Quantity of sucrose alters the tissue pattern and time course of insulin resistance in young rats

1995 ◽  
Vol 269 (3) ◽  
pp. R641-R646 ◽  
Author(s):  
M. J. Pagliassotti ◽  
P. A. Prach
Keyword(s):  
Insulin Resistance ◽  
Total Energy ◽  
Infusion Rate ◽  
Time Course ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Young Rats ◽  
Sucrose Diet

To determine the effects of the amount of sucrose in the diet on insulin-stimulated glucose metabolism, euglycemic hyperinsulinemic clamps were performed on male Wistar rats after one of the following dietary treatments (n = 6-8/treatment): 1) high-starch diet (68% of total energy) for 8 wk (ST8), 16 wk (ST16), or 30 wk (ST30); 2) high-sucrose diet (68% of total energy) for 8 wk (SU8), 16 wk (SU16), or 30 wk (SU30); or 3) low-sucrose diet (18% of total energy) for 8 wk (SUL8), 16 wk (SUL16), or 30 wk (SUL30). Body weights were similar in starch- and sucrose-fed rats at 8 wk (502 +/- 9 g), 16 wk (563 +/- 10 g), and 30 wk (607 +/- 26 g). The glucose infusion rate (mumol.g-1.min-1) required to maintain similar glycemia during clamps was 73.1 +/- 8.8 in ST8, 29.7 +/- 4.9 in SU8 (P < 0.05 vs. ST8 and SUL8), and 76.4 +/- 8.2 in SUL8; 69.9 +/- 8.1 in ST16, 35.1 +/- 5.1 in SU16 (P < 0.05 vs. ST16 and SUL16), and 63.2 +/- 6.5 in SUL16; and 65.4 +/- 7.7 in ST30, 26.0 +/- 5.3 (P < 0.05 vs. ST30), and 36.3 +/- 6.0 in SUL30 (P < 0.05 vs. ST30). Impaired suppression of hepatic glucose production accounted for 43, 39, and 34% of the decrease in the glucose infusion rate in SU8 compared with ST8, SU16 compared with ST16, and SU30 compared with ST30, respectively, but 78% in SUL30 compared with ST30. These results suggest that both high- and low-sucrose diets can produce insulin resistance in young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Difference in Glucose Infusion Rate on Quantification of Hepatic Glucose Production*

1990 ◽  
Vol 70 (5) ◽  
pp. 1354-1360 ◽  
Author(s):  
WAYNE H.-H. SHEU ◽  
CLARIE B. HOLLENBECK ◽  
MIN-SHUNG WU ◽  
JOHNATHAN B. JASPAN ◽  
Y.-D. IDA CHEN ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Hepatic Glucose

Underestimation of hepatic glucose production by radioactive and stable tracers

1987 ◽  
Vol 252 (5) ◽  
pp. E606-E615 ◽  
Author(s):  
G. M. Argoud ◽  
D. S. Schade ◽  
R. P. Eaton
Keyword(s):  
Infusion Rate ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Glucose Disposal ◽  
Methodological Error ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
The Difference

Although negative hepatic glucose production rates are physiologically impossible, they have been observed when hepatic glucose production is measured with the tracer-dilution technique during the hyperinsulinemic, euglycemic glucose clamp. Because hepatic glucose production is determined from the difference between tracer-derived glucose disposal and the known exogenous glucose infusion rate, the negative values for hepatic glucose production must result from an underestimation of glucose disposal by the tracer technique. In the current investigation, tracer-derived glucose disposal was measured in 25 subjects undergoing hyperinsulinemic, euglycemic clamps. Glucose disposal was measured with both radioactive and stable isotopes that utilize different methodologies, to determine whether discriminant metabolism of the isotopes versus methodological error leads to underestimation of tracer-derived glucose disposal. Both the radioactive and stable methodologies underestimated the exogenous glucose infusion rate during the hyperinsulinemic euglycemic clamp by 27 and 17%, respectively. Mean hepatic glucose production was -2.1 +/- 0.2 and -1.3 +/- 0.2 mg X kg-1 X min-1 as determined by the radioactive and stable isotope methodologies, respectively. Methodological error was an unlikely cause of this underestimation because it occurred with two different methodologies. The most likely explanation for underestimated rates of glucose disposal determined by the two types of isotope methodologies is discrepant metabolism of glucose tracers in comparison with unlabeled glucose.

