Administration Of Thiazolidinediones Research Articles

Enhanced Outcomes in Type 2 Diabetes Patients with Acute Kidney Disease Through Thiazolidinedione

Abstract Context Patients with diabetes are prone to acute kidney injury with the potential transition to chronic kidney disease. Few studies have investigated the role of thiazolidinedione (TZD) in these patients under acute kidney disease (AKD) phase. Objective We sought to examine whether using TZD during AKD could reduce the risk of future major adverse outcomes. Design and Methods We employed the TriNetX platform before September 30, 2022, for TZD administration to patients with type 2 diabetes mellitus (T2DM) within 90 days of an AKD diagnosis. Clinical endpoints include the risk of all-cause mortality, major adverse cardiovascular events (MACE), and major adverse kidney events (MAKE). Hazard ratios (HRs) and 95% confidence intervals were calculated with 1:1 ratio propensity score matching (PSM). Results Among the cohort of 263,101 patients with AKD and T2DM, we identified 2,723 individuals (1.03%) who were TZD users during the AKD period. After PSM, the final cohort of TZD users included 2,555 individuals, with 53.82% being male and a mean age of 64.0 ± 13.5 years. Over a median follow-up period of 1.5 years, the TZD group exhibited a lower risk across various outcomes, with hazard ratios (HR) of 0.68 (95% CI, 0.57-0.81) for all-cause mortality, 0.68 (95% CI, 0.58-0.80) for MACE, and 0.75 (95% CI, 0.66-0.86) for MAKE. Conclusion TZD demonstrated a notable reduction in mortality, cardiovascular events, and kidney-related adverse events among T2DM patients with AKD. These findings suggest a potential benefit of TZD usage for managing cardiovascular events in T2DM patients with AKD.

Adipocyte-Cancer Cell Interactions in the Bone Microenvironment.

When compared to adipocytes in other anatomical sites, the interaction of bone marrow resident adipocytes with the other cells in their microenvironment is less well understood. Bone marrow adipocytes originate from a resident, self-renewing population of multipotent bone marrow stromal cells which can also give rise to other lineages such as osteoblasts. The differentiation fate of these mesenchymal progenitors can be influenced to favour adipogenesis by several factors, including the administration of thiazolidinediones and increased age. Experimental data suggests that increases in bone marrow adipose tissue volume may make bone both more attractive to metastasis and conducive to cancer cell growth. Bone marrow adipocytes are known to secrete a variety of lipids, cytokines and bioactive signaling molecules known as adipokines, which have been implicated as mediators of the interaction between adipocytes and cancer cells. Recent studies have provided new insight into the impact of bone marrow adipose tissue volume expansion in regard to supporting and exacerbating the effects of bone metastasis from solid tumors, focusing on prostate, breast and lung cancer and blood cancers, focusing on multiple myeloma. In this mini-review, recent research developments pertaining to the role of factors which increase bone marrow adipose tissue volume, as well as the role of adipocyte secreted factors, in the progression of bone metastatic prostate and breast cancer are assessed. In particular, recent findings regarding the complex cross-talk between adipocytes and metastatic cells of both lung and prostate cancer are highlighted.

Molecular toxicological alterations in the mouse hearts induced by sub-chronic thiazolidinedione drugs administration.

