Glucose disposal by insulin, but not IGF-1, is dependent on the hepatic parasympathetic nerves

2000 ◽  
Vol 78 (10) ◽  
pp. 807-812 ◽  
Author(s):  
Parissa Sadri ◽  
W Wayne Lautt
Keyword(s):  
Skeletal Muscle ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Surgical Ablation ◽  
Insulin Resistant ◽  
Parasympathetic Nerves ◽  
Stimulation Of

Insulin-like growth factor-1 (IGF-1) has many insulin-like activities, including stimulation of glucose uptake in skeletal muscle. However, those with diabetes or chronic liver disease are insulin resistant but show a normal hypoglycemic response to IGF-1. We have previously shown that insulin sensitivity depends on a hepatic parasympathetic reflex release of a hormone from the liver. The hypothesis was tested that insulin action, but not IGF-1 action, is dependent on the hepatic parasympathetic reflex. Glucose disposal in response to three doses of IGF-1 (25, 100, 200 µg/kg) was determined in rats. IGF-1 at 200 µg/kg had similar effect on glucose disposal as did 50 mU/kg of insulin. Interruption of the hepatic parasympathetic reflex either by surgical ablation of the anterior nerve plexus or by atropine (1.0 mg/kg) resulted in insulin, but not IGF-1, resistance. Sixteen hours of fasting resulted in insulin, but not IGF-1, resistance. In conclusion, insulin, but not IGF-1, triggers the hepatic parasympathetic dependent release of a putative hepatic insulin sensitizing substance (HISS) that stimulates glucose uptake in skeletal muscle.Key words: HISS, RIST, atropine, insulin sensitivity, fasting.

scholarly journals Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

2008 ◽  
Vol 28 (18) ◽  
pp. 5634-5645 ◽  
Author(s):  
Francesco Oriente ◽  
Luis Cesar Fernandez Diaz ◽  
Claudia Miele ◽  
Salvatore Iovino ◽  
Silvia Mori ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Normal Glucose Tolerance ◽  
Glucose Disposal ◽  
Protein Levels ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
The Stability

ABSTRACT We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1 i / i ) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1 i / i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1 i / i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

scholarly journals Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats

2001 ◽  
Vol 280 (1) ◽  
pp. E130-E142 ◽  
Author(s):  
Ben B. Yaspelkis ◽  
James R. Davis ◽  
Maziyar Saberi ◽  
Toby L. Smith ◽  
Reza Jazayeri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Insulin Resistant ◽  
Skeletal Muscle Glucose Uptake ◽  
Uptake And Transport

In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg · kg−1 · day−1 sc), or food restriction (HF-FR) for 12–15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulin-stimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic β-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

2006 ◽  
Vol 100 (5) ◽  
pp. 1467-1474 ◽  
Author(s):  
Jong Sam Lee ◽  
Srijan K. Pinnamaneni ◽  
Su Ju Eo ◽  
In Ho Cho ◽  
Jae Hwan Pyo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Polyunsaturated Fatty Acids ◽  
Glucose Uptake ◽  
High Fat ◽  
Insulin Resistant ◽  
L6 Myotubes ◽  
Lipid Metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

scholarly journals MON-613 The Expression of TBC1 Domain Family, Member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nasser M Rizk ◽  
Amina Saleh ◽  
Abdelrahman ElGamal ◽  
Dina Elsayegh ◽  
Isin Cakir ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Skeletal Muscles ◽  
Glucose Disposal ◽  
Domain Family ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Blood Glucose Levels

