Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin dependent diabetes mellitus (IDDM; type I) is a chronic disease stemming from little or no insulin production and elevated blood glucose levels. IDDM is associated with osteoporosis and increased fracture rates. The mechanisms underlying IDDM associated bone loss are not known. Previously we demonstrated that osteoblasts exhibit a response to acute (1 and 24 h) hyperglycemia and hyperosmolality. Here we examined the influence of chronic hyperglycemia (30 mM) and its associated hyperosmolality on osteoblast phenotype. Our findings demonstrate that osteoblasts respond to chronic hyperglycemia through modulated gene expression. Specifically, chronic hyperglycemia increases alkaline phosphatase activity and expression and decreases osteocalcin, MMP-13, VEGF and GAPDH expression. Of these genes, only MMP-13 mRNA levels exhibit a similar suppression in response to hyperosmotic conditions (mannitol treatment). Acute hyperglycemia for a 48-h period was also capable of inducing alkaline phosphatase and suppressing osteocalcin, MMP-13, VEGF, and GAPDH expression in differentiated osteoblasts. This suggests that acute responses in differentiated cells are maintained chronically. In addition, hyperglycemic and hyperosmotic conditions increased PPARgamma2 expression, although this increase reached significance only in 21 days chronic glucose treated cultures. Given that osteocalcin is suppressed and PPARgamma2 expression is increased in type I diabetic mouse model bones, these findings suggest that diabetes-associated hyperglycemia may modulate osteoblast gene expression, function and bone formation and thereby contribute to type I diabetic bone loss.
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PMID:Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. 1661 59

Osteopenia was reported in patients with type I diabetes mellitus (DM). Also, serum levels of advanced glycation endproducts (AGEs) were reported to be elevated in DM. In this review, we showed the effect of AGEs on primary human osteoblasts, the precursor of human osteoclast like cells and parathyroid cells in culture. AGEs were made from incubating bovine serum albumin with glucose 6 phosphate for 8 weeks (AGEs-BSA). AGEs-BSA (1,000 microg/mL) showed inhibitory effect for human osteoblasts in terms of the productions of procolagen c propeptide and osteocalcin, which were regarded as bone forming parameters. On the other hand, the same concentration of AGEs-BSA inhibited the increase in the parathyroid hormone secretion from the cultured human parathyroid cells induced by low calcium medium concentration. AGEs-BSA increased time dependently intracellular calcium levels of HEK 293 cells, which expressed the wild type human calcium-sensing receptor. Also, AGEs-BSA increased IL-6 synthesis by primary human osteoblast. Our preliminary data also showed that AGEs-BSA increased osteoclast-like cells formation in number from the osteoclast precursor rich bone marrow cells. These data suggested the important role of AGEs for the pathogenesis of osteopenia in patients with DM through decreased bone formation and increased bone resorption.
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PMID:[The role of AGEs for the pathogenesis of osteopenia in diabetes mellitus]. 1688 40

Insulin-dependent diabetes mellitus (IDDM) is associated with increased risk of osteopenia/osteoporosis in humans. The mechanisms accounting for diabetic bone loss remain unclear. Pharmacologic inducers of IDDM, such as streptozotocin, mimic key aspects of diabetes in rodents, allow analysis at the onset of diabetes, and induce diabetes in genetically modified mice. However, side effects of streptozotocin, unrelated to diabetes, can complicate data interpretation. The nonobese diabetic (NOD) mouse model develops diabetes spontaneously without external influences, negating side effects of inducing agents. Unfortunately, in this model the onset of diabetes is unpredictable, occurs in a minority of male mice, and can only be studied in a single mouse strain. To validate the relevance of the more flexible streptozotocin-induced diabetes model for studying diabetes-associated bone loss, we compared its phenotype to the spontaneously diabetic NOD model. Both models exhibited hyperglycemia and loss of body, fat pad, and muscle weight. Furthermore, these genetically different and distinct models of diabetes induction demonstrated similar bone phenotypes marked by significant trabecular bone loss and increased bone marrow adiposity. Correspondingly, both diabetic models exhibited decreased osteocalcin mRNA and increased adipocyte fatty acid-binding protein 2 mRNA levels in isolated tibias and calvaria. Taken together, multiple streptozotocin injection-induced diabetes is a valid model for understanding the acute and chronic pathophysiologic responses to diabetes and their mechanisms in bone.
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PMID:Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice. 1705 23