Thiazolidinediones are well-known anti-diabetic drugs. However, they are not widely used due to their cardiotoxic effects. Therefore, in this study, we aimed to determine the molecular toxicological alterations induced in the mouse hearts after thiazolidinedione administration. Balb/c mice received doses clinically equivalent to those given to humans of the most commonly used thiazolidinediones, pioglitazone, and rosiglitazone for 30days. After that, RNA samples were isolated from the hearts. The mRNA expression of cytochrome (cyp) p450 genes that synthesize the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE) in addition to 92 cardiotoxicity biomarker genes were analyzed using quantitative polymerase chain reaction array technique. The analysis demonstrated that thiazolidinediones caused a significant upregulation (p<0.5) of the mRNA expression of cyp1a1, cyp4a12, itpr1, ccl7, ccr1, and b2m genes. In addition, thiazolidinediones caused a significant (p<0.05) downregulation of the mRNA expression of adra2a, bsn, col15a1, fosl1, Il6, bpifa1, plau, and reg3b genes. The most affected gene was itpr1 gene, which was upregulated by pioglitazone and rosiglitazone by sevenfold and 3.5-fold, respectively. In addition, pioglitazone caused significant upregulation of (p<0.05) hamp, ppbp, psma2, sik1, timp1, and ucp1 genes, which were not affected significantly (p>0.05) by rosiglitazone administration. In conclusion, this study showed that thiazolidinediones induce toxicological molecular alterations in the mouse hearts, such as the induction of cyp450s that synthesize 20-HETE, chemokine activation, inflammatory responses, blood clotting, and oxidative stress. These findings may help us understand the mechanism of cardiotoxicity involved in thiazolidinedione administration.

Association between colorectal cancer and thiazolidinediones administration in a case-control study.

Objectives: This study was designed to assess whether there was an association between colorectal cancer and thiazolidinediones use.Methods: A population-based case-control study was performed using the database of the Taiwan National Health Insurance Program. The case group consisted of 20218 type 2 diabetic subjects aged 20 to 84 years with newly diagnosed colorectal cancer between 2000 and 2011. The date of a subject being diagnosed with colorectal cancer was defined as the index date. The control group consisted of 20218 randomly selected type 2 diabetic subjects aged 20 to 84 years without colorectal cancer between 2000 and 2011. A subject who had at least a prescription of thiazolidinediones before the index date was defined as “ever used”. A subject who did not have a prescription of thiazolidinediones before the index date was defined as “never used”. The odds ratio (OR) and 95% confidence interval (CI) was used to estimate the association between colorectal cancer and thiazolidinediones use by the multivariable logistic regression model.Results: After adjustment for potential confounders, the odds of thiazolidinediones use in cases with colorectal cancer were lower than the odds of thiazolidinediones use in subjects without colorectal cancer (adjusted OR 0.94, 95% CI 0.89-0.99).Conclusions: The odds of thiazolidinediones use in cases with colorectal cancer were lower than subjects without colorectal cancer. A prospective study is required to test whether thiazolidinediones use has a protective effect against colorectal cancer.

Possible Protective Effects of Thiazolidinediones Antidiabetic Drugs in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and it is considered the fourth most common cause of life-threatening cancers. Diabetes mellitus, especially type 2 diabetes, is an independent risk factor for CRC, due to shared risk factors like physical inactivity and obesity. Thiazolidinediones (TZDs) are among the most common medications for type 2 diabetes mellitus. Recent investigations have suggested a correlation between TZD usage (in a time-dependent manner) and reduced risk of CRC such that a longer period of TZDs treatment can lead to higher protection against CRC. TZDs have antitumor effects in a wide variety of in vitro and in vivo cancer models through different mechanisms such as the impacts on cell cycle, apoptosis, cell differentiation, and angiogenesis. These effects can be mediated via both peroxisome proliferator-activated receptors γ (PPARγ)-dependent and PPARγ-independent pathways. Due to the protective effects of TZDs in cancer prevention and treatment, they can be considered potent adjuvants in cancer treatment. In the current review, we discuss the effects of TZDs on prevention and treatment of cancers, with special emphasis on CRC and the association of TZD administration with metabolic regulation of T cells in defense against tumor cells.

INFLUENCE OF FLUCONAZOLE ON HYPOGLYCAEMIC ACTIVITY OF ORAL ANTIDIABETIC AGENTS IN HEALTHY RATS

The influence of fluconazole pre-treatment on the hypoglycaemic effect of pioglitazone (10 mg/kg, p.o) and rosiglitazone (720 μg/kg, p.o) was studied. This study was conducted on healthy albino rats of either sex, randomly distributed into four different groups. They were pretreated with fluconazole (18 mg/kg and 36 mg/kg, p.o for 7 days) in 2% w/V gum acacia suspension for seven days. On eighth day, rosiglitazone and pioglitazone were administered to respective groups one hour after fluconazole treatment. Blood samples were collected by retro orbital plexus under light ether anesthesia at time intervals of 0, 1, 2, 4, 8, 12, 18 and 24 hours. The hypoglycaemic activity of thiazolidinediones was studied and it indicated that fluconazole pretreatment has enhanced the hypoglycaemic effect of rosiglitazone and pioglitazone significantly. Hence, it is suggested that during the concomitant usage of fluconazole and thiazolidinediones, therapeutic drug monitoring is essential and may also require readjusting the dose and frequency of administration of thiazolidinediones.