Abstract The Expression of TBC1 Domain Family, member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane. Background: Obesity is commonly accompanied by impaired glucose homeostasis. Decreased glucose transport to the peripheral tissues, mainly skeletal muscle, leads to reduced total glucose disposal and hyperglycemia. TBC1D4 gene is involved in the trafficking of GLUT4 to the outer cell membrane in skeletal muscle. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound acting by reducing blood glucose levels through mechanisms not fully understood (1). The aim of this study is to investigate the effects SFN on TBC1D4 and GLUT4 gene expression in skeletal muscles of DIO mice, in order to elucidate the mechanism(s) through which SFN improves glucose homeostasis. Methodology: C57BL/6 mice (n=20) were fed with a high fat diet (60%) for 16 weeks to generate diet induced obese (DIO) mice with body weights between 45–50 gm. Thereafter, DIO mice received either SFN (5mg/kg BW) (n=10) or vehicle (n=10) as controls daily by intraperitoneal injections for four weeks. Glucose tolerance test (1g/kg BW, IP) and insulin sensitivity test (ITT) were conducted (1 IU insulin/ g BW, IP route) at the beginning and end of the third week of the injection. At the end of 4 weeks of the injection, samples of blood and skeletal muscles of both hindlimbs were collected. The expression levels of GLUT4 and TBC1D4 genes were analyzed by qRT-PCR. Blood was also used for glucose, adiponectin and insulin measurements. Results: SFN-treated DIO mice had significantly lower non-fasting blood glucose levels than vehicle-treated mice (194.16 ± 14.12 vs. 147.44 ± 20.31 mg/dL, vehicle vs. SFN, p value=0.0003). Furthermore, GTT results indicate that the blood glucose levels at 120 minutes after glucose infusion in was (199.83±34.53 mg/dl vs. 138.55±221.78 mg/dl) for vehicle vs. SFN with p=0.0011 respectively. ITT showed that SFN treatment did not enhance insulin sensitivity in DIO mice. Additionally, SFN treatment did not significantly change the expression of TBC1D4, and GLUT4 genes in skeletal muscles compared to vehicle treatment (p values &gt;0.05). Furthermore, SFN treatment did not significantly affect the systemic insulin (1.84±0.74 vs 1.54±0.55 ng/ml, p=0.436), or adiponectin (11.96 ±2.29 vs 14.4±3.33 ug/ml, p=0.551) levels in SFN vs. vehicle-treated DIO mice, respectively. Conclusion: SFN treatment improves glucose disposal in DIO mice, which is not linked to the gene expression of GLUT4 and TBC1D4 and its mechanism of glucose disposal in skeletal muscles. Furthermore, SFN treatment did not improve insulin level, and the insulin sensitizer hormone adiponectin as potential players for enhancing insulin sensitivity. 1. Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, et al. Sci Transl Med. 2017;9(394).

Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction

2007 ◽  
Vol 293 (6) ◽  
pp. E1716-E1725 ◽  
Author(s):  
Sean W. Limesand ◽  
Paul J. Rozance ◽  
Danielle Smith ◽  
William W. Hay
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Glucose Transporter ◽  
Glucose Utilization ◽  
Hepatic Glycogen ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
And Control

In this study we determined body weight-specific fetal (umbilical) glucose uptake (UGU), utilization (GUR), and production rates (GPR) and insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but GUR was not different between IUGR and control fetuses. The difference between glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of GUR). The mRNA concentrations of the gluconeogenic enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high glucose concentrations occurred at mean plasma insulin concentrations in the IUGR fetuses that were ∼70% lower than controls, indicating increased insulin sensitivity. Furthermore, under basal conditions, hepatic glycogen content was similar, skeletal muscle glycogen was increased 2.2-fold, the fraction of fetal GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote glucose utilization, particularly for glucose storage, including increased insulin action, glucose production, shunting of glucose utilization to glycogen production, and maintenance of glucose transporter concentrations.

scholarly journals Improved insulin sensitivity with calorie restriction does not require reduced JNK1/2, p38, or ERK1/2 phosphorylation in skeletal muscle of 9-month-old rats

2012 ◽  
Vol 302 (1) ◽  
pp. R126-R136 ◽  
Author(s):  
Naveen Sharma ◽  
Abhijit D. Bhat ◽  
Anketse D. Kassa ◽  
Yuanyuan Xiao ◽  
Edward B. Arias ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Calorie Restriction ◽  
Protein Carbonyls ◽  
Glucose Disposal ◽  
Brown Norway ◽  
Protein Conjugates ◽  
Fischer 344 ◽  
Mitogen Activated Protein

Calorie restriction [CR; ∼40% below ad libitum (AL) intake] improves the health of many species, including rats, by mechanisms that may be partly related to enhanced insulin sensitivity for glucose disposal by skeletal muscle. Excessive activation of several mitogen-activated protein kinases (MAPKs), including JNK1/2, p38, and ERK1/2 has been linked to insulin resistance. Although insulin can activate ERK1/2, this effect is not required for insulin-mediated glucose uptake. We hypothesized that skeletal muscle from male 9-mo-old Fischer 344/Brown Norway rats CR (35–40% beginning at 3 mo old) versus AL rats would have 1) attenuated activation of JNK1/2, p38, and ERK1/2 under basal conditions; and 2) no difference for insulin-induced ERK1/2 activation. In contrast to our hypothesis, there were significant CR-related increases in the phosphorylation of p38 (epitrochlearis, soleus, and gastrocnemius), JNK1 (epitrochlearis and soleus), and JNK2 (gastrocnemius). Consistent with our hypothesis, CR did not alter insulin-mediated ERK1/2 activation. The greater JNK1/2 and p38 phosphorylation with CR was not attributable to diet effects on muscle oxidative stress (assessed by protein carbonyls and 4-hydroxynonenal protein conjugates). In muscles from the same rats used for the present study, we previously reported a CR-related increase in insulin-mediated glucose uptake by the epitrochlearis and the soleus (Sharma N, Arias EB, Bhat AD, Sequea DA, Ho S, Croff KK, Sajan MP, Farese RV, Cartee GD. Am J Physiol Endocrinol Metab 300: E966–E978, 2011). The present results indicate that the improved insulin sensitivity with CR is not attributable to attenuated MAPK phosphorylation in skeletal muscle.