The aims of this study were to evaluate bone mineral density (BMD) and bone turnover markers in patients with type 1 diabetes and screening-identified evidence of celiac disease, i.e., celiac autoimmunity. We screened 50 consecutive type 1 diabetic patients for IgA antitissue transglutaminase to identify those with celiac autoimmunity. Eight seropositive patients were identified on this screening, and 12 patients matched for gender and age range were selected as a control group from among the type 1 diabetic patients without celiac autoimmunity. Patients and controls underwent dual-energy X-ray absorptiometry (DEXA) for measurement of bone mineral status and had their blood levels of osteocalcin, carboxy-terminal telopeptide of type I collagen (CTX), calcium, and phosphorus determined. BMD was further adjusted for height, weight, and pubertal stage. Radiographic and blood markers of bone mineralization were compared between patients and controls. BMD (Z-score) at the lumbar spine was -1.44 +/- 0.5 SD for patients and 0.04 +/- 0.2 SD for controls (P = 0.02). Bone mineral content was 37.9 +/- 4.5 g for patients and 49.4 +/- 2.6 g for controls (P = 0.049). Adjusted BMD was -0.62 +/- 0.5 SD for patients and 0.81 +/- 0.09 SD for controls (P = 0.04). After adjustment, four patients and none of the controls presented BMD < -1 SD (P = 0.01). Osteocalcin, CTX, calcium, and phosphorus blood levels were not significantly different between patients and controls. Celiac autoimmunity is associated with reduced bone mineralization in type 1 diabetic patients. The pathophysiological mechanisms and clinical relevance of this finding remain to be further investigated.
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PMID:Bone mineralization in young patients with type 1 diabetes mellitus and screening-identified evidence of celiac disease. 1793 41

Type 1 diabetes mellitus is known to be associated with reduced bone mass and increased bone fractures. This is thought to be due to a decrease in osteoblastic bone formation rather than an increase in osteoclastic bone resorption, but the precise mechanism is unknown. In this study, we examined whether or not high glucose or advanced glycation end-products (AGEs), which play key roles in the pathogenesis and complications of diabetes, affect the differentiation of osteoblastic MC3T3-E1 cells. First, MC3T3-E1 cells were incubated in media containing either 22 mM glucose, 22 mM mannitol, 300 microg/ml AGE2, or 300 microg/ml AGE3. Each of these agents alone did not affect the mineralization of the cells by von Kossa staining and Alizarin red staining. However, high glucose but not mannitol or AGEs markedly increased mRNA expression of AGE receptor (RAGE) by real-time PCR. Next, we examined the combined effects of high glucose and AGEs on the differentiation of MC3T3-E1 cells. The combination of 22 mM glucose and 300 microg/ml AGE2 significantly inhibited the mineralization of MC3T3-E1 cells, and 22 mM glucose in combination with either 300 microg/ml AGE2 or AGE3 apparently decreased osteocalcin mRNA expression. These results suggest that high glucose or AGEs alone might have no effect on osteoblastic differentiation, but their combination could additionally or synergistically inhibit osteoblastic mineralization through glucose-induced increase in RAGE expression.
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PMID:The combination of high glucose and advanced glycation end-products (AGEs) inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs. 1796 May 13

