletal muscle enhanced insulin sensitivity, as evidenced by decreased fasting glucose and insulin concentrations, improved glucose tolerance, increased muscle glucose uptake in vivo, and increased glucose utilization during a hyperinsulinemic-euglycemic clamp. MLKB1KO mice had increased insulin-stimulated Akt phosphorylation and a >80% decrease in muscle expression of TRB3, a recently identified Akt inhibitor. Akt/TRB3 binding was present in skeletal muscle, and overexpression of TRB3 in C2C12 myoblasts significantly reduced Akt phosphorylation. These results demonstrate that skeletal muscle LKB1 is a negative regulator of insulin sensitivity and glucose homeostasis. LKB1-mediated TRB3 expression provides a novel link between LKB1 and Akt, critical kinases involved in both tumor genesis and cell metabolism.

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