Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
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PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

Arterial calcification is common in patients with type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and other chronic inflammatory disorders. Arterial calcification is associated with significant morbidity and increased early mortality. The molecular signature of vascular calcification in diabetes is strikingly similar to that of CKD. Low-grade arterial inflammation is common to both conditions, and increased levels of tumor necrosis factor-alpha (TNF-alpha) have been reported in both DM and CKD. Recently, we described a novel TNF-alpha regulated Msx2-Wnt osteogenic program that regulates arterial calcification in an animal model of type 2 DM. TNF-alpha induces the osteogenic bone morphogenetic protein-2 (BMP-2), Msx2, Wnt3a, and Wnt7a mRNAs and leads to increased aortic calcium accumulation. Treatment with the TNF-alpha neutralizing antibody infliximab abrogates aortic BMP-2-Msx2-Wnt3a and Wnt7a signaling and attenuates aortic calcium accumulation significantly. Mice with vascular TNF-alpha augmented by the SM22-TNF-alpha transgene upregulate the aortic Msx2-Wnt3a/Wnt7a axis. Furthermore, SM22-TNF-alphaTg;TOPGAL mice exhibit greater beta-galactosidase reporter staining versus TOPGAL siblings in the aorta and coronaries, which indicates enhanced mural Wnt signaling in response to TNF-alpha. Thus, inflammatory TNF-alpha signals promote aortic osteogenic Msx2-Wnt programs in type 2 DM, and arterial calcification in this model is a TNF-alpha-driven Wnt-opathy. Having established the role of TNF-alpha in diabetic vascular calcification, an unmet need exists to evaluate the role of TNF-alpha and Msx2-Wnt signals in CKD-related calcification models. If validated in these models, then these findings will have significant therapeutic applications.
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PMID:Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy. 1843 4

Recent evidence suggests that the risk of several types of fracture is increased in type 2 diabetes mellitus (T2DM). Thiazolidinediones (TZDs) are now widely used in the management of T2DM, and their use may increase in other diseases characterized by insulin resistance. The PPAR-gamma, the molecular target of the TZDs currently in clinical use, is expressed in skeletal tissue. Evidence from preclinical studies has demonstrated that activation of PPAR-gamma (i) inhibits bone formation by diverting mesenchymal stem cells from the osteogenic to the adipocytic lineage and (ii) may increase bone resorption by stimulating the development of osteoclasts. There is also potential for indirect adverse skeletal effects of PPAR-gamma activation by modulation of circulating levels of hormones and cytokines known to influence bone metabolism. Recent studies in humans have demonstrated that TZDs decrease markers of bone formation decrease bone mass, and increase fracture rates, at least in women. The implication of these findings is that fracture risk should be considered in patients with T2DM for whom TZD therapy is being considered, and appropriate therapy instigated to prevent fractures in individuals ascertained to be at high risk.
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PMID:Thiazolidinedione-induced skeletal fragility--mechanisms and implications. 1867 97

The insulin-sensitizing thiazolidinediones (commonly known as glitazones) are an important and widely prescribed class of antidiabetic agents. Glitazones exert their action through activation of proliferator-activated receptor gamma (PPAR-gamma) nuclear transcription factor and are effective drugs to achieve glycaemic control in patients with type 2 diabetes mellitus. Recent rapidly growing evidence suggests that glitazone use is associated with accelerated bone loss and an increased risk of fracture. This review aims to evaluate the current knowledge of adverse effects of glitazone therapy on the skeleton. Articles in English, Spanish, German and French published up until April 2009 are included. Results from preclinical studies have demonstrated that activation of PPAR-gamma inhibits bone formation by primarily diverting mesenchymal stem cells to the adipocytic rather than to the osteogenic lineage, and that glitazones may increase bone resorption by stimulating osteoclasts. Numerous studies in humans have demonstrated decreased bone turnover, accelerated bone loss and impaired bone mineral density both in healthy volunteers and in patients with type 2 diabetes. Furthermore, results from recent large, randomized controlled trials and from observational studies provided evidence for an increased fracture risk for glitazone users, mostly for women, but possibly also for men. As a consequence of these observations, clinicians should carefully assess the fracture risk in patients with type 2 diabetes before starting therapy with glitazones.
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PMID:Risk of fractures with glitazones: a critical review of the evidence to date. 1953 Jul 41

Diabetes mellitus is associated with bone loss. Patients with type 2 diabetes are frequently treated with oral antidiabetic drugs such as sulfonylureas, biguanides, and thiazolidinediones. Rosiglitazone treatment has been shown to increase adipogenesis in bone marrow and to induce bone loss. In this study we evaluated the effect of in vivo and in vitro treatment with metformin on bone marrow progenitor cells (BMPCs), as well as the involvement of AMPK pathway in its effects. The in vitro effect of coincubation with metformin and rosiglitazone on the adipogenic differentiation of BMPCs also was studied. In addition, we evaluated the effect of in vivo metformin treatment on bone regeneration in a model of parietal lesions in nondiabetic and streptozotocin-induced diabetic rats. We found that metformin administration both in vivo and in vitro caused an increase in alkaline phosphatase activity, type I collagen synthesis, osteocalcin expression, and extracellular calcium deposition of BMPCs. Moreover, metformin significantly activated AMPK in undifferentiated BMPCs. In vivo, metformin administration enhanced the expression of osteoblast-specific transcription factor Runx2/Cbfa1 and activation of AMPK in a time-dependent manner. Metformin treatment also stimulated bone lesion regeneration in control and diabetic rats. In vitro, metformin partially inhibited the adipogenic actions of rosiglitazone on BMPCs. In conclusion, our results indicate that metformin causes an osteogenic effect both in vivo and in vitro, possibly mediated by Runx2/Cbfa1 and AMPK activation, suggesting a possible action of metformin in a shift toward the osteoblastic differentiation of BMPCs.
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PMID:Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. 1959 6

