Diabetologia.
2005 May 11; [Epub ahead of print]
Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive
lipase and uncoupling protein-1, and down-regulates insulin-induced fatty
acid synthase gene expression in brown adipocytes of Wistar rats.
Teruel T, Hernandez R, Rial E, Martin-Hidalgo A, Lorenzo M.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy,
Complutense University, 28040, Madrid, Spain, mlorenzo@farm.ucm.es.
AIMS/HYPOTHESIS: Although thiazolidinediones are now widely used to treat
type 2 diabetes, their mechanism of action remains largely unknown. They
are agonists for the transcription factor PPARgamma, and in addition to
their insulin-sensitising effects, they can promote adipogenesis and control
gene expression in adipose tissues. We have explored the effect of rosiglitazone
on insulin-mediated induction of pivotal genes involved in lipid metabolism
and thermogenesis in brown fat. The genes studied were: (1) lipoprotein
lipase (lpl), which is involved in lipid uptake; (2) hormone-sensitive
lipase (hsl), which mobilises fatty acids from stored triglycerides; (3)
fatty acid synthase (fas), which regulates de novo lipogenesis; and (4)
the uncoupling proteins (ucp) 1 and 3, which control thermogenesis. METHODS:
We used fetal rat primary brown adipocytes cultured with insulin, rosiglitazone
or both combined. Then, we studied gene expression by northern and western
blotting, as well as 'run-on' and gel-shift assays to identify binding
of potential transcription factors to the fas promoter. RESULTS: Exposure
to rosiglitazone for 24 h induced ucp-1, lpl and hsl gene expression and
when rosiglitazone was combined with insulin a synergistic effect on lpl
and ucp-3 mRNA expression was produced. These effects were consistent
with increased LPL and HSL activities as well as respiration rates, mainly
in response to exogenous palmitate. In contrast, treatment with rosiglitazone
did not alter FAS mRNA basal levels but prevented the induction elicited
by insulin in a time- and dose-dependent manner. Correspondingly diminished
FAS protein levels and activity, as well as cellular lipid content, were
observed, indicating an antilipogenic action of rosiglitazone in brown
adipocytes. Furthermore, rosiglitazone impaired insulin increase in the
FAS transcription rate by antagonising insulin-induced binding of upstream
stimulatory factors to the E-box consensus sequence in the FAS promoter
and insulin-induced binding of activating protein-1. CONCLUSIONS/INTERPRETATION:
Rosiglitazone prevents insulin-induced up-regulation of the main lipogenic
enzyme but increases the expression of those enzymes involved in lipid
uptake and mobilisation, favouring fatty acid utilisation through uncoupled
respiration.
Biochem Pharmacol. 2005 May 2; [Epub ahead of print]
Rosiglitazone, an agonist of peroxisome proliferator-activated
receptor gamma, reduces chronic colonic inflammation in rats.
Sanchez-Hidalgo M, Martin AR, Villegas I, Alarcon De La Lastra
C.
Department of Pharmacology, Faculty of Pharmacy, University of Sevilla,
Profesor Garcia Gonzalez Street 2, 41012 Seville, Spain.
Recent studies have shown the implication of the peroxisome proliferator-activated
receptor gamma (PPARgamma) in control of inflammation, immune and apoptotic
responses during early experimental colitis. However, there is little
information about the effects of these agents on colonic mucosa under
chronic inflammatory conditions. In this study, we have evaluated the
effects of rosiglitazone, a PPAR-gamma agonist, on the chronic injury
caused by intra-colonic administration of trinitrobenzensulfonic acid
(TNBS) in rats. Rosiglitazone (1 and 5mg/kg p.o.) was administered by
oral gavage, 24h after TNBS instillation and daily during 2 weeks before
killing the rats. Colons were removed for histological and biochemical
analysis. Administration of rosiglitazone corrected the disorders in morphology
associated to lesions, significantly reduced the ulceration index, the
rise of myeloperoxidase (MPO) and the levels of tumour necrosis factor
alpha (TNF-alpha). In addition, rosiglitazone treatment increased prostaglandin
(PG)E(2) production and returned PGD(2) to basal levels. Also, reduced
cyclooxygenase (COX)-2 and nuclear transcription factor NF-kappa B (NF-kappaB)
p65 proteins expression. Furthermore, treatment of rats with rosiglitazone
caused a significant increase of TNBS-induced apoptosis. In summary, rosiglitazone
exerts protective effects in chronic experimental colitis. The anti-inflammatory
effects seem to be related to impairment of neutrophil function, absence
of up-regulation of TNF-alpha and decrease of nuclear NF-kappaB p65 expression.
