Lack of defect in insulin action on hepatic glycogen synthase and phosphorylase in insulin-resistant monkeys

1998 ◽  
Vol 274 (6) ◽  
pp. G1005-G1010
Author(s):  
Heidi K. Ortmeyer ◽  
Noni L. Bodkin
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Phosphorylase ◽  
Glycogen Synthase ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Insulin Resistant

It is well known that an alteration in insulin activation of skeletal muscle glycogen synthase is associated with insulin resistance. To determine whether this defect in insulin action is specific to skeletal muscle, or also present in liver, simultaneous biopsies of these tissues were obtained before and during a euglycemic hyperinsulinemic clamp in spontaneously obese insulin-resistant male rhesus monkeys. The activities of glycogen synthase and glycogen phosphorylase and the concentrations of glucose 6-phosphate and glycogen were measured. There were no differences between basal and insulin-stimulated glycogen synthase and glycogen phosphorylase activities or in glucose 6-phosphate and glycogen contents in muscle. Insulin increased the activities of liver glycogen synthase ( P < 0.05) and decreased the activities of liver glycogen phosphorylase ( P ≤ 0.001). Insulin also caused a reduction in liver glucose 6-phosphate ( P = 0.05). We conclude that insulin-resistant monkeys do not have a defect in insulin action on liver glycogen synthase, although a defect in insulin action on muscle glycogen synthase is present. Therefore, tissue-specific alterations in insulin action on glycogen synthase are present in the development of insulin resistance in rhesus monkeys.

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.

Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle

2005 ◽  
Vol 288 (6) ◽  
pp. E1188-E1194 ◽  
Author(s):  
Betsy B. Dokken ◽  
Julie A. Sloniger ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Zucker Rats ◽  
Type I ◽  
Insulin Resistant

Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin action on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 μM CT118637, Ki < 10 nM for GSK3α and GSK3β). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced ( P <0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR β-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3β serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals.

Leptin, skeletal muscle lipids, and lipid-induced insulin resistance

2007 ◽  
Vol 293 (2) ◽  
pp. R642-R650 ◽  
Author(s):  
John J. Dube ◽  
Bankim A. Bhatt ◽  
Nikolas Dedousis ◽  
Arend Bonen ◽  
Robert M. O'Doherty
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Lipid Metabolites

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (∼15%), and increased SkM Akt (∼30%) and glycogen synthase kinase 3α (∼52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; ∼61%), elevated ceramides (∼50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity (∼25%) and increased SkM DAG (∼33%) and ceramide (∼60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase Cθ (PKCθ), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKCθ and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

2003 ◽  
Vol 284 (5) ◽  
pp. E892-E900 ◽  
Author(s):  
Erik J. Henriksen ◽  
Tyson R. Kinnick ◽  
Mary K. Teachey ◽  
Matthew P. O'Keefe ◽  
David Ring ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Oral Glucose ◽  
Type I ◽  
Insulin Resistant ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
Glycogen Synthase Activity

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.

scholarly journals Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

2016 ◽  
Vol 229 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Hong Xu ◽  
Yang Zhou ◽  
Yongxia Liu ◽  
Jian Ping ◽  
Qiyang Shou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Function ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Akt Signaling ◽  
Hepatic Glycogen ◽  
Impaired Liver Function ◽  
Insulin Resistant

Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathwayin vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and Type 2 diabetes

2015 ◽  
Vol 128 (10) ◽  
pp. 707-713 ◽  
Author(s):  
Mavin Macauley ◽  
Fiona E Smith ◽  
Peter E Thelwall ◽  
Kieren G Hollingsworth ◽  
Roy Taylor
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Resonance Spectroscopy ◽  
Model Assessment ◽  
Glycogen Concentration

In health, food carbohydrate is stored as glycogen in muscle and liver, preventing a deleterious rise in osmotically active plasma glucose after eating. Glycogen concentrations increase sequentially after each meal to peak in the evening, and fall to fasting levels thereafter. Skeletal muscle accounts for the larger part of this diurnal buffering capacity with liver also contributing. The effectiveness of this diurnal mechanism has not been previously studied in Type 2 diabetes. We have quantified the changes in muscle and liver glycogen concentration with 13C magnetic resonance spectroscopy at 3.0 T before and after three meals consumed at 4 h intervals. We studied 40 (25 males; 15 females) well-controlled Type 2 diabetes subjects on metformin only (HbA1c (glycated haemoglobin) 6.4±0.07% or 47±0.8 mmol/mol) and 14 (8 males; 6 females) glucose-tolerant controls matched for age, weight and body mass index (BMI). Muscle glycogen concentration increased by 17% after day-long eating in the control group (68.1±4.8 to 79.7±4.2 mmol/l; P=0.006), and this change inversely correlated with homoeostatic model assessment of insulin resistance [HOMA-IR] (r=−0.56; P=0.02). There was no change in muscle glycogen in the Type 2 diabetes group after day-long eating (68.3±2.6 to 67.1±2.0 mmol/mol; P=0.62). Liver glycogen rose similarly in normal control (325.9±25.0 to 388.1±30.3 mmol/l; P=0.005) and Type 2 diabetes groups (296.1±16.0 to 350.5±6.7 mmol/l; P<0.0001). In early Type 2 diabetes, the major physiological mechanism for skeletal muscle postprandial glycogen storage is completely inactive. This is directly related to insulin resistance, although liver glycogen storage is normal.

