Metabolic Effects of Troglitazone on Fructose-Induced Insulin Resistance in the Rat

Lee, Moon-Kyu; Miles, P. D. G.; Khoursheed, Mousa; Gao, Keming; Moossa, A. R.; Olefsky, Jerrold M.

doi:10.2337/diab.43.12.1435

Cited by 170 publications

(84 citation statements)

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“…Our ®ndings imply that the mode of acute troglitazone action di ers considerably from insulin sensitization as observed in response to long-term oral treatment (Fujiwara et al, 1988;1995;Iwamoto et al, 1991;Lee et al, 1994;Nolan et al, 1994). Acute troglitazone stimulation of glucose transport did not require concomitant addition of insulin to the incubation bu er; this contrasts with a lack of improvement of glucose homeostasis in insulin-de®cient animals chronically treated with troglitazone in vivo (Fujiwara et al, 1988).…”

Section: Discussioncontrasting

confidence: 50%

“…It also remains to be elucidated, whether the non-insulin-like acute catabolic action described in vitro (i) is a pharmacological e ect that does not play a role during chronic treatment in vivo, (ii) is a secondary e ect independent of the PPARg-mediated insulin sensitization in vivo, or (iii) is an essential prerequisite for the well-documented antidiabetic potential in vivo (Fujiwara et al, 1988;1995;Iwamoto et al, 1991;Lee et al, 1994;Nolan et al, 1994). With regard to the latter possibility, it might be speculated that during prolonged exposure, modulation of muscle glucose metabolism can shift from short-term catabolic stimulation towards longterm insulin-sensitization.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic oral administration markedly improves insulin sensitivity as well as glucose and lipid metabolism in various animal models of obesity and type 2 diabetes (Fujiwara et al, 1988;1995;Lee et al, 1994). A bene®cial action of chronic troglitazone treatment has also been demonstrated in man (Iwamoto et al, 1991;Nolan et al, 1994) making the compound an important new alternative for the treatment of insulin resistance and type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

Fürnsinn

Neschen

Noe

et al. 1997

British J Pharmacology

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1 The direct short-term e ects of troglitazone on parameters of glucose metabolism were investigated in rat soleus muscle strips. 2 In muscle strips from Sprague-Dawley rats, troglitazone (3.25 mmol l 71 ) increased basal and insulinstimulated glucose transport by 24% and 41%, respectively (P50.01 each). 3 In the presence of 5 nmol l 71 insulin, stimulation of glucose transport by 3.25 mmol l 71 troglitazone was accompanied by a 36% decrease in glycogen synthesis, while glycolysis was increased (112% increase in lactate production) suggesting a catabolic response of intracellular glucose handling. 4 Whereas insulin retained its stimulant e ect on [ 3 H]-2-deoxy-glucose transport in hypoxia-stimulated muscle (by 44%; c.p.m. mg 71 h 71 : 852+77 vs 1229+75, P50.01), 3.25 mmol l 71 troglitazone failed to increase glucose transport under hypoxic conditions (789+40 vs 815+28, NS) suggesting that hypoxia and troglitazone address a similar, non-insulin-like mechanism. 5 No di erences between troglitazone and hypoxia were identi®ed in respective interactions with insulin. 6 Troglitazone acutely stimulated muscle glucose metabolism in a hypoxia/contraction-like manner, but it remains to be elucidated whether this contributes to the long-term antidiabetic and insulin enhancing potential in vivo or is to be regarded as an independent pharmacological e ect.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

Fürnsinn

Neschen

Noe

et al. 1997

British J Pharmacology

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“…* , P Ͻ 0.05; ** , P Ͻ 0.005; compared with control ASO we used 4 weeks of high-fructose combined with high-fat feeding, and a low dose of streptozotocin to decrease, but not eliminate, pancreatic ␤-cell function that mimics T2DM. Three weeks of high-fructose feeding has previously been shown to induce hepatic insulin resistance (19) and increased gluconeogenic gene expression (20). The T2DM model exhibited increased fasting glucose concentrations compared with normal chow-fed controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats

Erion

Yonemitsu

Nie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

169

120

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Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states in type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic gluconeogenesis during fasting through the induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease fasting hyperglycemia in a rat model of T2DM. SirT1 ASO lowered both fasting glucose concentration and hepatic glucose production in the T2DM rat model. Whole body insulin sensitivity was also increased in the SirT1 ASO treated rats as reflected by a 25% increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemiceuglycemic clamp and could entirely be attributed to increased suppression of hepatic glucose production by insulin. The reduction in basal and clamped rates of glucose production could in turn be attributed to decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer and activator of transcription 3 (STAT3), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), known substrates of SirT1. In addition to the effects on glucose metabolism, SirT1 ASO decreased plasma total cholesterol, which was attributed to increased cholesterol uptake and export from the liver. These results indicate that inhibition of hepatic SirT1 may be an attractive approach for treatment of T2DM. gluconeogenesis ͉ glucose 6 phosphatase ͉ phosphoenolpyruvate carboxykinase ͉ type 2 diabetes mellitus ͉ hepatic insulin resistance T ype 2 diabetes mellitus (T2DM) is associated with an increased rate of hepatic glucose production that contributes to fasting hyperglycemia (1-3). Specifically, increased endogenous glucose production can be accounted for by increased rates of hepatic gluconeogenesis (4). Inhibition of hepatic gluconeogenesis has been shown to improve fasting plasma glucose levels and decrease endogenous glucose production in T2DM patients (5). Furthermore, inhibition of transcriptional gluconeogenic activators, such as forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), in turn improved hepatic insulin resistance in rodent models of diabetes (6, 7). Therefore inhibitors of gluconeogenesis are potentially excellent targets for treatment of poorly controlled T2DM.Sirtuin1 (SirT1) is a NAD ϩ -dependent deacetylase activated in response to fasting and caloric restriction (8). In the ␤-cells of the pancreas, SirT1 has been shown to increase insulin secretion through repression of uncoupling protein 2 (UCP2) (9). In adipose tissue, SirT1 has been shown to inhibit adipogenesis and decrease lipolysis through inhibition of peroxisome proliferator-activated receptor-␥ (PPAR␥) (10). In liver tissue, SirT1 activates gluconeogenesis transcription through deacetylation of PGC-1␣, FOXO1, and signa...

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“…The involvement of PPAR␥ in systemic insulin sensitization is further supported by the fact that thiazolidinediones (TZDs), a class of antidiabetic agents, are high-affinity PPAR␥ ligands (3). These drugs enhance adipocyte differentiation (4,5) and ameliorate IR (6,7).…”

mentioning

confidence: 95%

Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

Barak²,

Hevener³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

898

737

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Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) ␥, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPAR␥ in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased levels of plasma leptin and ACRP30. In addition, increased hepatic glucogenesis and IR were observed. Despite these defects, blood glucose, glucose and insulin tolerance, and insulin-stimulated muscle glucose uptake were all comparable to those of control mice. However, targeted mice were significantly more susceptible to high-fat diet-induced steatosis, hyperinsulinemia, and IR. Surprisingly, TZD treatment effectively reversed liver IR, whereas it failed to lower plasma free fatty acids. These results suggest that syndrome X may be comprised of separable PPAR␥-dependent components whose origins and therapeutic sites may reside in distinct tissues.syndrome X

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Metabolic Effects of Troglitazone on Fructose-Induced Insulin Resistance in the Rat

Cited by 170 publications

References 0 publications

Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats

Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

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