Our results also suggest that the activation of the PPARgamma pathway
reduces COX-2 overexpression, returns the increased PGD(2) values to basal
levels and induces a significant increase of TNBS-induced apoptosis. We
conclude that rosiglitazone represents a novel approach to the treatment
of ulcerative colitis.
Metabolism. 2005 May;54(5):645-52.
Rosiglitazone reduces serum homocysteine levels, smooth muscle
proliferation, and intimal hyperplasia in Sprague-Dawley rats fed a high
methionine diet.
Murthy SN, Obregon DF, Chattergoon NN, Fonseca NA, Mondal D,
Dunne JB, Diez JG, Jeter JR, Kadowitz PJ, Agrawal KC, McNamara DB, Fonseca
VA.
Abstract Homocysteine (Hcy) is a metabolite of the essential amino acid
methionine. Hyperhomocysteinemia is associated with vascular disease,
particularly carotid stenosis. Rosiglitazone, a ligand of the peroxisome
proliferator-activated receptor gamma , attenuates balloon catheter-induced
carotid intimal hyperplasia in type 2 diabetic rats. We studied 4 groups
(n = 7 per group) of adult female Sprague-Dawley rats fed (a) powdered
laboratory chow (control), (b) control diet with rosiglitazone (3.0 mg/kg/d),
(c) diet containing 1.0% l -methionine, and (d) diet containing methionine
and rosiglitazone. After 1 week on high methionine diet, the rats were
administered an aqueous preparation of rosiglitazone by oral gavage. One
week after initiation of rosiglitazone, balloon catheter injury of the
carotid artery was carried out using established methods, and the animals
continued on their respective dietary and drug regimens for another 21
days. At the end of the experimental period, blood samples were collected,
and carotid arteries and liver were harvested. Serum Hcy increased significantly
on methionine diet compared with controls (28.9 +/- 3.2 vs 6.3 +/- 0.04
mu mol/L). Development of intimal hyperplasia was 4-fold higher in methionine-fed
rats; this augmentation was significantly reduced ( P < .018) in rosiglitazone-treated
animals. Rosiglitazone treatment significantly ( P < .001) suppressed
Hcy levels and increased the activity of the Hcy metabolizing enzyme,
cystathionine- beta -synthase in the liver samples. Hcy (100 mu mol/L)
produced a 3-fold increase in proliferation of rat aortic vascular smooth
muscle cells; this augmentation was inhibited by incorporating rosiglitazone
(10 mu mol/L). After balloon catheter injury to the carotid artery of
animals on a high methionine diet, there was an increase in the rate of
development of intimal hyperplasia consistent with the known effects of
Hcy. It is demonstrated for the first time that the peroxisome proliferator-activated
receptor gamma agonist rosiglitazone can attenuate the Hcy-stimulated
increase in the rate of development of intimal hyperplasia indirectly
by increasing the rate of catabolism of Hcy by cystathionine- beta -synthase
and directly by inhibiting vascular smooth muscle cell proliferation.
These findings may have important implications for the prevention of cardiovascular
disease and events in patients with hyperhomocysteinemia (HHcy).
Am J Hypertens. 2005 Feb;18(2):227-34.
The effect of rosiglitazone on urine albumin excretion in patients
with type 2 diabetes mellitus and hypertension.
Sarafidis PA, Lasaridis AN, Nilsson PM, Hitoglou-Makedou AD, Pagkalos
EM, Yovos JG, Pliakos CI, Tourkantonis AA.
1st Department of Medicine, AHEPA University Hospital, Aristotle University,
Thessaloniki, Greece.
