ABSTRACT
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.
Subject(s)
Bone Marrow Cells/drug effects , Cell Differentiation/drug effects , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Stem Cells/drug effects , Animals , Blotting, Western , Cells, Cultured , Diabetes Mellitus, Experimental/metabolism , Enzyme Activation/drug effects , Fibrinolytic Agents/pharmacokinetics , Male , Osteoblasts/drug effects , Rats , Rats, Sprague-Dawley , Rosiglitazone , Thiazolidinediones/pharmacologyABSTRACT
In all, 1,702 unselected pregnant women from the city of La Plata were tested for gestational diabetes mellitus (GDM) and evaluated to determine GDM prevalence and risk factors. In women with GDM, we evaluated compliance with guidelines for GDM management, and perinatal complications attributable to GDM. GDM prevalence was 5.8%, and its risk factors were pre-gestational obesity, previous hyperglycaemia, age > 30 years, previous GDM (and its surrogate markers). In primi-gravida (PG) subjects, GDM was equally prevalent in the presence (4.2%) or absence (4.0%) of risk factors. In multi-gravida (MG) women, although risk factors doubled the prevalence of GDM (8.6%), in the absence of risk factors GDM prevalence was similar to that of PG women (3.9%). Half of all women with GDM received inadequate post-diagnosis obstetric control, and this induced a fourfold increase in infant perinatal complications. In conclusion, all non-hyperglycaemic 24-28-week pregnant women should be tested for GDM, although particular attention must be paid to MG women with risk factors.
Subject(s)
Diabetes, Gestational/diagnosis , Diabetes, Gestational/epidemiology , Adult , Argentina/epidemiology , Body Mass Index , Diabetes, Gestational/prevention & control , Diabetes, Gestational/therapy , Female , Humans , Mass Screening/methods , Patient Compliance , Patient Education as Topic , Pregnancy , Pregnancy Trimester, Second , Prevalence , Prognosis , Risk Factors , Young AdultABSTRACT
Patients with long-standing Diabetes mellitus can develop osteopenia and osteoporosis. We have previously shown that advanced glycation endproducts reduce the bone-forming activity of osteoblasts. Bisphosphonates are used for the treatment of various bone disorders, since they reduce osteoclastic function and survival, and stimulate osteoblastic bone-forming capacity. In this work we have investigated whether bisphosphonates are able to revert advanced glycation endproducts-induced deleterious effects in osteoblasts. MC3T3E1 and UMR106 osteoblastic cells were incubated with control or advanced glycation endproducts-modified bovine serum albumin, in the presence or absence of different doses of the bisphosphonates Alendronate, Pamidronate or Zoledronate. After 24-72 h of culture, we evaluated their effects on cell proliferation and apoptosis, type-1 collagen production, alkaline and neutral phosphatase activity, and intracellular reactive oxygen species production. Advanced glycation endproducts significantly decreased osteoblast proliferation, alkaline phosphatase activity and type 1 collagen production, while increasing osteoblastic apoptosis and reactive oxygen species production. These effects were completely reverted by low doses (10(-8) M) of bisphosphonates. High doses of bisphosphonates (10(-4)-10(-5) M) were toxic for osteoblasts. Nifedipine (L-type calcium channel blocker) did not affect the advanced glycation endproducts-induced decrease in osteoblastic proliferation, although it blocked the reversion of this effect by 10(-8) M Alendronate. Both advanced glycation endproducts and Alendronate inhibited the activity of intracellular neutral phosphatases. In conclusion, we show that bisphosphonates revert the deleterious actions of advanced glycation endproducts on osteoblastic cells, and that these effects of bisphosphonates depend on: (a) Ca(2+) influx through L-type voltage-sensitive channels, and (b) blockage of advanced glycation endproducts-induced reactive oxygen species generation.
