PubMed Health⌕ Search

PubMed · 15639326

[The glitazones].

Abstract

INTRODUCTION: Type 2 diabetes mellitus is one of the biggest public health problem, responsible of major complications. The treatment of hyperglycaemia has been based on lifestyle changes, diet and physical exercise, and oral antidiabetic drugs for reducing the microangiopathic complications and the high cardiovascular risk of these patients. For decades we used sulfonylureas, metformin and alpha glucosidases inhibitors. However these drugs have no effect on muscle insulin resistance, high levels of free fatty acids, lipotoxicity and progressive pancreatic beta-cell loss. EXEGESIS: Thiazolidine-diones or glitazones are the pharmacological ligands of peroxisome proliferator activated receptor gamma mainly expressed in the white adipose tissue. New adipocytes are recruited with, finally, a decrease of free fatty acids, of some cytokines, of muscle and liver insulin resistance. The hypoglycaemic effect is moderate but more pronounced in association with other oral antidiabetic drugs. Long-term studies will possibly confirm the beneficial effects on the beta-cell loss and some cardiovascular parameters in type 2 diabetes and the metabolic syndrome. CONCLUSION: Glitazones enrich the treatment of type 2 diabetes allowing new and synergistic combinations for more precocious and efficient strategies. Moreover their action on peroxisome proliferator activated receptor opens on new therapeutics for cancer, immunology, rheumatology, and infection.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

S Halimi. 2005. [The glitazones].. https://doi.org/10.1016/j.revmed.2004.09.011

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

Maternal protein restriction permanently programs adipocyte growth and development in adult male rat offspring.

We previously demonstrated that maternal protein restriction (MPR) during pregnancy and lactation led to fetal growth restriction and development of increased visceral adiposity in adult male rat offspring. Here we studied the rate of proliferation and differentiation of adipocyte precursors (preadipocytes) in vitro to investigate whether MPR may permanently program adipocyte growth and development in adult male offspring. Preadipocytes were isolated from visceral adipose tissue of control and MPR offspring at 130 days of age, and cultured under standard conditions. The rate of proliferation was studied by [(3)H]-thymidine incorporation, and the rate of differentiation assessed with the use of biochemical and morphological markers. Although it did not affect the rate of differentiation, MPR increased the rate of preadipocyte proliferation by almost twofold. To ascertain if the increased proliferation was due to persisting in vivo influences or aberrations inherent in the precursor cells, we studied the rate of preadipocyte proliferation in subcultures. We found that the increased rate of proliferation of MPR preadipocytes persisted throughout the first two subcultures, indicative of an inherent abnormality. In addition, we examined the rate of preadipocyte proliferation under reduced serum conditions. We showed that MPR reduced the rate of preadipocyte proliferation to 56 and 35% of the control in the presence of 5 and 2.5% serum, respectively. Taken together, these results demonstrate that MPR permanently programs adipocyte growth and development such that adipocyte precursors derived from MPR offspring replicate excessively under standard culture conditions but exhibit markedly attenuated growth rate under reduced serum conditions.

Adipocytes↗

Oct-4, Rex-1, and Gata-4 expression in human MSC increase the differentiation efficiency but not hTERT expression.

Micro-environment seems to exert an important influence on human mesenchymal stem cell (MSC) differentiation and proliferative capacity in bone marrow as well as in culture ex vivo. Oct-4, Rex-1, and TERT genes are well-known for the maintenance of pluripotentiality differentiation and the proliferative capacity of embryonic stem cells. Some previous data report expression of these embryonic factors in selected clones from bone marrow adult stem cells. Our goal was to study expression of Oct-4, Rex-1, and TERT in primary cultured human MSC according to the serum concentration. In addition, we have studied the expression of Gata-4 since this factor plays a key role in organogenesis. We hypothesized that low serum concentration with appropriate growth factors may induce an undifferentiated status with a re-expression of embryonic factors and extend differentiation capacity. Thus, using a defined culture medium, we report on the increased expression of Oct-4, Rex-1, and Gata-4 in human MSC. We have correlated this expression to an increase in differentiation efficiency towards osteogenic and adipogenic phenotypes. Our data suggest that the culture medium used permits the emergence of adult stem cells with a high differentiation capacity and expression of embryonic factors. These cells may have important implications for cell therapy.

Adipocytes↗

VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells.

Osteoblasts and adipocytes are thought to derive from a common bone marrow stromal cell (BMSC) precursor. Activation of the canonical Wnt signaling pathway plays a pivotal role in the differentiation of BMSCs along either of these two lineages, promoting osteogenesis and inhibiting adipogenesis. Liganded nuclear receptors, including the vitamin D receptor (VDR) and peroxisomal proliferator-activated receptor gamma (PPARgamma), can also affect BMSCs differentiation. To address whether VDR ablation modulates the differentiation of BMSCs into the osteoblast or adipogenic lineages, BMSCs were isolated from VDR null mice and from their wild-type littermates. VDR ablation did not alter osteoblastic differentiation. However, when cultured under adipogenic conditions, BMSCs from the VDR null mice expressed higher mRNA levels of PPARgamma and of markers of adipogenic differentiation. An increase in the size and number of mature adipocyte foci was also observed in cultures isolated from VDR null mice relative to those isolated from wild-type mice. To address whether the increased adipogenesis observed in the VDR null cultures was associated with inhibition of the canonical Wnt signaling pathway, mRNA levels for DKK1 and SFRP2 were examined. Cultures from the VDR null mice expressed higher levels of mRNA encoding DKK1 and SFRP2 than did the wild-type cultures. This difference is, at least in part, due to ligand-dependent actions of the VDR, since 1,25-dihydroxyvitamin D3 suppressed DKK1 and SFRP2 expression in wild-type cultures. Thus, the VDR inhibits adipogenesis of BMSCs at least in part by suppressing the expression of inhibitors of the canonical Wnt signaling pathway.

Adipocytes↗