BACKGROUND: Thiazolidinediones are antidiabetic agents that improve insulin sensitivity (IS). Accumulating data indicate that these agents provide beneficial effects beyond glycemic control, such as improvement in vascular function. The aim of this study was to determine the effect of rosiglitazone on urine albumin excretion (UAE) in patients with type 2 diabetes mellitus (DM) and hypertension. METHODS: The study involved 20 subjects with type 2 DM who were already on 15 mg glibenclamide daily but were achieving poor glycemic control and who had either poorly controlled or newly diagnosed hypertension. In these patients, rosiglitazone (4 mg daily) was added to the existing therapeutic regimen for 26 weeks. At baseline and the end of the treatment, subjects gave a 24-h urine collection for direct measurement of albumin and a spot specimen for determination of the albumin-to-creatinine ratio (ACR). Subjects also had a hyperinsulinemic euglycemic clamp and an ambulatory blood pressure (BP) monitoring. RESULTS: At the end of the study, UAE was significantly reduced versus baseline, as measured either directly in the 24-h collection (22.4 +/- 4.6 v 13.8 +/- 3.0 mg/day, P < .05) or with ACR (20.9 +/- 3.8 v 14.0 +/- 2.8 mg/g, P < .05). The percentage changes in UAE (DeltaALB for the 24-h collection and DeltaACR for ACR) correlated with the respective changes in IS (r = -0.64, P < .01 for DeltaALB and r = -0.48, P < .05 for DeltaACR), systolic BP (r = 0.63, P < .01 and r = 0.58, P < .01 respectively), and diastolic BP (r = 0.56, P < .05 and r = 0.50, P < .05 respectively). CONCLUSIONS: In this study, treatment of type 2 diabetic hypertensive patients with rosiglitazone significantly decreased UAE. Lowering of BP and improvement of IS should play roles in this UAE reduction.
Metabolism. 2005 Mar;54(3):314-20.
The effects of rosiglitazone and metformin on the plasma concentrations
of resistin in patients with type 2 diabetes mellitus.
Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, Shin CS, Kim SY, Lee
HK, Park KS.
Abstract Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 mu g/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.
Obstet Gynecol Surv. 2005 Mar;60(3):178-9. Related Articles, Links
Effects of metformin and rosiglitazone, alone and in combination,
in nonobese women with polycystic ovary syndrome and normal indices of
insulin sensitivity.
Baillargeon JP, Jakubowicz DJ, Iuomo MJ, Jakubowicz S, Nestler
JE.
Hospital de Clinicas Caracas, Caracas, Venezuela; and the Medical
College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
The goal of this randomized, controlled, double-blind trial was to learn whether insulin-sensitizing drugs can improve ovulation frequency and serum-free testosterone (T) in nonobese women with polycystic ovary syndrome (PCOS) whose insulin sensitivity was normal. The 100 women enrolled in the study, 17 to 40 years of age, had normal glucose tolerance, fasting insulin, and peak insulin levels during oral glucose tolerance testing (OGTT). The fasting glucose-to-insulin ratio also was normal. Criteria for PCOS were 8 or fewer menstrual periods in the past year and a serum total T exceeding 70 ng/dL. Participants received 850 mg metformin, 4 mg rosiglitazone, a combination of both treatments, or at least 1 placebo twice a day for 6 months. Treatment began when the women were in the equivalent of the follicular phase of the cycle.Only women given rosiglitazone gained significant body weight (1.1 kg), and the posttreatment body mass index was significantly greater in this group. All actively treated women had a significant decline in their waist-to-hip ratio. Systolic blood pressure fell significantly in all actively treated groups but not in placebo recipients. Diastolic pressure decreased and was similar in all groups at the end of the study. Ovulatory cycles were 6- to 8-fold more frequent with treatment and were highest in women given metformin or combination therapy. Ovulation rates at 6 months were markedly increased except in the placebo group. Menstrual bleeding also was greater in treated women. Combination treatment did not yield additive results for either ovulation or menstrual bleeding. Serum total and free T levels decreased significantly with active treatment. Compared with placebo, fasting insulin levels, the area under the insulin curve during an OGTT, and the OGTT-based insulin sensitivity index improved significantly after metformin or combination therapy, but not after rosiglitazone.The investigators concluded that insulin-sensitizing drugs are effective in nonobese women with PCOS even if baseline insulin sensitivity is normal.
Vnitr Lek. 2004 Nov;50(11):818-24. Related Articles, Links
[Rosiglitazon in treatment of Type II diabetes mellitus--experience
of diabetologists in the Czech Republic. Part I: compensation of diabetes,
sugar metabolism]
[Article in Czech]
Perusicova J, Haas T.
Diabetologicke centrum, III. interni klinika 1. lekarske fakulty
UK a VFN, Praha.
