Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats

1985 ◽  
Vol 248 (5) ◽  
pp. E567-E574 ◽  
Author(s):  
D. E. James ◽  
A. B. Jenkins ◽  
E. W. Kraegen
Keyword(s):  
Insulin Sensitivity ◽  
Glycogen Content ◽  
Glycogen Synthesis ◽  
Relative Proportion ◽  
Glycogen Storage ◽  
Whole Body ◽  
Glucose Disposal ◽  
Maximal Effect ◽  
Euglycemic Hyperinsulinemic Clamp

The euglycemic hyperinsulinemic clamp technique in conscious unrestrained rats was used to examine the effect of insulin on glucose metabolism in metabolically distinct skeletal muscle in vivo. Tissue glucose metabolic rate (R'g) was estimated using 2-[3H]-deoxyglucose, and glucose disposal was examined by measuring glycogen content and [14C]glucose incorporation into glycogen in four different muscles. Insulin sensitivity varied among different muscle types in that the insulin concentration required for half-maximal stimulation of R'g was 80, 150, 280, and 320 mU/1 for soleus (SOL), red gastrocnemius (RG), white gastrocnemius (WG), and extensor digitorum longus, respectively. There were similar relative differences in the maximal effect of insulin on R'g in these muscles. Maximal insulin stimulation almost doubled muscle glycogen content in RG and SOL, whereas there was no change in WG. The relationship between R'g and glycogen synthesis indicated that increased glucose uptake resulted predominantly in glycogen storage. There was an excellent relationship between maximal R'g and blood flow in different muscles. We conclude that there is marked heterogeneity in insulin sensitivity and responsiveness among muscles of different fiber composition. Insulin-induced increases in total peripheral glucose disposal occur predominantly in muscles containing a high proportion of oxidative fibers. Therefore the relative proportion of oxidative to glycolytic muscle fibers may be important factors in determining whole body insulin sensitivity.

Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

1990 ◽  
Vol 259 (2) ◽  
pp. E210-E215 ◽  
Author(s):  
J. R. Lupien ◽  
M. F. Hirshman ◽  
E. S. Horton
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Glucose Turnover ◽  
Adrenergic Blockade ◽  
Sprague Dawley ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Peripheral Tissues

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

scholarly journals PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

1998 ◽  
Vol 274 (5) ◽  
pp. E834-E842 ◽  
Author(s):  
Karin Filipsson ◽  
Giovanni Pacini ◽  
Anton J. W. Scheurink ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Elimination Rate ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Maximal Effect ◽  
Intravenous Glucose

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1–5 min) insulin response was 3.8 ± 0.4 nmol/l (PACAP-27) and 3.3 ± 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after glucose alone ( P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% ( P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 ± 0.04 10−4min−1/(pmol/l) for PACAP-27 and 0.29 ± 0.06 10−4min−1/(pmol/l) for PACAP-38 vs. 0.46 ± 0.02 10−4min−1/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

Effect of exercise training on whole-body insulin sensitivity and responsiveness

1984 ◽  
Vol 56 (5) ◽  
pp. 1217-1222 ◽  
Author(s):  
D. E. James ◽  
E. W. Kraegen ◽  
D. J. Chisholm
Keyword(s):  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Utilization ◽  
Insulin Receptors ◽  
Whole Body ◽  
Glucose Disposal ◽  
Significant Shift ◽  
Insulin Levels ◽  
Plasma Insulin Levels

