Interactions Between Glucose and FFA Metabolism in Man

Saloranta, Carola; Groop, Leif

doi:10.1002/(sici)1099-0895(199603)12:1<15::aid-dmr155>3.0.co;2-0

Cited by 40 publications

(9 citation statements)

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“…Recent magnetic resonance spectroscopic studies have confirmed that this competition does occur and indicated the intracellular mechanisms involved [40]. Interaction between NEFAs and glucose at a hepatic level is another proposed mechanism, as an increase in the delivery rate of NEFAs to the liver leads to stimulation of gluconeogenesis [10,[41][42][43]. A 'toxic' effect of high NEFA concentration on pancreatic cells has also been implicated as contributing to the development of insulin resistance [44].…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Baldeweg

Golay

Natali

et al. 2000

Eur J Clin Investigation

112

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Section: Discussionmentioning

confidence: 99%

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Baldeweg

Golay

Natali

et al. 2000

Eur J Clin Investigation

112

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“…This significant decrease is likely due to a combination of the nonsignificant decrease in PP-1 activity seen with palmitate alone and the nonsignificant increase in PP-1 observed with insulin alone (data not shown). Inhibition of glycogen synthesis by fatty acids in man is only seen after the intake of large amounts of exogenous fat for a long period of time [Saloranta and Groop, 1996]. It is possible that the PP-1 activity being affected by palmitate in the LDM is not associated with the glycogen granules, such that the long-term inhibitory effect of fatty acids on glycogen synthesis is due to an effect on an inhibitor or scaffolding protein associated with PP-1, or secondary to a decrease in glucose transport.…”

Section: Discussionmentioning

confidence: 99%

Phosphatase activity in rat adipocytes: effects of insulin and insulin resistance

et al. 2000

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Insulin regulates the activity of both protein kinases and phosphatases. Little is known concerning the subcellular effects of insulin on phosphatase activity and how it is affected by insulin resistance. The purpose of this study was to determine insulin-stimulated subcellular changes in phosphatase activity and how they are affected by insulin resistance. We used an in vitro fatty acid (palmitate) induced insulin resistance model, differential centrifugation to fractionate rat adipocytes, and a malachite green phosphatase assay using peptide substrates to measure enzyme activity. Overall, insulin alone had no effect on adipocyte tyrosine phosphatase activity; however, subcellularly, insulin increased plasma membrane adipocyte tyrosine phosphatase activity 78 +/- 26% (n = 4, P < 0.007), and decreased high-density microsome adipocyte tyrosine phosphatase activity 42 +/- 13% (n = 4, P < 0.005). Although insulin resistance induced specific changes in basal tyrosine phosphatase activity, insulin-stimulated changes were not significantly altered by insulin resistance. Insulin-stimulated overall serine/threonine phosphatase activity by 16 +/- 5% (n = 4, P < 0.005), which was blocked in insulin resistance. Subcellularly, insulin increased plasma membrane and crude nuclear fraction serine/threonine phosphatase activities by 59 +/- 19% (n = 4, P < 0. 005) and 21 +/- 7% (n = 4, P < 0.007), respectively. This increase in plasma membrane fractions was inhibited 23 +/- 7% (n = 4, P < 0. 05) by palmitate. Furthermore, insulin increased cytosolic protein phosphatase-1 (PP-1) activity 160 +/- 50% (n = 3, P < 0.015), and palmitate did not significantly reduce this activity. However, palmitate did reduce insulin-treated low-density microsome protein phosphatase-1 activity by 28 +/- 6% (n = 3, P < 0.04). Insulin completely inhibited protein phosphatase-2A activity in the cytosol and increased crude nuclear fraction protein phosphatase-2A activity 70 +/- 29% (n = 3, P < 0.038). Thus, the major effects of insulin on phosphatase activity in adipocytes are to increase plasma membrane tyrosine and serine/threonine phosphatase, crude nuclear fraction protein phosphatase-2A, and cytosolic protein phosphatase-1 activities, while inhibiting cytosolic protein phosphatase-2A. Insulin resistance was characterized by reduced insulin-stimulated serine/threonine phosphatase activity in the plasma membrane and low-density microsomes. Specific changes in phosphatase activity may be related to the development of insulin resistance.

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“…In addition, elevated plasma concentrations of non‐esterified fatty acids (NEFA) have been associated with deterioration of glucose tolerance independent of other markers of insulin resistance that characterize subjects who are at risk from type 2 diabetes (Charles et al ., 1997). Prolonged elevations of NEFA in plasma can exacerbate the impairment in glucose homeostasis in individuals with obesity and type 2 diabetes (Saloranta and Groop, 1996) and may stimulate gluconeogenesis, the development of insulin resistance in muscle and liver, and may also impair insulin secretion in genetically predisposed individuals (Bergman and Ader, 2000). It has been suggested that NEFAs are a major link between obesity and insulin resistance/type 2 diabetes (McGarry, 2002; Bays et al ., 2004).…”

Section: Introductionmentioning

confidence: 99%

Irbesartan treatment up‐regulates hepatic expression of PPARα and its target genes in obese Koletsky (fa^k/fa^k) rats: a link to amelioration of hypertriglyceridaemia

Rong

Zhao

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEHypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT1) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear. ) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting. EXPERIMENTAL APPROACH KEY RESULTSIn Koletsky (fa k /fa k ) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)a and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARa expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARg and its downstream genes or hepatic genes that mediate fatty acid synthesis. CONCLUSIONS AND IMPLICATIONSThese findings demonstrate that irbesartan treatment up-regulates PPARa and several target genes in liver of obese spontaneously hypertensive Koletsky (fa k /fa k ) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan. AbbreviationsACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; AT1, angiotensin II type 1 receptor; ARB, angiotensin II type 1 receptor blocker; CPT, carnitine palmitoyltransferase; DGAT, diacylglycerol acyltransferase; eWAT, epididymal white adipose tissue; FAS, fatty acid synthase; FAT, fatty acid translocase; GLUT, glucose transporter; HOMA-IR, homeostasis model assessment of insulin resistance; NEFA, non-esterified fatty acids; PPAR, peroxisome proliferator-activated receptor; SBP, systolic blood pressure; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein

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Interactions Between Glucose and FFA Metabolism in Man

Cited by 40 publications

References 161 publications

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Phosphatase activity in rat adipocytes: effects of insulin and insulin resistance

Irbesartan treatment up‐regulates hepatic expression of PPARα and its target genes in obese Koletsky (fa^k/fa^k) rats: a link to amelioration of hypertriglyceridaemia

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Interactions Between Glucose and FFA Metabolism in Man

Cited by 40 publications

References 161 publications

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans

Phosphatase activity in rat adipocytes: effects of insulin and insulin resistance

Irbesartan treatment up‐regulates hepatic expression of PPARα and its target genes in obese Koletsky (fak/fak) rats: a link to amelioration of hypertriglyceridaemia

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Irbesartan treatment up‐regulates hepatic expression of PPARα and its target genes in obese Koletsky (fa^k/fa^k) rats: a link to amelioration of hypertriglyceridaemia