Thiazolidindione derivates (glitazones) make a very promising group of peroral antidiabetic drugs. They are represented by rosiglitazon which is available on our market to type II diabetics. As far as sugar metabolism is concerned, rosiglitazon can reduce glycaemia and insulin level both when fasting and postprandially. GOAL: The goal of the authors' work was to gain their own experience with rosiglitazon treatment in type II diabetics in the Czech Republic. Sample: The monitored sample consisted of 388 patients with insufficiently compensated type II diabetes when treated by sulphonylurea compounds or metformine. METHODS: 95 diabetologists from diabetology medical offices started a 6-month-long treatment with rosiglitazon (Avandia) dose of 4 mg a day as stated in European recommendations. In order to assess changes in sugar metabolism (compensation of diabetes) glycaemia and C peptide were monitored when fasting and postpradially and HbA1c was monitored in 2-month-long intervals. RESULTS: Weight, waist-hip ratio (WHR) and C-peptide levels remained unchanged. Statistically significant (p < 0.0001) was a HbA1c decrease over 6 month from 9.61% to 8.48%. Fasting glycaemia decreased by 2.49 and postprandial glycaemia by 2.71 mmol/l. No significant side effects were identified. CONCLUSION: Rosiglitazon administration combined with administration of sulphonylurea compounds or metformine significantly improved compensation of diabetes compared to initial therapy.
J Clin Endocrinol Metab. 2004 Dec;89(12):6048-53. Related Articles, Links
Rosiglitazone, but not glyburide, reduces circulating proinsulin
and the proinsulin:insulin ratio in type 2 diabetes.
Smith SA, Porter LE, Biswas N, Freed MI.
Scientific Affairs, Diabetes, GlaxoSmithKline, Harlow, Essex, CM19
5AW, United Kingdom. stephen.a.smith@gsk.com
An elevation in the ratio of proinsulin (PI) to immunoreactive insulin
(IRI) is inversely related to beta-cell function in type 2 diabetes, and
increased PI is an independent risk factor for coronary heart disease.
An objective of the present studies was to assess the effects of the thiazolidinedione
insulin sensitizer, rosiglitazone, on indirect markers of beta-cell function
and cardiovascular risk in people with type 2 diabetes by measuring plasma
PI and the PI:IRI ratio. Parameters of insulin processing, including plasma
PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled
in two randomized double-blind studies comparing the effects of rosiglitazone
(4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea
glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for
26 wk (study 1) produced significant dose-dependent decreases in both
plasma PI concentrations (18-29%) and the PI:IRI ratio compared with baseline
(7-14%) and placebo (19-29%) (P < 0.001). A significant increase in
the PI:IRI ratio in placebo-treated patients occurred (P < 0.001).
In study 2, rosiglitazone also significantly reduced both plasma PI and
the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide
significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI
ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone
and glyburide have differential effects on absolute PI levels and the
PI:IRI ratio in people with type 2 diabetes.
Metabolism. 2004 Dec;53(12):1552-7.
Effects of rosglitazone on plasma adiponectin, insulin sensitivity,
and insulin secretion in high-risk African Americans with impaired glucose
tolerance test and type 2 diabetes.
Osei K, Gaillard T, Kaplow J, Bullock M, Schuster D.
We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 mug/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 mug/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 mug/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.
J Lipid Res. 2004 Nov;45(11):2015-24. Epub 2004 Aug 16.
Rosiglitazone upregulates caveolin-1 expression in THP-1 cells
through a PPAR-dependent mechanism.
Llaverias G, Vazquez-Carrera M, Sanchez RM, Noe V, Ciudad CJ,
Laguna JC, Alegret M.
Unitat de Farmacologia, Facultat de Farmacia, Universitat de Barcelona,
Barcelona, Spain.
Peroxisome proliferator-activated receptor gamma (PPARgamma) activation or overexpression induces caveolin-1 (cav-1) expression in several cell types. The objective of this study was to investigate if PPAR agonists could also regulate the cav-1 gene in macrophages and to explore the mechanisms involved. Our experiments demonstrated that rosiglitazone dose- and time-dependently increased cav-1 mRNA and protein in THP-1 macrophages. This induction was not observed in the presence of inhibitors of transcription or de novo protein synthesis. We also showed that the increase in cav-1 elicited by rosiglitazone was not related either to macrophage differentiation or to cellular apoptosis. The inductive effect seems to be dependent on PPAR activation, as the PPAR antagonist GW9662 abolished it. The activation of the liver X receptor with 22(R)-hydroxycholesterol also increased cav-1 mRNA, whereas the inactive (S) isomer did not. Finally, we identified a functional peroxisome proliferator response element in the cav-1 promoter that was activated upon rosiglitazone treatment in THP-1 macrophages.
Treat Endocrinol. 2004;3(5):279-87.
Towards single-tablet therapy for type 2 diabetes mellitus. Rationale
and recent developments.