Characterization of alendronic- and undecylenic acid coated magnetic nanoparticles for the targeted delivery of rosiglitazone to subcutaneous adipose tissue

Obesity is a state of positive energy balance where excess white adipose tissue accumulates to the detriment of metabolic health. Improving adipocyte function with systemic administration of thiazolidinediones (TZDs) improves metabolic outcomes in obesity, however TZD use is limited clinically due to undesirable side effects. Here we evaluate magnetic nanoparticles (MNPs) as a tool to target rosiglitazone (Rosi) specifically to adipose tissue. Results show Rosi can be adsorbed to MNPs (Rosi-MNPs) with hydrophobic coatings for which we present binding and release kinetics. Rosi adsorbed to MNPs retained the ability to induce PPARγ target gene expression in cells. Biodistribution analysis of radiolabeled Rosi-MNPs revealed a fat-implanted magnet significantly enhanced localization of Rosi to the targeted adipose tissue when administered by subcutaneous injection to obese mice. We propose MNPs for targeted delivery of anti-diabetic agents to superficially located subcutaneous adipose tissue.

Thiazolidinediones improve flow-mediated dilation: a meta-analysis of randomized clinical trials.

Thiazolidinediones administration is assumed to be related with an improvement of endothelial dysfunction (ED); nevertheless, previous studies have been inconsistent. For this reason, the present meta-analysis was directed to estimate if thiazolidinediones were related to endothelial dysfunction improvement by using flow-mediated dilation (FMD) measurement. Literature search of the PubMed, the Cochrane Library, the Web of Science, and the Scopus databases was performed covering the period until July 01, 2015, for randomized clinical trials that investigated an influence of thiazolidinediones on FMD. For the calculation of the pooled overall effect, a random effect model was used. Meta-regression and subgroup analyses were performed to evaluate the impact of study characteristics on the effect of thiazolidinediones administration on FMD. This meta-analysis included 16 studies with 812 subjects. The obtained results demonstrated an improvement of endothelial dysfunction measured with FMD (16 studies, 812 subjects; WMD: 2.4 %, 95 % CI = 1.1 to 3.69 %; p = 0.0003). The significant heterogeneity was noted (I (2) = 95 %, p < 0.00001). Subgroup analysis demonstrated that pioglitazone and rosiglitazone were able to improve FMD. Also, thiazolidinediones improved FMD if treatment was longer than 12 weeks and if patients were younger than 65 years. Additionally, a lipid profile was found to influence thiazolidinediones effect on FMD. The results of this meta-analysis demonstrated that thiazolidinediones were able to improve FMD, which in clinical terms can be further translated to the improvement of an impaired endothelial function. Nevertheless, the link between FMD and its predictive clinical relevance still requires further clarification.

Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.

Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN.

Lipocalin 2 Regulates Brown Fat Activation via a Nonadrenergic Activation Mechanism