Insulin regulates liver glycogen synthase and glycogen phosphorylase activity reciprocally in rhesus monkeys

1997 ◽  
Vol 272 (1) ◽  
pp. E133-E138 ◽  
Author(s):  
H. K. Ortmeyer ◽  
N. L. Bodkin ◽  
B. C. Hansen
Keyword(s):  
Young Adult ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Phosphorylase ◽  
Activity Ratio ◽  
Glycogen Synthase ◽  
Whole Body ◽  
Glucose Disposal ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Time Points

In skeletal muscle of both humans and monkeys, the effects of in vivo insulin during a euglycemic hyperinsulinemic clamp on the enzymes and substrates of glycogen metabolism have been well established. In liver, such effects of insulin during a clamp have not been previously studied in primates. To examine insulin action at the liver, euglycemic hyperinsulinemic clamps were performed in 10 lean young adult male rhesus monkeys. Liver biopsies were obtained at three time points: basal (fasting), that is, immediately before the onset of the clamp, and during insulin infusion at 130 and 195 min. Glycogen synthase (GS), glycogen phosphorylase (GP), glucose 6-phosphate (G-6-P), and glycogen were determined at each time point, with the greatest effects observed most frequently at 195 min. Whole body insulin-mediated glucose disposal rate was related to the change in the independent activity of GS (r = 0.63, P < 0.05). Insulin increased the GS fractional activity (P < 0.005) and decreased the activity ratio of GP (P < 0.001) compared with basal. The changes in fractional activity of GS and in activity ratio of GP were inversely related (r = - 0.68, P < 0.05), G-6-P concentration was decreased during insulin stimulation compared with basal (P = 0.01). Glycogen concentration was not significantly different between the basal and insulin-stimulated time points. We conclude that insulin during a euglycemic clamp activates liver GS while inhibiting liver GP and that insulin action on liver GS is positively related to whole body insulin-mediated glucose disposal rates in lean young adult rhesus monkeys.

Abstract T P114: Insulin Resistance in Skeletal Muscle of Chronic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alice S Ryan ◽  
Heidi Ortmeyer ◽  
Frederick Ivey ◽  
Charlene Hafer-Macko
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Chronic Stroke ◽  
Whole Body ◽  
Wide Range

Risk of glucose intolerance and diabetes increases in chronic stroke. The purpose of this study was to assess insulin sensitivity and glycogen synthase (GS), a known benchmark index of insulin action in skeletal muscle, and to compare the activity of this important regulatory enzyme between paretic (P) and non-paretic (NP) skeletal muscle in chronic stroke. We measured insulin sensitivity (M) and bilateral GS fractional activity (ratio of independent to total activity), in lyophilized microdissected muscle samples obtained after an overnight fast and 2 hrs into a 3-hr 80 mU . m -2. min -1 hyperinsulinemic-euglycemic clamp in 21 stroke survivors (n=15 men, n=6 women) (age: 59±2 yrs, BMI: 31±2 kg/m 2 , X±SEM). All had hemiparetic gait after ischemic stroke (>6 months), low aerobic capacity (VO 2 peak, 19.7±1.3 ml/kg/min), and wide range of %body fat (11-48%). Leg lean mass was lower in P than NP (9.3±0.5 vs. 10.0±0.5 kg, P<0.001). Subjects had either normal glucose tolerance (n=7), impaired glucose tolerance (n=7), or diabetes (n=7) and insulin resistance (M: 38.5±2.6 umol/kgFFM/min). Insulin robustly increased GS fractional activity (basal vs. insulin) in P (2.8±0.4 vs.7.5±0.8%, P<0.00001) and NP (2.7±0.4 vs. 9.1±1.1%, P<0.00001) muscle. The %change was greater in NP than P (213±32 vs. 296±36%, P=0.04). The effect of in vivo insulin to increase GS fractional activity was associated with M in P and NP muscle (r=0.59 and r=0.49, P<0.05). In conclusion, muscle atrophy and a reduction in insulin action in paretic muscle likely contribute to whole body insulin resistance in chronic stroke.

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