Mooradian AD.
Division of Endocrinology, Diabetes and Metabolism, Department of Internal
Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri,
USA. mooradad@slu.edu
Type 2 diabetes mellitus emerges as a result of multiple pathophysiologic changes. If the pharmacotherapy of type 2 diabetes should be tailored to the underlying pathophysiology, it would be necessary to use a combination of agents with complementary mechanisms of action. The two principal defects in type 2 diabetes are insulin deficiency and insulin resistance. Therefore, combining an insulin-providing agent with an insulin-sensitizing agent will augment the efficacy of current antihyperglycemic agents. This is the rationale for the development and marketing of sulfonylurea/metformin combination tablets.Randomized double-blind clinical trials have shown the safety and efficacy of these fixed combination tablets in both drug-naive individuals as well as in those individuals not achieving glycemic goals on sulfonylurea or metformin monotherapy. These studies have also shown that these tablets may be associated with better postprandial glycemic control compared with monotherapy. However, the risk of hypoglycemia is increased with the use of combination tablets, especially in drug-naive individuals with baseline glycosylated hemoglobins of <8.0%.Combining two insulin-sensitizing agents that have different mechanisms of action and that target different biochemical pathways, would also enhance efficacy. This can be accomplished by combining metformin with rosiglitazone or pioglitazone. The recently developed fixed formulation tablet of metformin/rosiglitazone is available for use as second-line therapy in individuals who have not reached their glycemic goals while on metformin.The advantages of combining several agents in one tablet include convenience and enhanced adherence to therapy. The main disadvantage is the loss of administration flexibility.
Eur J Pharmacol. 2004 Nov 28;505(1-3):195-203.
Rosiglitazone, an agonist of peroxisome proliferator-activated
receptor gamma, protects against gastric ischemia-reperfusion damage in
rats: role of oxygen free radicals generation.
Villegas I, Ramon Martin A, Toma W, Alarcon de la Lastra C.
Department of Pharmacology, Faculty of Pharmacy, University of Sevilla,
Professor Garcia Gonzalez Street, 41012 Seville, Spain.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear hormone receptor super family that has recently been implicated in atherosclerosis, inflammation, cancer, infertility, and demyelination. Oxidative stress, neutrophil infiltration, proinflammatory cytokines, and the exhibition of luminal acid play a role in the pathogenesis of gastric injury induced by ischemia-reperfusion. Rosiglitazone, a specific PPAR-gamma ligand, has been shown to have antiinflammatory activity, but its effects on experimental ischemia-reperfusion gastric injury remain unknown. We have investigated the effects of the rosiglitazone on gastric injury caused by ischemia following reperfusion in rats. Tumour necrosis factor-alpha (TNF-alpha) levels and changes in enzymatic activities of myeloperoxidase, as a marker of neutrophils infiltration, xanthine oxidase, superoxide dismutase, and glutathione peroxidase, were determined. Histological analysis of the lesions was also carried out. Pretreatment with 1 or 4 mg/kg of rosiglitazone ameliorated the gastric damage induced by clamping the celiac artery for 30 min followed by 60 min of reperfusion. It significantly (P<0.05) reduced the index of neutrophil infiltration and the levels of the cytokine. Rosiglitazone did not revert the reduced glutathione peroxidase activity but enhanced significantly (P<0.01) the decreased xanthine oxidase and superoxide dismutase activities in gastric mucosa of ischemic rats. In conclusion, rosiglitazone reduces the damage in ischemia-reperfusion gastric injury and alleviates the inflammatory response and the oxidative events.
Pharmacoepidemiol Drug Saf. 2004 Nov 15; [Epub ahead of print]
Impact of regulatory labeling for troglitazone and rosiglitazone
on hepatic enzyme monitoring compliance: findings from the state of Ohio
medicaid program.
Cluxton RJ Jr, Li Z, Heaton PC, Weiss SR, Zuckerman IH, Moomaw
CJ, Hsu VD, Rodriguez EM.