In this study, we report that lipocalin 2 (Lcn2), a recently characterized adipokine/cytokine, is a novel regulator of brown adipose tissue (BAT) activation by modulating the adrenergic independent p38 MAPK-PGC-1α-UCP1 pathway. Global Lcn2 knock-out (Lcn2(-/-)) mice have defective BAT thermogenic activation caused by cold stimulation and decreased BAT activity under high fat diet-induced obesity. Nevertheless, Lcn2(-/-) mice maintain normal sympathetic nervous system activation as evidenced by normal catecholamine release and lipolytic activity in response to cold stimulation. Further studies showed that Lcn2 deficiency impairs peroxisomal and mitochondrial oxidation of lipids and attenuates cold-induced Pgc1a and Ucp1 expression and p38 MAPK phosphorylation in BAT. Moreover, in vitro studies showed that Lcn2 deficiency reduces the thermogenic activity of brown adipocytes. Lcn2(-/-) differentiated brown adipocytes have significantly decreased expression levels of brown fat markers, decreased p38 MAPK phosphorylation, and decreased mitochondrial oxidation capacity. However, Lcn2(-/-) brown adipocytes have normal norepinephrine-stimulated p38 MAPK and hormone-sensitive lipase phosphorylation and Pgc1a and Ucp1 expression, suggesting an intact β-adrenergic signaling activation. More intriguingly, recombinant Lcn2 was able to significantly stimulate p38 MAPK phosphorylation in brown adipocytes. Activating peroxisome proliferator-activated receptor γ, a downstream effector of PGC-1α, by thiazolidinedione administration fully reverses the BAT function of Lcn2(-/-) mice. Our findings provide evidence for the novel role Lcn2 plays in oxidative metabolism and BAT activation via an adrenergic independent mechanism.

Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression

Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n=40) were administered 0, 2.0, or 4.0mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21d before expected parturition until parturition. Plasma samples collected daily from 22d before expected parturition through 21d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d −14, −3, −1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d −14 but cows receiving 2.0mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5±0.1ng/mL for 0, 2.0, and 4.0mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0±0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose)+log(insulin)+log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of PPARγ mRNA (11.0, 13.3, and 12.8±1.9). Administration of TZD had a quadratic effect on gene expression of leptin (16.2, 10.7, and 17.4±1.6) and no effect on LPL expression, and expression of FAS was lower for TZD-treated cows than for controls (8.2, 4.2, and 6.1±1.8, respectively). Results imply altered expression and plasma concentrations of leptin, increased plasma TNFα concentrations, and increased expression of PPARγ in adipose tissue as potential mechanisms for the effects of TZD administration on transition dairy cattle.

Thiazolidinediones and bone fractures.

Thiazolidinediones and bone fractures.

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARgamma expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARgamma-expressing and PPARgamma-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARgamma-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARgamma deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOgamma) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARgamma-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression. These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment.

Endothelial and Vascular Muscle PPARγ in Arterial Pressure Regulation

Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcription factor belonging to the retinoic acid receptor and thyroid hormone receptor family of nuclear receptors. Classically, these transcription factors regulate expression of target genes by binding to PPAR response elements (PPRE) in the 5′ flanking region of target genes as a heterodimer with retinoid X receptors (RXR). PPARγ first gained prominence when it was discovered that it was expressed specifically in adipocytes and its expression induced their differentiation.1 It has now become clear that although expression of PPARγ may be the highest in adipose tissue, it is expressed in many, if not all, cell types and tissues. Among the many roles ascribed to PPARγ are adipogenesis, insulin action, glucose homeostasis, and lipid metabolism. Other tissue-specific functions for PPARγ in liver, muscle, heart, macrophages, bone, and, more recently, the vasculature have been proposed, ascribed mainly from the analysis of cultured cells and a large and rapidly expanding set of tissue-specific PPARγ knockouts. The standing of PPARγ as a clinically important molecule emerged when it was discovered that PPARγ is the molecular target of the thiazolidinediones (TZD) class of antidiabetic agents.2 Although of understandable interest to diabetes researchers and clinicians, interest among “hypertensionists” increased when it became clear that TZD, in addition to improving glycemic control, tended to lower blood pressure. Many of these studies involved high-risk patients with diabetes or metabolic syndrome and an average decrease of ≈5 mmHg systolic blood pressure and 3 mmHg (diastolic blood pressure [DBP]) was typically reported. According to guidelines from the American Heart Association, 65 million Americans have hypertension and millions of others have prehypertension. Therefore, an analysis of any drug effective at lowering arterial pressure or physiological pathway targeted by that drug involved in regulating arterial pressure deserves serious attention. In this …