A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

2007 ◽  
Vol 292 (5) ◽  
pp. E1358-E1363 ◽  
Author(s):  
Arvinder K. Dhalla ◽  
Mei Yee Wong ◽  
Peter J. Voshol ◽  
Luiz Belardinelli ◽  
Gerald M. Reaven
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Adenosine Receptor ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Oral Glucose ◽  
Acute Administration ◽  
High Fat ◽  
Adenosine Receptor Agonist

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A1 adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly ( P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

scholarly journals Ginsenoside Re Reduces Insulin Resistance through Inhibition of c-Jun NH2-Terminal Kinase and Nuclear Factor-κB

2008 ◽  
Vol 22 (1) ◽  
pp. 186-195 ◽  
Author(s):  
Zhiguo Zhang ◽  
Xiaoying Li ◽  
Wenshan Lv ◽  
Yisheng Yang ◽  
Hong Gao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Signaling Cascades ◽  
Glucose Infusion Rate ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Ginsenoside Re

Abstract Ginsenoside Re (Re), a compound derived from Panax ginseng, shows an antidiabetic effect. However, the molecular basis of its action remains unknown. We investigated insulin signaling and the antiinflammatory effect by Re in 3T3-L1 adipocytes and in high-fat diet (HFD) rats to dissect its anti-hyperglycemic mechanism. Glucose uptake was measured in 3T3-L1 cells and glucose infusion rate determined by clamp in HFD rats. The insulin signaling cascade, including insulin receptor (IR) β-subunit, IR substrate-1, phosphatidylinositol 3-kinase, Akt and Akt substrate of 160 kDa, and glucose transporter-4 translocation are examined. Furthermore, c-Jun NH2-terminal kinase (JNK), MAPK, and nuclear factor (NF)-κB signaling cascades were also assessed. The results show Re increases glucose uptake in 3T3-L1 cells and glucose infusion rate in HFD rats. The activation of insulin signaling by Re is initiated at IR substrate-1 and further passes on through phosphatidylinositol 3-kinase and downstream signaling cascades. Moreover, Re demonstrates an impressive suppression of JNK and NF-κB activation and inhibitor of NF-κBα degradation. In conclusion, Re reduces insulin resistance in 3T3-L1 adipocytes and HFD rats through inhibition of JNK and NF-κB activation.

scholarly journals Oxidative Stress Is Associated with Adiposity and Insulin Resistance in Men

2003 ◽  
Vol 88 (10) ◽  
pp. 4673-4676 ◽  
Author(s):  
Hideki Urakawa ◽  
Akira Katsuki ◽  
Yasuhiro Sumida ◽  
Esteban C. Gabazza ◽  
Shuichi Murashima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Body Mass Index ◽  
Body Mass ◽  
Body Fat ◽  
Plasma Levels ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Total Fat

Abstract To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2α (PGF2α) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2α than nonobese men (P &lt; 0.05). The plasma levels of 8-epi-PGF2α were significantly correlated with body mass index (r = 0.408; P &lt; 0.05), body fat weight (r = 0.467; P &lt; 0.05), visceral (r = 0.387; P &lt; 0.05) and total fat area (r = 0.359; P &lt; 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2α and glucose infusion rate in obese men (r = −0.552; P &lt; 0.05) and all men (r = −0.668; P &lt; 0.01). In all subjects, the plasma levels of 8-epi-PGF2α were significantly correlated with fasting serum levels of insulin (r = 0.487; P &lt; 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2α are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

scholarly journals Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

2016 ◽  
Vol 311 (3) ◽  
pp. E620-E627 ◽  
Author(s):  
Tianru Jin ◽  
Jianping Weng
Keyword(s):  
Insulin Resistance ◽  
Degradation Products ◽  
Hepatic Glucose Production ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Beneficial Effects ◽  
Metabolic Functions ◽  
Pathway Activation ◽  
Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

scholarly journals Long-term modulation of type L pyruvate kinase activity in young and mature rats

1982 ◽  
Vol 204 (1) ◽  
pp. 329-338 ◽  
Author(s):  
Milinda E. James ◽  
James B. Blair
Keyword(s):  
Protein Synthesis ◽  
Pyruvate Kinase ◽  
Total Protein ◽  
Time Course ◽  
Enzyme Level ◽  
Enzyme Synthesis ◽  
Synthesis Rate ◽  
Adult Rats ◽  
Young Rats ◽  
Sucrose Diet

The regulation of type L pyruvate kinase concentrations in liver of young (35–45 days old) and adult (60–85 days old) rats starved and re-fed a 71% sucrose diet was investigated. Re-feeding is accompanied by an increase in the enzyme level in liver determined kinetically and immunologically. A constant ratio of kinetic activity to immunological activity was observed under all conditions examined, indicating that activity changes are the result of a regulation of synthesis or degradation and not an interconversion between kinetically active and inactive forms of the enzyme. Synthesis of pyruvate kinase was directly examined by using hepatocytes isolated from starved and re-fed rats. A stimulation of pyruvate kinase synthesis is observed on re-feeding. This increase in synthesis of pyruvate kinase is retained by the isolated hepatocyte for up to 7h in the absence of hormonal stimuli. Administration of glucagon (1μm) to the isolated hepatocytes had no influence on synthesis of pyruvate kinase and no evidence for a glucagon-directed degradation of the enzyme was found. Re-feeding the rat was followed by a transient increase in the synthesis of pyruvate kinase. The peak rate of synthesis was observed before a detectable increase in the enzyme concentration. After a rapid synthesis period, a new steady-state level of the enzyme was achieved and synthesis rates declined. The time course and magnitude for the response to the sucrose diet was dependent on the age of the rat. In young rats, an increase in pyruvate kinase synthesis is observed within 6h and peak synthesis occurs at 11h after re-feeding sucrose. The peak synthesis rate for pyruvate kinase for young rats represents approx. 1% of total protein synthesis. With adult rats, increased pyruvate kinase synthesis is not observed for 11h, with peak synthesis occurring at 24h after re-feeding. In the older rats, peak pyruvate kinase synthesis constitutes greater than 4% of total protein synthesis. Continued re-feeding of the adult rat beyond 24h is accompanied by a decline of pyruvate kinase synthesis to approx. 1.5% of total protein synthesis. The concentration of the enzyme, however, does not decline during this period, suggesting that control of pyruvate kinase degradation as well as synthesis occurs.