College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
PURPOSE: Troglitazone, the first drug of the thiazolidinediones class for type II diabetes, was first marketed in March 1997 and was removed from the U.S. market 36 months later after 90 cases of liver failure were reported despite multiple warnings containing liver enzyme monitoring recommendations. Rosiglitazone has been available since June 1999 and is still on the market. The purpose of this study was to evaluate the impact of labeled hepatic enzyme monitoring for troglitazone and rosiglitazone. METHODS: Drug cohorts were assembled, using population-based fee-for-service Medicaid claims, for patients between 18 and 65 years of age who had received at least one troglitazone (n = 7226) or rosiglitazone (n = 1480) prescription between 1 April, 1997, and 21 March, 2000. The outcome of interest was the percentage of patients, based on their first treatment episode, who had baseline and post-baseline liver enzyme testing. RESULTS: Overall baseline testing was under 9% before regulatory actions, increased to 14% after the first two 'Dear Doctor' letters issued by the FDA in October and December 1997, and peaked to about 26% afterwards. Coincident with the marketing of rosiglitazone and the fourth 'Dear Doctor' letter issued in June 1999, baseline testing dropped to 18%. Baseline testing increased 2.5-fold (race-sex-age adjusted) after regulatory action. Achieving 50% post-baseline testing took approximately 6 months for both drugs. CONCLUSION: Regulatory actions had only modest effects on the incidence of liver monitoring. More effective and timely communication strategies, health provider prescribing interventions and modification of health provider behaviors to enhance compliance with recommended risk management measures need to be identified, evaluated and implemented. Copyright (c) 2004 John Wiley & Sons, Ltd.
Drugs Today (Barc). 2004 Jul;40(7):633-43.
Rosiglitazone maleate/metformin hydrochloride: a new formulation
therapy for type 2 diabetes.
Cox SL.
Medical Information Department, Prous Science, 08025 Barcelona, Spain.
support@prous.com
Many patients with type 2 diabetes require treatment with more than one antihyperglycemic drug to achieve optimal glycemic control. The thiazolidinediones are a novel class of oral antihyperglycemic drugs that improve glycemic control primarily by increasing peripheral insulin resistance and sensitizing the skeletal muscle, liver and adipose tissue to the actions of insulin, in addition to improving beta-cell function. One of the many features of the thiazolidinedione class of drugs is their synergism with other antihyperglycemic drugs that have a different mechanism of action. The combination of metformin hydrochloride, a biguanide that enhances glucose uptake in peripheral tissues and reduces hepatic gluconeogenesis, with rosiglitazone maleate, one of the newly available members of the thiazolidinedione family, offers a rational therapeutic approach to the treatment of type 2 diabetes. In patients whose type 2 diabetes is inadequately controlled with metformin monotherapy, the addition of rosiglitazone significantly improves glycemic control, insulin sensitivity and beta-cell function, compared with either drug alone. In addition, this combination therapy has beneficial effects on other cardiovascular risk factors. Rosiglitazone maleate/metformin hydrochloride combination therapy is well tolerated in patients with type 2 diabetes and has a favorable safety profile. This review summarizes the available evidence on the clinical efficacy and safety of rosiglitazone maleate and metformin hydrochloride combination therapy in patients with type 2 diabetes.
Diabetes Care. 2004 Nov;27(11):2654-60.
Preventative effects of rosiglitazone on restenosis after coronary
stent implantation in patients with type 2 diabetes.
Choi D, Kim SK, Choi SH, Ko YG, Ahn CW, Jang Y, Lim SK, Lee HC,
Cha BS.
Department of Internal Medicine, Yonsei University College of Medicine,
134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-749, Korea. bscha@yumc.yonsei.ac.kr.
OBJECTIVE: Despite the popularity of coronary stenting in coronary artery disease (CAD), restenosis remains a challenging clinical problem. This study evaluated the efficacy of rosiglitazone for preventing in-stent restenosis in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We conducted a prospective, randomized, case-controlled trial involving 95 diabetic patients with CAD who were randomly assigned to either the control or rosiglitazone group (48 and 47 patients, respectively). Quantitative coronary angiography (QCA) was performed at study entry and again at 6-month follow-up. The primary end point was the restenosis rate, which was determined by QCA. RESULTS: Eighty-three patients (45 patients with 55 lesions in the control group and 38 patients with 51 lesions in the rosiglitazone group) completed follow-up angiography. Rosiglitazone treatment for 6 months reduced fasting insulin concentration. The high-sensitivity C-reactive protein concentration was significantly reduced in the rosiglitazone group compared with that in the control group (from 2.92 +/- 1.98 to 0.62 +/- 0.44 mg/l, P < 0.001 vs. from 2.01 +/- 1.33 to 1.79 +/- 1.22 mg/l, P = NS). However, the baseline and follow-up glucose and lipid concentrations were not different between two groups. The rate of in-stent restenosis was significantly reduced in the rosiglitazone group compared with the control group (for stent lesions: 17.6 vs. 38.2%, P = 0.030). The rosiglitazone group had a significantly lower degree of diameter stenosis (23.0 +/- 23.4% vs. 40.9 +/- 31.9%, P = 0.004) compared with the control group. CONCLUSIONS: We demonstrated that treatment with rosiglitazone significantly reduces in-stent restenosis in diabetic patients with CAD who underwent coronary stent implantation.