Activation of peroxisome proliferator-activated receptor γ in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPARgamma) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARgamma actions, we postulated that brain PPARgamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARgamma ligands or vehicle. We found that ICV rosiglitazone (0.5-50 microg) or 15d-PGJ(2) (50-200 microg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 microg) and 15d-PGJ(2) (200 microg) had no effect. PPARgamma agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARgamma antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ(2). To evaluate the effects of PPARgamma agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARgamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

Depot specificities of PPARg ligand actions on lipid and glucose metabolism and their implication in PPARg-mediated body fat redistribution

PPARγ is a ligand-activated nuclear receptor mainly expressed in white and brown adipose tissues where it controls adipocyte differentiation, metabolism, adipokine secretion and survival. PPARγ is specifically and potently activated by thiazolidinediones, a class of synthetic agonists that, owing to their beneficial effect on whole-body insulin sensitivity, are widely used in the treatment of insulin-resistant states, such as Type 2 diabetes and metabolic syndrome. In association with the improvement in whole-body glucose homeostasis, PPARγ activation by thiazolidinediones administration in both humans and rodents results in white and brown adipose tissue remodeling associated with lipid redistribution from visceral to subcutaneous fat depots. Directing fat away from visceral to subcutaneous fat depots may constitute one mechanism whereby PPARγ activation prevents the deleterious effects of visceral fat accumulation on the development of metabolic syndrome and the progression to cardiovascular disease. This review, addresses the mechanisms underlying the depot-specific actions of PPARγ ligand therapy on subcutaneous and visceral fat morphology, cellularity and metabolism that are likely involved in the fat redistribution induced in vivo by pharmacological PPARγ activation.

Effects of prepartum 2,4-thiazolidinedione on metabolism and performance in transition dairy cows

Thiazolidinediones (TZD) are potent synthetic ligands for peroxisome proliferator-activated receptor-γ that have been shown previously to reduce plasma nonesterified fatty acids and increase peripartal dry matter intake (DMI) in dairy cows. Data from Holstein cows (n = 36) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism, milk production, and ovarian activity. Cows were administered 0, 2.0, or 4.0mg of TZD/kg of BW by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples were collected daily from 22 d before expected parturition through 21 d postpartum and twice weekly from wk 4 through 9 postpartum. In response to increasing TZD dosage, plasma nonesterified fatty acid concentrations decreased linearly during the postpartum period (d 0 to +21: 348, 331, 268±31μEq/L, respectively). Plasma concentrations of glucose were highest in cows administered 4.0mg of TZD/kg of BW during the peripartum and postpartum periods (d −7 to +7: 57.9, 57.8, 61.1±0.8 mg/dL and d 0 to +21: 51.6, 49.3, 54.7±1.1 mg/dL, respectively). Plasma concentrations of β-hydroxybutyrate were increased during the peripartum period by TZD administration (9.6, 9.9, 10.2±0.3 mg/dL) but were not affected during the postpartum period. Plasma insulin was not affected by treatment during any time period. Postpartum liver triglyceride content was decreased linearly (11.0, 10.4, 4.2±1.6%) and glycogen content was increased linearly (2.16, 2.38, 2.79±0.19%) by prepartum TZD administration. Prepartum TZD administration linearly increased DMI during the peripartum period (d −7 to +7: 16.1, 17.2, 17.3±0.5 kg/d). Cows administered TZD prepartum maintained higher postpartum body condition scores than control cows (wk 1 through 9: 2.77, 2.89, 3.02±0.05). There was no effect of prepartum TZD on milk yield; however, yields of 3.5% fat-corrected milk (52.2, 54.6, 48.0±1.6 kg/d) and most other milk components were decreased in cows that received 4.0mg of TZD/kg of BW prepartum. Prepartum TZD administration linearly decreased the number of days to first ovulation (29.3, 28.3, 19.0±3.6 d). These results suggest that prepartum administration of TZD improves metabolic health and DMI of periparturient dairy cows and may decrease reliance on body fat reserves during early lactation.

