IRON OVERLOAD CAUSES INCREASED INSULIN SENSITIVITY AND GLUCOSE DISPOSAL ACCOMPANIED BY INCREASED HEPATIC GLUCOSE RECYCLING FROM LACTATE.

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

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Changes in insulin sensitivity from stress during repetitive sampling in anesthetized rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.262.6.r1033 ◽

1992 ◽

Vol 262 (6) ◽

pp. R1033-R1039 ◽

Cited By ~ 3

Author(s):

R. H. Rao

Keyword(s):

Insulin Sensitivity ◽

Blood Loss ◽

Plasma Corticosterone ◽

Glucose Disposal ◽

Glucose Turnover ◽

Adrenal Steroid ◽

Anesthetized Rats ◽

Hepatic Glucose ◽

Glucose Output ◽

Source Of Error

The effect of repetitive sampling on insulin sensitivity was studied in anesthetized rats. During glucose clamp studies, glucose disposal decreased from 9.3 +/- 0.9 (SE) to 6.5 +/- 1.1 mg.kg-1.min-1 (P less than 0.05), and hepatic glucose output (HGO) increased from 1.2 +/- 0.8 to 2.4 +/- 1.1 mg.kg-1.min-1 (P less than 0.05) after a cumulative blood loss of 9 ml/kg. After a loss of 15 ml/kg, HGO rose further to 4.7 +/- 1.6 mg.kg-1.min-1 (P less than 0.05). During repetitive sampling under identical conditions, plasma adrenocorticotropic hormone (ACTH) increased, despite simultaneous saline infusion, from 68 +/- 11 to 102 +/- 15 pg/ml (P less than 0.05) with a loss of 8 ml/kg, while plasma insulin increased from 39 +/- 7 to 124 +/- 20 mU/l (P less than 0.01) with a loss of 10 ml/kg. Thereafter, ACTH and insulin rose progressively. Plasma corticosterone closely followed the pattern of the ACTH response, indicating that the stress of cumulative blood loss had a significant effect on adrenal steroid production. Increases in ACTH were retarded by reduced volume loss and accelerated by increased loss. It is concluded that stress from blood loss greater than 7 ml/kg may be a source of error in the evaluation of glucose turnover and insulin sensitivity during clamp experiments in rats.

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Effects of physiological hyperinsulinemia on the intracellular metabolic partition of plasma glucose

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.6.e943 ◽

1993 ◽

Vol 265 (6) ◽

pp. E943-E953 ◽

Cited By ~ 3

Author(s):

R. C. Bonadonna ◽

S. del Prato ◽

E. Bonora ◽

G. Gulli ◽

A. Solini ◽

...

Keyword(s):

Plasma Glucose ◽

Healthy Subjects ◽

Glucose Oxidation ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Glucose Production ◽

Glucose Infusion ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Glucose Recycling

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring 3H2O and 14CO2 rates of production during [3-3H]- and [U-14C]glucose infusion, was tested in healthy subjects. In study 1, during staircase 3H2O infusion in six subjects, calculated rates of 3H2O appearance agreed closely with 3H2O infusion rates. In study 2, when [2-3H]glucose and NaH14CO3 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 microU/ml) clamp, accurate estimates of the rates of [2-3H]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of NaH14CO3 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 microU/ml) clamp with [3-3H]- and [U-14C]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0.17 mg.min-1 x kg-1 of lean body mass (LBM), respectively, P < 0.01] and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.

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Fibroblast Growth Factor 21 Controls Glycemia via Regulation of Hepatic Glucose Flux and Insulin Sensitivity

Endocrinology ◽

10.1210/en.2009-0221 ◽

2009 ◽

Vol 150 (9) ◽

pp. 4084-4093 ◽

Cited By ~ 182

Author(s):

Eric D. Berglund ◽

Candice Y. Li ◽

Holly A. Bina ◽

Sara E. Lynes ◽

M. Dodson Michael ◽

...