Diabetes Care. 2004 Nov;27(11):2585-9.
Effect of rosiglitazone versus insulin on the pancreatic beta-cell
function of subjects with type 2 diabetes.
Ovalle F, Bell DS.
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism,
The University of Alabama at Birmingham School of Medicine, Birmingham,
Alabama, USA.
OBJECTIVE: In a previous study, we found observational evidence of improvement in beta-cell function when rosiglitazone was added to a failing oral antihyperglycemic regimen consisting of sulfonylureas and metformin. To confirm our previous observations, we designed and performed a prospective, randomized, and controlled study. RESEARCH DESIGN AND METHODS: A total of 17 subjects with type 2 diabetes, inadequately controlled on a maximized oral antihyperglycemic double regimen of glimepiride and metformin, were randomized to the addition of rosiglitazone or insulin to their treatment regimens for a period of 6 months. At baseline and at 6 months, the following were performed: measurement of fasting plasma glucose, fasting proinsulin, and insulin levels; frequently sampled intravenous glucose tolerance test; and glucagon stimulation test for C-peptide. RESULTS: Nine subjects were randomized to the addition of 8 mg rosiglitazone, and eight subjects were randomized to the addition of one injection of insulin (premixed 70/30) before their evening meal. The treatment groups were well matched for age, duration of diabetes, and BMI. Most important, the HbA(1c) was well matched between groups before treatment (8.7 +/- 0.3 and 9.0 +/- 0.3%; NS) and at the end of the 6 months (7.8 +/- 0.5 and 7.8 +/- 0.3%; NS). After 6 months, at the end of the study, there was a significant improvement in acute insulin response to glucose in the rosiglitazone group (+15.3 microIU x ml(-1) x 10 min(-1); P < 0.001) that led to an increase in the disposition index from 0.18 at baseline to 4.18 at 6 months (P = 0.02). Furthermore, at the end of the study, the proinsulin-to-insulin ratio had decreased in the rosiglitazone group by 36% (P = 0.03) but did not change significantly in the insulin treatment group. CONCLUSIONS: Rosiglitazone, but not insulin, induced a recovery of pancreatic beta-cell function, as evidenced by the restoration of the first-phase insulin response to glucose, improvement in the disposition index, and a decrease in the proinsulin-to-insulin ratio in subjects with type 2 diabetes in whom oral antihyperglycemic therapy failed. This improvement was independent of the correction of glucotoxicity.
J Clin Endocrinol Metab. 2004 Oct 13; [Epub ahead of print]
Effects of Rosiglitazone in Obese Women with Polycystic Ovary
Syndrome and Severe Insulin Resistance.
Sepilian V, Nagamani M.
Department of Obstetrics & Gynecology, Division of Reproductive Endocrinology
& Infertility, University of Texas Medical Branch, Galveston, Texas.
Our objective was to evaluate the effectiveness of the insulin-sensitizing agent rosiglitazone in obese women with polycystic ovary syndrome (PCOS) and severe insulin resistance. Twelve obese women with PCOS were recruited. All were hirsute and anovulatory with acanthosis nigricans indicating severe insulin resistance. All women were treated with 4 mg of rosiglitazone daily for 6 months. A standard 75 g oral glucose tolerance test (OGTT) with insulin levels was performed before and after the women were treated with rosiglitazone. Glucose and insulin area under the curve (AUC) were calculated. Serum levels of total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), LH (LH), and 17 hydroxy progesterone (17 OH-P) were also measured before and after treatment. The body mass index (BMI) was determined before and after treatment. There was a highly significant (r = 0.881, P < 0.0001) positive correlation between insulin response during OGTT and basal total testosterone levels. After treatment with rosiglitazone, there were significant decreases in fasting insulin levels (46.0 +/- 6.5 vs. 16.9 +/- 2.0 microU/mL; P < 0.001), insulin AUC (749.3 +/- 136.3 vs. 225.0 +/- 15.7 microU/mL; P = 0.003), fasting glucose levels (90.8 +/- 3.0 vs. 81.8 +/- 1.9 mg/dL; P = 0.003), and glucose AUC (437.9 +/- 25.0 vs. 322.5 +/- 14.7; P < 0.001). Both total testosterone (96.3 +/- 17.3 vs. 56.1 +/- 5.8 ng/dL; P = 0.01) and free testosterone (5.8 +/- 0.6 vs. 3.4 +/- 0.5 pg/mL; P < 0.001) decreased significantly after treatment, even though there was no significant change in LH levels. Levels of sex hormone-binding globulin increased significantly (18.3 +/- 3.4 vs. 25.8 +/- 6.6 nmol/L; P = 0.009) after treatment, and DHEA-S levels decreased significantly (P = 0.04). There was no significant change in BMI (40.4 +/- 2.4 vs. 41.1 +/- 2.7 kg/m(2)). Eleven of the women reverted to regular ovulatory cycles during the treatment period. We conclude that 1) rosiglitazone therapy improves insulin resistance and glucose tolerance in obese women with PCOS; 2) rosiglitazone decreases ovarian androgen production, which appears to be independent of any changes in LH levels; 3) hyperinsulinemia appears to play a key role in the overproduction of ovarian androgens in these women as attenuation of insulin levels is associated with decreased testosterone levels; and 4) short-term rosiglitazone therapy helps restore spontaneous ovulation.