The effect of thiazolidinediones on bone mineral density in Chinese older patients with type 2 diabetes

The effect of thiazolidinediones (TZDs) on bone mineral density (BMD) and bone metabolism in patients with type 2 diabetes is still in debate. Accumulating evidence has emerged that long-term administration of TZDs may increase the occurrence of osteoporosis, at least in postmenopausal women. Because little clinical data has been reported on Chinese people, a retrospective study was performed. One-hundred ninety-eight Chinese people, all from our inpatients, were selected for a 24-28 month review (26 +/- 0.5 m). Four groups divided according to gender and TZD use were designated fTZD, mTZD, f and m. Changes of subjects' BMD and bone metabolism markers were noted and analyzed. Compared with group f, bone loss from fTZD in this over 24-month review was more significant in lumbar spine (L1-L4) (0.1 +/- 0.15 vs. 0.06 +/- 0.11) and right hip (0.09 +/- 0.15 vs. 0.05 +/- 0.14) (g/cm(3)) (P < 0.05). However, the opposite result was found in male patients with less bone loss in group mTZD. Two bone metabolism markers, including beta C-terminal telopeptide of type I collagen (beta-CTX) and osteocalcin (OC), in this study did not prove valuable in revealing changes among groups. We concluded that long-term TZD use may increase the risk of bone loss in Chinese postmenopausal patients with type 2 diabetes, which may provide caution on drug treatment in clinical practice. Whether TZD can protect male patients against BMD loss or not awaits further research.

Peroxisome proliferator‐activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance. To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels. A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks. Patients received either pioglitazone 30 mg (N = 10) or placebo (N = 10) once daily for 12 weeks. Adiponectin levels almost doubled during pioglitazone treatment (P = 0.0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels (P = 0.02) and lipid oxidation (P = 0.02). Basal glucose oxidation rate (P = 0.004) and insulin sensitivity (P = 0.03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal (R = 0.69, P = 0.04). The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.

Circulating Adiponectin Levels and Expression of Adiponectin Receptors in Relation to Lung Cancer: Two Case-Control Studies

Background: Decreased circulating levels of adiponectin, an adipocyte-secreted hormone and endogenous insulin sensitizer, have been associated with several obesity-related malignancies. Thiazolidinedione administration, which increases adiponectin levels, decreases risk for lung cancer. Whether circulating adiponectin levels are associated with lung cancer and/or whether adiponectin receptors are expressed in lung cancer remains unknown. Methods: We conducted a case-control study of 85 patients with incidental, histologically confirmed lung cancer and 170 healthy controls matched by gender and age. In a separate study, archival lung specimens from 134 cancerous and 8 noncancerous tissues were examined for relative expression of adiponectin receptors AdipoR1 and AdipoR2 using immunohistochemistry. Results: Tobacco smoking, heavy alcohol intake and education were all associated with lung cancer risk, whereas serum adiponectin levels were not significantly different between cases and controls (multiple logistic regression, odds ratio per SD of adiponectin among controls: 1.13, 95% confidence interval: 0.64–2.02). Adiponectin levels were significantly lower (odds ratio: 0.25, 95% confidence interval: 0.10–0.78) among patients with advanced compared to those with limited disease stage. Expression of adiponectin receptors was apparent only in the cancerous lung tissue (64.2% AdipoR1 and 61.9% AdipoR2 in cancerous vs. 0% among noncancerous tissue). Specifically, AdipoR1 was expressed in all disease types, but no difference was noted with disease stage, whereas AdipoR2 was mainly expressed in the non-small cell carcinomas and more prominently in the advanced disease stage (80%). Conclusions: Circulating adiponectin levels are not different in cases of this malignancy – which seems to be unrelated to obesity and insulin resistance – compared to their healthy controls, though hormonal levels were significantly lower in advanced versus limited lung cancer. Both adiponectin receptors were expressed in cancerous lung tissue, but not in normal control tissue and there was a differential expression by disease stage. These findings should be further explored, especially in the context of the recently reported protective effect of thiazolidinediones in diabetic patients with lung cancer.