It is well known that patients with type 1 diabetes mellitus exhibit bone abnormalities as one of the complications of the disease. Whether this occurs in type 2 diabetes is controversial. This uncertainty could be because type 2 diabetes includes several pathological types such as obese and non-obese. To examine the bone abnormalities in non-obese type 2 diabetes, we used Spontaneously Diabetic Torii (SDT) rats, which is a newly established model of non-obese type 2 diabetes. Sprague-Dawley (SD) rats were used as a control group (n=17). SDT rats were divided into two groups: the diabetic (DM) group (n=18) and the DM+insulin (INS) group (n=18) at 20 weeks of age. The DM+INS group received subcutaneously implanted insulin pellets every 2 weeks. At 36 weeks of age, the rats were killed, and we evaluated bone formation and the effect of insulin on bone formation, blood and urine analyses, bone mineral density (BMD), histomorphometry, and mRNA expression of alkaline phosphatase (ALP) and osteocalcin (OCN). Despite renal function not being impaired, BMD and bone strength were significantly lower in the DM group than in the control group. Osteoid volume per bone volume, osteoblast surface per bone surface, eroded surface per bone surface, osteoclast surface per bone surface, the mineral apposition rate, and the bone formation rate per bone surface were significantly lower in the DM group than in the control and DM+INS groups. The mRNA expression of ALP and OCN was significantly lower in the DM group than in the control group. Furthermore, 8-hydroxydeoxyguanosine, which is an oxidative stress marker, was remarkably elevated in the DM group. These abnormalities were recovered by insulin therapy. Our data support the notion that non-obese type 2 diabetes is associated with a low turnover of bone and that the abnormalities are ameliorated by insulin. The SDT rat may be a useful animal model for examining the mechanisms of bone abnormalities in non-obese type 2 diabetes.
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PMID:Bone formation in spontaneously diabetic Torii-newly established model of non-obese type 2 diabetes rats. 1803 64

Type 1 diabetes mellitus is associated with a number of disorders of skeletal health, conditions that rely, in part, on dynamic bone formation. A mouse model of distraction osteogenesis was used to study the consequences of streptozotocin-induced diabetes and insulin treatment on bone formation and osteoblastogenesis. In diabetic mice compared with control mice, new bone formation was decreased, and adipogenesis was increased in and around, respectively, the distraction gaps. Although insulin treatment restored bone formation to levels observed in nondiabetic control mice, it failed to significantly decrease adipogenesis. Molecular events altered during de novo bone formation in untreated type 1 diabetes mellitus, yet restored with insulin treatment were examined so as to clarify specific osteogenic genes that may contribute to diabetic bone disease. RNA from distraction gaps was analyzed by gene microarray and quantitative RT-PCR for osteogenic genes of interest. Runt-related transcription factor 2 (RUNX2), and several RUNX2 target genes, including matrix metalloproteinase-9, Akp2, integrin binding sialoprotein, Dmp1, Col1a2, Phex, Vdr, osteocalcin, and osterix, were all significantly down-regulated in the insulin-deficient, hyperglycemic diabetic animals; however, insulin treatment of diabetic animals significantly restored their expression. Expression of bone morphogenic protein-2, transcriptional coactivator with PDZ-binding motif, and TWIST2, all important regulators of RUNX2, were not impacted by the diabetic condition, suggesting that the defect in osteogenesis resides at the level of RUNX2 expression and its activity. Together, these data demonstrate that insulin and/or glycemic status can regulate osteogenesis in vivo, and systemic insulin therapy can, in large part, rescue the diabetic bone phenotype at the tissue and molecular level.
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PMID:Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. 1816 13