scholarly journals Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis

2019 ◽  
Vol 241 (3) ◽  
pp. 293-305 ◽  
Author(s):  
Srilaxmi Kalavalapalli ◽  
Fernando Bril ◽  
Joy Guingab ◽  
Ariana Vergara ◽  
Timothy J Garrett ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
G Protein ◽  
Nonalcoholic Steatohepatitis ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Tca Cycle ◽  
Lipogenic Genes ◽  
Relative Contribution ◽  
High Fructose ◽  
Triglyceride Content

Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.e., a NASH model previously validated by our laboratory). For the final 8 weeks, mice were treated with Exe (30 µg/kg/day) or vehicle. Mitochondrial metabolism was assessed by infusion of [13C3]propionate, [3,4-13C2]glucose and NMR-based 13C-isotopomer analysis. Exenatide significantly decreased fasting plasma glucose, free fatty acids and triglycerides, as well as adipose tissue insulin resistance. Moreover, Exe reduced 23% hepatic glucose production, 15% tri-carboxylic acid (TCA) cycle flux, 20% anaplerosis and 17% pyruvate cycling resulting in a significant 31% decrease in intrahepatic triglyceride content (P = 0.02). Exenatide improved the lipidomic profile and decreased hepatic lipid byproducts associated with insulin resistance and lipotoxicity, such as diacylglycerols (TFD: 111 ± 13 vs Exe: 64 ± 13 µmol/g protein, P = 0.03) and ceramides (TFD: 1.6 ± 0.1 vs Exe: 1.3 ± 0.1 µmol/g protein, P = 0.03). Exenatide lowered expression of hepatic lipogenic genes (Srebp1C, Cd36) and genes involved in inflammation and fibrosis (Tnfa, Timp1). In conclusion, in a diet-induced mouse model of NASH, Exe ameliorates mitochondrial TCA cycle flux and significantly decreases insulin resistance, steatosis and hepatocyte lipotoxicity. This may have significant clinical implications to the potential mechanism of action of GLP-1 receptor agonists in patients with NASH. Future studies should elucidate the relative contribution of direct vs indirect mechanisms at play.

Plasma glucose concentration determines direct versus indirect liver glycogen synthesis

1986 ◽  
Vol 251 (5) ◽  
pp. E584-E590 ◽  
Author(s):  
C. H. Lang ◽  
G. J. Bagby ◽  
H. L. Blakesley ◽  
J. L. Johnson ◽  
J. J. Spitzer
Keyword(s):  
Plasma Glucose ◽  
Glucose Concentration ◽  
Infusion Rate ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Hepatic Glycogen ◽  
Glucose Load ◽  
Indirect Pathway

In the present study hepatic glycogenesis by the direct versus indirect pathway was determined as a function of the glucose infusion rate. Glycogen synthesis was examined in catheterized conscious rats that had been fasted 48 h before receiving a 3-h infusion (iv) of glucose. Glucose, containing tracer quantities of [U-14C]- and [6-3H]glucose, was infused at rates ranging from 0 to 230 mumol X min-1 X kg-1. Plasma concentrations of glucose, lactate, and insulin were positively correlated with the glucose infusion rate. Despite large changes in plasma glucose, lactate, and insulin concentrations, the rate of hepatic glycogen deposition (0.46 +/- 0.03 mumol X min-1 X g-1) did not vary significantly between glucose infusion rates of 20 and 230 mumol X min-1 X kg-1. However, the percent contribution of the direct pathway to glycogen repletion gradually increased from 13 +/- 2 to 74 +/- 4% in the lowest to the highest glucose infusion rates, with prevailing plasma glucose concentrations from 9.4 +/- 0.5 to 21.5 +/- 2.1 mM. Endogenous glucose production was depressed (by up to 40%), but not abolished by the glucose infusions. Only a small fraction (7-14%) of the infused glucose load was incorporated into liver glycogen via the direct pathway irrespective of the glucose infusion rate. Our data indicate that the relative contribution of the direct and indirect pathways of hepatic glycogen synthesis are dependent on the glucose load or plasma glucose concentration and emphasize the predominance of the indirect pathway of glycogenesis at plasma glucose concentrations normally observed after feeding.

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