Keyword(s):

Insulin Sensitivity ◽

Growth Factor ◽

Glycemic Control ◽

Fibroblast Growth Factor ◽

Glucose Disposal ◽

Daily Injection ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Glucose Flux ◽

Hepatic Glucose

Abstract Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator shown to improve glycemic control. However, the molecular and functional mechanisms underlying FGF21-mediated improvements in glycemic control are not completely understood. We examined FGF21 effects on insulin sensitivity and glucose fluxes upon chronic (daily injection for 8 d) and acute (6 h infusion) administration in ob/+ and ob/ob mice. Results show that chronic FGF21 ameliorated fasting hyperglycemia in ob/ob mice via increased glucose disposal and improved hepatic insulin sensitivity. Acute FGF21 suppressed hepatic glucose production, increased liver glycogen, lowered glucagon, and improved glucose clearance in ob/+ mice. These effects were blunted in ob/ob mice. Neither chronic nor acute FGF21 altered skeletal muscle or adipose tissue glucose uptake in either genotype. In conclusion, FGF21 has potent glycemic effects caused by hepatic changes in glucose flux and improved insulin sensitivity. Thus, these studies define mechanisms underlying anti-hyperglycemic actions of FGF21 and support its therapeutic potential.

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Liraglutide Enhances Insulin Sensitivity by Activating AMP-Activated Protein Kinase in Male Wistar Rats

Endocrinology ◽

10.1210/en.2013-2157 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3288-3301 ◽

Cited By ~ 26

Author(s):

Satoru Yamazaki ◽

Hiroaki Satoh ◽

Tsuyoshi Watanabe

Keyword(s):

Insulin Sensitivity ◽

Skeletal Muscles ◽

Glucose Disposal ◽

Control Group ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Male Wistar Rats ◽

Glucose Output ◽

Amp Activated Protein Kinase ◽

Glucose Disposal Rate

Abstract We investigated the effects of liraglutide on insulin sensitivity and glucose metabolism in male Wistar rats. The rats were fed a normal chow diet (NCD) or a 60% high-fat diet (HFD) for a total of 4 weeks. After 3 weeks of feeding, they were injected with liraglutide once a day for 7 days. Subsequently, euglycemic-hyperinsulinemic clamp studies were performed after fasting the animals for 8 hours. During the clamp studies on the NCD-fed rats, the glucose infusion rate required for euglycemia was significantly higher in the liraglutide group than in the control group. The clamp hepatic glucose output was significantly lower in the liraglutide group than in the control group, but the insulin-stimulated glucose disposal rate did not change significantly in the liraglutide groups. The clamp studies on the HFD-fed rats revealed that the glucose infusion rate required to achieve euglycemia was significantly higher in the liraglutide group than in the control HFD group, and the insulin-stimulated glucose disposal rate increased significantly in the liraglutide groups. The clamp hepatic glucose output decreased significantly in the liraglutide groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMP-activated protein kinase was enhanced in the livers of the NCD- and HFD-fed rats and in the skeletal muscles of the HFD-fed rats. Oil red O staining indicated that liraglutide also improved hepatic steatosis. In summary, our studies suggest that in normal glucose tolerance states, liraglutide enhances insulin sensitivity in the liver but not in skeletal muscles. However, in insulin-resistant states, liraglutide improves insulin resistance in the liver and muscles and improves fatty liver.

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Chronic estradiol and progesterone treatment in conscious dogs: effects on insulin sensitivity and response to hypoglycemia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00311.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. R1064-R1073 ◽

Cited By ~ 8

Author(s):

Marcia R. Batista ◽

Marta S. Smith ◽

Wanda L. Snead ◽

Cynthia C. Connolly ◽

D. Brooks Lacy ◽

...

Keyword(s):