Administration of the isoflavone genistein (GEN) has been described to result in bone protection but also to induce uterotrophic responses. To compare bone protective effects of GEN with an isoflavone-rich diet (IRD) and to further elucidate molecular mechanisms involved in bone-protection, ovariectomized rats (OVX) received either a diet low in isoflavone content (IDD) enriched with GEN (42 mg kg(-1)b.wtd(-1)) (GEN(d)), an IRD (14 mg kg(-1)b.wtd(-1) GEN, 14 mg kg(-1)b.wtd(-1) daidzein) or were treated subcutaneously (s.c.) with GEN (10 mg kg(-1)b.wtd(-1)) (GEN(sc)) for 12 weeks. Intact (SHAM), vehicle treated OVX animals and those substituted with 17beta-estradiol (2microg kg(-1)b.wtd(-1)) (E(2)), served as controls. OVX-induced bone loss could be antagonized in E(2), GEN(sc), GEN(d) and IRD groups. Uterine wet weight (UWW) was only stimulated in E(2) and GEN(sc) animals. Serum biomarkers of bone-formation (osteocalcin, osteopontin) and bone-resorption (telopeptides of collagen type I, pyridinoline cross-links) were elevated in OVX compared to SHAM and E(2) animals. Feeding IRD stimulated bone-formation and inhibited bone-resorption, whereas s.c. or dietary administration of GEN only resulted in a stimulation of bone-formation. The results of the present study indicate that in contrast to s.c. administration, dietary intake of GEN resulted in bone protection without stimulation of UWW. Dietary intake of isoflavones by an IRD also did not result in a stimulation of UWW, yet IRD appeared to be more effective in bone protection than administration of pure GEN.
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PMID:Comparison of the bone protective effects of an isoflavone-rich diet with dietary and subcutaneous administrations of genistein in ovariectomized rats. 1906 53

Diabetic patients have an increased risk of prosthesis failure requiring revision surgery. Furthermore, skeletal defects are observed in conjunction with type 1 diabetes. Using a titanium particle-induced calvarial osteolysis model in diabetic mice, we investigated the effect of diabetes on the osteolytic process and the role of naringin in its prevention. Three groups each of nondiabetic or diabetic mice were treated with vehicle only, with particles only, or with particles then naringin for 10 days. Alteration of bone indices near the midline suture were then analyzed by microcomputed tomography scanning and histology. Serum levels of osteocalcin (OCN) and cross-linked N-telopeptide of type I collagen (NTx) were measured by enzyme-linked immunosorbent assay. The decreases in new bone formation (p < 0.05), calvaria thickness (p < 0.05), bone volume (p < 0.05), midline suture area (p < 0.05), and OCN concentration (p < 0.05) found in diabetic mice were normalized with naringin treatment. Diabetic state promoted particle-induced osteolysis. Naringin, an osteoanabolic agent, improved bone indices apparently by stimulating bone formation. Therefore, naringin may be beneficial in preventing and treating debris-mediated periprosthetic osteolysis after total joint replacement, especially in diabetics.
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PMID:Promotion of bone formation by naringin in a titanium particle-induced diabetic murine calvarial osteolysis model. 1982 55

Insulin-dependent diabetes mellitus (IDDM) is associated with an increased risk of osteopenia/osteoporosis in humans. The effects of IDDM on osteoblastogenesis and osteoclastogenesis were investigated using diabetic rats at 2 weeks after the streptozotocin (STZ) injection. The weight of the tibia and proximal tibia and the amount of hydroxyproline and calcium in the proximal tibia were significantly lower in diabetic rats than control rats. Markers of bone formation, alkaline phosphatase (ALP) activity and the number of osteoblasts in the proximal tibia and the serum osteocalcin level, were significantly lower. Markers of bone resorption, activity of tartrate-resistant acid phosphatase (TRAP) and cathepsin K and the number of osteoclasts in the proximal tibia and urinary excretion of deoxypyridinoline, were higher in diabetic rats than control rats. mRNA levels of receptor for activation of NF-kappaB (RANK), c-fos, c-jun, TRAP and cathepsin K were significantly increased in diabetic rats, although RANK ligand, osteoprotegerin, macrophage colony-stimulating factor and c-fms levels were similar to the control value. The decreased expression of ALP, osteoclacin and collagen mRNA in diabetic rats was associated with decreases in the expression of Runx2, Dlx5 and osterix and an unaltered expression of bone morphogenic protein-2. The level of RANK protein increased and Runx2 protein decreased in diabetic rats. These changes in the bone of STZ-induced diabetic rats were reversed by insulin-treatment. These suggested that short-term IDDM induced upregulation of osteoclastogenesis with an increase in RANK and downregulation of osteoblastogenesis with a decrease in Runx2 in bone.
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PMID:Increased expression of the receptor for activation of NF-kappaB and decreased runt-related transcription factor 2 expression in bone of rats with streptozotocin-induced diabetes. 2081 3


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