Fertil Steril. 2004 Oct;82(4):893-902.
Effects of metformin and rosiglitazone, alone and in combination,
in nonobese women with polycystic ovary syndrome and normal indices of
insulin sensitivity.
Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler
JE.
Department of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec,
Canada.
OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.
Diabetes Metab Res Rev. 2004 Aug 23;
Rosiglitazone combined with insulin preserves islet beta cell
function in adult-onset latent autoimmune diabetes (LADA).
Zhou Z, Li X, Huang G, Peng J, Yang L, Yan X, Wang J.
Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central
South University, Changsha, China.
BACKGROUND: LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic beta cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. METHODS: LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet beta cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet beta cell function was evaluated by PCP and DeltaCP(DeltaCP = PCP-FCP). RESULTS: All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for DeltaCP and PCP levels in both groups. (2) PCP and DeltaCP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and DeltaCP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and DeltaCP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and DeltaCP levels in insulin + RSG group patients still stayed steady, while PCP and DeltaCP levels decreased more in the insulin alone group. CONCLUSIONS: This pilot study suggests that rosiglitazone combined with insulin may preserve islet beta cell function in LADA patients. Copyright 2004 John Wiley & Sons, Ltd.
Endocrinology. 2004 Dec;145(12):5665-70. Epub 2004 Sep 16.
Rosiglitazone enhances glucose tolerance by mechanisms other than
reduction of fatty acid accumulation within skeletal muscle.
Lessard SJ, Lo Giudice SL, Lau W, Reid JJ, Turner N, Febbraio
MA, Hawley JA, Watt MJ.
Exercise Metabolism Group, RMIT University School of Medical Sciences,
Bundoora, Victoria, Australia.
We hypothesized that improved glucose tolerance with rosiglitazone treatment would coincide with decreased levels of i.m. triacylglycerol (IMTG), diacylglycerol, and ceramide. Obese Zucker rats were randomly divided into two experimental groups: control (n = 9) and rosiglitazone (n = 9), with lean Zucker rats (n = 9) acting as a control group for obese controls. Rats received either vehicle or 3 mg/kg rosiglitazone for 6 wk. Glucose tolerance was impaired (P < 0.01) in obese compared with lean rats, but was normalized after rosiglitazone treatment. IMTG content was higher in obese compared with lean rats (70.5 +/- 5.1 vs. 27.5 +/- 2.0 micromol/g dry mass; P < 0.05) and increased an additional 30% (P < 0.05) with rosiglitazone treatment. Intramuscular fatty acid composition shifted toward a higher proportion of monounsaturates (P < 0.05) in obese rosiglitazone-treated rats due to an increase in palmitoleate (16:1; P < 0.05). Rosiglitazone treatment increased (P < 0.05) skeletal muscle diacylglycerol and ceramide levels by 65% and 100%, respectively, compared with obese rats, but elevated muscle diacylglycerol was not associated with changes in the total or membrane contents of the diacylglycerol-sensitive protein kinase C isoforms theta;, delta, alpha, and beta. In summary, we observed a disassociation among skeletal muscle IMTG, diacylglycerol and ceramide content, and glucose tolerance with rosiglitazone treatment in obese Zucker rats. Our data suggest, therefore, that rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle.