Increased skeletal muscle capillarization enhances insulin sensitivity

2014 ◽  
Vol 307 (12) ◽  
pp. E1105-E1116 ◽  
Author(s):  
Thorbjorn Akerstrom ◽  
Lasse Laub ◽  
Kenneth Vedel ◽  
Christian Lehn Brand ◽  
Bente Klarlund Pedersen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Blood Stream ◽  
Whole Body ◽  
Glucose Disposal ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. Therefore, we investigated whether increased skeletal muscle capillarization increases insulin sensitivity. Skeletal muscle-specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist prazosin to the drinking water of Sprague-Dawley rats ( n = 33), whereas 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-wk prazosin treatment, which ensured that prazosin was cleared from the blood stream. Whole body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin sensitivity was assessed by administration of 2-deoxy-[3H]glucose during the plateau phase of the clamp. Whole body insulin sensitivity increased by ∼24%, and insulin-stimulated skeletal muscle 2-deoxy-[3H]glucose disposal increased by ∼30% concomitant with an ∼20% increase in skeletal muscle capillarization. Adipose tissue insulin sensitivity was not affected by the treatment. Insulin-stimulated muscle glucose uptake was enhanced independent of improvements in skeletal muscle insulin signaling to glucose uptake and glycogen synthesis, suggesting that the improvement in insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose in the muscle. The prazosin treatment did not affect the rats on any other parameters measured. We conclude that an increase in skeletal muscle capillarization is associated with increased insulin sensitivity. These data point toward the importance of increasing skeletal muscle capillarization for prevention or treatment of type 2 diabetes.

scholarly journals Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

2015 ◽  
Vol 309 (12) ◽  
pp. E949-E959 ◽  
Author(s):  
Gregory D. Cartee
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Acute Exercise ◽  
Insulin Dose ◽  
Whole Body ◽  
Exercise Session ◽  
End Effector ◽  
Insulin Resistant ◽  
Normal Individuals

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise.

Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Atul S. Deshmukh
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Disposal ◽  
Facilitated Diffusion ◽  
Primary Target ◽  
Insulin Resistant ◽  
Transporter Protein ◽  
Signaling Events

AbstractSkeletal muscle is the largest tissues in the human body and is considered the primary target for insulin-stimulated glucose disposal. In skeletal muscle, binding of the insulin to insulin receptor (IR) initiates a signaling cascade that results in the translocation of the insulin-sensitive glucose transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle.

scholarly journals A Thiazolidinedione ImprovesIn VivoInsulin Action on Skeletal Muscle Glycogen Synthase in Insulin-Resistant Monkeys

2000 ◽  
Vol 1 (3) ◽  
pp. 195-202 ◽  
Author(s):  
Heidi K. Ortmeyer ◽  
Noni L. Bodkin ◽  
Joseph Haney ◽  
Shinji Yoshioka ◽  
Hiroyoshi Horikoshi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Disposal ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Insulin Resistant ◽  
Skeletal Muscle Glycogen

Thiazolidinediones (TZD) have been shown to have anti-diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin-mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R-102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate-limiting enzyme in glycogen synthesis, 4 insulin-resistant obese monkeys were given I mg/kg/ day R-102380 p.o. for a 6-week period. Skeletal muscle GS activity and glucose 6-phosphate (G6P) content were compared between pre-dosing and dosing periods before and during the maximal insulin-stimulation of a euglycemic hyperinsulinemic clamp.Compared to pre-dosing, insulin-stimulated GS activity and G6P content were increased by this TZD: GS independent activity (p= 0.02), GS total activity (p= 0.005), GS fractional activity (p= 0.06) and G6P content (p= 0.02). The change in GS activity induced byin vivoinsulin (insulin-stimulated minus basal) was also increased by this TZD: GS independent activity (p= 0.03) and GS fractional activity (p= 0.04).We conclude that the TZD R-102380 improves insulin action at the skeletal muscle in part by increasing the activity of glycogen synthase. This improvement in insulin sensitivity may be a key factor in the anti-diabetic effect of the thiazolidinedione class of agents.

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