Exercise training causes a decline in basal and glucose-stimulated plasma insulin levels and improves glucose tolerance. Furthermore evidence has been presented for effects on both insulin receptors and postreceptor events. However, it is unclear how these changes affect the in vivo dose-response relationship between insulin levels and whole-body glucose utilization. The aim was to examine the effect of exercise training on this relationship and distinguish between changes in insulin sensitivity and responsiveness. Euglycemic clamps were performed in trained (ET, running 1 h/day for 7 wk), sedentary (CON), and sedentary food-restricted ( SFR ) rats. ET rats showed no increase in maximal net glucose utilization in response to insulin (ET 29.5 +/- 0.6 vs. CON 28.2 +/- 1.5 mg X kg-1 X min-1, NS), whereas insulin sensitivity was increased as indicated by the insulin concentration causing half-maximal stimulation (ED50) (49 +/- 20 for ET and 133 +/- 30 mU/l for CON). Thus 7 wk of moderate exercise training resulted in a significant shift of whole-body insulin sensitivity to place ED50 well within the physiological range of insulin concentrations. This would undoubtedly result in improved glucose disposal in the postprandial state and emphasizes the potential benefit of exercise in obesity and type II diabetes.

scholarly journals Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

1997 ◽  
Vol 273 (5) ◽  
pp. E859-E867 ◽  
Author(s):  
M. Hettiarachchi ◽  
S. Chalkley ◽  
S. M. Furler ◽  
Y.-S. Choong ◽  
M. Heller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Human Growth ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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.

Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies

2007 ◽  
Vol 293 (6) ◽  
pp. E1663-E1669 ◽  
Author(s):  
Jong-Hee Hwang ◽  
Daniel T. Stein ◽  
Nir Barzilai ◽  
Min-Hui Cui ◽  
Julia Tonelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Magnetic Resonance ◽  
Subcutaneous Fat ◽  
Liver Fat ◽  
Whole Body ◽  
Glucose Disposal ◽  
Resonance Spectroscopy ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Triglyceride Accumulation

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive 1H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (Rd) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body Rd and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body Rd ( r = −0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.

Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome

2007 ◽  
Vol 292 (6) ◽  
pp. E1871-E1878 ◽  
Author(s):  
Roland Buettner ◽  
Iris Ottinger ◽  
Christiane Gerhardt-Salbert ◽  
Christian E. Wrede ◽  
Jürgen Schölmerich ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Protein Content ◽  
Insulin Action ◽  
Whole Body ◽  
Glucose Disposal ◽  
Standard Diet ◽  
The Metabolic Syndrome ◽  
Lipid Phosphatase

The lipid phosphatase SH2 domain-containing lipid phosphatase (SHIP2) has been implicated in the regulation of insulin sensitivity, but its role in the therapy of insulin-resistant states remains to be defined. Here, we examined the effects of an antisense oligonucleotide (AS) therapy directed against SHIP2 on whole body insulin sensitivity and insulin action in liver and muscle tissue in a dietary rodent model of the metabolic syndrome, the high-fat-fed (HF) rat. Whole body insulin sensitivity was examined in vivo by insulin tolerance tests before and after the intraperitoneal application of an AS directed against SHIP2 (HF-SHIP2-AS) or a control AS (HF-Con-AS) in HF rats. Insulin action in liver and muscle was assayed by measuring the activation of protein kinase B (Akt) and insulin receptor substrate (IRS)-1/2 after a portal venous insulin bolus. SHIP2 mRNA and protein content were quantified in these tissues by real-time PCR and immunoblotting, respectively. In HF-SHIP2-AS, whole body glucose disposal after an insulin bolus was markedly elevated compared with HF-Con-AS. In liver, insulin activated Akt similarly in both groups. In muscle, insulin did not clearly activate Akt in HF-Con-AS animals, whereas insulin-induced Akt phosphorylation was sustained in SHIP2-AS-treated rats. IRS-1/2 activation did not differ between the experimental groups. SHIP2 mRNA and protein content were markedly reduced only in muscle. In standard diet-fed controls, SHIP2-AS reduced SHIP2 protein levels in liver and muscle, but it had no significant effect on insulin sensitivity. We conclude that treatment with SHIP2-AS can rapidly improve muscle insulin sensitivity in dietary insulin resistance. The long-term feasability of such a strategy should be examined further.