Insulin Sensitivity ◽

Serum Levels ◽

Glucose Infusion ◽

Whole Body ◽

Glucose Disposal ◽

Skeletal Muscle Insulin Resistance ◽

Hepatic Glucose ◽

Glucose Output ◽

Hepatic Glucose Uptake ◽

Arteriovenous Difference

We evaluated the effect of chronic (3 wk) subcutaneous treatment with progesterone and estradiol (PE; producing serum levels observed in the 3rd trimester of pregnancy) or placebo (C) on hepatic and whole body insulin sensitivity and response to hypoglycemia in conscious, overnight-fasted nonpregnant female dogs, using tracer and arteriovenous difference techniques. Insulin was infused peripherally for 3 h at 1.8 mU·kg−1·min−1. Glucose was allowed to fall to 3 mM (Hypo) or maintained at 6 mM (Eugly) by peripheral glucose infusion. Insulin concentrations were significantly higher in Eugly-PE ( n = 7) and Hypo-PE ( n = 7) than in Eugly-C ( n = 6) and Hypo-C groups ( n = 7), but there were no significant differences in hepatic insulin extraction. Concentrations of glucagon, cortisol, epinephrine, and norepinephrine did not differ significantly between Eugly groups or between Hypo groups. Whole body glucose disposal, adjusted for the differences in insulin between groups, was 35% higher in Eugly-C vs. Eugly-PE groups ( P < 0.05). Eugly-C and Eugly-PE groups exhibited similar rates of net hepatic glucose uptake, but the rate of glucose appearance was greater in Eugly-PE in the last hour ( P < 0.05). Net hepatic glucose output was greater ( P < 0.05) in Hypo-PE than in Hypo-C groups, and the glucose infusion rate required to maintain equivalent hypoglycemia was less ( P < 0.05). The rate of gluconeogenic flux did not differ between Hypo groups. Chronic progesterone and estradiol exposure caused whole body (primarily skeletal muscle) insulin resistance and enhanced the liver's response to hypoglycemia without altering counterregulatory hormone concentrations.

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Ciliary Neurotrophic Factor Prevents Acute Lipid-Induced Insulin Resistance by Attenuating Ceramide Accumulation and Phosphorylation of c-Jun N-Terminal Kinase in Peripheral Tissues

Endocrinology ◽

10.1210/en.2005-1074 ◽

2006 ◽

Vol 147 (5) ◽

pp. 2077-2085 ◽

Cited By ~ 63

Author(s):

Matthew J. Watt ◽

Andrea Hevener ◽

Graeme I. Lancaster ◽

Mark A. Febbraio

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Ciliary Neurotrophic Factor ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Ceramide Accumulation ◽

Glucose Disposal Rate

Ciliary neurotrophic factor (CNTF) is a member of the gp130 receptor cytokine family recently identified as an antiobesity agent in rodents and humans by mechanisms that remain unclear. We investigated the impact of acute CNTF treatment on insulin action in the presence of lipid oversupply. To avoid confounding effects of long-term high-fat feeding or genetic manipulation on whole-body insulin sensitivity, we performed a 2-h Intralipid infusion (20% heparinized Intralipid) with or without recombinant CNTF pretreatment (Axokine 0.3 mg/kg), followed by a 2-h hyperinsulinemic-euglycemic clamp (12 mU/kg·min) in fasted, male Wistar rats. Acute Intralipid infusion increased plasma free fatty acid levels from 1.0 ± 0.1 to 2.5 ± 0.3 mm, which subsequently caused reductions in skeletal muscle (insulin-stimulated glucose disposal rate) and liver (hepatic glucose production) insulin sensitivity by 30 and 45%, respectively. CNTF pretreatment completely prevented the lipid-mediated reduction in insulin-stimulated glucose disposal rate and the blunted suppression of hepatic glucose production by insulin. Although lipid infusion increased triacylglycerol and ceramide accumulation and phosphorylation of mixed linage kinase 3 and c-Jun N-terminal kinase 1 in skeletal muscle, CNTF pretreatment prevented these lipid-induced effects. Alterations in hepatic and muscle insulin signal transduction as well as phosphorylation of c-Jun N-terminal kinase 1/2 paralleled alterations in insulin sensitivity. These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance.

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Sleep-associated fall in glucose disposal and hepatic glucose output in normal humans. Putative signaling mechanism linking peripheral and hepatic events

Diabetes ◽

10.2337/diabetes.38.3.285 ◽

1989 ◽

Vol 38 (3) ◽

pp. 285-290 ◽

Cited By ~ 11

Author(s):

J. N. Clore ◽

J. E. Nestler ◽

W. G. Blackard

Keyword(s):

Glucose Disposal ◽

Hepatic Glucose Output ◽

Signaling Mechanism ◽

Hepatic Glucose ◽

Normal Humans ◽

Glucose Output

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

Molecular and Cellular Biology ◽

10.1128/mcb.00117-08 ◽

2008 ◽

Vol 28 (18) ◽

pp. 5634-5645 ◽

Cited By ~ 35

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.

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

Acta Endocrinologica ◽

10.1530/acta.0.1270344 ◽

1992 ◽

Vol 127 (4) ◽

pp. 344-350 ◽

Cited By ~ 32

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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