The insulin-sensitizing thiazolidinediones are effective drugs to achieve glycemic control in patients with type 2 diabetes. Results from preclinical studies have demonstrated that activation of PPAR-gamma inhibits primarily bone formation by diverting mesenchymal stem cells to the adipocytic rather than to the osteogenic lineage. In humans studies demonstrated accelerated bone loss, impaired bone mineral density as well as an increased fracture risk for thiazolidinedione users, mostly for women. As a consequence of these observations, clinicians have to carefully assess the fracture risk in patients with type 2 diabetes before starting a therapy with thiazolidinediones.
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PMID:[Thiazolidinediones and skeletal health]. 1962 30

Type 2 diabetes mellitus (T2DM) is an independent risk factor for ossification of the posterior longitudinal ligament, but the mechanism is unclear. We isolated cells from rat cervical spine ligaments and studied the effects of high glucose on expression of osteoblast genes to provide insight into molecular mechanism. Using these cells, high glucose stimulated the synthesis of type I collagen and significantly potentiated expression of early osteoblast genes (Runx2; alkaline phosphatase, ALP; and osteopontin, OP) induced by bone morphogenetic protein-2 (BMP-2). Notably, these effects of high glucose were fully mimicked and augmented by H(2)O(2), although blocked by the reactive oxygen species inhibitor N-acetyl cysteine. Furthermore, exposure of these cells to high glucose significantly suppressed the phosphorylation of p38MAPK while enhancing the phosphorylation of protein kinase C (PKC) in the cells. Consistent with these observations, an inhibitor of p38 augmented the potentiation of high glucose on BMP-2-induced early osteogenic gene expression, whereas the PKC inhibitor repressed the effect of high glucose on type I collagen synthesis of the cells. In conclusion, high glucose, via production of reactive oxygen species, subsequent activation of PKC, and inhibition of p38, enhances type I collagen synthesis and expression of early osteogenesis genes induced by BMP-2 in rat spinal ligament cells. Hyperglycemia may play an important role in the onset or progression of ossification of the posterior longitudinal ligament by promoting the responsiveness of ligament cells to osteogenic differentiation.
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PMID:High glucose potentiates collagen synthesis and bone morphogenetic protein-2-induced early osteoblast gene expression in rat spinal ligament cells. 1991 65

Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.
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PMID:Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes. 2003 69

In patients with type 2 diabetes mellitus (DM) there is poorer quality osseointegration than in other patients, and the success of oral implants is less. The aim of the present study was to investigate the influence of local infiltration of insulin at the implant-bone interface after implantation in diabetic rats. We used GK rats (8-week-old Goto-Kakizaki Wistar rats, n=20) in a newly established model of type 2 DM, and Sprague-Dawley rats were used as controls (n=10). GK rats were divided into two groups: those with DM alone and those with DM given insulin (INS) (n=10 in each group). The INS group was given controlled-release insulin at the implant-bone interface. Rats were killed at 2 and 6 weeks after implantation. We evaluated bone-implant contact and bony volume in all rats. Implant-bone contact, osteoid and osteogenic volume, and the amount of newly formed bone in the DM group were significantly less than in the control (p<0.05) and INS (p<0.01) groups. Implant-bone contact in the INS group was less than that in the control group, but the amount of newly formed bone was greater. In conclusion, we suggest that although the implant-bone contact in the INS group did not reach the control level, direct infiltration of insulin could improve implant-bone contact. Local infiltration of insulin at the implant-bone interface may have important clinical implications by naturally improving the success of oral implantation in diabetic rats.
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PMID:Effects of local infiltration of insulin around titanium implants in diabetic rats. 2040 Feb 13

Metformin is an oral anti-diabetic drug of the biguanide class that is commonly used to treat type 2 diabetes mellitus. This study examined the molecular mechanism for the action of metformin on osteoblast differentiation. Metformin-induced mRNA expression of the osteogenic genes and small heterodimer partner (SHP) in MC3T3E1 cells were determined by RT-PCR and real-time PCR. Metformin increased significantly the expression of the key osteogenic genes, such as alkaline phosphatase (ALP), osteocalcin (OC) and bone sialoprotein (BSP) as well as SHP. Transient transfection assays were performed in MC3T3E1 cells to confirm the effects of metformin on SHP, OC and Runx2 promoter activities. Metformin increased the transcription of the SHP and OC genes, and the metformin effect was inhibited by dominant negative form of AMPK (DN-AMPK) or compound C (an inhibitor of AMPK). The adenoviral overexpression of SHP increased significantly the level of ALP staining and OC production. However, metformin did not have any significant effect on osteogenic gene expression, ALP staining and activity, and OC production in SHP null (SHP-/-) primary calvarial cells. Moreover, upstream stimulatory factor-1 (USF-1) specifically mediated metformin-induced SHP gene expression. In addition, metformin-induced AMPK activation increased the level of Runx2 mRNA and protein. However, USF-1 and SHP were not involved in metformin-induced Runx2 expression. Transient transfection and chromatin immunoprecipitation assays confirmed that metformin-induced SHP interacts physically and forms a complex with Runx2 on the osteocalcin gene promoter in MC3T3E1 cells. These results suggest that metformin may stimulate osteoblast differentiation through the transactivation of Runx2 via AMPK/USF-1/SHP regulatory cascade in mouse calvaria-derived cells.
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PMID:Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. 2114 83


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