Unlike insulin, amino acids stimulate p70S6Kbut not GSK-3 or glycogen synthase in human skeletal muscle

2004 ◽  
Vol 286 (4) ◽  
pp. E523-E528 ◽  
Author(s):  
Zhenqi Liu ◽  
Yangsong Wu ◽  
Edward W. Nicklas ◽  
Linda A. Jahn ◽  
Wendie J. Price ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Human Skeletal Muscle ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Glucose Disposal ◽  
Vastus Lateralis Muscle ◽  
Euglycemic Hyperinsulinemic Clamp

Insulin stimulates muscle glucose disposal via both glycolysis and glycogen synthesis. Insulin activates glycogen synthase (GS) in skeletal muscle by phosphorylating PKB (or Akt), which in turn phosphorylates and inactivates glycogen synthase kinase 3 (GSK-3), with subsequent activation of GS. A rapamycin-sensitive pathway, most likely acting via ribosomal 70-kDa protein S6 kinase (p70S6K), has also been implicated in the regulation of GSK-3 and GS by insulin. Amino acids potently stimulate p70S6K, and recent studies on cultured muscle cells suggest that amino acids also inactivate GSK-3 and/or activate GS via activating p70S6K. To assess the physiological relevance of these findings to normal human physiology, we compared the effects of amino acids and insulin on whole body glucose disposal, p70S6K, and GSK-3 phosphorylation, and on the activity of GS in vivo in skeletal muscle of 24 healthy human volunteers. After an overnight fast, subjects received intravenously either a mixed amino acid solution (1.26 μmol·kg-1·min-1× 6 h, n = 9), a physiological dose of insulin (1 mU·kg-1·min-1euglycemic hyperinsulinemic clamp × 2 h, n = 6), or a pharmacological dose of insulin (20 mU·kg-1·min-1euglycemic hyperinsulinemic clamp × 2 h, n = 9). Whole body glucose disposal rates were assessed by calculating the steady-state glucose infusion rates, and vastus lateralis muscle was biopsied before and at the end of the infusion. Both amino acid infusion and physiological hyperinsulinemia enhanced p70S6Kphosphorylation without affecting GSK-3 phosphorylation, but only physiological hyperinsulinemia also increased whole body glucose disposal and GS activity. In contrast, a pharmacological dose of insulin significantly increased whole body glucose disposal, p70S6K, GSK-3 phosphorylation, and GS activity. We conclude that amino acids at physiological concentrations mediate p70S6Kbut, unlike insulin, do not regulate GSK-3 and GS phosphorylation/activity in human skeletal muscle.

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.

Effects of prolonged Acipimox treatment on glucose and lipid metabolism and on in vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus

1992 ◽  
Vol 127 (4) ◽  
pp. 344-350 ◽  
Author(s):  
Allan A Vaag ◽  
Henning Beck-Nielsen
Keyword(s):  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Treatment Period ◽  
Blood Glucose Control ◽  
Glucose Disposal ◽  
Prolonged Treatment ◽  
Double Blind Study ◽  
Glucose And Lipid Metabolism ◽  
Fasting Plasma

The effect of prolonged treatment with Acipimox on in vivo peripheral insulin sensitivity, and on glucose and lipid metabolism, was investigated in patients with NIDDM in a double-blind study. Twelve NIDDM patients were randomized to treatment with either placebo or Acipimox in pharmacological doses (250 mg×3) for three months. Fasting plasma glucose, insulin, C-peptide and HbA1c concentrations were unaffected after three months of acipimox treatment. However, fasting plasma non-esterifled fatty acid (NEFA) concentrations were twofold elevated after Acipimox treatment (1.34±0.09 vs 0.66±0.09 mmol/l; p<0.05). Despite this, repeated acute Acipimox administration after the three months' treatment period enhanced total insulin-stimulated glucose disposal to the same extent as acute Acipimox administration before the treatment period (367±59 vs 392±66 mg·m−2·min−1, NS; both p<0.05 vs placebo glucose disposal) (267±44 mg·m−2·min−1). In conclusion, insulin resistance or tachyphylaxis towards the effects of Acipimox on insulin stimulated glucose disposal was not induced during prolonged Acipimox treatment. The lack of improvement of blood glucose control in the patients with NIDDM may be due to the demonstrated rebound effect of lipolysis.

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